Brazilian initial experience with lung transplantation due to irreversible lung fibrosis post-COVID-19 in a national reference center: a cohort study

ABSTRACT BACKGROUND: Lung transplantation (LTx) has been discussed as an option for treating irreversible lung fibrosis post-coronavirus disease 2019 (COVID-19), in selected cases. OBJECTIVES: To report on the initial experience and management of end-stage lung disease due to COVID-19 at a national center reference in Brazil. DESIGN AND SETTING: Cohort study conducted at a national reference center for lung transplantation. METHODS: Medical charts were reviewed regarding patients’ demographics and pre-COVID-19 characteristics, post-LTx due to COVID-19. RESULTS: Between March 2020 and September 2021, there were 33 cases of LTx. During this period, we evaluated 11 cases of severe COVID-19-related acute respiratory distress syndrome (ARDS) that were potentially candidates for LTx. Among these, LTx was only indicated for three patients (9.1%). All of these patients were on venovenous extracorporeal membrane oxygenation (ECMO), and the procedure that they underwent was central venoarterial ECMO. All three patients were still alive after the first 30 postoperative days. However, patient #1 and patient #2 subsequently died due to fungal sepsis on the 47th and 52nd postoperative days, respectively. Patient #3 was discharged on the 30th postoperative day. CONCLUSIONS: LTx is feasible among these complex patients. Survival over the first 30 days was 100%, and this favors surgical feasibility. Nonetheless, these were critically ill patients.


INTRODUCTION
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an infectious disease with potentially severe manifestations. 1 Most patients with COVID-19 have a mild or asymptomatic disease course; however, about 10% require admission to an intensive care unit (ICU) because of acute respiratory distress syndrome (ARDS). 2 Mortality rates of up to 60% have been reported for this subgroup 3 but, in Brazil, this rate rises to 80%. 4 Much has been discussed about mechanical ventilation, neuromuscular blockade and prone and extracorporeal membrane oxygenation for ventilatory support 5-7 for these patients. However, some patients evolve with severe lung fibrosis. 8 For this group of patients, lung transplantation (LTx) has been discussed as a treatment option. The first reports of lung transplantation post-COVID-19 were in 2020, first from China 9 and then from Austria. 10 Lung transplantation is potentially lifesaving, but the true effect of the procedure in the acute setting of COVID-19 needs to be very well discussed because these patients are critically ill, with a long hospital stay and associated morbidity. 11

OBJECTIVE
The objective of this article was to report on the initial experience of LTx for management of end-stage lung disease due to Covid-19 at a national reference center in Brazil.  The lung transplantation procedure was sequential and bilateral. During the reperfusion, the cardiopulmonary assistance was reduced to 1.5 liters per minute and arterial clamping was opened.
Following this, the atrial clamping was opened and cardiopulmonary assistance was returned to the previous level. At the end of the procedure, a transesophageal echocardiogram was performed to check that the right and left ventricular function had been preserved. If so, we proceeded with weaning off central ECMO. After the thorax had been closed, the blood gas showed a pO 2 /FiO 2 ratio > 250, after weaning off VV ECMO.

ECMO installation
Central VA ECMO with right atrial cannulation for venous drain- Only one of the cases evaluated by means of telemedicine met all the criteria (Appendix 1). This patient was transferred to our institution on mechanical ventilation. However, after the initial treatment and rehabilitation, she achieved pulmonary improvement and is now in the ward and not dependent on oxygen. We decided to decline to perform lung transplantation at this time, and she will be referred to the clinic after hospital discharge.
During the pandemic, 33 cases of lung transplantation were performed and three of these (9.1%) were due to irreversible pulmonary fibrosis associated with COVID-19. Before COVID-19,  Table 1.
Details of the donors are provided in Table 2. All of them were brain death donors, through traumatic brain injury. They had normal bronchoscopy and pO 2 /FiO 2 ratios of up to 300.
The technical features of the operation are presented in the methods section. The lengths of the surgical procedures (skin to skin) were 465, 515 and 550 minutes, respectively. The total durations of ischemia were 345, 275 and 360 minutes, respectively. There was no need for fresh frozen plasma during the procedures ( Table 3).
All the patients were still alive after the first 30 postoperative days. However, patient #1 and patient #2 died due to fungal sepsis on the 47 th and 52 nd postoperative days, respectively. Patient #3 was discharged on the 30 th postoperative day. Patient #2 had primary graft dysfunction at 72 hours (grade 2). No bleeding problems occurred.
Patient #1 presented acute cholecystitis and underwent laparoscopic cholecystectomy. All three patients presented acute cellular rejection (grade 2), for which patient #1 and patient #2 received treatments with high doses of steroids. Table 4 shows the post-LTx features.

DISCUSSION
The world is currently living through the worst pandemic in human history, with more than four million deaths due to COVID-19. There has been widespread discussion of how to prevent and treat COVID-19. In this manner, LTx has become a treatment option for patients with severe ARDS and irreversible pulmonary fibrosis. Nonetheless, the outcomes remain unclear and few data are yet available in the international literature.
Patients with severe COVID-19 are critically ill and develop considerable degrees of ICU-related comorbidities at the time that lung transplantation is considered. 11 When LTx as a treatment for acute illnesses like COVID-19 has been discussed with lung transplantation teams, several ethical questions have been raised. 12 During the pandemic, there has been a reduction in the offer of donors, and procurement teams have had to be more prudent because of the risk of donor-derived infection, given that there are great numbers of COVID-19 asymptomatic patients. 13,14 Cypel and Keshavjee recommended that transplantation centers should have access to a broad donor pool and would need to have low waiting-list mortality. This will maintain fair and equitable donor organ allocation and provide the chance of life-saving organ transplantation for patients who are more likely to survive. 12 On the other hand, in Brazil, there is no organ allocation score, and the waiting list is generated in accordance with entry time.   Our results were similar to those of other groups. [9][10][11]17 After the first cases were published, Cypel and Keshavjee suggested in Lancet Respiratory that recipient selection should be done on the basis of ratifying previous reports, with all ethical considerations. 12 The study that forms the largest publication so far was conducted in accordance with these same considerations. 11

CONCLUSIONS
This report represents our initial experience with LTx after severe COVID-19, in Brazil. Unfortunately, data remain scarce, as also seen in this study, especially regarding information about longterm outcomes. However, SARS-COV-2 continues to infect hundreds of thousands of people worldwide each day and LTx will always be an option for saving patients with severe COVID-19.
Our report showed that LTx is feasible among these complex patients. Survival over the first 30 days was 100%, and this favors surgical feasibility. Nonetheless, these were critically ill patients.
We recommend that a multidisciplinary team with institutional engagement should be assembled for such cases. Patients presenting end-stage lung disease alone who are undergoing rehabilitation and are awake can be considered for transplantation.
If these patients' conditions deteriorate or improve, they should be withdrawn from the waitlist. For this reason, implementation of a concomitant palliative care approach is fundamental.