Emergency Lung Transplantation after COVID-19: Immunopathological Insights on Two Affected Patients

Giorgio A Croci,Daria Trabattoni,Mara Biasin,Mario Clerici,Stefano Ferrero,Evgeny Fominskiy,Mario Nosotti,Luca Valenti,Valentina Vaira,Lorenzo Rosso,Elena Guerini Rocco,Guido Baselli,Alessandro Palleschi,Massimo Barberis,Mara Scandroglio,Giuliana Gregato

doi:10.3390/cells10030611

Abstract

We herein characterize the immunopathological features of two Italian COVID-19 patients who underwent bilateral lung transplantation (bLTx). Removed lungs underwent histopathological evaluation. Gene expression profiling (GEP) for immune-related signatures was performed on lung specimens and SARS-CoV-2-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine levels were measured on lungs, bronchoalveolar lavage fluids and in culture supernatants. Pathological assessment showed extensive lung damage with the pattern of proliferative to fibrotic phases, with diffuse alveolar damage mimicking usual interstitial pneumonia (UIP). Lungs’ GEP revealed overexpression of pathogen recognition receptors, effector cytokines and chemokines, immune activation receptors and of the inflammasome components. Multiplex cytokine analysis confirmed a proinflammatory state, with high levels of monocyte/macrophage chemotactic and activating factors and of IL-6 and TNF-α. A similar profile was observed in SARS-CoV-2-stimulated PBMCs collected 7 days after transplant. The pattern of tissue damage observed in the lungs suggests that this may represent the output of protracted disease, resembling a diffuse UIP-like picture. The molecular immune profiling supports the paradigm of a persistent proinflammatory state and sustained humoral immunity, conditions that are maintained despite the iatrogenic immunosuppression.

Highlights

The clinical phenotype of coronavirus disease 2019 (COVID-19), following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, encompasses a wide spectrum of clinical manifestations, ranging from asymptomatic to severely complicated cases, with the highest rate of mortality due to acute respiratory distress syndrome (ARDS) [1,2,3,4]
The knowledge of the physiopathology of COVID-19 is still in its early phases, but a key mechanism seems to stem from the interaction between SARS-CoV-2 and angiotensinconverting enzyme 2 (ACE2), which is notably expressed by the epithelial layers of the upper airways and by the endothelial cells [12,13,14]
We describe the immunopathological phenotype detected in the lungs and peripheral blood mononuclear cells (PBMCs) from two adult males who underwent bLTx after end-stage COVID-19

Summary

Introduction

The clinical phenotype of coronavirus disease 2019 (COVID-19), following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, encompasses a wide spectrum of clinical manifestations, ranging from asymptomatic to severely complicated cases, with the highest rate of mortality due to acute respiratory distress syndrome (ARDS) [1,2,3,4]. The knowledge of the physiopathology of COVID-19 is still in its early phases, but a key mechanism seems to stem from the interaction between SARS-CoV-2 and angiotensinconverting enzyme 2 (ACE2), which is notably expressed by the epithelial layers of the upper airways and by the endothelial cells [12,13,14]. This interaction likely explains the elective tropism of SARS-CoV-2 for the respiratory district [9] and, possibly, the pathological features of neoangiogenesis and microangiopathy, with consequent complement activation and elicitation of an inflammatory cascade [15]. These younger patients represent a cohort where extreme lifesaving interventions such as lung transplantation could be envisioned [16]

Methods

Results

Conclusion