Unsupervised home spirometry versus supervised clinic spirometry for respiratory disease: a systematic methodology review and meta-analysis.

BACKGROUND: The number of patients completing unsupervised home spirometry has recently increased due to more widely available portable technology and the COVID-19 pandemic, despite a lack of solid evidence to support it. This systematic methodology review and meta-analysis explores quantitative differences in unsupervised spirometry compared with spirometry completed under professional supervision. METHODS: We searched four databases to find studies that directly compared unsupervised home spirometry with supervised clinic spirometry using a quantitative comparison (e.g. Bland-Altman). There were no restrictions on clinical condition. The primary outcome was measurement differences in common lung function parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC)), which were pooled to calculate overall mean differences with associated limits of agreement (LoA) and confidence intervals (CI). We used the I2 statistic to assess heterogeneity, the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool to assess risk of bias and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence certainty for the meta-analyses. The review has been registered with PROSPERO (CRD42021272816). RESULTS: 3607 records were identified and screened, with 155 full texts assessed for eligibility. We included 28 studies that quantitatively compared spirometry measurements, 17 of which reported a Bland-Altman analysis for FEV1 and FVC. Overall, unsupervised spirometry produced lower values than supervised spirometry for both FEV1 with wide variability (mean difference -107 mL; LoA= -509, 296; I2=95.8%; p<0.001; very low certainty) and FVC (mean difference -184 mL, LoA= -1028, 660; I2=96%; p<0.001; very low certainty). CONCLUSIONS: Analysis under the conditions of the included studies indicated that unsupervised spirometry is not interchangeable with supervised spirometry for individual patients owing to variability and underestimation.

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.

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).

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.

Modelling preeclampsia: a comparative analysis of the common human trophoblast cell lines.

Preeclampsia remains a challenge without an effective therapy. Evidence supports targetability of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which are released excessively from the placenta under ischemic and hypoxic stresses. We compared four trophoblast cell lines, BeWo, Jar, Jeg-3, and HTR-8/SVneo, in order to identify a suitable model for drug screening. Cultured trophoblasts were exposed to 1% oxygen vs. normoxia for 24-48 hr; human umbilical vein and aortic endothelial cells were included for comparison. Supernatant sFlt-1 and sEng concentrations were measured by ELISA, and sFlt-1 mRNA expression determined by RT-PCR. Cellular responses to experimental therapeutics were explored. All four trophoblast lines secreted sEng, which did not increase by hypoxia. BeWo, Jar, and Jeg-3 exhibited significantly enhanced expression of sFlt-1 i13 and e15a mRNA in response to hypoxia; however, only BeWo released a detectable level of sFlt-1 protein, which was doubled by hypoxia. In contrast, hypoxia decreased sFlt-1 mRNA expression and protein release in HTR-8/SVneo, similarly to endothelial cells. The cellular mechanism involved HIFα. BeWo responded to representative agents similarly to human primary placental tissues in the literature. These data support that the BeWo-hypoxia model mimics a key pathogenic mechanism of preeclampsia and has potential value for translational drug discovery.

Effects of modified lipoproteins on human trophoblast cells: a role in pre-eclampsia in pregnancies complicated by diabetes.

INTRODUCTION: Pre-eclampsia (PE) is increased ~4-fold by maternal diabetes. Elevated plasma antiangiogenic factors, soluble fms-like tyrosine kinase (sFLT-1) and soluble endoglin (sENG), precede PE onset. We investigated whether diabetes-related stresses, modified lipoproteins and elevated glucose enhance trophoblast sFLT-1 and sENG release and/or alter placental barrier function and whether oxidized low-density lipoprotein (Ox-LDL) is in placental tissue. RESEARCH DESIGN AND METHODS: HTR8/SVneo cells were exposed to 'heavily-oxidized, glycated' LDL (HOG-LDL) versus native LDL (N-LDL) (10-200 mg protein/L) for 24 hours ±pretreatment with glucose (30 mmol/L, 72 hours). Concentrations of sFLT-1 and sENG in supernatants (by ELISA) and expressions of sFLT-1-I13 and sFLT-1-E15A isoforms, endoglin (ENG) and matrix metalloproteinase-14 (MMP-14; by RT-PCR) were quantified. For barrier studies, JAR cells were cultured in Transwell plates (12-14 days), then exposed to LDL. Transepithelial electrical resistance (TEER) was measured after 6, 12 and 24 hours. In placental sections from women with and without type 1 diabetes, immunostaining of apolipoprotein B100 (ApoB, a marker of LDL), Ox-LDL and lipoxidation product 4-hydroxynonenal was performed. RESULTS: HOG-LDL (50 mg/L) increased sFLT-1 (2.7-fold, p<0.01) and sENG (6.4-fold, p<0.001) in supernatants versus N-LDL. HOG-LDL increased expression of sFLT-1-I13 (twofold, p<0.05), sFLT-1-E15A (1.9-fold, p<0.05), ENG (1.6-fold, p<0.01) and MMP-14 (1.8-fold, p<0.05) versus N-LDL. High glucose did not by itself alter sFLT-1 or sENG concentrations, but potentiated effects of HOG-LDL on sFLT-1 by 1.5-fold (p<0.05) and on sENG by 1.8-fold (p<0.01). HOG-LDL (200 mg/L) induced trophoblast barrier impairment, decreasing TEER at 6 hours (p<0.01), 12 hours (p<0.01) and 24 hours (p<0.05) versus N-LDL. Immunostaining of term placental samples from women both with and without diabetes revealed presence of intravillous modified lipoproteins. CONCLUSION: These findings may explain, in part, the high risk for PE in women with diabetes. The trophoblast culture model has potential for evaluating novel therapies targeting barrier dysfunction.

Effects of Modified Low-Density Lipoproteins and Fenofibrate on an Outer Blood-Retina Barrier Model: Implications for Diabetic Retinopathy.

Purpose: There is a lack of treatment for early diabetic retinopathy (DR), including blood-retina barrier (BRB) breakdown. The robust clinical benefit of fenofibrate in DR provides an opportunity to explore disease mechanisms and therapeutic targets. We have previously found that modified lipoproteins contribute to DR and that fenofibrate protects the inner BRB. We now investigate (1) whether modified lipoproteins elicit outer BRB injury and (2) whether fenofibrate may alleviate such damage. Methods: Human retinal pigment epithelium ARPE-19 cells were cultured in semipermeable transwells to establish a monolayer barrier and then exposed to heavily oxidized, glycated low-density lipoprotein (HOG-LDL, 25-300 mg/L, up to 24 h) versus native (N)-LDL. Transepithelial electric resistance (TEER) and FITC-dextran permeability were measured. The effects of fenofibrate, its active metabolite fenofibric acid, and other peroxisome proliferator-activated receptor (PPARα) agonists (gemfibrozil, bezafibrate, and WY14643) were evaluated, with and without the PPARα antagonist GW6471 or the adenosine monophosphate-activated protein kinase (AMPK) inhibitor Compound C. Results: HOG-LDL induced concentration- and time-dependent barrier impairment, decreasing TEER and increasing dextran leakage, effects that were amplified by high glucose. Fenofibric acid, but not fenofibrate, gemfibrozil, bezafibrate, or WY14643, attenuated barrier impairment. This effect was reversed significantly by Compound C, but not by GW6471. Conclusions: Modified lipoproteins elicited outer BRB injury in an experimental model, which was reduced by fenofibric acid through a PPARα-independent, AMPK-mediated mechanism. These findings suggest a protective role of fenofibric acid on the outer BRB in diabetic retina.

Beneficial Effects of Berberine on Oxidized LDL-Induced Cytotoxicity to Human Retinal Müller Cells.

PURPOSE: Limited mechanistic understanding of diabetic retinopathy (DR) has hindered therapeutic advances. Berberine, an isoquinolone alkaloid, has shown favorable effects on glucose and lipid metabolism in animal and human studies, but effects on DR are unknown. We previously demonstrated intraretinal extravasation and modification of LDL in human diabetes, and toxicity of modified LDL to human retinal Müller cells. We now explore pathogenic effects of modified LDL on Müller cells, and the efficacy of berberine in mitigating this cytotoxicity. METHODS: Confluent human Müller cells were exposed to in vitro-modified 'highly oxidized, glycated (HOG-) LDL versus native-LDL (N-LDL; 200 mg protein/L) for 6 or 24 hours, with/without pretreatment with berberine (5 µM, 1 hour) and/or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitor, Compound C (5 µM, 1 hour). Using techniques including Western blots, reactive oxygen species (ROS) detection assay, and quantitative real-time PCR, the following outcomes were assessed: cell viability (CCK-8 assay), autophagy (LC3, Beclin-1, ATG-5), apoptosis (cleaved caspase 3, cleaved poly-ADP ribose polymerase), oxidative stress (ROS, nuclear factor erythroid 2-related factor 2, glutathione peroxidase 1, NADPH oxidase 4), angiogenesis (VEGF, pigment epithelium-derived factor), inflammation (inducible nitric oxide synthase, intercellular adhesion molecule 1, IL-6, IL-8, TNF-α), and glial cell activation (glial fibrillary acidic protein). RESULTS: Native-LDL had no effect on cultured human Müller cells, but HOG-LDL exhibited marked toxicity, significantly decreasing viability and inducing autophagy, apoptosis, oxidative stress, expression of angiogenic factors, inflammation, and glial cell activation. Berberine attenuated all the effects of HOG-LDL (all P < 0.05), and its effects were mitigated by AMPK inhibition (P < 0.05). CONCLUSIONS: Berberine inhibits modified LDL-induced Müller cell injury by activating the AMPK pathway, and merits further study as an agent for preventing and/or treating DR.