Post-COVID-19 Lung Transplantation Italian Pivotal Protocol: Some Ethical Considerations.

SARS‑CoV‑2 mostly affects the respiratory system with clinical patterns ranging from the common cold to fatal pneumonia. During the first wave of the COVID-19 pandemic, owing to the high number of patients who were infected with SARS‑CoV‑2 and subsequently recovered, it has been shown that some patients with post-COVID-19 terminal respiratory failure need lung transplantation for survival. There is increasing evidence coming from worldwide observations that this procedure can be performed successfully in post-COVID-19 patients. However, owing to the scarcity of organs, there is a need to define the safety and efficacy of lung transplant for post-COVID-19 patients as compared to patients waiting for a lung transplant for other pre-existing conditions, in order to ensure that sound ethical criteria are applied in organ allocation. The Milan's Policlinic Lung Transplant Surgery Unit, with the revision of the National Second Opinion for Infectious Diseases and the contribution of the Italian Lung Transplant Centres and the Italian National Transplant Centre, set up a pivotal observational protocol for the lung transplant of patients infected and successively turned negative for SARS‑CoV‑2, albeit with lung consequences such as acute respiratory distress syndrome or some chronic interstitial lung disease. The protocol was revised and approved by the Italian National Institute of Health Ethics Committee. Description of the protocol and some ethical considerations are reported in this article.

Coronaviruses are enveloped RNA viruses that cause respiratory diseases of varying severity, ranging from cold-like symptoms to fatal pneumonia. Death occurs most frequently as a consequence of acute respiratory distress syndrome (ARDS) or from subsequent pulmonary fibrosis.

As of early 2022, the new SARS-CoV-2 coronavirus pandemic has caused almost 5 hundred million infections and more than 6 million deaths worldwide [1]. In Italy, approximately 14.5 million infections and >159,000 COVID-19 related deaths were reported [2].

During the early months of the pandemic it was readily assumed that some patients, who had been suffering from COVID-19 lung infection and, subsequently, tested negative for the presence of the virus, might suffer post–COVID-19 terminal respiratory failure and require lung transplantation as a treatment.

However, transplantation for COVID-19-associated ARDS poses ethical dilemmas. Transplantation for irreversible lung disease is strongly characterized by a global shortage of donor organs; patients may die while on a waiting list and, consequently, recipients should be accurately selected [3].

Although in Italy patients with acute lung injury due to infections are generally not considered for transplantation, in 2020, there was already evidence that lung transplantation—the only option for survival in some patients with severe unresolved COVID-19–associated ARDS—could be done successfully [4].

End-stage lung disease from COVID-19 is however a new entity: patients may benefit from transplant but there are limited data, especially on the long-term outcomes.

In order to monitor the outcomes of these transplants, the Milan's Policlinico Lung Transplant Surgery Unit, with the revision by the National Second Opinion for Infectious Diseases, and with the contribution of the Italian Lung Transplant Centres and the Italian National Transplant Centre, set-up an observational pilot protocol for lung transplantation in patients with ARDS or interstitial pulmonary fibrosis after the end of the COVID-19 infections. A fundamental assumption for the safety of the transplant is that the patient is negative for virus detection.

Materials and Methods

The aim of the Italian protocol is to evaluate the safety and efficacy of lung transplantation in patients with ARDS (group 1) and post–COVID-19 interstitial pulmonary fibrosis (group 2) on the basis of follow-up of treated patients. These 2 clinical settings represent the 2 different pathogenetic pictures of lung damage in patients affected by COVID-19: ARDS is characterized by a rapid progression of vascular endothelial damage that evolves in a few weeks into terminal respiratory failure; and fibrosis has a less rapid progression and is due to a progressive involvement of the pulmonary interstitium. From a clinical point of view, patients with ARDS require respiratory and/or mechanical assistance earlier than patients with respiratory failure derived from fibrosis [5]. Post–COVID-19 ARDS cases, with extracorporeal vascular support and/or invasive respiratory support, fall under the national emergency protocol while post–COVID-19 interstitial pulmonary fibrosis candidates fall under the transplant center allocation policy.

It may happen that a patient in serious clinical conditions, who does not meet all the requirements for access to the emergency program, urgently needs a transplant. In this case requests must be approved by the board for exceptions to the national protocol for pulmonary emergencies and the second national opinion for infectious diseases; if patients require invasive ventilatory assistance or extracorporeal vascular support because of their severe fibrosis, even after the acute phase, they will be managed according to the national emergency lung protocol.

Transplantation outcomes are compared with a third arm (control group) consisting of patients with ARDS or fibrosis not secondary to SARS-CoV-2 infection, and submitted to either elective or emergency lung transplantation.

Regardless of the clinical picture of COVID-19 lung injury, according to the indication in force in 2020, the absence of an active pre-transplant infection should be documented by polymerase chain reaction negativity for SARS-CoV-2 in 2 bronco alveolar lavage specimens collected at least 24 hours apart. If the patient is not being intubated, a nasopharyngeal swab is sufficient. Monitoring is aimed primarily at documenting or excluding any recurrence of SARS-CoV-2 infection; assessment of perioperative mortality; and lung transplant-specific follow-up (ie, at the moment of discharge at 1, 3, 6 months, and 1 year). The probability of transplant success and the risks associated with the procedure and complications overlap with those of standard transplantation.

Patients have to sign an informed consent for enrollment and have to be referred to the National Transplant Centre, with a brief case report highlighting the presence of inclusion criteria and the absence of exclusion criteria. In September 2020, this protocol was approved by the Ethics Committee of the Istituto Superiore di Sanità (Italian National Institute of Health), Rome, Italy.