key: cord-0821266-36pvjk8i
authors: Urlik, Maciej; Stącel, Tomasz; Latos, Magdalena; Pasek, Piotr; Pióro, Anna; Zawadzki, Fryderyk; Gmerek, Marta; Księżopolska, Paulina; Przybyłowski, Piotr; Ochman, Marek
title: Lung transplantation as a treatment for patients with end-stage respiratory failure due to Coronavirus disease of 2019 (COVID-19)
date: 2022-04-11
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2022.03.017
sha: 5df2a2be2ee86a1a29c586521224732758a4b497
doc_id: 821266
cord_uid: 36pvjk8i

Introduction : Coronavirus disease of 2019 (COVID-19) may lead to development of irreversible acute respiratory distress syndrome. Some patients sustain severe respiratory failure after infection subsides. They may require lung transplantation as a last resort treatment. Aim of the study is to assess the effect and feasibility of lung transplantation as a treatment for patients with severe irreversible respiratory failure due to COVID-19. Materials and Methods : This retrospective study pertains analysis of 119 patients in critical condition, who were referred to Lung Transplant Ward between July 2020 and June 2021 after developing respiratory failure requiring extracorporeal membrane oxygenation, invasive ventilation or both as well as few patients on high flow oxygen therapy. Inclusion criteria for referral were confirmed lack of viral disease and exhaustion of other therapeutic options. Results : 21,84% of the referred patients were disqualified from such treatment due to existing contraindications. Among suitable patients 75,8% died without transplantation. Among all patients, who were qualified for lung transplantation only 9 patients became double lung transplant recipients. Intraoperative mortality for this procedure was 33%. 4 patients were discharged after the procedure and are currently self-reliant with full respiratory capacity. Conclusion : Patients with severe irreversible respiratory failure after COVID-19 present significantly high mortality without lung transplantation. This procedure may present satisfactory results, but must be performed timely due to critical condition and scarcity of lung donors, only aggravated around the time of peak infection waves.

Materials and Methods: This retrospective study pertains analysis of 119 patients in critical condition, who were referred to Lung Transplant Ward between July 2020 and June 2021 after developing respiratory failure requiring extracorporeal membrane oxygenation, invasive ventilation or both as well as few patients on high flow oxygen therapy. Inclusion criteria for referral were confirmed lack of viral disease and exhaustion of other therapeutic options.

Results: 21,84% of the referred patients were disqualified from such treatment due to existing contraindications. Among suitable patients 75,8% died without transplantation. Among all patients, who were qualified for lung transplantation only 9 patients became double lung transplant recipients. Intraoperative mortality for this procedure was 33%. 4 patients were discharged after the procedure and are currently self-reliant with full respiratory capacity.

Conclusion: Patients with severe irreversible respiratory failure after COVID-19 present significantly high mortality without lung transplantation. This procedure may present satisfactory results, but must be performed timely due to critical condition and scarcity of lung donors, only aggravated around the time of peak infection waves. support [1] . Available data show extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis [2] . When all other therapeutic options have been exhausted, some patients might be considered to become lung transplant recipients. Certain criteria has been established in order to assess, who would benefit for lung transplantation [3] . First and foremost, decision to qualify for such procedure must only be made for patients, who did not present any contraindications not only for transplantation, but also for life-long immunosuppressive treatment. Second of all, as a number of world-wide lung transplantation is generally limited by scarcity of donors, ethical framework was established in form of consensus statement from International Society for Heart and Lung Transplantation (ISHLT) [4] .

Aforementioned framework is based on values such as Justice, Utility and Efficiency. It states that patients, who are the most severely ill must be given highest priority provided they present high chance of reaching long-time benefits from lung transplantation. Such approach enables transplant centers to offer transplantation as a therapeutic treatment to certain patients, who are dependent on invasive ventilation or/and ECMO after COVID-19. It is important to remember that patients with such support have a very limited time to wait for suitable organ as those therapeutic options provide necessary gas exchange, but also are associated with severe, often fatal complications. As COVID-19 was a new disease, it was difficult to assess the potential benefit of lung transplantation among those so severely ill. First known cases of lung transplantation as a treatment were published by Chinese team [5] . In a short time, more and more cases of successful lung transplantations for such patients were published [6] , [7] [2] . Due to the severity of the first COVID-19 wave in Poland, many intensive care units and pulmonology departments were contacting our Lung Transplant Team regarding such treatment. Our first patient transplanted due to COVID-19 was a man supported by ECMO for couple of weeks. He underwent double lung transplantation on the last day of July 2020 and has successfully reached 1-year posttransplant survival with full respiratory capacity, as we reported [8] .

Aim of the study is to assess the effect and feasibility of lung transplantation as a treatment for patients with severe irreversible respiratory failure due to COVID-19,as well as analyze patients, who were referred as potential lung transplant candidates.

MATERIALS AND METHODS: This retrospective study pertained data gathered from 119 potential lung transplant candidates due to irreversible respiratory failure after developing COVID-19 between July 2020 and July 2021. All patients were referred to a single center. Inclusion criteria to begin qualification process were as follows: confirmed absence of SARS-COV-2 by reverse transcription polymerase chain reaction (RT-PCR) assessment twice with at least 1 day apart; no clinical and radiological signs of improvement over at least 3 weeks after obtaining negative RT-PCR results; lack of severe failure of organs other than lungs. Detailed characteristics of all referred patients were presented in Table 1 . Data (age, gender, comorbidities, body mass index, extend of respiratory support) was gathered from standard potential lung transplant recipient questionnaire. Additional assessment of pulmonary function tests was performed for patients, who actually underwent lung transplantation. Lung function was assessed by means of spirometry (forced expiratory volume in 1 second as percentage of predicted value (FEV1%); forced vital capacity as percentage of predicted value (FVC%); Tiffeneau -Pinelli index (FEV1/FVC)) as well as 6-minute walk tests' (6MWT) results, particularly distance, oxygen saturation before the test (pre-sat) and after finishing the test (post-sat). Presently, she is self-reliant but requires passive oxygen supply at greater exertion. Her daughter is alive and well. At 8 months old, she does not present any developmental deficits. However, she is under care and supervision from the pediatric cardiology due to mild atrial septal defect. Detailed respiratory function of all patients is presented in Table 2. DISCUSSION: It became clear that patients in aforementioned condition were not expected to survive without lung transplantation. However due to lack of data, it was difficult to assess whether they will benefit from this kind of treatment. As pandemic lasted and more data was gathered, the more publications were pointing out the feasibility of lung transplantation as a treatment. It was also reported that ARDS due to COVID-19 (CARDS) may subside leaving patient with satisfactory respiratory function in couple of weeks [3] . Careful consideration is advised while qualifying patients for lung transplantation after COVID-19. Article published by Cypel and Keshavjee points out Lung transplant teams should be certain that patient's lungs have no significant potential for recovery, as regaining respiratory capacity without transplant seems more beneficial [3] . Additionally patient must undergo proper qualification process and cannot present any contraindications what would prohibit pre-COVID19 lung transplantation.

Such opinion is supported by King et al. [9] . They report that the major obstacles in patients with severe CARDS treated with ECMO or mechanical invasive ventilation are the inability to conduct proper psychosocial evaluation and pretransplantation education, marked deconditioning from critical illness and infectious concerns pertaining viral reinfection as well as bacterial pathogens from ICU. Limited knowledge about the natural history of recovery after COVID-19 infection was also assessed as problematic. Volume of the chest, particularly in both pleural cavities may significantly decrease in the course of COVID-19. Proper sizing of 1:1 or less is advised by Urlik et al [8] . The authors of this paper took the liberty of more liberal size-matching of the lungs due to critical condition of the patient and increasing risk of ECMO-related fatal complications [8] . First reported cases of lung transplantation as a treatment of postCOVID-19 respiratory failure pertained two 66-and 70-year old Chinese patients [5] . Despite thorough report, certain issues (need for posttransplant ECMO; age of the patients and lack of description of the more than couple of days follow-up) were concerning. Those issues as well as lack of transparency of the Chinese solid organ transplant programs were also voiced by Baquero et al. [10] . Over time, more reports emphasizing different aspects of lung transplantations due to COVID-19 were occurring [11] [6], [12] . Austrian team performed lung transplantation for 44-year old woman with positive RT-PCR results after assessing viral activity by Vero cultures as negative after 7 days in three passages, as described by Lang et al. [7] . This case report shows limitations of RT-PCR testing. However, viral activity and presence must be excluded with high certainty. Hawkins et al. carried out the systematic review regarding the topic of lung transplantation as a treatment for postCOVID-19 respiratory failure [13] . Based on 21 cases of lung transplantations worldwide, they evaluated the early survival rate at 95% even though 85% of described recipients required preoperative ECMO. During almost 2 years of the pandemic, technical feasibility of lung transplantation after proper thorough qualification process seems to be established. However, other important issues should also be taken under consideration. Lepper et al. [14] wrote an interesting comment to the case series published by Bharat et al. [15] . German team was concerned that as lung transplantation faces the scarcity of donors, each lung must be used for patients, who have general good prognosis of surviving couple of years with transplant despite presenting end-stage respiratory failure before procedure. To quate Lepper et al. '' The success of a transplantation procedure cannot solely be judged by the fact that a patient can be discharged from the ICU''. Another concern is that, by accepting high-urgency candidates with ARDS during the pandemic lung transplant teams will disadvantage patients on the waiting list, increase waiting-list mortality, decrease post-transplantation survival and distort the discriminatory capacity of any organ allocation systems [16] . In conclusion, Lepper et al. agree that lung transplantation can be an option for certain patients after careful consideration. French team also voices their concerns, as Messika et al. reminds that the healing potential of lung parenchyma should not be underestimated, even after 50 days of ECMO support with some patients regaining respiratory capacity after 90 days on ECMO [17] . On the other hand, Kurihara et al. made an assessment of patients, who were treated with ECMO due to end-stage lung failure in course of COVID-19 [18] . Even though, CARDS was not associated with a higher post-ECMO mortality than non-COVID-19-associated ARDS patients, CARDS patients presented significantly higher rates of bleeding and thrombotic complications. What is more, 100% of patients, who were on invasive ventilation for linger than 7 days prior to ECMO, died without lung transplantation.

Such examples of concern are important as during 2020, COVID-19 and its complications were something unknown and all the patients were treated with the best care and knowledge accessible at the time being.

Nowadays, at the end of 2021, almost a year has passed since introduction of the efficient vaccines against this virus [19] . Adult population in Poland have been granted nation-wide, unlimited access to free vaccination against SARS-COV-2 on 10 th May 2020 [20] . However, vaccine hesitancy is reported to be 48.5% among males and 45.6% among females, particularly younger with the main reason being the fear of vaccine side-effects for entire study group [20] . A safe and effective vaccine offers direct (high-risk groups are vaccinated to prevent disease) and indirect ( those in contact with high-risk individuals are vaccinated to reduce transmission) protection [21] . It seems to be the only way of ending COVID-19 pandemic, which hopefully will restore full capacity of performing lung transplantations in regard to availability of the donors. However, many potential lung transplant candidates will still remain after the pandemic is over. All of the aforementioned papers regarding lung transplantation were published before effortless, free of charge access to efficient vaccine. The newest consensus statement published by ISHLT pertains the topic of qualification for such procedure [22] . COVID-19 survivors should be evaluated for transplant only if they have demonstrated lack of clinical improvement, persistent parenchymal infiltrates as well as severely reduced lung compliance after prolonged support. It was also assessed that it is too early to make more conclusive recommendations now [22] . According to its initial statement, lung transplant programs should have the explicit goal of maximizing long-term survival in order to provide net survival gains for society as a whole. It is also explained as an unsuccessful lung transplantation also affects a potential alternative recipient who did not have the opportunity to be transplanted due to the prevailing organ shortage, especially aggravated during each COVID-19 wave. In the current Autumn- BMI -body mass index; ECMO VV -veno-venous extracorporeal membrane oxygenation; MVmechanical ventilation; O2 -passive oxygen therapy; SD -standard deviation Table 2 Lung function of patients, who were discharged after lung transplantation due to COVID-19 

Lung transplantation during the COVID-19 pandemic

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The starfish story and lung transplantation for COVID-19

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Lung transplantation for patients with severe COVID-19

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Lung transplantation for COVID-19-associated ARDS

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Authors would like to acknowledge the work of patient's primary pretransplant medical teams and Polish