Daily Ards Research Analysis
Across three studies related to respiratory failure, a multicenter cohort suggests sivelestat (a neutrophil elastase inhibitor) is associated with improved outcomes in COVID-19–related ARDS, an international registry delineates lung involvement patterns and ARDS occurrence in Still’s disease, and a locally derived NIV failure nomogram performs poorly on external validation, underscoring the need for local model calibration.
Summary
Across three studies related to respiratory failure, a multicenter cohort suggests sivelestat (a neutrophil elastase inhibitor) is associated with improved outcomes in COVID-19–related ARDS, an international registry delineates lung involvement patterns and ARDS occurrence in Still’s disease, and a locally derived NIV failure nomogram performs poorly on external validation, underscoring the need for local model calibration.
Research Themes
- ARDS therapeutics and outcome associations
- Inflammation-driven lung injury in systemic disease
- Model generalizability and local validation in critical care
Selected Articles
1. Neutrophil elastase inhibitor (Sivelestat) in the treatment of acute respiratory distress syndrome induced by COVID-19: a multicenter retrospective cohort study.
In a multicenter propensity-matched cohort of COVID-19–induced ARDS, sivelestat use was associated with better oxygenation, lower Murray lung injury scores, more ICU-free days, shorter ICU stay, and improved 28-day survival (HR 2.78; 95% CI 1.32–5.88). These findings support further randomized testing of neutrophil elastase inhibition in ARDS.
Impact: Provides clinically meaningful outcome associations for a mechanistically targeted therapy in ARDS during COVID-19, using robust matching and survival analyses.
Clinical Implications: For COVID-19–related ARDS, sivelestat may be considered within clinical trials or protocolized use while awaiting RCTs; it underscores targeting neutrophil elastase–driven injury.
Key Findings
- In propensity-matched patients (n=158), sivelestat was associated with improved oxygenation and lower Murray lung injury scores.
- Sivelestat increased alive and ICU-free days within 28 days (HR 1.85; 95% CI 1.29–2.64; log-rank p<0.001) and shortened ICU stay.
- Overall survival improved with sivelestat (28-day HR 2.78; 95% CI 1.32–5.88; log-rank p=0.0074).
Methodological Strengths
- Multicenter cohort with propensity score matching and robust variance Cox modeling
- Clinically relevant endpoints including oxygenation, ICU-free days, and survival
Limitations
- Retrospective design with potential residual confounding
- COVID-19–specific ARDS; generalizability to non–COVID-19 ARDS and optimal dosing remain uncertain
Future Directions: Conduct adequately powered RCTs of sivelestat in ARDS (COVID-19 and non–COVID-19), define optimal timing/dosing, and explore biomarkers to enrich responders.
BACKGROUND: Recent studies suggest that neutrophil elastase inhibitor (Sivelestat) may improve pulmonary function and reduce mortality in patients with acute respiratory distress syndrome. We examined the association between receipt of sivelestat and improvement in oxygenation among patients with acute respiratory distress syndrome (ARDS) induced by COVID-19. METHODS: A large multicentre cohort study of patients with ARDS induced by COVID-19 who had been admitted to intensive care units (ICUs). We used propensity score matching to compare the outcomes of patients treated with sivelestat to those who were not. The differences in continuous outcomes were assessed with the Wilcoxon signed-rank test. Kaplan-Meier method was used to show the 28-day survival curves in the matched cohorts. A log-rank P-test stratified on the matched pairs was used to test the equality of the estimated survival curves. A Cox proportional hazards model that incorporated a robust sandwich-type variance estimator to account for the matched nature of the data was used to estimate hazard ratios (HR). All statistical analyses were performed with SPSS 26.0 and R 4.2.3. A two-sided p-value of < 0.05 was considered statistically significant. RESULTS: A total of 387 patients met inclusion criteria, including 259 patients (66.9%) who were treated with sivelestat. In 158 patients matched on the propensity for treatment, receipt of sivelestat was associated with improved oxygenation, decreased Murray lung injury score, increased non-mechanical ventilation time within 28 days, increased alive and ICU-free days within 28 days (HR, 1.85; 95% CI 1.29 to 2.64; log-rank p < 0.001), shortened ICU stay and ultimately improved survival (HR, 2.78; 95% CI 1.32 to 5.88; log-rank p = 0.0074). CONCLUSIONS: Among patients with ARDS induce by COVID-19, sivelestat administration is associated with improved clinical outcomes.
2. The clinical assessment of lung involvement in patients with Still's disease, results from the multicentre international AIDA Network Still's Disease Registry.
In an international multicenter registry of Still’s disease with lung involvement (n=90), pleuritis was most common (72.2%), parenchymal disease occurred in 34.4%, and ARDS in 9.5%. Parenchymal involvement correlated with sore throat, pericarditis, and higher systemic scores, while use of IL-1/IL-6 inhibitors was not associated with parenchymal disease.
Impact: Defines the spectrum and correlates of lung involvement including ARDS in Still’s disease, informing risk stratification and surveillance.
Clinical Implications: In Still’s disease, proactive assessment for pleuritis and parenchymal lung disease is warranted; ARDS risk, though lower, is clinically relevant. Screening for parenchymal involvement should consider associated clinical features (sore throat, pericarditis, higher systemic activity).
Key Findings
- Among 90 Still’s patients with lung involvement, pleuritis (72.2%) and parenchymal features (34.4%) predominated; ARDS occurred in 9.5%.
- Parenchymal lung disease associated with sore throat, pericarditis, and higher systemic scores.
- Use of IL-1 or IL-6 inhibitors was not associated with parenchymal lung involvement.
Methodological Strengths
- International multicenter registry with standardized definitions of lung involvement
- Focus on clinically meaningful phenotypes including ARDS and parenchymal disease
Limitations
- Observational registry with potential selection and information bias
- Heterogeneity in imaging and management across centers; causality cannot be inferred
Future Directions: Prospective studies to validate risk factors for parenchymal lung disease and ARDS in Still’s disease and to evaluate preventive/therapeutic strategies.
OBJECTIVES: To assess the lung involvement in patients with Still's disease, an inflammatory disease assessing both children and adults. To exploit possible associated factors for parenchymal lung involvement in these patients. METHODS: A multicentre observational study was arranged assessing consecutive patients with Still's disease characterized by the lung involvement among those included in the AIDA (AutoInflammatory Disease Alliance) Network Still's Disease Registry. Still's disease-lung involvement was defined by the presence of pleuritis, parenchymal features, acute respiratory distress syndrome (ARDS) and/or pulmonary arterial hypertension. RESULTS: In total, 90 patients with Still's disease and lung involvement were assessed (mean age 36.3 ± 17.8 years, 35.6% male sex). Among them, 13.3% of patients were paediatrics. These patients with lung involvement mainly showed pleuritis in 72.2% of cases, parenchymal features in 34.4%, ARDS in 9.5% and pulmonary arterial hypertension in 2.3%. After that we focused on patients characterised by parenchymal lung involvement, which is an emergent issue of clinical concern. These patients with parenchymal lung disease were significantly characterized by sore throat, pericarditis and higher values of systemic score than others. Finally, the administration of both IL-1 or IL-6 inhibitors was not associated with the presence of parenchymal lung involvement. CONCLUSION: The clinical characteristics of patients with Still's disease and lung involvement were described in the AIDA network. We also provided a clinical profile of patients with parenchymal lung involvement considering its prognostic relevance. Although providing a clinical landscape of these patients, further studies are needed to fully clarify this issue.
3. The value of local validation of a predictive model. A nomogram for predicting failure of non-invasive ventilation in patients with SARS-COV-2 pneumonia.
A single-center retrospective model using age, obesity, admission SOFA, and 24-hour HR and HACOR predicted NIV failure well locally (AUC 0.89) but failed on external validation (AUC 0.547), emphasizing the necessity of local validation and calibration before clinical deployment.
Impact: Highlights the limitations of transporting predictive models across ICUs and provides a practical variable set for local risk stratification.
Clinical Implications: Clinicians should avoid uncritically adopting NIV failure nomograms developed elsewhere; local recalibration and validation are essential before use.
Key Findings
- NIV failure rates were 37.6% (training) and 18% (validation) in SARS-CoV-2 pneumonia cohorts.
- Predictors included age, obesity, admission SOFA, and 24-hour HR and HACOR after NIV initiation.
- Model performed well locally (AUC 0.89; HL 0.861) but poorly on external validation (AUC 0.547).
Methodological Strengths
- Explicit external validation with calibration assessment (HL test, calibration curve)
- Use of readily available clinical variables enabling bedside applicability
Limitations
- Retrospective single-center model derivation; potential changes in practice over time
- Poor transportability to external ICU limits generalizability
Future Directions: Develop and test federated or multi-institution models with dynamic recalibration; evaluate decision-analytic impact on intubation timing and outcomes.
OBJECTIVE: We aimed to determine predictors of non-invasive ventilation (NIV) failure and validate a nomogram to identify patients at risk of NIV failure. DESIGN: Observational, analytical study of a retrospective cohort from a single center, compared with an external cohort (March 2020 to August 2021). SETTING: Two intensive care units (ICUs). PATIENTS: Patients with pneumonia due to severe acute respiratory syndrome (SARS-CoV-2) and NIV > 24 h (154 and 229 in each cohort). INTERVENTIONS: The training cohort identified NIV failure predictors. A nomogram, created via logistic regression, underwent validation with the Hosmer-Lemeshow (HL), calibration curve and test and area under the curve (AUC). Its external validity was tested using AUC. MAIN VARIABLES OF INTEREST: Demographics, comorbidities, severity scores, NIV settings, vital signs, blood gases, and oxygenation at the start and 24 h after NIV, NIV failure. RESULTS: NIV failure was 37.6% and 18% in the training and validation cohorts, respectively. Risk factors for NIV failure inluded age, obesity, sequential organ failure assessment (SOFA) score at admission, and heart rate (HR) and heart rate, acidosis, consciousness, oxygenation, respiratory rate (HACOR) 24 h post-NIV. The model's HL test result was 0.861, with an AUC of 0.89 (confidence interval [CI] 0.839-0.942); validation AUC was 0.547 (CI 0.449-0.645). CONCLUSIONS: A predictive model using age, obesity, SOFA score, HR, and HACOR at 24 h predicts NIV failure in our COVID-19 patients but may not apply to other ICUs.