Single and multiple breath nitrogen washout compared with the methacholine test in patients with suspected asthma and normal spirometry.

BACKGROUND: Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We hypothesised that nitrogen single or multiple breath washout tests, respectively nitrogen single breath washout (N2SBW) and nitrogen multiple breath washout (N2MBW), may be pathological in patients with clinical suspicion of asthma but normal spirometry. Our aim was to assess whether N2SBW and N2MBW are associated with methacholine challenge test (MCT) results in this population. We also postulated that an alteration in SIII at N2SBW could be detected before the 20% fall of forced expiratory volume in the first second (FEV1) in MCT. STUDY DESIGN AND METHODS: This prospective, observational, single-centre study included patients with suspicion of asthma with normal spirometry. Patients completed questionnaires on symptoms and health-related quality-of-life and underwent the following lung function tests: N2SBW (SIII), N2MBW (Lung clearance index (LCI), Scond, Sacin), MCT (FEV1 and sGeff) as well as N2SBW between each methacholine dose. RESULTS: 182 patients were screened and 106 were included in the study, with mean age of 41.8±14 years. The majority were never-smokers (58%) and women (61%). MCT was abnormal in 48% of participants, N2SBW was pathological in 10.6% at baseline and N2MBW abnormality ranged widely (LCI 81%, Scond 18%, Sacin 43%). The dose response rate of the MCT showed weak to moderate correlation with the subsequent N2SBW measurements during the provocation phases (ρ 0.34-0.50) but no correlation with N2MBW. CONCLUSIONS: Both MCT and N2 washout tests are frequently pathological in patients with suspicion of asthma with normal spirometry. The weak association and lack of concordance across the tests highlight that they reflect different but not interchangeable pathological pathways of the disease.

Long-term outcome of patients with combined post- and pre-capillary pulmonary hypertension.

Aims: Pulmonary hypertension (PH) is a complex clinical condition, and left heart disease is the leading cause. Little is known about the epidemiology and prognosis of combined post- and pre-capillary PH (CpcPH). Methods and results: This retrospective analysis of the Swiss PH Registry included incident patients with CpcPH registered from January 2001 to June 2019 at 13 Swiss hospitals. Patient baseline characteristics [age, sex, mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure (PAWP), pulmonary vascular resistance (PVR), and risk factors, including World Health Organization (WHO)-functional class (FC), 6 min walk distance (6MWD), and N-terminal pro-brain natriuretic peptide (NT-proBNP), treatment, days of follow-up, and events (death or loss to follow-up) at last visit] were analysed by Kaplan-Meier and Cox regression analyses. Two hundred and thirty-one patients (59.3% women, age 65 ± 12 years, mPAP 48 ± 11 mmHg, PAWP 21 ± 5 mmHg, PVR 7.2 ± 4.8 WU) were included. Survival analyses showed a significantly longer survival for women [hazard ratio (HR) 0.58 (0.38-0.89); P = 0.01] and a higher mortality risk for mPAP > 46 mmHg [HR 1.58 (1.03-2.43); P = 0.04] but no association with age or PVR. Patients stratified to high risk according to four-strata risk assessment had an increased mortality risk compared with patients stratified to low-intermediate risk [HR 2.44 (1.23-4.84); P = 0.01]. A total of 46.8% of CpcPH patients received PH-targeted pharmacotherapy; however, PH-targeted medication was not associated with longer survival. Conclusion: Among patients with CpcPH, women and patients with an mPAP ≤46 mmHg survived longer. Furthermore, risk stratification by using non-invasively assessed risk factors, such as WHO-FC, 6MWD, and NT-proBNP, as proposed for pulmonary arterial hypertension, stratified survival in CpcPH, and might be helpful in the management of these patients.

Airway smooth muscle area to predict steroid responsiveness in COPD patients receiving triple therapy (HISTORIC): a randomised, placebo-controlled, double-blind, investigator-initiated trial.

BACKGROUND: Although inhaled corticosteroids (ICS) are highly effective in asthma, they provide significant, but modest, clinical benefit in COPD. Here, we tested the hypothesis that high bronchial airway smooth muscle cell (ASMC) area in COPD is associated with ICS responsiveness. METHODS: In this investigator-initiated and -driven, double-blind, randomised, placebo-controlled trial (HISTORIC), 190 COPD patients, Global Initiative for Chronic Obstructive Lung Disease stage B-D, underwent bronchoscopy with endobronchial biopsy. Patients were divided into groups A and B, with high ASMC area (HASMC: >20% of the bronchial tissue area) and low ASMC area (LASMC: ≤20% of the bronchial tissue area), respectively, and followed a run-in period of 6 weeks on open-label triple inhaled therapy with aclidinium (ACL)/formoterol (FOR)/budesonide (BUD) (400/12/400 µg twice daily). Subsequently, patients were randomised to receive either ACL/FOR/BUD or ACL/FOR/placebo and followed for 12 months. The primary end-point of the study was the difference in post-bronchodilator forced expiratory volume in 1 s (FEV1) over 12 months between patients with LASMC and HASMC receiving or not receiving ICS. RESULTS: In patients with LASMC, ACL/FOR/BUD did not significantly improve FEV1 over 12 months, as compared to ACL/FOR/placebo (p=0.675). However, in patients with HASMC, ACL/FOR/BUD significantly improved FEV1, as compared to ACL/FOR/placebo (p=0.020). Over 12 months, the difference of FEV1 change between the ACL/FOR/BUD group and the ACL/FOR/placebo group was 50.6 mL·year-1 within the group of patients with LASMC and 183.0 mL·year-1 within the group of patients with HASMC. CONCLUSION: COPD patients with ΗASMC respond better to ICS than patients with LASMC, suggesting that this type of histological analysis may predict ICS responsiveness in COPD patients receiving triple therapy.

Fast multiplex bacterial PCR of bronchoalveolar lavage for antibiotic stewardship in hospitalised patients with pneumonia at risk of Gram-negative bacterial infection (Flagship II): a multicentre, randomised controlled trial.

BACKGROUND: PCR-based testing has transformed the management of suspected respiratory viral infections. We aimed to determine whether multiplex bacterial PCR of bronchoalveolar lavage fluid aids antibiotic stewardship in patients with pneumonia. METHODS: This investigator-initiated, multicentre, randomised controlled trial was conducted at two tertiary care centres in Switzerland (University Hospital of Basel and Kantonsspital St Gallen). Patients aged 18 years or older who were admitted to hospital with suspected pneumonia, had a clinical indication for bronchoscopy with bronchoalveolar lavage, and were at risk of Gram-negative bacterial infection were included. Patients were randomly assigned (1:1) to either the multiplex bacterial PCR group or the conventional microbiology control group using a random allocation sequence. Treating physicians were not masked, but the committee panel was masked to patient randomisation. All patients underwent bronchoscopy with bronchoalveolar lavage and samples were assessed by conventional microbiological culture (and additionally, in the PCR group, by multiplex bacterial PCR for Gram-negative rods using the Unyvero Hospitalized Pneumonia [HPN] Cartridge; Curetis, Holzgerlingen, Germany). Patients received empirical antibiotic therapy as clinically indicated by the treating physician. In the PCR group, a recommendation regarding antibiotic therapy was made approximately 5 h after taking the sample. The primary outcome was the time in hours on inappropriate antibiotic therapy from bronchoscopy to discharge or to 30 days after bronchoscopy. This trial was registered with the International Clinical Trials Registry Platform, ISRCTN95828556. FINDINGS: Between May 31, 2017, and Sept 25, 2019, 740 patients with pneumonia were screened for eligibility and 208 were included and randomly assigned to the PCR group (n=100) or conventional microbiology control group (n=108). The mean age of patients was 65·9 years (SD 14·0) and 135 (65%) were male. After daily follow-up until hospital discharge or for a maximum of 30 days, the duration of inappropriate antibiotic treatment was significantly shorter by 38·6 h (95% CI 19·5-57·7) in the PCR group than in the control group (adjusted mean 47·1 h [34·7-59·5] vs 85·7 h [78·8-95·6]; p<0·0001), which translates as a decrease in the duration of inappropriate antibiotic therapy of 45·0% (37·9-52·1). Adverse events due to antimicrobial therapy occurred in nine patients (five [5%] in the PCR group vs four [4%] in the control group) and due to bronchoscopy occurred in four patients (two [1%] vs two [1%]). There were eight (8%) deaths in the PCR group and 11 (10%) in the control group. All in-hospital deaths were attributed to a respiratory cause. INTERPRETATION: Multiplex bacterial PCR examination of bronchoalveolar lavage decreases the duration of inappropriate antibiotic therapy of patients admitted to hospital with pneumonia and at risk of Gram-negative rod infection. This approach warrants further consideration in future antibiotic stewardship strategies. FUNDING: Curetis and the Clinic of Respiratory Medicine and Pulmonary Cell Research, University Hospital Basel, Switzerland.

Oxygen desaturation during flexible bronchoscopy with propofol sedation is associated with sleep apnea: the PROSA-Study.

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by repetitive episodes of complete or partial obstruction of the upper airways during sleep. Conscious sedation for flexible bronchoscopy (FB) places patients in a sleep-like condition. We hypothesize that oxygen desaturation during flexible bronchoscopy may help to detect undiagnosed sleep apnea. METHODS: Single-centre, investigator-initiated and driven study including consecutive patients undergoing FB for clinical indication. Patients completed the Epworth Sleepiness Scale (ESS), Lausanne NoSAS score, STOP-BANG questionnaire and the Berlin questionnaire and underwent polygraphy within 7 days of FB. FB was performed under conscious sedation with propofol. Oxygen desaturation during bronchoscopy was measured with continuous monitoring of peripheral oxygen saturation with ixTrend (ixellence GmbH, Germany). RESULTS: 145 patients were included in the study, 62% were male, and the average age was 65.8 ± 1.1 years. The vast majority of patients (n = 131, 90%) proved to fulfill OSA criteria based on polygraphy results: 52/131 patients (40%) had mild sleep apnea, 49/131 patients (37%) moderate sleep apnea and 30/131 patients (23%) severe sleep apnea. Patients with no oxygen desaturation had a significantly lower apnea-hypopnea index than patients with oxygen desaturation during bronchoscopy (AHI 11.94/h vs 21.02/h, p = 0.011). This association remained significant when adjusting for the duration of bronchoscopy and propofol dose (p = 0.023; 95% CI 1.382; 18.243) but did not hold when also adjusting for age and BMI. CONCLUSION: The severity of sleep apnea was associated to oxygen desaturation during flexible bronchoscopy under conscious sedation. Patients with oxygen desaturation during bronchoscopy might be considered for sleep apnea screening. TRIAL REGISTRATION: The Study was approved by the Ethics Committee northwest/central Switzerland, EKNZ (EK 16/13) and was carried out according to the Declaration of Helsinki and Good Clinical Practice guidelines. Due to its observational character, the study did not require registration at a clinical trial registry.