Assessment of breath volatile organic compounds in acute cardiorespiratory breathlessness: a protocol describing a prospective real-world observational study

Introduction Patients presenting with acute undifferentiated breathlessness are commonly encountered in admissions units across the UK. Existing blood biomarkers have clinical utility in distinguishing patients with single organ pathologies but have poor discriminatory power in multifactorial presentations. Evaluation of volatile organic compounds (VOCs) in exhaled breath offers the potential to develop biomarkers of disease states that underpin acute cardiorespiratory breathlessness, owing to their proximity to the cardiorespiratory system. To date, there has been no systematic evaluation of VOC in acute cardiorespiratory breathlessness. The proposed study will seek to use both offline and online VOC technologies to evaluate the predictive value of VOC in identifying common conditions that present with acute cardiorespiratory breathlessness. Methods and analysis A prospective real-world observational study carried out across three acute admissions units within Leicestershire. Participants with self-reported acute breathlessness, with a confirmed primary diagnosis of either acute heart failure, community-acquired pneumonia and acute exacerbation of asthma or chronic obstructive pulmonary disease will be recruited within 24 hours of admission. Additionally, school-age children admitted with severe asthma will be evaluated. All participants will undergo breath sampling on admission and on recovery following discharge. A range of online technologies including: proton transfer reaction mass spectrometry, gas chromatography ion mobility spectrometry, atmospheric pressure chemical ionisation-mass spectrometry and offline technologies including gas chromatography mass spectroscopy and comprehensive two-dimensional gas chromatography-mass spectrometry will be used for VOC discovery and replication. For offline technologies, a standardised CE-marked breath sampling device (ReCIVA) will be used. All recruited participants will be characterised using existing blood biomarkers including C reactive protein, brain-derived natriuretic peptide, troponin-I and blood eosinophil levels and further evaluated using a range of standardised questionnaires, lung function testing, sputum cell counts and other diagnostic tests pertinent to acute disease. Ethics and dissemination The National Research Ethics Service Committee East Midlands has approved the study protocol (REC number: 16/LO/1747). Integrated Research Approval System (IRAS) 198921. Findings will be presented at academic conferences and published in peer-reviewed scientific journals. Dissemination will be facilitated via a partnership with the East Midlands Academic Health Sciences Network and via interaction with all UK-funded Medical Research Council and Engineering and Physical Sciences Research Council molecular pathology nodes. Trial registration number NCT0367299

High prevalence of bronchiectasis on chest CT in a selected cohort of children with severe Asthma.

BACKGROUND: Chest computed tomography (CT) scans have a recognised role in investigating adults with severe asthma to exclude alternative diagnoses, but its role in children is less clear. The objective of this study was to review the CT findings of our local cohort of children with severe asthma and to explore whether clinical or pathobiological parameters predicted CT changes. METHODS: Retrospective observational single centre study including all children attending the Leicester difficult asthma clinic (DAC) who underwent a chest CT from 2006 to 2011. Additionally, we recruited eight age-matched, non-asthmatic controls to compare differences in CT findings between asthmatic and non-asthmatic children. All CT images were independently scored by two radiologists. The DAC patients were sub-divided into binary groups for each abnormality identified so that comparisons could be made against recorded clinical variables including age, lung function, serum total IgE levels, and sputum leukocyte differential cell counts. RESULTS: Thirty DAC patients (median 12 yrs., range 5-16) were included. The most common abnormalities were bronchial wall thickening (BWT) and air trapping (AT), observed in 80 and 60% of DAC patients. Bronchiectasis (BE) was identified in 27% of DAC patients. DAC patients with evidence of BE on CT images were older than those without BE (13.9 ± 0.67 vs 11.5 ± 0.61, p = 0.038). We also identified a positive correlation between increasing BE severity and extent with age (r = 0.400, p = 0.028). CONCLUSION: Abnormal CT findings were highly prevalent in our cohort of children with severe asthma, with bronchiectasis identified in approximately one third of children. We found no alternative diagnoses that resulted in a change in clinical management

Chronic Aspergillus fumigatus colonisation of the paediatric cystic fibrosis airway is common and may be associated with a more rapid decline in lung function

Filamentous fungi are commonly isolated from the respiratory tract of CF patients, but their clinical significance is uncertain and the reported incidence variable. We report on the degree of Aspergillus fumigatus airway colonization in a tertiary pediatric CF cohort, evaluate the sensitivity of routine clinical sampling at detecting A. fumigatus, and compare lung function of A. fumigatus-colonized and non-colonized children. We carried out an 8-year retrospective cohort analysis using local databases, examining 1024 respiratory microbiological specimens from 45 children. Nineteen (42%) had a positive A. fumigatus culture at least once during the 8-year period, with 10 (22%) children persistently colonized. Overall, 29% of 48 bronchoalveolar lavage (BAL) samples tested positive for A. fumigatus, compared with 14% of 976 sputum samples. Of 33 children for whom lung function data were available during the study period, seven were classed as having severe lung disease, of whom four (57%) were persistently colonized with A. fumigatus. We conclude that chronic A. fumigatus colonization of the CF airway is common, and may be associated with worse lung function. In our practice, BAL appears superior at detecting lower airway A. fumigatus compared to sputum samples

Real-time analysis of exhaled volatile organic compounds (eVOC) in wheezy preschool children

Introduction: Investigating airway inflammation and pathology in wheezy preschool children is challenging from both a technical and ethical standpoint. Novel non-invasive tests need to be identified and validated. Real-time analysis of eVOC may be useful in the diagnosis and monitoring of these children

Association between socioeconomic deprivation, ethnicity, and health outcomes in preschool children with recurrent wheeze in England: a retrospective cohort study

Background Preschool-aged children have amongst the highest burden of acute wheeze. We investigated differences in healthcare use, treatment, and outcomes for recurrent wheeze/asthma inpre-schoolers from different ethno-socioeconomic backgrounds.  Methods Retrospective cohort studyusing data from the Clinical Practice Research Datalink linked toHospital Episode Statistics in England. We reported number of acute presentations, and hospitalisations stratified by index of multiple deprivation (IMD), and ethnicity; and factors associated with treatment non-escalation, and hospitalisation rates using multivariable logistic and Poisson regression models.  Results 194,291 preschool children were included. In children not trialled on asthma preventer medications, children from the most deprived IMD quintile (adjusted OR 1.67; 95%CI 1.53-to-1.83), and South Asian (1.77; 1.64-to-1.91) children were more likely to have high reliever usage; and where specialist referral had not occurred, the odds of referral being indicated was higher in the most deprived quintile (1.39; 1.28-to-1.52), and South Asian (1.86; 1.72-to-2.01) children compared with the least deprived quintile and White children respectively. Hospitalisation rates for wheeze/asthma were significantly higher in children from the most deprived quintile (adjusted IRR 1.20; 95%CI 1.13-to-1.27) compared with the least, and in South Asian (1.57; 1.44-to-1.70) and Black (1.32; 1.22-to-1.42) compared with White children. ConclusionsWe identified inequalities in wheeze/asthma treatment and morbidity in preschool children from more deprived, and non-White backgrounds. A multifaceted approach to tackle healthinequality at both the national and local level, which includes a more integrated and standardised approach to treatment, is needed to improve health outcomes in children with preschool wheeze/asthma.</p

Visualisation of exhaled breath metabolites reveals distinct diagnostic signatures for acute cardiorespiratory breathlessness

Breath analysis can be a useful noninvasive way to detect disease. Here, Ibrahim et al. studied the volatile organic compound (VOC) signatures associated with acute cardiorespiratory diseases in patients presenting breathlessness. Using two-dimensional gas chromatography and mass spectrometry, the authors found clusters of VOCs associated with acute heart failure, asthma, chronic obstructive pulmonary disease, and pneumonia. These breath biomarkers correlated with blood-based biomarkers. An acute disease VOC score based on a 101-biomarker panel was associated with 2-year all-cause mortality. This study demonstrates how breathomics can help diagnose disease and further our understanding of metabolic subgroups

Treatment guided by fractional exhaled nitric oxide in addition to standard care in 6- to 15-year-olds with asthma: the RAACENO RCT

Background The role of fractional exhaled nitric oxide in guiding asthma treatment in children is uncertain. Objective To compare treatment guided by both fractional exhaled nitric oxide and symptoms (intervention) with treatment guided by symptoms alone (standard care) in children with asthma who are at risk of an asthma exacerbation, in terms of the number of asthma exacerbations over 12 months. Design This was a pragmatic, multicentre, randomised controlled trial with embedded cost-effectiveness and qualitative process evaluations. Randomisation (1 : 1) was carried out using a remote web-based system and was minimised on recruitment centre, age, sex and British Thoracic Society treatment step. Clinical teams and participants were not blind to treatment allocation. Setting The trial took place in 35 hospitals and seven primary care practices in the UK. Participants Children aged 6–15 years with a diagnosis of asthma who were currently prescribed inhaled corticosteroids and who had one or more parent-/patient-reported asthma exacerbation treated with oral corticosteroids in the 12 months prior to recruitment. Interventions Asthma treatment guided by symptoms alone (standard care) and asthma treatment guided by symptoms plus fractional exhaled nitric oxide (intervention). Treatment recommendations in both groups were protocolised within a web-based algorithm, incorporating inhaled corticosteroid adherence (objectively measured using an electronic logging device) and current treatment. Main outcome measures The primary outcome measure was asthma exacerbations treated with oral corticosteroids in the year post randomisation. Secondary outcomes included time to first exacerbation, number of exacerbations, lung function, fractional exhaled nitric oxide, daily dose of inhaled corticosteroid, asthma control and quality of life. Results In total, 509 eligible participants were recruited and the primary outcome was available for 506 participants. The primary outcome occurred in 123 out of 255 (48.2%) participants in the intervention group and 129 out of 251 (51.4%) participants in the standard-care group (adjusted odds ratio 0.88, 95% confidence interval 0.61 to 1.27). There was algorithm non-compliance on 21% of assessments. Per-protocol and complier-average causal effect analysis did not change the interpretation. This non-statistically significant estimate was consistent across predefined subgroups. There were no differences between the groups in secondary outcomes. There were no serious adverse events or deaths. No meaningful differences in health service costs, direct patient costs or indirect costs to society were identified between the groups. The economic evaluation does not provide evidence to support the cost-effectiveness of the intervention. In the qualitative process evaluation, 15 trial staff and six families were interviewed. Overall, their experiences were positive. The intervention was broadly acceptable, with caveats around clinicians using the algorithm recommendation as a guide and wariness around extreme step ups/downs in treatment in the light of contextual factors not being taken into account by the algorithm. Limitations Potential limitations included the choice of cut-off point to define uncontrolled asthma and the change in fractional exhaled nitric oxide to trigger a change in treatment. Furthermore, the treatment decisions in the two groups may not have been sufficiently different to create a difference in outcomes. Conclusions The RAACENO (Reducing Asthma Attacks in Children using Exhaled Nitric Oxide) trial findings do not support the routine use of fractional exhaled nitric oxide measurements as part of asthma management in a secondary care setting. The potential for other objective markers to guide asthma management in children needs to be evaluated. Trial registration This trial was registered as ISRCTN67875351. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 4. See the NIHR Journals Library website for further project information.</p

The variability of volatile organic compounds in the indoor air of clinical environments

The development of clinical breath-analysis is confounded by the variability of background volatile organic compounds (VOC). Reliable interpretation of clinical breath-analysis at individual, and cohort levels requires characterisation of clinical-VOC levels and exposures. Active-sampling with thermal-desorption/gas chromatography-mass spectrometry recorded and evaluated VOC concentrations in 245 samples of indoor air from three sites in a large NHS provider trust in the UK over 27 months. Data deconvolution, alignment and clustering isolated 7344 features attributable to VOC and described the variability (composition and concentration) of respirable clinical VOC. 328 VOC were observed in more than 5% of the samples and 68 VOC appeared in more than 30% of samples. Common VOC were associated with exogenous and endogenous sources and 17 VOC were identified as seasonal differentiators. The presence of metabolites from the anaesthetic sevoflurane, and putative-disease biomarkers in room air, indicated that exhaled VOC were a source of background-pollution in clinical breath-testing activity. With the exception of solvents, and PPE waxes, exhaled VOC concentrations above 3 µg m-3 are unlikely to arise from room air contamination, and in the absence of extensive survey-data, this level could be applied as a threshold for inclusion in studies, removing a potential environmental confounding-factor in developing breath-based diagnostics