Critical illness poses a significant global health challenge, disproportionately affecting low- and middle-income countries (LMICs) and other low-resource settings, where healthcare resources and infrastructure are often...Critical illness poses a significant global health challenge, disproportionately affecting low- and middle-income countries (LMICs) and other low-resource settings, where healthcare resources and infrastructure are often limited. This narrative review explores the multifaceted dynamics of critical care research in low-resource settings, focusing on socioeconomic, demographic and structural barriers that impact the delivery of intensive care services and its consequences for clinical research. Research is a cornerstone in addressing these challenges. Locally relevant evidence is crucial for informing healthcare policies and clinical guidelines, particularly in adapting high-income country recommendations to resource-constrained contexts. This review describes research challenges and findings on several fields of critical care in LMICs. It underscores the pressing need for sustained investment in critical care research and infrastructure in LMICs to overcome health disparities and improve outcomes for critically ill patients.
BACKGROUND: The sit-to-stand (STS) test can assess physical function in people with chronic obstructive pulmonary disease (COPD); however, there are multiple versions. No study has used current guidelines to assess the m...BACKGROUND: The sit-to-stand (STS) test can assess physical function in people with chronic obstructive pulmonary disease (COPD); however, there are multiple versions. No study has used current guidelines to assess the measurement properties of the STS tests in people with COPD. METHODS: We conducted a systematic review using current COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines. Full text peer-reviewed publications were included if they assessed the measurement properties (validity, reliability and/or responsiveness) of at least one STS test among community-dwelling people with COPD. We searched six databases and imported results into Covidence where title/abstract screening and full text selection was completed independently and in duplicate. Extraction was conducted independently and in duplicate using the COSMIN extraction file. We assessed study risk of bias (very good, adequate, doubtful or inadequate), measurement property quality (sufficient, indeterminate or insufficient) and overall certainty of evidence (high, moderate, low or very low) using the COSMIN recommended tools. RESULTS: We assessed 2577 titles/abstracts and 102 full texts for inclusion; 30 publications met eligibility. Seven unique STS tests were located with the most common being the 1 min STS test (n=14, 39%), 5-repetition STS test (n=10, 28%) and the 30 s STS test (n=8, 22%). Where assessed, reliability was sufficient for the 1 min, the 5-repetition and the 30 s STS tests. Only the 1 min STS test had high-quality evidence of sufficient construct validity, while the 30 s STS test was the sole test with at least moderate quality evidence of sufficient responsiveness. CONCLUSIONS: The 1 min STS test has the most robust measurement properties for cross-sectional assessments while the 30 s STS test is more robust to assess change.
Reizine F, Stiegler V, Lecuyer R
… +12 more, Tessoulin B, Rieul G, Camou F, Morio F, Cady A, Gabriel F, Canet E, Raffi F, Boutoille D, Issa N, Gaborit BJ, pronocystis study group
BACKGROUND: pneumonia (PcP) in HIV-negative patients is associated with high mortality rates. While early adjunctive corticosteroid (AC) therapy benefits HIV-positive patients with severe PcP, its efficacy and safety in...BACKGROUND: pneumonia (PcP) in HIV-negative patients is associated with high mortality rates. While early adjunctive corticosteroid (AC) therapy benefits HIV-positive patients with severe PcP, its efficacy and safety in HIV-negative patients remain poorly investigated. METHODS: This multicentre retrospective observational study included consecutive patients diagnosed with proven or probable PcP, from January 2011 to January 2021. This study assessed the prognostic impact and safety of early AC in HIV-negative patients with PcP. To address baseline characteristic imbalances between patients, a non-parsimonious propensity matching analysis was performed with a 1/1 ratio. Survival analysis, day-90 mortality rate and healthcare-associated infections (HCAI) were compared using Cox and logistic regressions. RESULTS: 350 consecutive HIV-negative patients with proven or probable PcP were included. Of these, 116 (33.1%) received early AC within 5 days of anti-PcP therapy initiation. The median arterial oxygen partial pressure to fractional inspired oxygen (PaO/FiO) ratio was 224 (114-229). The 90-day mortality rate was 29.4% (103/350). There was no significant difference in 90-day mortality according to AC, both in overall and matched populations (OR 1.27 (0.78-2.05); p=0.336 and 0.92 (0.52-1.62); p=0.772, respectively). HCAI incidences appeared similar between groups. In the matched population, a higher proportion of AC patients required high-flow oxygen therapy (OR 2.15 (1.17-4.05); p=0.015) and mechanical ventilation duration was higher in corticosteroid recipients (OR 1.04 (1.01-1.09); p=0.048). CONCLUSION: Early AC therapy was not associated with reduced 90-day mortality in HIV-negative PcP patients. Although recommended in hypoxemic HIV-positive PcP patients, the benefit of this strategy in HIV-negative patients remains to be proven.
BACKGROUND: Tuberculous pleurisy (TBP) is a leading aetiology of exudative pleural effusion in tuberculosis (TB)-endemic regions and poses significant diagnostic challenges due to its paucibacillary nature of (MTB) in p...BACKGROUND: Tuberculous pleurisy (TBP) is a leading aetiology of exudative pleural effusion in tuberculosis (TB)-endemic regions and poses significant diagnostic challenges due to its paucibacillary nature of (MTB) in pleural fluid. This study aims to characterise MTB-derived cell-free DNA (cfDNA) in pleural effusion and to develop an optimised molecular assay to improve TBP diagnostic accuracy. METHODS: We quantified MTB cfDNA/genomic DNA (gDNA) concentrations and characterised cfDNA fragment profiles in pleural effusion specimens using ddPCR. A multiplex droplet digital PCR (ddPCR) assay was developed, targeting two insertion sequences (IS6110 and IS1081) using ultra-short amplicons (49-59 bp) to enhance detection efficiency. Diagnostic performance was prospectively evaluated in 356 consecutive adults with radiologically confirmed pleural effusion, using composite microbiological criteria as the reference standard. RESULTS: MTB cfDNA exhibited significantly higher detection rates than gDNA in definite TBP cases (p=0.0006), with dominant fragment lengths of 60-80 bp. The multiplex ddPCR assay demonstrated a limit of detection of 0.2 genome equivalents per reaction. Among microbiologically confirmed TBP cases (n=69), the assay achieved a sensitivity of 94.2%, significantly outperforming Xpert MTB/RIF (52.0%, p<0.0001) and liquid culture (35.3%, p<0.0001). Specificity remained high at 97.0% among cases of non-TB effusion (n=208). CONCLUSIONS: Our findings establish MTB cfDNA as the predominant nucleic acid form in tuberculous pleural effusion. The optimised multiplex ddPCR platform, leveraging multicopy targets and fragment-length-adapted amplification, achieves improved diagnostic sensitivity without compromising specificity in a high-prevalence TB setting. This approach may help address key limitations of TBP diagnostics and shows promise for clinical implementation.
BACKGROUND: Personalised management of cystic fibrosis (CF) lung disease in the era of CF transmembrane conductance regulator (CFTR) modulator therapy will require novel approaches to assess treatment response and monito...BACKGROUND: Personalised management of cystic fibrosis (CF) lung disease in the era of CF transmembrane conductance regulator (CFTR) modulator therapy will require novel approaches to assess treatment response and monitor longitudinal progression. METHODS: We evaluated the heterogeneity of short-term response to elexacaftor-tezacaftor-ivacaftor (ETI) using Xe MRI, multiple breath washout (MBW) and spirometry. For CFTR modulator-naïve people ≥6 years old starting commercial ETI, we measured same-day XeMRI ventilation defect per cent (VDP), lung clearance index (LCI), forced expiratory volume in 1 s (FEV) and CF Questionnaire-Revised respiratory-domain (CFQ-R(R)) at pre-ETI baseline and up to 4 months post-ETI. Baseline versus follow-up measures were compared using Wilcoxon-signed-rank tests with r effect size coefficients. Abnormal follow-up measures determined using z-scores and upper/lower limits of normal; correlations evaluated using Spearman ρ coefficients. RESULTS: VDP, FEV, LCI and CFQ-R(R) significantly improved in the total group (n=40; all p<0.001, r=0.69, r=0.79, r=0.70, r=0.77) and both ≥12-year-old subgroups (n=15 FEV<80%, p=0.005/r=0.69, p<0.001/r=0.87, p=0.004/r=0.70, p<0.001/r=0.88; n=17 FEV≥80%, p=0.003/r=0.54, p=0.003/r=0.74, p=0.01/r=0.56, p=0.006/r=0.73). VDP (p=0.008/r=0.89), LCI (p=0.03/r=0.83) and percent-predicted FEV (p=0.03/r=0.83) significantly improved in the 6-11-year-old subgroup, with VDP having the greatest effect size in children. VDP remained abnormal at follow-up in 21 participants with normal FEV, whereas LCI was abnormal in 12. Baseline VDP (ρ=0.39/p=0.01) and LCI (ρ=0.43/p=0.008) were significantly correlated with the change in CFQ-R(R). CONCLUSION: Though all outcome measures showed a positive response, response to ETI was heterogeneous between individuals and between XeMRI, MBW and spirometry. Leveraging the rich information provided by multimodal tools will be critical to understanding the nature of CF lung disease and measuring response to future therapies in the era of CFTR modulators.
OBJECTIVE: Systemic corticosteroids for 5-7 days are standard care for asthma exacerbations, but the optimal duration and potential for precision prescribing remain unclear. Biomarker-guided approaches could reduce corti...OBJECTIVE: Systemic corticosteroids for 5-7 days are standard care for asthma exacerbations, but the optimal duration and potential for precision prescribing remain unclear. Biomarker-guided approaches could reduce corticosteroid exposure without compromising outcomes. We aimed to evaluate whether the blood eosinophil count can be used to safely reduce systemic corticosteroid exposure in hospitalised asthma exacerbations. METHODS: In this open-label, two-centre randomised trial, adults hospitalised for asthma exacerbation were assigned 1:1 to usual care (5 days prednisolone) or eosinophil-guided care using blood eosinophil counts obtained prior to corticosteroid administration (3 days if eosinophils <300 cells/µL; 5 days if ≥300 cells/µL). The primary outcome was non-inferiority of treatment failure rates (composite of extension of steroid duration, mechanical ventilation or death), with a prespecified 20% non-inferiority margin. RESULTS: Among 110 randomised patients (55 per group), 60% were eosinophilic, and 40% non-eosinophilic. Treatment failure occurred in 6/55 (10.9%) of eosinophil-guided versus 4/55 (7.3%) of usual care patients, with a 3.6% absolute difference (95% CI -8.9% to 16.2%), meeting non-inferiority. Cumulative corticosteroid dose per patient was similar between groups but significantly lower for non-eosinophilic than eosinophilic exacerbations in the eosinophil-guided group (136 vs 214 mg; p=0.0004), a difference not observed in usual care (186 vs 211 mg; p=0.18). Length of stay, Asthma Control Questionnaire-5 change, additional steroid bursts at 14 days or time to next exacerbation up to 1 year showed no significant differences. CONCLUSION: Eosinophil-guided therapy safely reduced systemic corticosteroid exposure in non-eosinophilic exacerbations while maintaining non-inferior outcomes in this proof-of-concept trial. TRIAL REGISTRATION NUMBER: NCT05417906.
Popovic M, Maule M, Moccia C
… +18 more, Isaevska E, Avraam D, Cadman T, Elhakeem A, Grote V, Guerlich K, Haakma S, Harris JR, Jansen PW, Thorbjørnsrud Nader JL, Pinot de Moira A, Strandberg-Larsen K, Swertz M, Welten M, Yang T, Jaddoe V, Duijts L, Richiardi L
BACKGROUND: While maternal depression and anxiety have been linked to adverse childhood respiratory outcomes, the role of eating disorders (EDs) remains less understood. This study examined associations between maternal...BACKGROUND: While maternal depression and anxiety have been linked to adverse childhood respiratory outcomes, the role of eating disorders (EDs) remains less understood. This study examined associations between maternal EDs and offspring respiratory outcomes, considering ED subtypes, exposure windows and comorbid depression/anxiety. METHODS: Data from 131 495 mother-child pairs across seven cohorts from the EU Child Cohort Network were analysed. Primary analyses assessed associations between maternal pre-pregnancy EDs and preschool wheezing and school-age asthma. Secondary analyses explored associations in women without comorbid depression/anxiety, specific ED subtypes (anorexia nervosa, bulimia nervosa), exposure periods (pregnancy, post-pregnancy) and - within two cohorts - school-age lung function. Logistic regression models were fitted for each cohort, and results pooled using random-effects meta-analysis. RESULTS: Maternal pre-pregnancy ED prevalence ranged from 0.8% (health records) to 17.0% (self-reported lifetime EDs). Preschool wheezing prevalence ranged from 20.7% to 49.6%, and school-age asthma from 2.1% to 17.3%. Pre-pregnancy EDs were associated with preschool wheezing (OR: 1.25, 95% CI: 1.06 to 1.47, I: 74%) and school-age asthma (OR: 1.26, 95% CI: 1.10 to 1.46, I: 9%). These estimates were slightly attenuated but remained directionally consistent with the main analyses after exclusion of mothers with depression/anxiety. There was evidence of a weak positive association with lung function. Associations across ED subtypes were largely consistent with the pre-pregnancy any ED estimate, while no clear pattern emerged by timing of exposure. CONCLUSIONS: Maternal EDs are associated with a higher risk of wheezing and asthma in children, independently of comorbid depression/anxiety. These findings highlight the need to understand mechanisms and long-term respiratory consequences of maternal EDs to inform interventions for improving offspring respiratory health.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an often-progressive respiratory disease associated with disabling breathlessness. Breathlessness intervention services (BIS), which coach patients to self-mana...BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an often-progressive respiratory disease associated with disabling breathlessness. Breathlessness intervention services (BIS), which coach patients to self-manage breathlessness using non-pharmacological strategies, are effective in a variety of populations, including those with cancer and serious respiratory disease. This study aimed to compare the impact of the Westmead Breathlessness Service in people with moderate to severe COPD. METHODS: We analysed 113 participants randomised (1:1) with moderate/severe COPD (forced expiratory volume in 1 s (FEV)/forced vital capacity <0.70 and FEV ≤60% predicted) and disabling breathlessness (modified Medical Research Council (mMRC) Breathlessness Score ≥2) to either an 8-week intervention involving breathing techniques, handheld fan use, exercise, energy conservation, dietetic advice (n=54) or 8-week wait-list control group (n=59). The primary outcome was change in Chronic Respiratory Questionnaire (CRQ) Mastery of breathlessness subscale. Secondary outcomes included change in other CRQ subscales (Fatigue, Emotion and Dyspnoea), exertional breathlessness intensity/unpleasantness (0-10 Numerical Rating Scale Score), anxiety and depression. Difference in change over 8 weeks between groups was compared using ANCOVA; p<0.05 statistically significant. FINDINGS: Participants were aged 70.9 (±8.5) years, 50% female, mean FEV =0.8 L (±0.3 L; 34% predicted), mMRC Breathlessness Score 3 (IQR 3-4). CRQ-Mastery improved following intervention compared with control (between-group difference 0.5 units; 95% CI 0.2 to 0.8; p=0.0262) using modified intention-to-treat analysis. Better CRQ-Dyspnoea and CRQ-Fatigue were seen in the intervention group (between-group difference-CRQ-Dyspnoea 0.4 units; CI 0.1 to 0.7; p=0.005, and CRQ-Fatigue 0.4 units; CI 0.1 to 0.7; p=0.014). Exertional breathlessness intensity (difference -0.8 units; CI -1.4 to -0.2; p=0.013) and breathlessness unpleasantness (difference -1.2 units; CI -1.7 to -0.6; p=0.001) also improved. INTERPRETATION: An 8-week BIS improved CRQ-Mastery, Dyspnoea and Fatigue, exertional breathlessness intensity and unpleasantness in people with severe COPD.
BACKGROUND: Current guidelines for the evaluation of chronic obstructive pulmonary disease (COPD) do not recommend screening for pulmonary hypertension (PH), despite the high prevalence and impact on outcomes. A simple s...BACKGROUND: Current guidelines for the evaluation of chronic obstructive pulmonary disease (COPD) do not recommend screening for pulmonary hypertension (PH), despite the high prevalence and impact on outcomes. A simple screening tool to identify patients with an elevated pulmonary vascular resistance (PVR) is urgently needed, as they may benefit from PH-specific therapy and more urgent referral for lung transplantation. RESEARCH QUESTION: We sought to examine whether a ratio of forced expiratory volume in 1 s (FEV) to diffusing capacity (DLCO) predicts haemodynamic patterns in COPD. STUDY DESIGN AND METHODS: Individuals with COPD who underwent right heart catheterisation from two academic medical centres were included. Adjusted multinomial models tested associations between FEV/DLCO and haemodynamic patterns. Receiver operating curves were generated to assess the discriminative performance of the FEV/DLCO ratio in predicting PH with an elevated PVR. RESULTS: Approximately 40% of the 411 individuals included had PH with an elevated PVR. For every 0.1 increase in the FEV/DLCO ratio, there was a 12-14% increased rate of PH with an elevated PVR compared with No PH. FEV/DLCO ratio had moderate discriminative performance (C-statistic 0.68-0.72), which was strengthened when combined in a model with elevated tricuspid regurgitant jet velocity on echocardiography (C-statistic 0.78-0.82). Above a threshold of 1.4, FEV/DLCO demonstrated good specificity (75%) in predicting PH with an elevated PVR. INTERPRETATION: These findings suggest that disproportionate reductions in DLCO predict PH with an elevated PVR in a COPD population. The FEV/DLCO ratio should be considered in the evaluation of PH in COPD.
BACKGROUND: The impact of delays to diagnosis for individuals presenting with chronic breathlessness is unknown. We investigated the time to diagnosis after presenting with chronic breathlessness and associations with fu...BACKGROUND: The impact of delays to diagnosis for individuals presenting with chronic breathlessness is unknown. We investigated the time to diagnosis after presenting with chronic breathlessness and associations with future unplanned hospitalisation and mortality. METHODS: A retrospective cohort study using the UK Clinical Practice Research Datalink involving adults with a first recorded code for breathlessness and no pre-existing cardiorespiratory disease. Adjusted Cox regression was used to investigate the associations with unplanned hospitalisation and mortality during all follow-up and within 2 years after the first code of breathlessness between those with and without a diagnosis, and using landmark analysis for time to diagnosis. RESULTS: 66 909/101 369 (66%) of adults with a first recorded code for breathlessness received an explanatory diagnosis during a median 5 years of follow-up. 43 394 (43%) of adults received an explanatory diagnosis within 2 years and had a higher risk (HR (95% CI)) of unplanned hospitalisation (1.25, 1.19 to 1.31) and mortality (1.84, 1.42 to 2.38) in the subsequent 2 years compared with adults without a diagnosis. In those with a recorded diagnosis, waiting ≥6 months was associated with increased mortality (6-24 months: 3.33 (2.13 to 5.20); ≥24 months: 13.30 (8.98 to 19.80)). CONCLUSION: We describe better outcomes in adults coded for breathlessness without subsequent explanatory diagnoses. In adults with an explanatory diagnosis, waiting ≥6 months for a diagnosis was associated with reduced survival. Diagnostic pathways for chronic breathlessness need to differentiate between these two groups and achieve earlier diagnosis in those at higher risk.
BACKGROUND: Asbestos, mineral wool (MW), refractory ceramic fibres (RCF) and silica are among the most common exposures to mineral particles in the workplace. OBJECTIVE: To study the effect of coexposure to asbestos and...BACKGROUND: Asbestos, mineral wool (MW), refractory ceramic fibres (RCF) and silica are among the most common exposures to mineral particles in the workplace. OBJECTIVE: To study the effect of coexposure to asbestos and MW, crystalline silica or RCFs and the risk of lung cancer and mesothelioma. METHODS: The Asbestos-Related Diseases Cohort is a surveillance programme in retired workers exposed to asbestos during their working life. Complete job histories were collected and occupational exposure to asbestos was assessed by an expert, while occupational exposure to MW, RCFs and silica was assessed using French job-exposure matrices. Cox proportional hazards models were used to estimate HR and 95% CI for lung cancer mortality and lung cancer incidence and for mesothelioma mortality or mesothelioma incidence. RESULTS: In this population of workers exposed to asbestos, in the mortality study, exposures to MW, crystalline silica and RCFs were not found to be associated with lung cancer after adjustment for smoking and asbestos, nor with mesothelioma after adjustment for asbestos. In the incidence study, there was an association between exposure to crystalline silica (ever exposed) and mesothelioma (HR=1.75, 95% CI 1.17 to 2.62). CONCLUSION: Crystalline silica is not known to induce mesothelioma but coexposure to asbestos could increase the effect of asbestos on the mesothelial cells.
BACKGROUND: Bronchoscopic limitations in reaching peripheral pulmonary lesions (PPLs) can compromise biopsy sensitivity, especially for small PPLs. Therefore, we developed the balloon dilatation for bronchoscope delivery...BACKGROUND: Bronchoscopic limitations in reaching peripheral pulmonary lesions (PPLs) can compromise biopsy sensitivity, especially for small PPLs. Therefore, we developed the balloon dilatation for bronchoscope delivery (BDBD) technique to dilate bronchial pathways and facilitate bronchoscope advancement into the periphery. This study evaluated the diagnostic performance and safety profile of transbronchial biopsy using this technique. METHODS: This multicentre, single-arm, prospective study included patients with bronchus sign-positive PPLs measuring <20 mm. Bronchoscopy was performed using ultrathin or thin bronchoscopes under conscious sedation. When the bronchoscope could not advance further, the BDBD technique was used to approach closer to the target, followed by biopsies. The primary endpoint was the diagnostic sensitivity for malignancy in specimens obtained through the specified procedure, defined as bronchoscope advancement using balloon dilatation, direct biopsy site visualisation and absence of serious adverse events. RESULTS: Eighteen of 22 patients who underwent bronchoscopy with the BDBD technique were ultimately diagnosed with cancer. BDBD enabled bronchoscope advancement in all 18 cases without serious complications, allowed direct biopsy site visualisation in 17 and detected cancer in 14. Thus, the diagnostic sensitivity for malignancy was 77.8% (14/18). Beyond these cases, one patient who met all procedural criteria was diagnosed with cryptococcosis. Another patient was diagnosed with cancer without direct visualisation. On average, BDBD enabled bronchoscope advancement by 2.3 bifurcations. CONCLUSION: In this small observational study, BDBD appeared to be a promising technique for improving the diagnostic sensitivity of bronchoscopy for small PPLs. Further validation is necessary in large cohorts. TRIAL REGISTRATION NUMBER: jRCT2052220174.