Biomolecular Phenotyping of Lung Transplant Recipients (LUTX_phenotype)

Biomolecular Phenotyping of Lung Transplant Recipients: a Prospective Observational Study

Primary graft dysfunction (PGD) is a common problem after a lung transplant. It's a sudden lung injury that affects around 30% of patients within 72 hours of getting a new lung. PGD can vary in severity, from mild issues seen on X-rays to severe lung problems, and it can also affect other parts of the body, like the heart and kidneys.

The investigators believe that using precision medicine can identify different groups of patients with varying levels of inflammation and provide them with treatments tailored to their specific conditions. This approach has been successful in treating other serious conditions like acute respiratory distress syndrome (ARDS). Currently, researchers haven't classified lung transplant patients in this way, and there's limited information on early blood markers for PGD.

In an upcoming study, the investigators aim to group lung transplant patients based on their blood markers related to inflammation, blood clotting, and blood vessel problems. The investigators also want to see if these groups are linked to their overall outcomes, especially when it comes to PGD.

Study Overview

• Status: Completed
• Conditions: Lung Transplant Failure
• Intervention / Treatment: Diagnostic test: Sub-phenotyping by biomarkers concentration

Detailed Description

Primary graft dysfunction (PGD) is the most common complication after lung transplant (LUTX). PGD is an acute form of lung injury with an incidence of 30%, defined upon alteration of oxygenation and radiographic criteria occurring <72 hours after graft reperfusion.

The PGD definition does not consider the heterogeneity of clinical manifestations of ischemia-reperfusion (I/R) injury. First, PGD severity may vary from mild radiographic signs to life-threatening lung injury. Second, duration may differ: most patients manifest transient hypoxia, but a minority have persistent respiratory failure. Finally, PGD is associated with hemodynamic and renal failure, suggesting that it might be considered a heterogeneous syndrome characterized by multisystemic widespread endothelial barrier damage and inflammation activation due to I/R injury rather than an alteration of the sole lung function.

Following the new paradigm of precision medicine, the investigators hypothesize that predictive enrichment may allow for detecting different - and potentially treatable - traits (i.e., hypo vs. hyperinflammatory) of PGD and applying targeted treatments to sub-cohorts. As for other critical illnesses (i.e., acute respiratory distress syndrome - ARDS, sepsis), the investigators envision the possibility of carrying out biological subtyping of LUTX patients to select the patients with the lowest chance of harm for treatment. In the similar -but not equivalent- context of ARDS, it has been proven that treatments (e.g., positive end-expiratory pressure, fluid management, simvastatin) that disappointingly failed to benefit the overall patients' population provided benefit in specific patients' subcohorts. Biological phenotyping of LUTX recipients has never been carried out, and literature is ample but sparse regarding early PGD plasmatic biomarkers.

With this prospective observational study, the investigators aim to assess: 1/ whether LUTX recipients can be clustered based on early plasma concentration of biomarkers of inflammation, coagulation, and endothelial activation, and 2/ whether these clusters could be associated with clinical outcomes (and specifically PGD).

• Study Type: Observational
• Enrollment (Actual): 80

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20122
    • Fondazione IRCCS Ca'Granda - Ospedale Maggiore Policlinico

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All the consecutive adult patients have undergone primary double LUTX at the promoting institution.

Description

Inclusion Criteria:

• undergone double LUTX
• age > 18 years old

Exclusion Criteria:

• single LUTX
• re-transplantation

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Hypoinflammatory; By means of latent class analysis, a sub-phenotype of LUTX recipients with down-regulated inflammatory biomarkers	Diagnostic test: Sub-phenotyping by biomarkers concentration; Plasma will be collected at ICU admission (i.e., < 6 hours from graft reperfusion), centrifuged (1500G for 15 min), frozen at -80°c, and then centralized at the Institutional laboratory. The following biomarkers will be assessed: Interleukin-1β, Interleukin-2, Interleukin-6, Interferon-γ, Tumor Necrosis Factor-alpha (TNF-α), chemokine (C-C motif) ligand-2 (CCL-2), Interleukin-15 (IL-15), Ferritin, and D-dimer, by a point-of-care biochip-array device (RANDOX, Multistat)
Hyperinflammatory; By means of latent class analysis, a sub-phenotype of LUTX recipients with up-regulated inflammatory biomarkers	Diagnostic test: Sub-phenotyping by biomarkers concentration; Plasma will be collected at ICU admission (i.e., < 6 hours from graft reperfusion), centrifuged (1500G for 15 min), frozen at -80°c, and then centralized at the Institutional laboratory. The following biomarkers will be assessed: Interleukin-1β, Interleukin-2, Interleukin-6, Interferon-γ, Tumor Necrosis Factor-alpha (TNF-α), chemokine (C-C motif) ligand-2 (CCL-2), Interleukin-15 (IL-15), Ferritin, and D-dimer, by a point-of-care biochip-array device (RANDOX, Multistat)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Graft Dysfunction	PGD incidence, defined and graded following the most recent ISHLT society guidelines, as hypoxia (i.e., PaO2/FiO2 < 300 mmHg) with bilateral lung infiltrates.	<= 72 hours from graft reperfusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-days organ support free-days	Number of days at 28 days from ICU admission free from: - extracorporeal membrane oxygenation; - mechanical ventilation; - renal replacement therapy; - vasoactive support.	28 days from ICU admission

Collaborators and Investigators

• Sponsor: Policlinico Hospital
• Collaborators: University of Milan
• Investigators: Study Director: Giacomo Grasselli, Porf, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; Principal Investigator: Vittorio Scaravilli, MD, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Actual): March 1, 2024
• Study Completion (Actual): June 1, 2025

Study Registration Dates

• First Submitted: November 4, 2023
• First Submitted That Met QC Criteria: November 4, 2023
• First Posted (Actual): November 9, 2023

Study Record Updates

• Last Update Posted (Actual): June 18, 2025
• Last Update Submitted That Met QC Criteria: June 13, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: biomarkers; lung transplant; primary graft dysfunction; prospective observational study
• Other Study ID Numbers: LUTX_phenotype

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual anonymized data will be available from the promoting center after a reasonable request
• IPD Sharing Time Frame: Any timeframe
• IPD Sharing Access Criteria: Request to the PI
• IPD Sharing Supporting Information Type: ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No