Kerry Gove

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. Nasal nitric oxide is a useful and increasingly versatile screening tool in primary ciliary dyskinesia at all ages http://ow.ly/AR5mq

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.

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.

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. RCTs of biological therapies in severe asthma are poorly generalisable with most patients excluded by outmoded disease concepts despite possessing the targetable trait addressed by the treatment http://ow.ly/iog930md0J3

Comparison of two methods of determining lung de-recruitment, using the forced oscillation technique

Airway closure has proved to be important in a number of respiratory diseases and may be the primary functional defect in asthma. A surrogate measure of closing volume can be identified using the forced oscillation technique (FOT), by performing a deflation maneuver and examining the resultant reactance (Xrs) lung volume relationship. This study aims to determine if a slow vital capacity maneuver can be used instead of this deflation maneuver and compare it to existing more complex techniques. Three subject groups were included in the study; healthy (n = 29), asthmatic (n = 18), and COPD (n = 10) for a total of 57 subjects. Reactance lung volume curves were generated via FOT recordings during two different breathing manoeuvres (both pre and post bronchodilator). The correlation and agreement between surrogate closing volume (Volcrit) and reactance (Xrscrit) at this volume was analysed. The changes in Volcrit and Xrscrit pre and post bronchodilator were also analysed. Across all three subject groups, the two different measures of Volcrit were shown to be statistically equivalent (p > 0.05) and demonstrated a strong fit to the data (R2 = 0.49, 0.78, 0.59, for asthmatic, COPD and healthy subject groups, respectively). A bias was evident between the two measurements of Xrscrit with statistically different means (p < 0.05). However, the two measurements of Xrscrit displayed the same trends. In conclusion, we have developed an alternative technique for measuring airway closure from FOT recordings. The technique delivers equivalent and possibly more sensitive results to previous methods while being simple and easily performed by the patient.

The Wessex AsThma CoHort (WATCH) difficult asthma study; integrating research into the clinic

The WATCH Study is a longitudinal study of patients under the Difficult Asthma Clinic at University Hospital Southampton, UK. To create a better real life understanding of difficult asthma (British Thoracic Society (BTS) step 4/5), a process of clinical dataset compilation, meeting clinical and research needs, was adopted. One objective was to trial feasibility of longitudinal data collection in a large outpatient clinic cohort. Other aims included; a) Merging research and clinical objectives; meeting needs of the BTS Difficult Asthma registry plus data collation needed for research purposes b) Ensuring all eligible patients have the opportunity to participate in research, current and future. c) Gathering all relevant clinical data to support clinical phenotyping d) Ensuring data was collected in a time efficient manner Number of patients recruited to date (175). Recruitment rate (18.2 per month). Total recruitment failures; due to lack of asthma severity (10). Number declining participation (8). Number withdrawn (1) (no reason given). Using a method combining clinical and research services to collect longitudinal data from this large cohort of patients attending the Difficult Asthma clinic was feasible and successful. The majority of patients approached were consented, participated and stayed in the study.