DIGIPREDICT: physiological, behavioural and environmental predictors of asthma attacks-a prospective observational study using digital markers and artificial intelligence-study protocol.

INTRODUCTION: Asthma attacks are a leading cause of morbidity and mortality but are preventable in most if detected and treated promptly. However, the changes that occur physiologically and behaviourally in the days and weeks preceding an attack are not always recognised, highlighting a potential role for technology. The aim of this study 'DIGIPREDICT' is to identify early digital markers of asthma attacks using sensors embedded in smart devices including watches and inhalers, and leverage health and environmental datasets and artificial intelligence, to develop a risk prediction model to provide an early, personalised warning of asthma attacks. METHODS AND ANALYSIS: A prospective sample of 300 people, 12 years or older, with a history of a moderate or severe asthma attack in the last 12 months will be recruited in New Zealand. Each participant will be given a smart watch (to assess physiological measures such as heart and respiratory rate), peak flow meter, smart inhaler (to assess adherence and inhalation) and a cough monitoring application to use regularly over 6 months with fortnightly questionnaires on asthma control and well-being. Data on sociodemographics, asthma control, lung function, dietary intake, medical history and technology acceptance will be collected at baseline and at 6 months. Asthma attacks will be measured by self-report and confirmed with clinical records. The collected data, along with environmental data on weather and air quality, will be analysed using machine learning to develop a risk prediction model for asthma attacks. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the New Zealand Health and Disability Ethics Committee (2023 FULL 13541). Enrolment began in August 2023. Results will be presented at local, national and international meetings, including dissemination via community groups, and submission for publication to peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12623000764639; Australian New Zealand Clinical Trials Registry.

Global mortality and readmission rates following COPD exacerbation-related hospitalisation: a meta-analysis of 65 945 individual patients.

Background: Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods: A systematic review was performed identifying studies that reported in-hospital mortality, post-discharge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results: Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisations <12 months prior to the index event. Conclusions: This IPDMA stresses the poor outcomes and high heterogeneity of ECOPD-related hospitalisation across the world. Whilst global standardisation of the management and follow-up of ECOPD-related hospitalisation should be at the heart of future implementation research, policy makers should focus on reimbursing evidence-based therapies that decrease (recurrent) ECOPD.

The impact of bronchoalveolar lavage on the diagnosis of undifferentiated interstitial lung disease alongside a multidisciplinary discussion.

BACKGROUND AND OBJECTIVE: Cellular analysis of bronchoalveolar lavage (BAL) fluid may aid diagnosis in patients with undifferentiated interstitial lung disease (ILD). The utility of this test in the diagnostic process in conjunction with a multidisciplinary discussion (MDD) is not known. We aim to assess and compare interobserver agreement and diagnostic confidence before and after presenting BAL results in an ILD-MDD. METHODS: Patients undergoing investigations for ILD at Waikato Hospital were recruited. At the ILD-MDD two respiratory physicians and one respiratory radiologist participated in the discussion, and their diagnosis and diagnostic confidence were assessed at four sequential time points. Assessors were blinded to each others diagnosis and diagnostic confidence scores. The four sequential time points were (1) after clinical and radiology presentation; (2) after subsequent MDD; (3) after reviewing BAL results; (4) after final MDD with all results. Interobserver agreements were calculated using Fleiss κ statistic. RESULTS: 36 patients were recruited, and 77.8% were male. In the first step, the interobserver agreement was substantial κ = 0.622 (95% CI 0.47-0.77), improving in step 2 following MDD to κ = 0.78 (95% CI 0.624-0.935), in step 3 κ = 0.776 (95% CI 0.614-0.937) and step 4 achieved almost perfect agreement of κ = 0.969 (95% CI 0.828-1.11). The diagnostic confidence for individual and group diagnosis increased with the presentation of BAL with and without multidisciplinary MDD. CONCLUSION: We found that BAL cellular analysis improves interobserver agreement and confidence in diagnosis following MDD, thus aiding decision-making in cases with undifferentiated ILD.

Influences of breath sample re-use on the accuracy of lung cancer detection dogs.

Evaluations of dogs as lung cancer detectors using breath samples have produced a variety of results, some quite promising. Breath samples are typically collected onto a substrate and stored in a sealed container when not in use, but volatile compounds dissipate when the substrate is exposed during training and evaluation sessions. Collection of appropriate samples for training and testing dogs requires significant resources and strict control of recruitment and sample collection processes. Therefore, some researchers re-use samples while training dogs. No systematic evaluation of the effect of sample re-use on dogs' training performance has been conducted, so the influence of this potentially important training factor is not known. We trained seven dogs to indicate the presence of lung cancer positive breath samples using an automated apparatus. The samples were stored at -60 °C or -80 °C. Samples from 460 individuals who were classified as positive or negative for lung cancer were used for training samples. Individual samples were presented to dogs up to four times over a period of 2 years. As sample re-use increased, sensitivity declined (-6.65,p= < .001, 95% CI [-10.56, -2.76]), specificity increased (2.87,p= .036, 95% CI [.19, 5.55]), and the dogs' bias shifted in the direction of a negative indication bias (-.094,p= < .001, 95% CI [-.149, -.39]). However, there were no significant changes in the measure associated with the detectability of the target (-0.30,p= .285, 95% CI [-.087, .26]). All observed changes in performance across sample re-use were small. Therefore, these findings suggest that sample re-use may be appropriate for training, but additional research is required to determine which factors underly changes in performance as breath samples are re-used.

Non-invasive ventilation for acute hypoxaemic respiratory failure: a propensity-matched cohort study.

BACKGROUND: Non-invasive ventilation (NIV), although effective in treating hypercapnic respiratory failure, has not demonstrated the same efficacy in treating acute hypoxaemic respiratory failure. We aimed to examine the effect of NIV use on ventilator-free days in patients with acute hypoxaemic respiratory failure admitted to the intensive care unit (ICU). METHODS: We conducted a retrospective study of patients admitted to the ICU with acute hypoxaemic respiratory failure at Waikato Hospital, New Zealand, from 1 January 2009 to 31 December 2018. Patients treated with NIV as the initial oxygenation strategy were compared with controls treated with early intubation. The two groups were matched using a propensity score based on baseline characteristics. The primary outcome was the number of ventilator-free days at day 28. The secondary outcomes were ICU and hospital length of stay and in-hospital mortality. RESULTS: Out of 175 eligible patients, 79 each out of the NIV and early intubation groups were matched using a propensity score. Early NIV was associated with significantly higher median ventilator-free days than early intubation (17 days vs 23 days, p=0.013). There was no significant difference in median ICU length of stay (112.5 hours vs 117.7 hours), hospital length of stay (14 days vs 14 days) or in-hospital mortality (31.6% vs 37.9%) between the NIV and the early intubation group. CONCLUSION: Compared with early intubation, NIV use was associated with more ventilator-free days in patients with hypoxaemic respiratory failure. However, this did not translate into a shorter length of stay or reduced mortality based on our single-centre experience.

Tiotropium treatment for bronchiectasis: a randomised, placebo-controlled, crossover trial.

BACKGROUND: Tiotropium via the HandiHaler device is an established long-acting, anticholinergic bronchodilator that prevents exacerbations and improves lung function in patients with chronic obstructive pulmonary disease. We hypothesised that tiotropium would reduce pulmonary exacerbations and improve lung function in patients with stable bronchiectasis and airflow limitation, and assessed the effect of tiotropium on these outcomes. METHODS: In a randomised, double-blind, two-period crossover trial, we recruited adult patients from three hospitals in New Zealand. Patients were excluded if they had a smoking history of >20 pack-years. Patients were assigned to either the tiotropium-placebo or placebo-tiotropium sequence in a 1:1 ratio, using randomly permuted blocks stratified by centre. Participants and investigators were masked to treatment allocation. Eligible patients received tiotropium 18 µg via HandiHaler daily for 6 months followed by 6 months of placebo, or vice versa, with a washout period of 4 weeks. The primary end-point was rate of event-based exacerbations during the 6-month period. Primary analyses were carried out in an intention-to-treat set. RESULTS: 90 patients were randomly assigned and 85 completed both treatment cycles. The rate of exacerbations was 2.17 per year under the tiotropium treatment and 2.27 per year under placebo (rate ratio 0.96, 95% CI 0.72-1.27; p=0.77). Tiotropium, compared with placebo, improved forced expiratory volume in 1 s by 58 mL (95% CI 23-92 mL; p=0.002). Adverse events were similar under both treatments. CONCLUSIONS: Tiotropium via HandiHaler over 6 months significantly improved lung function but not frequency of exacerbations. Further research is required to understand the clinical context and significance of these findings.

Lichenoid cutaneous skin eruption and associated systemic inflammatory response following Pfizer-BioNTech mRNA COVID-19 vaccine administration.

The global effects of coronavirus disease 2019 (COVID-19) have driven unprecedented rapid development and mass deployment of vaccinations against the novel coronavirus. However, the short- and long-term adverse reactions following COVID-19 vaccinations are still under investigation as insufficient time has passed to fully explore these. The Pfizer-BioNTech COVID-19 mRNA vaccine has thus far shown a favourable safety profile in phase I-III studies. Although infrequent cases of generalized cutaneous reactions and systemic inflammatory response have been reported following other mRNA vaccines, these have not been reported following the Pfizer-BioNTech vaccine. We report a case of generalized lichenoid skin eruptions and systemic inflammatory response occurring together following the first dose of the Pfizer-BioNTech vaccine. Our case report adds to an accumulating body of literature connecting autoimmunity with the pathophysiology of the novel coronavirus disease.

Preventing adverse cardiac events (PACE) in chronic obstructive pulmonary disease (COPD): study protocol for a double-blind, placebo controlled, randomised controlled trial of bisoprolol in COPD.

INTRODUCTION: Heart disease in chronic obstructive pulmonary disease (COPD) is a common but neglected comorbidity. Patients with COPD are frequently excluded from clinical trials of treatments aimed at reducing cardiac morbidity and mortality, which has led to undertreatment of cardiovascular disease in patients with COPD. A particular concern in COPD is the underuse of beta (ß)-blockers. There is observational evidence that cardioselective ß-blockers are safe and may even reduce mortality risk in COPD, although some evidence is conflicting. There is an urgent need to answer the research question: Are cardioselective ß-blockers safe and of benefit in people with moderately severe COPD? The proposed study will investigate whether cardioselective ß-blocker treatment in patients with COPD reduces mortality and cardiac and respiratory morbidity. METHODS AND ANALYSES: This is a double-blind, randomised controlled trial to be conducted in approximately 26 sites in Australia, New Zealand, India, Sri Lanka and other countries as required. Participants with COPD will be randomised to either bisoprolol once daily (range 1.25-5 mg, dependent on tolerated dose) or matched placebo, in addition to receiving usual care for their COPD over the study duration of 24 months.The study will enrol 1164 participants with moderate to severe COPD, aged 40-85 years. Participants will be symptomatic from their COPD and have a postbronchodilator forced expiratory volume in 1 s (FEV1) ≥30% and ≤70% predicted and a history of at least one exacerbation requiring systemic corticosteroids, antibiotics or both in the prior 24 months. ETHICS AND DISSEMINATION: The study protocol has been approved by the Sydney Local Health District Human Research Ethics Committee at The Concord Repatriation General Hospital. TRIAL REGISTRATION NUMBERS: NCT03917914; CTRI/2020/08/027322.

Impact of COVID-19 pandemic restrictions on the cardio-respiratory health of New Zealanders.

BACKGROUND AND OBJECTIVE: The COVID-19 pandemic has caused disruption to health, social interaction, travel and economies worldwide. In New Zealand, the government closed the border to non-residents and required all arrivals to quarantine for 14 days. They also implemented a strict contact-restriction system to eliminate COVID-19 from the community. These measures also reduced the circulation of other respiratory viruses such as influenza and respiratory syncytial virus. We assessed the impact of these measures on hospital admissions for respiratory and cardiac diseases. METHODS: National data on hospital admissions for each week of 2020 were compared to admissions for the previous 5 years. Analyses were curtailed after week 33, when a COVID-19 outbreak in Auckland led to different levels of pandemic restrictions making national data difficult to interpret. RESULTS: The numbers of acute infectious respiratory admissions were similar to previous years before the introduction of COVID-19 restrictions, but then fell lower and remained low after the pandemic restrictions were eased. The usual winter peak in respiratory admissions was not seen in 2020. Other than small reductions during the period of the strictest contact restrictions, non-infectious respiratory and cardiac admissions were similar to previous years and the usual winter peak in heart failure admissions was observed. CONCLUSION: The observed patterns of hospital admissions in 2020 are compatible with the hypothesis that circulating respiratory viruses drive the normal seasonal trends in respiratory admissions. By contrast, these findings suggest that respiratory viruses do not drive the winter peak in heart failure.

Cardiac biomarkers in acute respiratory distress syndrome: a systematic review and meta-analysis.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality in the intensive care unit. Biochemical markers of cardiac dysfunction are associated with high mortality in many respiratory conditions. The aim of this systematic review is to examine the link between elevated biomarkers of cardiac dysfunction in ARDS and mortality. METHODS: A systematic review of MEDLINE, EMBASE, Web of Science and CENTRAL databases was performed. We included studies of adult intensive care patients with ARDS that reported the risk of death in relation to a measured biomarker of cardiac dysfunction. The primary outcome of interest was mortality up to 60 days. A random-effects model was used for pooled estimates. Funnel-plot inspection was done to evaluate publication bias; Cochrane chi-square tests and I2 tests were used to assess heterogeneity. RESULTS: Twenty-two studies were included in the systematic review and 18 in the meta-analysis. Biomarkers of cardiac stretch included NT-ProBNP (nine studies) and BNP (six studies). Biomarkers of cardiac injury included Troponin-T (two studies), Troponin-I (one study) and High-Sensitivity-Troponin-I (three studies). Three studies assessed multiple cardiac biomarkers. High levels of NT-proBNP and BNP were associated with a higher risk of death up to 60 days (unadjusted OR 8.98; CI 4.15-19.43; p<0.00001). This association persisted after adjustment for age and illness severity. Biomarkers of cardiac injury were also associated with higher mortality, but this association was not statistically significant (unadjusted OR 2.21; CI 0.94-5.16; p= 0.07). CONCLUSION: Biomarkers of cardiac stretch are associated with increased mortality in ARDS.

Cardiac biomarkers and long-term outcomes of exacerbations of COPD: a long-term follow-up of two cohorts.

BACKGROUND: COPD patients often have cardiac comorbidities. Cardiac involvement at the time of a COPD exacerbation is associated with a high short-term mortality, but whether this influences long-term outcomes is unknown. We explored whether biomarkers of cardiac dysfunction at the time of a COPD exacerbation predict long-term outcomes. METHODS: Two prospective cohorts of patients admitted to Waikato Hospital for exacerbations of COPD were recruited during 2006-2007 and 2012-2013. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin T were measured on admission and were used to indicate cardiac stretch and myocardial injury, respectively. 5-year survival after discharge and subsequent admissions for cardiac disease and COPD exacerbations were analysed using Kaplan-Meier and Cox proportional hazards tests. RESULTS: The overall 5-year mortality was 61%. Patients with high NT-proBNP on admission had higher mortality than those with normal cardiac biomarkers (adjusted hazard ratio (aHR) 1.76, 95% CI 1.18-2.62). High NT-proBNP was also associated with a higher risk of future cardiac admissions (aHR 1.75, 95% CI 1.2-2.55). Troponin T levels were not associated with long-term survival (aHR 0.86, 95% CI 0.40-1.83) or future cardiac admissions (aHR 0.74, 95% CI 0.34-1.57). Neither biomarker predicted future COPD exacerbations. CONCLUSION: The long-term prognosis following a hospitalisation for an exacerbation of COPD is poor with less than half of patients surviving for 5 years. Elevated NT-proBNP at the time of a COPD exacerbation is associated with higher long-term mortality and a greater likelihood of future cardiac admissions, but not future COPD exacerbations.

The safety of cardioselective ß1-blockers in asthma: literature review and search of global pharmacovigilance safety reports.

INTRODUCTION: Beta-blockers are key in the management of cardiovascular diseases but blocking airway ß2-receptors can cause severe and sometimes fatal bronchoconstriction in people with asthma. Although cardioselective ß1-blockers may be safer than non-selective ß-blockers, they remain relatively contraindicated and under-prescribed. We review the evidence of the risk associated with cardioselective ß1-blocker use in asthma. METHODS: We searched "asthma" AND "beta-blocker" in PubMed and EmbaseOvid from start to May 2020. The World Health Organization (WHO) global database of individual case safety reports (VigiBase) was searched for reports of fatal asthma or bronchospasm and listed cardioselective ß1-blocker use (accessed February 2020). Reports were examined for evidence of pre-existing asthma. RESULTS: PubMed and EmbaseOvid searches identified 304 and 327 publications, respectively. No published reports of severe or fatal asthma associated with cardioselective ß1-blockers were found. Three large observational studies reported no increase in asthma exacerbations with cardioselective ß1-blocker treatment. The VigiBase search identified five reports of fatalities in patients with pre-existing asthma and reporting asthma or bronchospasm during cardioselective ß1-blocker use. Four of these deaths were unrelated to cardioselective ß1-blocker use. The circumstances of the fifth death were unclear. CONCLUSIONS: There were no published reports of cardioselective ß1-blockers causing asthma death. Observational data suggest that cardioselective ß1-blocker use is not associated with increased asthma exacerbations. We found only one report of an asthma death potentially caused by cardioselective ß1-blockers in a patient with asthma in a search of VigiBase. The reluctance to use cardioselective ß1-blockers in people with asthma is not supported by this evidence.

The impact of regular bisoprolol on the response to salbutamol in asthma: A double-blind randomized placebo-controlled crossover trial.

BACKGROUND AND OBJECTIVE: Non-selective beta-blockers impair the bronchodilator response to beta2 -agonists. Cardio-selective beta1 -blockers are less likely to cause this effect, yet they remain relatively contraindicated in asthma. We investigated whether the response to salbutamol is impaired during cardio-selective beta1 -blocker treatment in people with asthma. METHODS: A random-order, double-blind, placebo-controlled, non-inferiority, crossover study was conducted comparing up to 5 mg bisoprolol daily for 2 weeks with matching placebo, with an open-label extension of up to 10 mg bisoprolol daily. After each treatment period, mannitol was inhaled to induce bronchoconstriction with a 15% fall in forced expiratory volume in 1 s (FEV1 ). Immediately after mannitol challenge, salbutamol (100, 100 and 200 µg) was administered via spacer at 5-min intervals with repeated FEV1 measures. The FEV1 recovery with salbutamol was measured as an area under recovery curve (AUC). Based on earlier research, a clinically relevant non-inferiority limit of a 30% reduction in the AUC was set. RESULTS: A total of 19 adults with mild asthma and positive inhaled mannitol challenge completed the study. Adjusting for the FEV1 fall induced by mannitol and treatment sequence, the mean AUC response to salbutamol after bisoprolol was 5% lower than after placebo, with a one-sided 95% confidence interval (CI) of 26% lower. Thirteen participants completed the open-label extension up to 10 mg bisoprolol daily with mean AUC 11% higher after bisoprolol with a 95% CI of 5% lower. CONCLUSION: The bronchodilator response to rescue salbutamol after mannitol-induced bronchoconstriction is non-inferior during regular treatment with the cardio-selective beta1 -blocker, bisoprolol, compared to placebo. CLINICAL TRIAL REGISTRATION: ACTRN12618000306213 at https://www.anzctr.org.au.

Thunderstorm-related asthma can occur in New Zealand.

Thunderstorm asthma is induced by specific weather conditions causing breakdown and widespread distribution of allergens. Thunderstorm asthma had previously been considered unlikely to occur in New Zealand (NZ), given its local weather patterns. Storm events on 2 December 2017 led to increased asthma presentations at Waikato Hospital in Hamilton. Analyses of patient presentations led us to conclude that these presentations were similar to international descriptions of thunderstorm asthma. This is the first time such presentations have been reported in NZ. Documenting these events accurately is important as this is the first step to making a plan that would enable paramedics and emergency facilities across NZ to respond to any larger scale thunderstorm asthma events in the future.

Co-diagnoses of acute myeloid leukaemia and COVID-19: presentation and management implications.

We report a case of concurrent new diagnoses of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute myeloid leukaemia (AML). We review the existing literature on coronavirus disease 2019 (COVID-19) in the immunocompromised patient and the implications for managing our patient's haematological neoplasm. The implications of severe immunocompromise are unclear in the context of infection with SARS-CoV-2. Respiratory and viral systemic symptoms remained mild in this patient and this is consistent with the existing literature on COVID-19 in immunocompromised patients. To our knowledge, this is the first description of a case of SARS-CoV-2 infection with AML.

Dyspnoea and restrictive lung disease due to mediastinal and pleural lipomatosis in morbid obesity.

Dyspnoea in obese patients can be multifactorial and complex. Mediastinal and pleural lipomatosis can be associated with obesity and is usually considered asymptomatic and benign. We report an obese 39-year-old man who presented with progressive dyspnoea, where in addition to obstructive sleep apnoea and obesity hypoventilation syndrome, was found to have massive mediastinal and pleural lipomatosis causing restrictive lung disease. Pleural lipomatosis are generally slow growing so conservative management is recommended. However, complications such as haemorrhage and compression of adjoining organs can occur in pleural lipomas, so surgical excision can be considered in some instances.

Cardiac dysfunction in exacerbations of chronic obstructive pulmonary disease is often not detected by electrocardiogram and chest radiographs.

BACKGROUND: Cardiac dysfunction is common in exacerbations of chronic obstructive pulmonary disease (COPD), even in patients without clinically suspected cardiac disorders. AIM: To investigate associations between electrocardiogram (ECG) and chest radiograph abnormalities and biochemical evidence of cardiac dysfunction (N-terminal pro-B-type natriuretic peptide and troponin T) in patients hospitalised with exacerbations of COPD at Waikato Hospital. METHODS: Independent examiners, blinded to NT-proBNP and troponin T levels, assessed ECG for tachycardia, atrial fibrillation, ventricular hypertrophy and ischaemic changes in 389 patients and chest radiographs for signs of heart failure in 350 patients. Associations between electrocardiographic and radiographic abnormalities with at least moderate interrater agreement and cardiac biomarkers were analysed. RESULTS: High NT-proBNP values (>220 pmol/L) were associated with atrial fibrillation (22 vs 6%), right ventricular hypertrophy (24 vs 15%), left ventricular hypertrophy (15 vs 4%), ischaemia (59 vs 33%) and cardiomegaly (42 vs 20%). High troponin T values (>0.03ug/L or high-sensitivity >50 ng/L) were associated with tachycardia (65 vs 41%), right ventricular hypertrophy (26 vs 15%) and ischaemia (60 vs 36%). None of the electrocardiographic or radiographic abnormalities was sensitive or specific for cardiac biomarker abnormalities. Ischaemia on ECG was the best indicator for raised NT-proBNP (sensitivity 59%, specificity 67%). Tachycardia and ischaemia were the best indicators of raised troponin T (sensitivity 65 and 60%, specificity 59 and 64% respectively). CONCLUSIONS: ECG and chest radiograph abnormalities have poor sensitivity and specificity for diagnosing acute cardiac dysfunction in exacerbations of COPD. Cardiac biomarkers provide additional diagnostic information about acute cardiac dysfunction in exacerbations of COPD.