Laboratory Biomarkers and Pulmonary Interstitial Emphysema in ARDS (PIE-ARDS) (PIE-ARDS)

August 6, 2025 updated by: Giovanni Landoni, Università Vita-Salute San Raffaele

Pulmonary Interstitial Emphysema (Macklin Effect), Quantitative Imaging Analysis and CytoKine Profiling to Predict Lung Frailty IN ARDS

Barotrauma (pneumothorax, pneumomediastinum) is a well-described complication of Acute Respiratory Distress Syndrome (ARDS), especially in patients with coronavirus disease 2019 (COVID-19) (16.1% in COVID-19, and about 6% in non-COVID-19 ARDS). Macklin effect was recently discovered by our group as an accurate radiological predictor of barotrauma in COVID-19 ARDS; the Investigators also found that density histograms automatically extracted from chest CT images provide a reliable insight into lung composition

. Since lung frailty is a major issue also in non-COVID-19 ARDS, the Investigators want to confirm the predictive role of Macklin effect also in this setting. In addition, the Investigators aim to explore inflammatory profiling to decipher different biological aspects of the same clinical issue. Finally, the Investigators want to develop a specific management algorithm for patients diagnosed, according to our findings, with a specific ARDS sub phenotype characterized by increased lung frailty

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Barotrauma occurs frequently in acute respiratory distress syndrome (ARDS), and has a difficult, non-standardized management. Unfortunately, mortality rates remain high (> 60% in COVID-19 ARDS, around 46% in non-COVID-19 ARDS). Interestingly, data from COVID-19 patients suggested that barotrauma may occur also in spontaneously breathing patients with ARDS. Accordingly, frailty of lung parenchyma represents a major issue in ARDS. Protective mechanical ventilation (i.e. ventilation with low tidal volume and low airway pressures) remains a cornerstone of supportive management of ARDS. Unfortunately, mechanical ventilation may worsen pulmonary damage (ventilator-induced lung injury) and, in high-risk patients, may induce barotrauma even when ventilator settings are maintained within the "safe" limit of protective ARDS. Early identification of high-risk features could therefore allow clinicians to individualize management of high-risk patients, by tailoring respiratory support and potentially select candidates for advanced support (i.e. extracorporeal membrane oxygenation) before development of overt barotrauma.

Macklin effect is a well-described radiological sign originally intended to differentiate between "peripheral" (distal airway rupture, "respiratory" barotrauma) and "central" (lesion to large airways/esophaegal injury) causes of air leakage in the mediastinum. However, the Investigators recently identified Macklin effect as a strong radiological predictor of barotrauma development in mechanically ventilated COVID-19 ARDS patients (sensitivity: 89.2%; specificity: 95.6%). In our cohort, radiologically-detected Macklin effect was identified 8-12 days before development of pneumomediastinum/pneumothorax. These preliminary results have been confirmed in a subsequent multicenter study (sample size 697 patients; sensitivity: 100%; specificity: 99.8%).

Furthermore, preliminary data suggest that early application of awake veno/venous extracorporeal membrane oxygenation (ECMO) before invasive mechanical ventilation in COVID-19 patients with severe ARDS and at high-risk for barotrauma (defined as presence of Macklin effect on chest CT imaging) might result in no barotrauma events with a low intubation rate.

Concurrently, a hyper inflammatory sub phenotype has been associated with overall worse outcome both in terms of mortality and ventilator-free days in ARDS. Moreover, the occurrence of lung injury during mechanical ventilation has been proven to be significantly related to the recruitment of mast cells via CXCL10/CXCR3 signaling .

In this view, confirmation of Macklin effect predictive role and identification of further, novel laboratory biomarkers could provide instruments for early risk stratification in ARDS patients.

Taken together, i) quantitative imaging analysis and ii) systemic inflammatory profiling could decipher different biological aspects of the same clinical issue, possibly laying foundation for the definition of a multimodality signature of lung frailty in ARDS patients..

Accordingly, the driving hypotheses of this retrospective/prospective study is that identification of a novel ARDS sub phenotype characterized, irrespective of the underlying etiology, by increased lung frailty could substantially improve the poor prognosis routinely associated with this condition, possibly being a landmark for personalized management strategies.

To further validate the role of Macklin effect, the Investigators will:

  • evaluate the accuracy of Macklin effect in a retrospective cohort of 350 ARDS patients (COVID-19 and non-COVID-19)
  • identify, throughout densitometry, machine learning and artificial intelligence-based approaches, novel imaging biomarkers characteristics of higher lung frailty in the same cohort.

In the main prospective study, the Investigators will:

  • analyse the following biomarkers in the serum and bronchoalveolar lavage fluid of 100 ARDS patients prospectively enrolled: Interleukin-8 (IL-8), Interleukin (IL)-6, IL-1Ra, IL-18, interferon (IFN ), Angiopoietin-2 (Ang-2), Tumour Necrosis Factor receptor-1 (TNFr1), Plasminogen Activator Inhibitor-1(PAI-1), Receptor for Advanced Glycation Endproducts (RAGE), Intercellular adhesion molecule-1 (ICAM-1), Surfactant Protein D (SPD), protein C, Von Willebrand Factor (VWF), CXCL10/CXCR3, and metalloproteases (MMP9, MMP10).
  • Develop a specific management algorithm for ARDS patients at high risk for barotrauma by collecting clinical and outcome data from 10 ARDS patients receiving unconventional management (e.g. awake ECMO, ultraprotective ventilation, etc)

Study Type

Observational

Enrollment (Estimated)

110

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Cagliari, Italy
        • Not yet recruiting
        • A.O.U. di Cagliari
        • Contact:
          • Gabriele Finco, MD
      • Milan, Italy, 20132
        • Recruiting
        • IRCCS San Raffaele Scientific Institute
        • Principal Investigator:
          • Michele De Bonis, MD
        • Contact:
        • Contact:
      • Pisa, Italy
        • Not yet recruiting
        • A.O.U. Pisana
        • Contact:
          • Fabio Guarracino, MD
      • Potenza, Italy
        • Not yet recruiting
        • Ospedale San Carlo
        • Contact:
          • Gianluca Paternoster, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patients with ARDS diagnosis will be enrolled. With the exception of blood and BAL samples collection, all patients enrolled in the prospective cohort will follow their normal course of diagnosis/treatment without any further requirements for the scope of this study other than those provided in the normal management of patients with this condition. Furthermore, any decision regarding drug or procedure will be made by the physician based on her/his clinical judgment, independently from the decision to include the patient in this study. No follow-up medical and/or imaging examinations/laboratory analysis after hospital discharge are needed by the present study design.

Description

Inclusion Criteria:

  • Clinical and radiological signs of ARDS, according to Berlin criteria, requiring ICU admission;
  • Obtain duly signed informed consent
  • Availability of at least one chest CT scan during hospital stay

Exclusion Criteria:

• Poor quality imaging (because of motion/respiratory artefacts).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Acute Respiratory Distress Syndrome
Patients with ARDS requiring or not requiring invasive ventilation
Diagnostic test: Blood and bronchoalveolar fluid collection and analysis
Blood and bronchoalveolar lavage fluid will be collected within 12 hours after intubation. Blood samples will be centrifuged, and the serum immediately stored at less than 70° C. The following biomarkers will be analysed in the serum and bronchoalveolar lavage fluid: Interleukin-8 (IL-8), Interleukin (IL)-6, IL-1Ra, IL-18, interferon (IFN ), Angiopoietin-2 (Ang-2), Tumour Necrosis Factor receptor-1 (TNFr1), Plasminogen Activator Inhibitor-1(PAI-1), Receptor for Advanced Glycation Endproducts (RAGE), Intercellular adhesion molecule-1 (ICAM-1), Surfactant Protein D (SPD), protein C, Von Willebrand Factor (VWF), CXCL10/CXCR3, and metalloproteases (MMP9, MMP10). Blood samples obtained from the patients will be placed in specimen tubes containing heparin, centrifuged at 1500 G for 10 minutes, and then the plasma will be aspirated and stored at -70° C. Bronchoalveolar lavage fluid will be centrifuged at 1500 G for 10 minutes to remove cellular contents and stored at -70° C.
Diagnostic test: Chest CT scan
Computed Tomography Scan per normal clinical practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of clinically relevant barotrauma
Time Frame: 30 days or until hospital discharge. Specifically, from date of basal CT scan until the date of first radiologically documented barotrauma

Barotrauma is diagnosed only in the case of clear radiological evidence (free air at chest X-ray and/or chest CT scan).

Rate of barotrauma will be compared between patients with an hyperinflammatory pattern as compared with control.
30 days or until hospital discharge. Specifically, from date of basal CT scan until the date of first radiologically documented barotrauma

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Università Vita-Salute San Raffaele

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 27, 2023

Primary Completion (Estimated)

April 1, 2027

Study Completion (Estimated)

July 1, 2027

Study Registration Dates

First Submitted

July 31, 2023

First Submitted That Met QC Criteria

August 17, 2023

First Posted (Actual)

August 21, 2023

Study Record Updates

Last Update Posted (Actual)

August 12, 2025

Last Update Submitted That Met QC Criteria

August 6, 2025

Last Verified

August 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PNRR-MAD-2022-12376

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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