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

Comparison of Forced and Impulse Oscillometry Measurements: A Clinical Population and Printed Airway Model Study.

The use of commercialised forced oscillation (FOT) devices to assess impedance in obstructive diseases such as asthma has gained popularity. However, it has yet to be fully established whether resistance and reactance measurements are comparable across different FOT devices, particularly in disease. We compared two commercially available FOT devices: Impulse Oscillometry (IOS) and TremoFlo FOT (Thorasys) in a) clinical adult population of healthy controls (n = 14), asymptomatic smokers (n = 17) and individuals with asthma (n = 73) and b) a 3D printed CT-derived airway tree model resistance, as well as a 3 L standardised volume reactance. Bland-Altman Plots and linear regressions were used to evaluate bias between the devices. Resistance measurements at both 5 and 20 Hz were numerically higher with IOS compared to FOT, with evidence of small and statistically significant proportional systematic bias and a positive Bland-Altman regression slope at both 5 and 20 Hz. In contrast, the IOS device recorded reactances that were less negative at both 5 Hz and 20 Hz and significantly smaller reactance areas when compared to TremoFlo. Larger statistically significant proportional systematic biases were demonstrated with both reactance at 5 Hz and reactance area (AX) between the devices with a negative Bland-Altman regression slope. The printed airway resistance and standardised volume reactance confirmed the observations seen in patients. We have demonstrated that the impulse oscillation system and TremoFlo FOT demonstrate comparative bias, particularly when comparing airway reactance in patients. Our results highlight the need for further standardisation across FOT measurement devices, specifically using variable test loads for reactance standardisation

Prediction of miscarriage in women with viable intrauterine pregnancy-A systematic review and diagnostic accuracy meta-analysis.

Both ultrasound and biochemical markers either alone or in combination have been described in the literature for the prediction of miscarriage. We performed this systematic review and meta-analysis to determine the best combination of biochemical, ultrasound and demographic markers to predict miscarriage in women with viable intrauterine pregnancy. The electronic database search included Medline (1946-June 2017), Embase (1980-June 2017), CINAHL (1981-June 2017) and Cochrane library. Key MESH and Boolean terms were used for the search. Data extraction and collection was performed based on the eligibility criteria by two authors independently. Quality assessment of the individual studies was done using QUADAS 2 (Quality Assessment for Diagnostic Accuracy Studies-2: A Revised Tool) and statistical analysis performed using the Cochrane systematic review manager 5.3 and STATA vs.13.0. Due to the diversity of the combinations used for prediction in the included papers it was not possible to perform a meta-analysis on combination markers. Therefore, we proceeded to perform a meta-analysis on ultrasound markers alone to determine the best marker that can help to improve the diagnostic accuracy of predicting miscarriage in women with viable intrauterine pregnancy. The systematic review identified 18 eligible studies for the quantitative meta-analysis with a total of 5584 women. Among the ultrasound scan markers, fetal bradycardia (n=10 studies, n=1762 women) on hierarchical summary receiver operating characteristic showed sensitivity of 68.41%, specificity of 97.84%, positive likelihood ratio of 31.73 (indicating a large effect on increasing the probability of predicting miscarriage) and negative likelihood ratio of 0.32. In studies for women with threatened miscarriage (n=5 studies, n=771 women) fetal bradycardia showed further increase in sensitivity (84.18%) for miscarriage prediction. Although there is gestational age dependent variation in the fetal heart rate, a plot of fetal heart rate cut off level versus log diagnostic odds ratio showed that at ≤110 beat per minutes the diagnostic power to predict miscarriage is higher. Other markers of intra uterine hematoma, crown rump length and yolk sac had significantly decreased predictive value. Therefore in women with threatened miscarriage and presence of fetal bradycardia on ultrasound scan, there is a role for offering repeat ultrasound scan in a week to ten days interval

Prospective observational cohort study of symptom control prediction in paediatric asthma by using the Royal College of Physicians three questions.

The Royal College of Physicians three questions (RCP3Q) is widely used for assessing asthma control within primary care in the UK, despite limited evidence in children. This study compared the RCP3Q as a tool for assessing asthma control in children (5-16 years) against the validated Asthma Control Test (ACT), Childhood Asthma Control Test (C-ACT), and Mini-Paediatric Quality of Life Questionnaire (MiniPAQLQ). We conducted a prospective observational cohort study involving children from eight primary care practices in Leicestershire. Children with doctor diagnosed asthma, or receiving regular asthma medication, were invited to participate. A total of 319 participants completed the MiniPAQLQ and the C-ACT/ACT questionnaires, before RCP3Q responses were collected as part of their routine asthma review conducted immediately afterwards. RCP3Q sensitivity for detecting uncontrolled asthma ranged from 43-60% and specificity from 80-82%. Using an RCP3Q score ≥2 to predict uncontrolled asthma and an RCP3Q score of zero to predict well-controlled asthma resulted in 10% of participants misclassified as uncontrolled and 8% as well-controlled, respectively. Using an RCP3Q threshold score of ≥1 resulted in 25% of participants being misclassified as uncontrolled. Our data suggests limited utility of the RCP3Q to assess asthma control in children. Alternative indicators of asthma control, such as the validated Asthma Control Test and the Children's Asthma Control Test should be considered instead

Additional file 1: of A nested case–control study of predictors for tuberculosis recurrence in a large UK Centre

Summary of definitions used in the study. Tables detailing: immunosuppressive medication received by patients; site of tuberculosis disease for cases and controls; MIRU VNTR strain type data for paired isolates; demographic data for reinfection and relapse cases. (DOCX 107 kb

Does cardiac rehabilitation for people with stroke in the sub-acute phase of recovery lead to physical behaviour change? Results from compositional analysis of accelerometry-derived data

ObjectivesDoes adapted cardiac rehabilitation (CR) improve the physical behaviours of people with mild-to-moderate stroke in the sub-acute recovery phase using a compositional data analysis (CoDA) approach?DesignBefore-after.SettingUniversity Hospitals of Leicester, Glenfield Hospital, UK.Participants24 individuals completed CR and provided valid physical activity (PA) data (mean (SD) 63.1 (14.6) years, 58% male (14/24)).Intervention6-week adapted CR program within 6-months of stroke.Main outcome measuresPhysical behaviours were assessed using waist-worn accelerometry. Step count, stationary time (ST), light PA (LPA), and moderate-to-vigorous PA (MVPA) were compared pre post CR using conventional analyses and CoDA. Analysed compositions were: Waking day (ST, LPA, MVPA); ST (1–9-minutes, 10–29-minutes, ≥30-minutes bouts); and MVPA (1–4-minutes, 5–9-minutes, ≥10-minutes bouts).ResultsFollowing CR, patients took significantly more steps (mean (SD) 3255 (2864) vs 3908 (3399) steps/day, P = 0.004) and engaged in more bouts of MVPA lasting ≥5 and ≥10-minutes (≥5-minutes: mean (SD) 0.7 (1.4) vs 1.2 (1.8) bouts/day, P = 0.008). Using CoDA, no changes in waking day or ST compositions occurred. For waking day, 42% (10/24) increased their LPA and MVPA at the expense of ST. For ST, 33% (8/24) increased their short bouts at the expense of medium and long bouts. For MVPA, 13% (3/24) increased their medium and long bouts at the expense of short bouts.ConclusionPeople with stroke in the sub-acute stage of recovery exhibited low levels of PA. CR appears to be an effective intervention to increase step count but did not alter the overall proportion of time individuals spent being sedentary, or engaging in LPA or in MVPA.RegistrationISRCTN65957980.</div

A nested case-control study of predictors for tuberculosis recurrence in a large UK Centre

Background: Tuberculosis (TB) recurrence represents a challenge to control programs. In low incidence countries, the prevailing risk factors leading to recurrence are poorly characterised. Methods: We conducted a nested case-control study using the Leicester TB service TBIT database. Cases were identified from database notifications between 1994 and 2014. Controls had one episode and were matched to cases on a ratio of two to one by the date of notification. Multiple imputation was used to account for missing data. Multivariate conditional logistic regression analysis was employed to identify clinical, sociodemographic and TB specific risk factors for recurrence. Results: From a cohort of 4628 patients, 82 TB recurrences occurred (1.8%). Nineteen of 82 patients had paired isolates with MIRU-VNTR strain type profiles available, of which 84% were relapses and 16% reinfections. On multivariate analysis, smoking (OR 3.8; p = 0.04), grade 3/4 adverse drug reactions (OR 5.6; p = 0.02), ethnicity 'Indian subcontinent' (OR 8.5; p = <0.01), ethnicity 'other' (OR 31.2; p = 0.01) and receipt of immunosuppressants (OR 6.8; p = <0.01) were independent predictors of TB recurrence. CONCLUSIONS: Within this UK setting, the rate of TB recurrence was low, predominantly due to relapse. The identification of an elevated recurrence risk amongst the ethnic group contributing most cases to the national TB burden presents an opportunity to improve individual and population health

Spirometry and FeNO testing for asthma in children in UK primary care: a prospective observational cohort study of feasibility and acceptability.

BACKGROUND:The National Institute for Health and Care Excellence recommends the use of spirometry and measuring the fraction of exhaled nitric oxide (FeNO) as part of the diagnostic work-up for children with suspected asthma, and spirometry for asthma monitoring, across all care settings. However, the feasibility and acceptability of these tests within primary care are not known. AIM:To investigate the feasibility, acceptability, training, and capacity requirements of performing spirometry and FeNO testing in children managed for asthma in UK primary care. DESIGN AND SETTING:Prospective observational study involving 10 general practices in the East Midlands, UK, and 612 children between 2016 and 2017. METHOD:Training and support to perform spirometry and FeNO in children aged 5 to 16 years were provided to participating practices. Children on the practice's asthma registers, and those with suspected asthma, were invited for a routine asthma review. Time for general practice staff to achieve competencies in performing and/or interpreting both tests, time to perform the tests, number of children able to perform the tests, and feedback on acceptability were recorded. RESULTS:A total of 27 general practice staff were trained in a mean time of 10.3 (standard deviation 2.7) hours. Usable spirometry and FeNO results were obtained in 575 (94%) and 472 (77%) children respectively. Spirometry is achievable in the majority of children aged ≥5 years, and FeNO in children aged ≥7 years. All of the staff and 97% of families surveyed provided positive feedback for the tests. CONCLUSION:After training, general practice staff obtained quality spirometry and FeNO data from most children tested. Testing was acceptable to staff and families. The majority of general practice staff reported that spirometry helped them to manage children's asthma better

ACE2, TMPRSS2 AND FURIN GENE EXPRESSION IN THE AIRWAYS OF PEOPLE WITH ASTHMA - IMPLICATIONS FOR COVID-19.

To-date, there has not been a clear signal suggesting that asthma or treatment with inhaled steroids are a risk factor for severe COVID-19 disease. We have therefore explored ACE2 receptor mRNA expression, and co-factors for Sars-CoV-2 infectivity (TMPRSS2 and furin) in bronchial brushes and biopsies from people with asthma and healthy controls, and looked for relationships between asthma severity, Th2- and IL-17 dependent gene signatures, and clinical demographics (age, sex). We have looked at a cohort of 356 research participants from previously described studies. The only significant association was a positive correlation between ACE2 and IL-17-dependent gene expression, and an inverse correlation between ACE2 and Th2-cytokine-dependent gene expression. These data suggest that differences in ACE2, TMPRSS2 and furin epithelial and airway gene expression are unlikely to confer enhanced COVID-19 pneumonia risk in patients with asthma across all treatment intensities and severity

Usability of wearable multiparameter technology to continuously monitor free-living vital signs in people living with chronic obstructive pulmonary disease: prospective observational study

Background: Vital signs monitoring (VSM) is routine for inpatients, but monitoring during free-living conditions is largely untested in chronic obstructive pulmonary disease (COPD). Objective: This study investigated the usability and acceptability of continuous VSM for people with COPD using wearable multiparameter technology. Methods: In total, 50 people following hospitalization for an acute exacerbation of COPD (AECOPD) and 50 people with stable COPD symptoms were asked to wear an Equivital LifeMonitor during waking hours for 6 weeks (42 days). The device recorded heart rate (HR), respiratory rate (RR), skin temperature, and physical activity. Adherence was defined by the number of days the vest was worn and daily wear time. Signal quality was examined, with thresholds of ≥85% for HR and ≥80% for RR, based on the device’s proprietary confidence algorithm. Data quality was calculated as the percentage of wear time with acceptable signal quality. Participant feedback was assessed during follow-up phone calls. Results In total, 84% of participants provided data, with average daily wear time of 11.8 (SD 2.2) hours for 32 (SD 11) days (average of study duration 76%, SD 26%). There was greater adherence in the stable group than in the post-AECOPD group (≥5 weeks wear: 71.4% vs 45.7%; P=.02). For all 84 participants, the median HR signal quality was 90% (IQR 80%-94%) and the median RR signal quality was 93% (IQR 92%-95%). The median HR data quality was 81% (IQR 58%-91%), and the median RR data quality was 85% (IQR 77%-91%). Stable group BMI was associated with HR signal quality (rs=0.45, P=.008) and HR data quality (rs=0.44, P=.008). For the AECOPD group, RR data quality was associated with waist circumference and BMI (rs=–0.49, P=.009; rs=–0.44, P=.02). In total, 36 (74%) participants in the Stable group and 21 (60%) participants in the AECOPD group accepted the technology, but 10 participants (12%) expressed concerns with wearing a device around their chest. Conclusions: This wearable multiparametric technology showed good user acceptance and was able to measure vital signs in a COPD population. Data quality was generally high but was influenced by body composition. Overall, it was feasible to continuously measure vital signs during free-living conditions in people with COPD symptoms but with additional challenges in the post-AECOPD context