Protocol for the Wessex AsThma CoHort of difficult asthma (WATCH): a pragmatic real-life longitudinal study of difficult asthma in the clinic.

BACKGROUND: Asthma is now widely recognised to be a heterogeneous disease. The last two decades have seen the identification of a number of biological targets and development of various novel therapies. Despite this, asthma still represents a significant health and economic burden worldwide. Why some individuals should continue to suffer remains unclear. METHODS: The Wessex Asthma Cohort of Difficult Asthma (WATCH) is an ongoing 'real-life', prospective study of patients in the University Hospital Southampton Foundation Trust (UHSFT) Difficult Asthma service. Research data capture is aligned with the extensive clinical characterisation required of a commissioned National Health Service (NHS) Specialist Centre for Severe Asthma. Data acquisition includes detailed clinical, health and disease-related questionnaires, anthropometry, allergy and lung function testing, radiological imaging (in a small subset) and collection of biological samples (blood, urine and sputum). Prospective data are captured in parallel to clinical follow up appointments, with data entered into a bespoke database. DISCUSSION: The pragmatic ongoing nature of the WATCH study allows comprehensive assessment of the real world clinical spectrum seen in a Specialist Asthma Centre and allows a longitudinal perspective of deeply phenotyped patients. It is anticipated that the WATCH cohort would act as a vehicle for potential collaborative asthma studies and will build upon our understanding of mechanisms underlying difficult asthma.

Randomised controlled trials in severe asthma: selection by phenotype or stereotype.

Previous publications have highlighted the disparity between research trial populations and those in clinical practice, but it has not been established how this relates to randomised controlled trials (RCTs) of phenotype-targeted biological therapies in severe asthma.Detailed characterisation data for 342 severe asthma patients within the Wessex Severe Asthma Cohort (WSAC) was compared against comprehensive trial eligibility criteria for published phase IIB and phase III RCTs evaluating biological therapies in severe asthma since 2000.37 RCTs evaluating 20 biological therapies were identified. Only a median of 9.8% (range 3.5-17.5%) of severe asthma patients were found to be eligible for enrolment in the phase III trials. Stipulations for airflow obstruction, bronchodilator reversibility and smoking history excluded significant numbers of patients. A median of 78.9% (range 73.2-86.6%) of patients with severe eosinophilic asthma would have been excluded from participation in the phase III licensing trials of interleukin (IL)-5/IL-5R targeted therapies.Despite including only well characterised and optimally treated severe asthmatics under specialist care within the WSAC study, the vast majority were excluded from trial participation by criteria designed to re-confirm diagnostic labels rather than by biomarker criteria that predict the characteristic addressed by the treatment.

The dangers of widespread nitric oxide screening for primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is underdiagnosed and requires complex testing at specialist diagnostic centres. Measurement of nasal nitric oxide (nNO) has good sensitivity and specificity screening for PCD, but is currently usually measured at PCD centres rather than prior to referral. Proposals to include NO testing for asthma diagnoses could widen access to PCD screening if nasal mode analysers are available. Data from 282 consecutive referrals to our PCD diagnostic centre (31 PCD positive) were used to model predictive values for nNO testing with varying pretest probability and showed that predictive values were good in the referral population, but extending screening to more general populations would result in excessive false positives that may overwhelm diagnostic services. Although nNO remains a useful test, a 'normal' result with classical clinical history should still be considered for further testing.

Nasal nitric oxide screening for primary ciliary dyskinesia: systematic review and meta-analysis.

Nasal nitric oxide (nNO) concentrations are low in patients with primary ciliary dyskinesia (PCD) providing a noninvasive screening test. We conducted a systematic review of the literature to examine the utility of nNO in screening for PCD, in particular 1) different respiratory manoeuvres during sampling (velum closure, tidal breathing, etc.), 2) accuracy in screening young/uncooperative children, 3) stationary versus portable analysers, and 4) nNO in "atypical" PCD. 96 papers were assessed according to modified PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and 22 were included in this review. Meta-analysis of 11 studies comparing nNO during a velum closure breath hold gave a mean±SD nNO of 19.4±18.6 nL·min(-1) in PCD (n = 478) and 265.0±118.9 nL·min(-1) in healthy controls (n = 338). Weighted mean difference for PCD versus healthy controls was 231.1 nL·min(-1) (95% CI 193.3-268.9; n = 338) and 114.1 nL·min(-1) (95% CI 101.5-126.8; n = 415) for PCD versus cystic fibrosis. Five studies of nNO measurement during tidal breathing demonstrated that this is an acceptable manoeuvre in young children where velum closure is not possible, but the discriminatory value was reduced. Four small studies of portable NO analysers suggest these are reliable tools for screening for PCD. However, nNO must be interpreted alongside clinical suspicion. Future studies should focus on standardising sampling techniques and reporting.

Validation of a portable nitric oxide analyzer for screening in primary ciliary dyskinesias.

BACKGROUND: Nasal nitric oxide (nNO) levels are very low in primary ciliary dyskinesia (PCD) and it is used as a screening test. METHODS: We assessed the reliability and usability of a hand-held analyser in comparison to a stationary nitric oxide (NO) analyser in 50 participants (15 healthy, 13 PCD, 22 other respiratory diseases; age 6-79 years). Nasal NO was measured using a stationary NO analyser during a breath-holding maneuver, and using a hand-held analyser during tidal breathing, sampling at 2 ml/sec or 5 ml/sec. The three methods were compared for their specificity and sensitivity as a screen for PCD, their success rate in different age groups, within subject repeatability and acceptability. Correlation between methods was assessed. RESULTS: Valid nNO measurements were obtained in 94% of participants using the stationary analyser, 96% using the hand-held analyser at 5 ml/sec and 76% at 2 ml/sec. The hand-held device at 5 ml/sec had excellent sensitivity and specificity as a screening test for PCD during tidal breathing (cut-off of 30 nL/min,100% sensitivity, >95% specificity). The cut-off using the stationary analyser during breath-hold was 38 nL/min (100% sensitivity, 95% specificity). The stationary and hand-held analyser (5 ml/sec) showed reasonable within-subject repeatability(% coefficient of variation = 15). CONCLUSION: The hand-held NO analyser provides a promising screening tool for PCD.

Using Novel Computed Tomography Analysis to Describe the Contribution and Distribution of Emphysema and Small Airways Disease in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, caused by emphysema and small airways disease (SAD). Computed tomography (CT) coupled with image analysis enables the quantification of these abnormalities; however, the optimum method for doing so has not been determined.Objectives: This study aims to compare two CT quantitative analysis techniques, disease probability measure (DPM) and parametric response mapping (PRM), and assess their relationship with specific physiological measures of SAD.Methods: Subjects with mild to moderate COPD, never smokers, and healthy ex-smokers were recruited. Each had airway oscillometry and multiple-breath nitrogen washout, measuring peripheral airway resistance, peripheral airway reactance, and acinar airway inhomogeneity. Subjects also had an inspiratory and expiratory chest CT, with DPM and PRM analysis performed by coregistering images and classifying each voxel as normal, emphysema, or nonemphysematous gas trapping related to SAD.Results: Thirty-eight subjects with COPD, 18 never smokers, and 23 healthy ex-smokers were recruited. There were strong associations between DPM and PRM analysis when measuring gas trapping (ρ = 0.87; P < 0.001) and emphysema (ρ = 0.99; P < 0.001). DPM assigned significantly more voxels as emphysema and gas trapped than PRM (P < 0.001). Both techniques showed significantly greater emphysema and gas trapping in subjects with COPD than in never smokers and ex-smokers (P < 0.001). All CT measures had significant associations with peripheral airway resistance and reactance, with disease probability measure of nonemphysematous gas trapping related to SAD having the strongest independent association with peripheral airway resistance (ß = 0.42; P = 0.001) and peripheral airway reactance (ß = 0.41; P = 0.001). Emphysema measures had the strongest associations with acinar airway inhomogeneity (ß = 0.35-0.38).Conclusions: These results provide further validation for the use of DPM/PRM analysis in COPD by demonstrating significant relationships with specific physiological measures of SAD.

Systematic review of evidence for relationships between physiological and CT indices of small airways and clinical outcomes in COPD.

BACKGROUND: Small airways disease (SAD) is considered pivotal in the pathology of COPD. There are numerous publications describing physiological and Computed Tomography (CT) imaging markers to detect SAD. However, there is no agreed gold standard and limited understanding of the clinical associations of these measures to disease outcomes. METHODS: We conducted a systematic review using Embase, Medline and Pubmed to explore the relationship between physiological and CT SAD measures in COPD (GOLD Stages 1-4). Furthermore, evidence linking these physiological measures with defined clinical outcomes such as health status, functional assessment and exacerbation frequency were summarised. RESULTS: The search yielded 1160 abstracts of which 19 met the search criteria. Six studies examined physiological and CT measures while 13 publications identified physiological measures and clinical outcomes. Strong correlations were seen between CT and physiological measures of SAD. Varying associations between physiological measures and defined clinical outcomes were noted. CONCLUSIONS: Physiological and CT measures of SAD correlate and infer similar information. Physiological measures of SAD may offer valuable insight into clinical expression of the disease. A consensus on the standardisation and recommendation of tests to measure SAD is needed in order to better understand any clinical benefits of targeted drug therapy to the small airways.

Clinical assessment of speech correlates well with lung function during induced bronchoconstriction.

Clinical assessment of asthma often includes a crude assessment of speech, for example whether the patient can speak in full sentences. To date, this statement, despite appearing in national asthma guidelines, has not been related to lung function testing in asthma exacerbation. Seven asthmatics underwent a bronchial challenge and were then recorded reading a standardised text for 1 min. The recordings were played to 88 healthcare professionals who were asked to estimate FEV1% predicted. Health care professionals' estimations showed moderate correlation to FEV1% predicted (rho=0.61 P<0.01). There were no significant differences between professionals grouped by seniority or speciality. Speech can intuitively be estimated by health care professionals with moderate accuracy. This gives an evidence basis for the assessment in speech in acute asthma and may provide a new avenue for monitoring.