The predictive role of symptoms in COVID-19 diagnostic models: A longitudinal insight.

To investigate the symptoms of SARS-CoV-2 infection, their dynamics and their discriminatory power for the disease using longitudinally, prospectively collected information reported at the time of their occurrence. We have analysed data from a large phase 3 clinical UK COVID-19 vaccine trial. The alpha variant was the predominant strain. Participants were assessed for SARS-CoV-2 infection via nasal/throat PCR at recruitment, vaccination appointments, and when symptomatic. Statistical techniques were implemented to infer estimates representative of the UK population, accounting for multiple symptomatic episodes associated with one individual. An optimal diagnostic model for SARS-CoV-2 infection was derived. The 4-month prevalence of SARS-CoV-2 was 2.1%; increasing to 19.4% (16.0%-22.7%) in participants reporting loss of appetite and 31.9% (27.1%-36.8%) in those with anosmia/ageusia. The model identified anosmia and/or ageusia, fever, congestion, and cough to be significantly associated with SARS-CoV-2 infection. Symptoms' dynamics were vastly different in the two groups; after a slow start peaking later and lasting longer in PCR+ participants, whilst exhibiting a consistent decline in PCR- participants, with, on average, fewer than 3 days of symptoms reported. Anosmia/ageusia peaked late in confirmed SARS-CoV-2 infection (day 12), indicating a low discrimination power for early disease diagnosis.

Airway clearance treatments in bronchiectasis: feasibility of linking survey results to registry data and a survey of patients' and physiotherapists' practices.

Background and objective: There are limited data on airway clearance treatment (ACT) practices. This study aimed to: 1) assess the feasibility of collecting online surveys on ACTs from patients and physiotherapists and linking the patient survey data to outcome data in the Bronch-UK/EMBARC Registry; 2) assess the association between ACT practices and outcome data; and 3) ascertain the factors affecting physiotherapist ACT practices. Methods: Survey methodology was used to collect data from patients with bronchiectasis and physiotherapists in Northern Ireland. Associations between patient survey data and linked Bronch-UK/EMBARC Registry patient outcome data were explored. Results: It was feasible to conduct an online survey with patients with bronchiectasis and link the data to the Bronch-UK/EMBARC Registry. 13% of patients did not perform ACTs. ACTs were used more often by patients who were symptomatic/had more severe disease compared to those with milder symptoms/disease. Patients used ACTs when they were symptomatic rather than as a preventative management strategy. Physiotherapists generally followed the bronchiectasis guidelines, using the stepwise approach to management. Conclusion: Our survey provided information about the feasibility of linking online survey and patient registry data. This study provides up-to-date information on ACT practice throughout the course of the disease trajectory as well as insight into the implementation of bronchiectasis guidelines by physiotherapists. Future work should explore how to optimise ACT data collection to maximise the use of real-world ACT data in bronchiectasis research and inform priority ACT research questions.

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial.

BACKGROUND: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. METHODS: Adults aged 18-84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. RESULTS: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%-88.8%). Vaccine efficacy was 100% (95% CI, 17.9%-100.0%) against severe disease and 76.3% (95% CI, 57.4%-86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein-specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. CONCLUSIONS: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. CLINICAL TRIALS REGISTRATION: EudraCT, 2020-004123-16.

Clinimetric Properties of Outcome Measures in Bronchiectasis.

Rationale: There is a lack of outcome measures with robust clinimetric properties in bronchiectasis. Objectives: To determine the clinimetric properties (reliability over 1 year during clinical stability and responsiveness over the course of antibiotics for pulmonary exacerbation) of objective and patient-reported outcome measures. Methods: This multicenter cohort study included adults with bronchiectasis from seven hospitals in the United Kingdom. Participants attended four visits, 4 months apart over 1 year while clinically stable and at the beginning and end of exacerbation and completed lung function (spirometry and multiple breath washout), provided a blood sample for C-reactive protein (CRP) measurement, and completed health-related quality of life (HRQoL) questionnaires (Quality of Life-Bronchiectasis, St. George's Respiratory Questionnaire, and EuroQoL 5-Dimensions 5-Levels). Results: Participants (n = 132) had a mean (standard deviation) age of 66 (11) years, and 64% were female. Lung function parameters (forced expiratory volume in one second [FEV1], standard lung clearance index [LCI2.5]) were reliable over time [coefficient of variation (CV): <10%]). Regarding responsiveness, FEV1 demonstrated better properties than LCI2.5; therefore, a clear justification for the use of LCI2.5 in future trials is needed. CRP was less reliable (CV > 20%) over time than FEV1 and LCI2.5, and whereas CRP had a large mean change between the start and end of an exacerbation, this may have been driven by a small number of patients having a large change in CRP. Reliability of HRQoL questionnaires and questionnaire domains ranged from acceptable (CV: 20-30%) to good (CV: 10-20%), and HRQoL were responsive to treatment of exacerbations. Considering the specific questionnaire domain relevant to the intervention and its associated clinimetric properties is important. Additional statistics will support future power and/or sample size analysis. Conclusions: This information on the clinimetric properties of lung function parameters, CRP, and HRQoL parameters should be used to inform the choice of outcome measures used in future bronchiectasis trials.

Multiple-Breath Washout Outcome Measures in Adults with Bronchiectasis.

Rationale: Lung clearance index (LCI) has good intravisit repeatability with better sensitivity in detecting lung disease on computed tomography scan compared with forced expiratory volume in 1 second (FEV1) in adults with bronchiectasis. Alternative multiple-breath washout parameters have not been systematically studied in bronchiectasis. Objectives: To determine the validity, repeatability, sensitivity, specificity, and feasibility of standard LCI (LCI2.5), shortened LCI (LCI5.0), ventilation heterogeneity arising within proximal conducting airways (ScondVT), and ventilation heterogeneity arising within the acinar airways (SacinVT) in a cross-sectional observational cohort of adults with bronchiectasis. Methods: Cross-sectional multiple-breath nitrogen washout data (Exhalyzer D; Eco Medics AG) from 132 patients with bronchiectasis across five United Kingdom centers (BronchUK Clinimetrics study) and 88 healthy control subjects were analyzed. Results: Within-test repeatability (mean coefficient of variation) was <5% for both LCI2.5 and LCI5.0 in patients with bronchiectasis, and there was no difference in mean coefficient of variation for LCI2.5 and LCI5.0 in patients with bronchiectasis compared with healthy volunteers. Moderate-strength correlations were seen between FEV1 and LCI2.5 (r = -0.54), LCI5.0 (r = -0.53), ScondVT (r = -0.35), and SacinVT (r = -0.38) z-scores. The proportion of subjects with abnormal multiple-breath washout (z-score > 2) but in normal FEV1 (z-score < -2) was 42% (LCI2.5) and 36% (LCI5.0). Overall results from the receiver operating characteristic curve analysis indicated that LCI2.5 had the greatest combined sensitivity and specificity to discriminate between bronchiectasis and control subjects, followed by LCI5.0, FEV1, and ScondVT z-scores. There was a 57% time saving with LCI5.0. Conclusions: LCI2.5 and LCI5.0 had good within-test repeatability and superior sensitivity compared with spirometry measures in differentiating between health and bronchiectasis disease. LCI5.0 is quicker and more feasible than LCI2.5. Clinical trial registered with www.clinicaltrials.gov (NCT02468271).

Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial.

Importance: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. Objective: To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. Design, Setting, and Participants: A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. Interventions: Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). Main Outcomes and Measures: The primary outcome was a composite of tracheal intubation or mortality within 30 days. Results: The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings. Trial Registration: isrctn.org Identifier: ISRCTN16912075.

Psychometrics of health-related quality of life questionnaires in bronchiectasis: a systematic review and meta-analysis.

INTRODUCTION: Understanding the psychometric properties of health-related quality of life (HRQoL) questionnaires can help inform selection in clinical trials. Our objective was to assess the psychometric properties of HRQoL questionnaires in bronchiectasis using a systematic review and meta-analysis of the literature. METHODS: A literature search was conducted. HRQoL questionnaires were assessed for psychometric properties (reliability, validity, minimal clinically important difference (MCID) and floor/ceiling effects). Meta-analyses assessed the associations of HRQoL with clinical measures and responsiveness of HRQoL in clinical trials. RESULTS: 166 studies and 12 HRQoL questionnaires were included. The Bronchiectasis Health Questionnaire (BHQ), Leicester Cough Questionnaire (LCQ), Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) had good internal consistency in all domains reported (Cronbach's α≥0.7) across all studies, and the Quality of Life-Bronchiectasis (QOL-B), St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Disease Questionnaire (CRDQ) and Seattle Obstructive Lung Disease Questionnaire (SOLQ) had good internal consistency in all domains in the majority of (but not all) studies. BHQ, SGRQ, LCQ and CAT had good test-retest reliability in all domains reported (intraclass correlation coefficient ≥0.7) across all studies, and QOL-B, CRDQ and SOLQ had good test-retest reliability in all domains in the majority of (but not all) studies. HRQoL questionnaires were able to discriminate between demographics, important markers of clinical status, disease severity, exacerbations and bacteriology. For HRQoL responsiveness, there was a difference between the treatment and placebo effect. CONCLUSIONS: SGRQ was the most widely used HRQoL questionnaire in bronchiectasis studies and it had good psychometric properties; however, good psychometric data are emerging on the bronchiectasis-specific HRQoL questionnaires QOL-B and BHQ. Future studies should focus on the medium- to long-term test-retest reliability, responsiveness and MCID in these HRQoL questionnaires which show potential in bronchiectasis.

BronchUK: protocol for an observational cohort study and biobank in bronchiectasis.

Bronchiectasis has been a largely overlooked disease area in respiratory medicine. This is reflected by a shortage of large-scale studies and lack of approved therapies, in turn leading to a variation of treatment across centres. BronchUK (Bronchiectasis Observational Cohort and Biobank UK) is a multicentre, prospective, observational cohort study working collaboratively with the European Multicentre Bronchiectasis Audit and Research Collaboration project. The inclusion criteria for patients entering the study are a clinical history consistent with bronchiectasis and computed tomography demonstrating bronchiectasis. Main exclusion criteria are 1) patients unable to provide informed consent, 2) bronchiectasis due to known cystic fibrosis or where bronchiectasis is not the main or co-dominant respiratory disease, 3) age <18 years, and 4) prior lung transplantation for bronchiectasis. The study is aligned to standard UK National Health Service (NHS) practice with an aim to recruit a minimum of 1500 patients from across at least nine secondary care centres. Patient data collected at baseline includes demographics, aetiology testing, comorbidities, lung function, radiology, treatments, microbiology and quality of life. Patients are followed up annually for a maximum of 5 years and, where able, blood and/or sputa samples are collected and stored in a central biobank. BronchUK aims to collect robust longitudinal data that can be used for analysis into current NHS practice and patient outcomes, and to become an integral resource to better inform future interventional studies in bronchiectasis.

Multiple breath washout in bronchiectasis clinical trials: is it feasible?

BACKGROUND: Evaluation of multiple breath washout (MBW) set-up including staff training, certification and central "over-reading" for data quality control is essential to determine the feasibility of MBW in future bronchiectasis studies. AIMS: To assess the outcomes of a MBW training, certification and central over-reading programme. METHODS: MBW training and certification was conducted in European sites collecting lung clearance index (LCI) data in the BronchUK Clinimetrics and/or i-BEST-1 studies. The blended training programme included the use of an eLearning tool and a 1-day face-to-face session. Sites submitted MBW data to trained central over-readers who determined validity and quality. RESULTS: Thirteen training days were delivered to 56 participants from 22 sites. Of 22 sites, 18 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p<0.001). By the end of the study recruitment, 15 of 22 sites (68%) had completed certification with a mean (range) time since training of 6.2 (3-14) months. In the BronchUK Clinimetrics study, 468 of 589 (79%) tests met the quality criteria following central over-reading, compared with 137 of 236 (58%) tests in the i-BEST-1 study. CONCLUSIONS: LCI is feasible in a bronchiectasis multicentre clinical trial setting; however, consideration of site experience in terms of training as well as assessment of skill drift and the need for re-training may be important to reduce time to certification and optimise data quality. Longer times to certification, a higher percentage of naïve sites and patients with worse lung function may have contributed to the lower success rate in the i-BEST-1 study.

RECOVERY- Respiratory Support: Respiratory Strategies for patients with suspected or proven COVID-19 respiratory failure; Continuous Positive Airway Pressure, High-flow Nasal Oxygen, and standard care: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVE: The trial objective is to determine if Continuous Positive Airway Pressure (CPAP) or High-Flow Nasal Oxygen (HFNO) is clinically effective compared to standard oxygen therapy in patients with confirmed or suspected COVID-19. TRIAL DESIGN: Adaptive (group-sequential), parallel group, pragmatic, superiority randomised controlled, open-label, multi-centre, effectiveness trial. PARTICIPANTS: The trial is being conducted across approximately 60 hospitals across England, Wales, Scotland, and Northern Ireland. Inpatients at participating hospitals are eligible to participate if they have respiratory failure with suspected or proven COVID-19, and meet all of the inclusion criteria and none of the exclusion criteria. INCLUSION CRITERIA: 1) Adults ≥ 18 years; 2) Admitted to hospital with suspected or proven COVID-19; 3) Receiving oxygen with fraction of inspired oxygen (FiO2) ≥0.4 and peripheral oxygen saturation (SpO2) ≤94%; and 4) Plan for escalation to tracheal intubation if needed. EXCLUSION CRITERIA: 1) Planned tracheal intubation and mechanical ventilation imminent within 1 hour; 2) Known or clinically apparent pregnancy; 3) Any absolute contraindication to CPAP or HFNO; 4) Decision not to intubate due to ceiling of treatment or withdrawal of treatment anticipated; and 5) Equipment for both CPAP and HFNO not available. INTERVENTION AND COMPARATOR: Intervention one: Continuous positive airway pressure delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention two: High-flow nasal oxygen delivered by any device. Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Comparator group: Standard care- oxygen delivered by face mask or nasal cannula (excluding the use of continuous positive airway pressure or high-flow nasal oxygen). Set-up and therapy titration is not protocolised and is delivered in accordance with clinical discretion. Intervention delivery continues up to the point of death, tracheal intubation, or clinical determination that there is no ongoing need (palliation or improvement). MAIN OUTCOMES: The primary outcome is a composite outcome comprising tracheal intubation or mortality within 30 days following randomisation. Secondary outcomes include tracheal intubation rate, time to tracheal intubation, duration of invasive ventilation, mortality rate, time to mortality, length of hospital stay, and length of critical care stay. RANDOMISATION: Participants are randomised in a 1:1:1 ratio to receive either continuous positive airway pressure, high-flow nasal oxygen or standard care. Due to the challenging environment of study delivery, a specific intervention may not always be available at the hospital site. The study uses two integrated randomisation systems to allow, where required, the site to randomise between all three interventions, between CPAP and standard care, and between HFNO and standard care. System integration ensures maintenance of balance between interventions. Randomisation is performed using a telephone-based interactive voice response system to maintain allocation concealment. The randomisation sequence was computer-generated using the minimisation method. Participant randomisation is stratified by site, gender (M/F), and age (<50, >=50 years). BLINDING (MASKING): The nature of the trial interventions precludes blinding of the researcher, patient and clinical team. Primary and secondary outcomes are all objective outcomes, thereby minimising the risk of detection bias. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 4002 participants (1334 to be randomized to each of the three study arms) TRIAL STATUS: Current protocol: Version 4.0, 29th May 2020. Recruitment began on April 6, 2020 and is anticipated to be complete by April 5, 2021. The trial has been awarded Urgent Public Health status by the National Institute of Health Research on 13th April 2020. TRIAL REGISTRATION: ISRCTN, ISRCTN16912075. Registered 6th April 2020, http://www.isrctn.com/ISRCTN16912075 FULL PROTOCOL: The full protocol (version 4.0, 29th May 2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Mucoactive agents for acute respiratory failure in the critically ill: a systematic review and meta-analysis.

PURPOSE: Acute respiratory failure (ARF) is a common cause of admission to intensive care units (ICUs). Mucoactive agents are medications that promote mucus clearance and are frequently administered in patients with ARF, despite a lack of evidence to underpin clinical decision making. The aim of this systematic review was to determine if the use of mucoactive agents in patients with ARF improves clinical outcomes. METHODS: We searched electronic and grey literature (January 2020). Two reviewers independently screened, selected, extracted data and quality assessed studies. We included trials of adults receiving ventilatory support for ARF and involving at least one mucoactive agent compared with placebo or standard care. Outcomes included duration of mechanical ventilation. Meta-analysis was undertaken using random-effects modelling and certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation. RESULTS: Thirteen randomised controlled trials were included (1712 patients), investigating four different mucoactive agents. Mucoactive agents showed no effect on duration of mechanical ventilation (seven trials, mean difference (MD) -1.34, 95% CI -2.97 to 0.29, I2=82%, very low certainty) or mortality, hospital stay and ventilator-free days. There was an effect on reducing ICU length of stay in the mucoactive agent groups (10 trials, MD -3.22, 95% CI -5.49 to -0.96, I2=89%, very low certainty). CONCLUSION: Our findings do not support the use of mucoactive agents in critically ill patients with ARF. The existing evidence is of low quality. High-quality randomised controlled trials are needed to determine the role of specific mucoactive agents in critically ill patients with ARF. PROSPERO REGISTRATION NUMBER: CRD42018095408.

Composition of airway bacterial community correlates with chest HRCT in adults with bronchiectasis.

BACKGROUND AND OBJECTIVE: In bronchiectasis (BE) not caused by cystic fibrosis, chronic, polymicrobial airway infection contributes to the underlying pathogenesis of disease. There is little information on whether bacterial community composition relates to clinical status. We determined the relationship between bacterial community composition, chest high-resolution computed tomography (HRCT) scores and clinical markers in BE. METHODS: A subgroup of BE patients from a previous cross-sectional study were analysed. Spontaneously expectorated sputum was analysed using culture-independent sequencing on the Roche 454-FLX platform covering the V1-V3 region of the 16S rRNA marker gene. Chest HRCT scans, multiple breath washout, spirometry and blood inflammatory markers were collected. Spearman's rank (r) correlation coefficient was used to assess relationships. RESULTS: Data from 21 patients were analysed (mean (SD) age: 64.0 (7.7); female : male 14:7; mean (SD) forced expiratory volume in 1 s (FEV1 ): 76.5 (17.2)). All bacterial community composition metrics (bacterial richness, diversity, evenness and dominance) correlated with percentage BE score, with more severe HRCT abnormality relating to lower bacterial richness, evenness and diversity (range r = -0.47 to -0.66; P < 0.05). Inflammation (C-reactive protein and white cell count) was greater in patients with lower diversity and richness (range r = -0.44 to -0.47; P < 0.05). Bacterial community characteristics did not correlate with lung function. CONCLUSION: This is the first study to indicate a relationship between bacterial community characteristics by 16S rRNA marker gene sequencing, structural damage as determined by chest HRCT and clinical measures in BE. The association between loss of diversity and chest HRCT severity suggests that bacterial dominance with pathogenic bacteria may contribute to disease pathology.

Airway clearance, mucoactive therapies and pulmonary rehabilitation in bronchiectasis.

This paper aims to provide physiological rationale for airway clearance, mucoactive therapy and pulmonary rehabilitation (PR) (or exercise interventions) in bronchiectasis. There is increasing emphasis on the role of airway clearance techniques (ACT) in the management of bronchiectasis. No single ACT has currently shown superior effect over another. Given the large range of different techniques available, consideration of the physiological effects underpinning a technique including expiratory flow, ventilation and oscillation, is essential to effectively personalize ACT. Key clinical trials of mucoactives in bronchiectasis are underway and will provide clarity on the role of these agents in the management of patients with bronchiectasis. Prescription of mucoactive therapies should be done in conjunction with ACT and therefore the mechanism of action of mucoactive drugs and their timing with ACT should be taken into consideration. PR and/or exercise training are recommended in all current bronchiectasis guidelines. There is a clear physiological rationale that muscle weakness and physical inactivity may play a role in disease progression as well as impacting health-related quality of life, frequency of pulmonary exacerbations and ability to mobilize sputum. However, there are residual unanswered questions surrounding the delivery and accessibility to PR. This review summarizes the physiological principles and supporting evidence for airway clearance, mucoactive medication and PR, which are key components in the management of bronchiectasis.

Patients' Perceptions of an Exercise Program Delivered Following Discharge From Hospital After Critical Illness (the Revive Trial).

BACKGROUND: The REVIVE randomized controlled trial (RCT) investigated the effectiveness of an individually tailored (personalized) exercise program for patients discharged from hospital after critical illness. By including qualitative methods, we aimed to explore patients' perceptions of engaging in the exercise program. METHODS: Patients were recruited from general intensive care units in 6 hospitals in Northern Ireland. Patients allocated to the exercise intervention group were invited to participate in this qualitative study. Independent semistructured interviews were conducted at 6 months after randomization. Interviews were audio-recorded, transcribed, and content analysis used to explore themes arising from the data. RESULTS: Of 30 patients allocated to the exercise group, 21 completed the interviews. Patients provided insight into the physical and mental sequelae they experienced following critical illness. There was a strong sense of patients' need for the exercise program and its importance for their recovery following discharge home. Key facilitators of the intervention included supervision, tailoring of the exercises to personal needs, and the exercise manual. Barriers included poor mental health, existing physical limitations, and lack of motivation. Patients' views of outcome measures in the REVIVE RCT varied. Many patients were unsure about what would be the best way of measuring how the program affected their health. CONCLUSIONS: This qualitative study adds an important perspective on patients' attitude to an exercise intervention following recovery from critical illness, and provides insight into the potential facilitators and barriers to delivery of the program and how programs should be evolved for future trials.

Quality control for multiple breath washout tests in multicentre bronchiectasis studies: Experiences from the BRONCH-UK clinimetrics study.

INTRODUCTION: Multiple Breath Washout (MBW) to measure Lung Clearance Index (LCI) is increasingly being used as a secondary endpoint in multicentre bronchiectasis studies. LCI data quality control or "over-reading" is resource intensive and the impact is unclear. OBJECTIVES: To assess the proportion of MBW tests deemed unacceptable with over-reading, and to assess the change in LCI (number of turnovers), LCI coefficient of variation (CV%) and tidal volume (VT) CV% results after over-reading. METHODS: Data were analysed from 250 MBW tests (from 98 adult bronchiectasis patients) collected as part of the Bronch-UK Clinimetrics study in 5 UK centres. Each MBW test was over-read centrally using pre-defined criteria. MBW tests with <2 technically valid and repeatable trials were deemed unacceptable to include in analysis. In accepted tests, values for LCI, LCI CV% and VT CV% before and after over-reading, were compared. RESULTS: Insufficient data was collected in 10/250 tests. With over-reading, 30/240 (12%) were deemed unacceptable to include in analysis. In those accepted tests, overall the change in LCI, LCI CV% and VT CV% with over-reading was not statistically significant. When MBW new sites were compared to MBW expert sites, the change in LCI with over-reading was significantly greater in MBW new sites (p = 0.047). Data suggests that over-reading could be important up to at least 12 months post initiation of MBW activity. CONCLUSION: MBW over-reading was important in this study as 12% of tests were considered unacceptable. Over-reading improved test result accuracy in sites new to MBW.

Training in multiple breath washout testing for respiratory physiotherapists.

INTRODUCTION: The development of multiple breath washout (MBW) testing in respiratory disease highlights the need for increased awareness amongst respiratory physiotherapists and a potential opportunity for professional development in the use of an important outcome measure for clinical trials. OBJECTIVES: To rationalise how MBW may be a useful assessment tool for respiratory physiotherapists and to describe a local MBW training and certification programme for physiotherapists. RESULTS: The respiratory Multidisciplinary Team in the Belfast Health and Social Care Trust (BHSCT) identified a need for MBW testing to be available to facilitate clinical research and assessment. A 2day training programme consisting of prereading preparation, self-directed learning, theory presentations, practical demonstrations and hands-on practice was developed and delivered. All participants underwent a certification process. CONCLUSION: We have demonstrated the successful training and certification of clinical and research physiotherapists and encourage other respiratory physiotherapists to consider MBW test training.

Non-invasive ventilation for cystic fibrosis.

BACKGROUND: Non-invasive ventilation may be a means to temporarily reverse or slow the progression of respiratory failure in cystic fibrosis by providing ventilatory support and avoiding tracheal intubation. Using non-invasive ventilation, in the appropriate situation or individuals, can improve lung mechanics through increasing airflow and gas exchange and decreasing the work of breathing. Non-invasive ventilation thus acts as an external respiratory muscle. This is an update of a previously published review. OBJECTIVES: To compare the effect of non-invasive ventilation versus no non-invasive ventilation in people with cystic fibrosis for airway clearance, during sleep and during exercise. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We searched the reference lists of each trial for additional publications possibly containing other trials.Most recent search: 08 August 2016. SELECTION CRITERIA: Randomised controlled trials comparing a form of pressure preset or volume preset non-invasive ventilation to no non-invasive ventilation used for airway clearance or during sleep or exercise in people with acute or chronic respiratory failure in cystic fibrosis. DATA COLLECTION AND ANALYSIS: Three reviewers independently assessed trials for inclusion criteria and methodological quality, and extracted data. MAIN RESULTS: Ten trials met the inclusion criteria with a total of 191 participants. Seven trials evaluated single treatment sessions, one evaluated a two-week intervention, one evaluated a six-week intervention and one a three-month intervention. It is only possible to blind trials of airway clearance and overnight ventilatory support to the outcome assessors. In most of the trials we judged there was an unclear risk of bias with regards to blinding due to inadequate descriptions. The six-week trial was the only one judged to have a low risk of bias for all other domains. One single intervention trial had a low risk of bias for the randomisation procedure with the remaining trials judged to have an unclear risk of bias. Most trials had a low risk of bias with regard to incomplete outcome data and selective reporting.Six trials (151 participants) evaluated non-invasive ventilation for airway clearance compared with an alternative chest physiotherapy method such as the active cycle of breathing techniques or positive expiratory pressure. Three trials used nasal masks, one used a nasal mask or mouthpiece and one trial used a face mask and in one trial it is unclear. Three of the trials reported on one of the review's primary outcome measures (quality of life). Results for the reviews secondary outcomes showed that airway clearance may be easier with non-invasive ventilation and people with cystic fibrosis may prefer it. We were unable to find any evidence that non-invasive ventilation increases sputum expectoration, but it did improve some lung function parameters.Three trials (27 participants) evaluated non-invasive ventilation for overnight ventilatory support compared to oxygen or room air using nasal masks (two trials) and nasal masks or full face masks (one trial). Trials reported on two of the review's primary outcomes (quality of life and symptoms of sleep-disordered breathing). Results for the reviews secondary outcome measures showed that they measured lung function, gas exchange, adherence to treatment and preference, and nocturnal transcutaneous carbon dioxide. Due to the small numbers of participants and statistical issues, there were discrepancies in the results between the RevMan and the original trial analyses. No clear differences were found between non-invasive ventilation compared with oxygen or room air except for exercise performance, which significantly improved with non-invasive ventilation compared to room air over six weeks.One trial (13 participants) evaluated non-invasive ventilation on exercise capacity (interface used was unclear) and did not reported on any of the review's primary outcomes. The trial found no clear differences between non-invasive ventilation compared to no non-invasive ventilation for any of our outcomes.Three trials reported on adverse effects. One trial, evaluating non-invasive ventilation for airway clearance, reported that a participant withdrew at the start of the trial due to pain on respiratory muscle testing. One trial evaluating non-invasive ventilation for overnight support reported that one participant could not tolerate an increase in inspiratory positive airway pressure. A second trial evaluating non-invasive ventilation in this setting reported that one participant did not tolerate the non-invasive ventilation mask, one participant developed a pneumothorax when breathing room air and two participants experienced aerophagia which resolved when inspiratory positive airway pressure was decreased. AUTHORS' CONCLUSIONS: Non-invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with cystic fibrosis who have difficulty expectorating sputum. Non-invasive ventilation, used in addition to oxygen, may improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate to severe disease. The effect of NIV on exercise is unclear. These benefits of non-invasive ventilation have largely been demonstrated in single treatment sessions with small numbers of participants. The impact of this therapy on pulmonary exacerbations and disease progression remain unclear. There is a need for long-term randomised controlled trials which are adequately powered to determine the clinical effects of non-invasive ventilation in cystic fibrosis airway clearance and exercise.

Timing of hypertonic saline and airway clearance techniques in adults with cystic fibrosis during pulmonary exacerbation: pilot data from a randomised crossover study.

BACKGROUND: Streamlining the timing of treatments in cystic fibrosis (CF) is important to optimise adherence while ensuring efficacy. The optimal timing of treatment with hypertonic saline (HTS) and airway clearance techniques (ACT) is unknown. OBJECTIVES: This study hypothesised that HTS before ACT would be more effective than HTS during ACT as measured by Lung Clearance Index (LCI). METHODS: Adults with CF providing written informed consent were randomised to a crossover trial of HTS before ACT or HTS during ACT on consecutive days. ACT treatment consisted of Acapella Duet. Patients completed LCI and spirometry at baseline and 90 min post treatment. Mean difference (MD) and 95% CIs were reported. RESULTS: 13 subjects completed the study (mean (SD) age 33 (12) years, forced expiratory volume in 1second % (FEV1%) predicted 51% (22), LCI (no. turnovers) 14 (4)). Comparing the two treatments (HTS before ACT vs HTS during ACT), the change from baseline to 90 min post treatment in LCI (MD (95% CI) -0.02 (-0.63 to 0.59)) and FEV1% predicted (MD (95% CI) -0.25 (-2.50 to 1.99)) was not significant. There was no difference in sputum weight (MD (95% CI) -3.0 (-14.9 to 8.9)), patient perceived ease of clearance (MD (95% CI) 0.4 (-0.6 to 1.3) or satisfaction (MD (95% CI) 0.4 (-0.6 to 1.5)). The time taken for HTS during ACT was significantly shorter (MD (95% CI) 14.7 (9.8 to 19.6)). CONCLUSIONS: In this pilot study, HTS before ACT was no more effective than HTS during ACT as measured by LCI. TRIAL REGISTRATION NUMBER: NCT01753869; Pre-results.