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

Abstract

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: NCT03672994.

Keywords: breath analysis; breathlessness; observational study; volatile organic compound.

Conflict of interest statement

Competing interests: SS has performed advisory services for Owlstone Medical.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Relationship between lung proximity and degree of invasiveness of different lung matrices. The figure plots the level of invasiveness of various lung matrices in relation to their proximity to the lung. Given their pathological relevance, the degree of invasiveness of bronchoalveolar lavage (BAL) and lung biopsy makes them less favourable in diagnosing respiratory diseases.

Figure 2

Multi-instrument use in breath sampling. Figure illustrates the various combinations of offline and online devices used in breath sampling and the relevant pros and cons. Offline and online technologies are used for the discovery and validation phases of the study, respectively.

Figure 3

Study flow chart. Figure outlines the patient journey from admission through to discharge and follow-up. Participants with self-reported acute breathlessness presenting to University Hospitals of Leicester are recruited within 24 hours following a senior decision maker review. Breath sampling is carried out on the first visit, at recruitment, and the second visit, up to 6 months after discharge. Patients are admitted through the standard operational emergency medical streaming and care pathways at the University Hospitals of Leicester National Health Service Trust. Early outcomes (hospital readmission) are measured at 30 days and 60 days and late outcomes (mortality) including respiratory and all-cause mortality are measured at 2 years. Assessments carried out at each time point are summarised in table 1. APCI-MS, atmospheric pressure chemical ionisation-mass spectrometry; GC-IMS, gas chromatography ion mobility spectrometry; GC-MS, gas chromatography mass spectroscopy; GC×GC-MS, two-dimensional gas chromatography-mass spectrometry.

Figure 4

Multi-instrument use in breath sampling. Operational space of the analytical technologies used in EMBER for the analysis of volatile organic compounds in exhaled breath, including proton transfer reaction mass spectrometry (PTR-MS), atmospheric pressure chemical ionisation-mass spectrometry (CMS), gas chromatography ion mobility spectrometry (GC-IMS), gas chromatography mass spectrometry (GC-MS) and two-dimensional gas chromatography-mass spectrometry (GC×GC-MS). Comparing the typical molar mass range detectable; selectivity in detection owing to the type of ionisation involved and the proton affinity of analytes; and the inclusion of a chromatographic separation affecting total time of analysis. The online technologies involving chemical ionisation (PTR-MS, CMS and GC-IMS) can be used in-clinic owing to short analysis times but only detect lower molar mass molecules with a proton affinity higher than 697 KJ/mol. Offline chromatographic techniques (GC-MS and GC×GC-MS) detect a wider range of compounds independent of proton affinity; however, the techniques have longer analysis times and involve sample transportation and storage. EMBER, East Midlands Breathomics Pathology Node.