key: cord-0760924-wk1ixls8
authors: Lang, Christian; Ritschl, Valentin; Augustin, Florian; Lang, Gyoergy; Moser, Bernhard; Taghavi, Shahrokh; Murakoezy, Gabriella; Lambers, Christopher; Flick, Holger; Koestenberger, Markus; Brooks, Roxane; Muhr, Tina; Knotzer, Johann; Mydza, Daniel; Kaufmann, Marc; Staudinger, Thomas; Zauner, Christian; Krenn, Claus; Schaden, Eva; Bacher, Andreas; Rössler, Bernhard; Faybik, Peter; Tschernko, Edda; Anwar, Maria; Markstaller, Klaus; Höfer, Daniel; Stamm, Tanja; Jaksch, Peter; Hoetzenecker, Konrad
title: Clinical relevance of lung transplantation for COVID-19 ARDS: a nationwide study
date: 2022-03-17
journal: Eur Respir J
DOI: 10.1183/13993003.02404-2021
sha: 7a55ca9805496daf7cc64228cdef1d8e166378da
doc_id: 760924
cord_uid: wk1ixls8

BACKGROUND: Although the number of lung transplantations (LTx) performed worldwide for COVID-19 induced acute respiratory distress syndrome (ARDS) is still low, there is general agreement that this treatment can save a subgroup of most severly ill patients with irreversible lung damage. However, the true proportion of patients eligible for LTx, the overall outcome and the impact of LTx to the pandemic are unknown. METHODS: A retrospective analysis was performed using a nationwide registry of hospitalised patients with confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-Cov-2) infection admitted between January 1, 2020 and May 30, 2021 in Austria. Patients referred to one of the two Austrian LTx centers were analyzed and grouped into patients accepted and rejected for LTx. Detailed outcome analysis was performed for all patients who received a LTx for post-COVID-19 ARDS and compared to patients who underwent LTx for other indications. RESULTS: Between January 1, 2020 and May 30, 2021, 39.485 patients were hospitalised for COVID-19 in Austria. 2323 required mechanical ventilation, 183 received extra-corporeal membrane oxygenation (ECMO) support. 106 patients with severe COVID-19 ARDS were referred for LTx. Of these, 19 (18%) underwent LTx. 30-day mortality after LTx was 0% for COVID-19 ARDS transplant recipients. With a median follow-up of 134 (47–450) days, 14/19 patients are alive. CONCLUSIONS: Early referral of ECMO patients to a LTx center is pivotal in order to select patients eligible for LTx. Transplantation offers excellent midterm outcomes and should be incorporated in the treatment algorithm of post-COVID-19 ARDS.

The COVID-19 pandemic represents a unique challenge to global health care. Although most patients infected with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)

show a mild or even asymptomatic course, up to 30% of patients admitted to hospital require treatment in intensive care units (ICU) due to the development of acute respiratory distress syndrome (ARDS). 1 In this critically ill patient cohort, unchanged high mortality rates of 30-60% have been described. [1] [2] [3] [4] Lung transplantation (LTx) is a well-established therapeutic option for chronic end-stage lung diseases. However, it is rarely performed for acute lung failure. 5 This results in a worldwide still limited experience with LTx in patients with treatment-refractory ARDS. Nevertheless, longterm outcomes in patients receiving LTx for non-COVID ARDS were shown to be comparable with the results of LTx for other indications. [6] [7] [8] An international consortium of 6 participating centers has recently reported encouraging early outcomes of 12 patients receiving LTx for COVID-19 associated ARDS and has updated its experience with meanwhile 34 cases at the annual meeting of the International Society of Heart and Lung Transplantation. 9 Based on these reports, a consensus has been established within the transplant community that LTx can be offered for carefully selected patients suffering from irreversible ARDS due to COVID-19. [10] [11] [12] [13] [14] [15] Despite the growing number of LTx performed for post-COVID-19 ARDS, the true impact of this treatment on the pandemic and the proportion of COVID-19 ARDS patients that are eligible for LTx are unknown.

Austria was among the first countries worldwide, which adopted LTx in the treatment of post-COVID-19 ARDS patients. 16 In Austria, LTx is exclusively performed in one of the two national LTx programs (Medical University of Vienna or Medical University of Innsbruck). Notably, LTx for ARDS arising from non-COVID infections (e.g. influenza) has been performed for several years in Austria and a nationwide referring system for ICUs has been established. 8 The aim of this study was to retrospectively summarize the management of patients with ARDS due to COVID-19 ARDS patients, who had been considered for LTx across Austria since the beginning of the pandemic. Clinical data were evaluated for all COVID-19 patients who were admitted to hospital, received ICU treatment, and were referred and accepted for LTx due to COVID-19 ARDS. Furthermore, clinical outcome after transplantation for COVID-19 ARDS was analyzed and compared to the outcome of other transplant indications. Finally, the overall impact of offering LTx for COVID-19 ARDS cases on institutional LTx programs was assessed.

This study was designed as a nationwide retrospective analysis covering the time period between January 1, 2020 (arbitrarily considered as the beginning of the pandemic) and May 30, 2021 (end of the third wave 

Patients were considered infected with SARS-CoV-2 if the main ICD 10 diagnosis upon hospital admission was " U07.1 / confirmed coronavirus infection ". This definition required two positive PCR tests of nasopharyngeal swabs. Right ventricular (RV) dysfunction was registered when RV hypokinesis and heightened pulmonary artery pressure (PAP) were detected in transthoracic echocardiography. Acute kidney injury was (AKI) staged as AKI 1 to 3 as previously defined in the recommendations of the International Society of Nephrology for adults in accordance to the Kidney Disease Improving Global Outcomes. 18 Liver dysfuntion was defined as a serum bilirubin >1.9mg/dl based on a definition previously published for patients with ARDS. 19 The end of mechanical ventilation was defined as extubation without early reintubation (within 5 days). In case of reintubation, end of mechanical ventilation was reached after the final extubation. As intermittent continuous positive airway pressure is usually part of the weaning process in tra-cheostomized patients, toleration of mere oxygen insufflation for more than 6 consecutive hours was defined as the end of mechanical ventilation.

Eight patients were referred to the two LTx centres with chronic lung diseases complicated by a COVID-19 infection during the study period and were excluded from the analysis. In general, COVID-19 ARDS patients were considered eligible for LTx in case of persistent pulmonary consolidations affecting all lobes, no radiological or clinical improvement despite mechanical ventilation (MV) or ECMO support for at least 4 weeks, negative virus culture or at least two sequential negative real-time PCR-tests for SARS-CoV-2 (or cycle-thresholds > 32), absence of severe extra-pulmonary comorbidities and potential for long-term recovery. As by our institutional policy, COVID-19 ARDS patients > 65 years were not considered as suitable LTx candidates since their potential for rehabilitation from ARDS after prolonged ICU stay is low.

Continuous variables are presented as median, mean, interquartile range (IQR) or minimum/maximum. To compare continuous variables between two or more than two groups, Student's t-test or analysis of variance (ANOVA) was performed, respectively. Categorical variables are presented with total numbers and percentages. Chi-squared tests were used for comparing categorical frequencies between two or more groups. If the expected frequency was below 5, Fisher's exact test was applied. P values below 0.05 were considered statistically significant. All 

Between Jan 1, 2020 and May 30, 2021, a total of 39.485 patients were admitted to the hospital in Austria due to a confirmed COVID-19 infection. Of these 39.485 patients, 6408 were admitted to ICU, 2323 required mechanical ventilation and 183 received ECMO support. A total of 106 patients were referred to one of the two Austrian LTx centers to assess the necessity/possibility for a LTx (Figure 1) . Detailed clinical data of all patients are shown in Supplementary Table 1 .

The dynamic evolution of the COVID-19 pandemic in Austria correlated well with the number of 

Of the 106 patients with COVID-19 ARDS who had been referred, 90 (85%) were male and the median age was 58 years. At the time of referral, median length of mechanical ventilation was 35 days (6 -68). 89 (84%) patients had been on ECMO support for a median duration of 26 (1-60) days. Eight (8%) patients showed signs of right ventricular dysfunction and 17 (16%) required continuous renal replacement therapy (CRRT). The median bilirubin level was 0.83 mg/dl, whereas 15 (14%) patients had levels >1.9 mg/dl. Most common contraindicating medi-cal conditions for a LTx were severe obesity (30%), sepsis (27%) and significant coronary artery disease (12.5%) ( Table 1) .

All referrals were screened by a multidisciplinary LTx team that included thoracic surgeons, transplant pulmonologists, critical care physicians and transplant psychologists. Of the 106 re- 

Detailed patient characteristics and postoperative outcome of patients receiving a LTx for COVID-19-induced ARDS is provided in Table 2 All patients received a bilateral transplantation with central VA ECMO support. Due to retracted chest cavities, which are usually evident in COVID-19 ARDS patients, size-reduction of the graft was performed in 6 (32%) cases (5x resection of the middle lobe and lingula, 1x trilobar LTx).

The transplantation was usually complicated by dense pleural adhesions. In addition to this, hilar structures were often embedded in hyperinflamed lymphatic tissue, thus making hilar dissection challenging. In comparison to standard LTx, this led to a high intraoperative blood turnover and to a median of 9 (range 2-34) packed red blood cells. 6 patients had to be brought back to the OR for hematothorax evacuation and secondary hemostasis. After LTx, 4 (26%) patients required prolonged VA ECMO and one (5%) patient prolonged VV ECMO support for a median length of 3 (range 1-5) days. Pathological assessement of the of the explanted lungs revealed that diffuse alveolar damage was evident across wide areas of the parenchyma in all recipients. Furthermore, acute fibrinous and organizing pneumonia was seen in 13 (68%), nonspecific interstitial pneumonia in 12 (63%), multiple thromboembolism with large areas of infarction in 9 (47%) and hemosiderosis in 1 (5%) of the explanted lungs.

LTx recipients received pulse of corticosteroids starting intraoperatively and continuing through postoperative day (POD) 3. Maintenance immunosuppression (IS) was administered according to standard clinical practice with a tacrolimus based tripe IS regimen together with mycophenolate mofetil (MMF) and steroids. The target trough levels of FK 506 were between 10-12ng/ml, 1-2g MMF and steroids according to previously published institutional protocols. 20 Two female recipients were pre-LTx highly sensitized with more than 80% panel-reactive antibodies (due to previous pregnancies) and received pre-and post-LTx immunadsorption in combination with rabbit anti-thymocyte globulin induction for 5 days (2mg/kg body weight /day).

None of our patients developed any episodes of acute cellular rejection and no cases with de novo donor specific antibodies or antibody mediated rejection was detected. 

In this nationwide study, we aimed to investigate the overall relevance of lung transplantation as a treatment option for severe COVID-19 ARDS. During the study period, 2323 COVID-19 patients required mechanical ventilation, and 183 received ECMO support. The screening for LTx The feasibility of LTx as an ultimate treatment option in case of irreversible COVID-19-induced lung damage has recently been highlighted by an international multi-center study and an excellent early-outcome has been reported in 12 candidates. 9 Criteria to select eligible ARDS patients for LTx were defined as: i) negative virus status (virus culture or PCR) ii) no clinical/radiological improvement despite MV and/or ECMO support >4 weeks, iii) mono-organ failure (normal kidney and liver function), iv) absence of severe extra-pulmonary comorbidities, and v) a realistic potential for long-term recovery. These initial cases of 'ideal' transplant candidates triggered a discussion about comorbidities which might be acceptable for a LTx and comorbidities still remaining an absolute contraindication.

An important aspect of this study is the relatively high rate of severe liver dysfunction observerd after LTx. Dizier et al. highlighted the prognostic significance of liver dysfunction in the initial phase of 805 ARDS patients. 19 In this study, a serum bilirubin >1.9 mg/dL upon ICU admission was shown to represent a reliable surrogate marker for increased 90-day mortality. Focusing on COVID-19, cholangiopathy was recently shown to be a significant comorbidity and correlates with overall disease severity. 21 Compared to non-COVID LTx, early postoperative outcome was worse in COVID-ARDS patients.

As these patients are critically ill at the time of LTx, higher early mortality can be anticipated.

However, it can be assumed from the literature on LTx for non-COVID ARDS that patients surviving the complex perioperative period have an excellent long-term outcome.

One of the key aspects of LTx for COVID-19 ARDS is to allow sufficient time for the native lungs to recover. Patients can only be considered for LTx in case of irreversible pulmonary damage, however, lack or reversibility is difficult to determine. Despite recent advances in ECMO patients cannot be supported indefinitely and at a certain time point the risk for complications increases significantly. Based on these considerations it is now recommended to wait for 6-8 weeks before listing a patient. [23] [24] [25] However, this time frame is only a rough guidance given the fact that COVID-19 ARDS patients are critically ill and clinical deterioration can occur at anytime. Overlooking an increasing number of lung transplantations for COVID-19 (at least 100 in North America and 40 in Europe as by personal communication) it seems that two major subgroups of COVID-19 related-LTx candidates can be distinguished. The first group of patients is referred to the LTx team during the acute phase of ARDS. These patients are usually deeply sedated and waking them up is often impossible. They require full circulatory/respiratory support and decision making for/against LTx takes place in a critical clinical phase. As mentioned above, these patients can have necrosis of their lungs or septic episodes due to pulmonary bacterial superinfection. From the surgical point of view, LTx is challenging in these patients due to destroyed anatomical structures and high intraoperative blood turn-over. In addition, the postoperative rehabilitation period is often prolonged. Besides, this group of severly ill patients, where LTx is more or less a rescue procedure, there is another group of patients presenting with a more chronic disease mainly characterized by fibrotic changes in their lungs. These patients are sta-ble, awake, often able to participate in physiotherapy but cannot be weaned from ECMO or MV. Their overall clinical management is comparable to patients suffering from an acute deterioration of a chronic interstitial lung disease (ILD) requiring extra-corporal life support bridging.

Of note, during the study period, only 8 (7%) of all COVID-19 (n=114) related referrals and 2 (1.3%) of all LTx (n=156) can be assigned to this 'chronic' subgroup.

With an increasing number of lung transplant centers offering transplantation to post-COVID-19 ARDS patients, ethical concerns have been raised if the high urgency status is justified in these patients. Especially during the first wave of the pandemic, donation rates dropped dramatically resulting in an increasing wait list mortality for 'traditional' LTx indications such as chronic obstructive pulmonary disease, interstitial lung disease, cystic fibrosis, pulmonary arterial hypertension. 26, 27 In the study period, median time on waiting list was 40 days for all LTx candidates listed in Austria. Furthermore, overall waitlist mortality was extremely low with 1.11% during the study period. Despite a termorary drop in donation rate during the first wave of the pandemic the overall number of LTx performed in Austria remained unchanged. Moreover, we did not register an increased assessment time and time on the waitlist for non-COVID ARDS patients. ARDS patients who require ECMO are usually granted a high lung allocation score since their mortality without transplantation is exceptionally high. Still, one-year survival is excellent based on the severity of their disease (85% one-year survival according to a recent UNOS analysis). 6 Based on these considerations, COVID-19 ARDS patients are prioritized over non-COVID-19

indications.

The importance of LTx as a therapeutic option in severe COVID-19 can be best conceived by comparing of survival of COVID-19 ARDS with and without LTx. Mortality rates for severe COVID-19 ARDS (without the possibility of a rescue LTx) remains high with 30-60%. [2] [3] [4] Although long-term survival for LTx in post-COVID ARDS patients is still not available, it can be assumed that 1-year survival will range between 70-90% based on available data of non-COVID ARDS patients. Our analysis could show that by a nationwide LTx referral structure, a considerable number of COVID-19 patients can be saved by LTx. Although LTx was only an option for around 20% of referred patients, it has the potential to reduce the overall mortality of COVID-19 disease.

Our study has several limitations that must be acknowledged. The follow-up period is still limited, therefore, data on long-term survival cannot be provided. In conclusion, our study could demonstrate that LTx is a relevant treatment modality for severe COVID-19 ARDS. Although it is only an option for a selected group of patients, it is highly effective and has the potential to reduce COVID-19 related mortality. Centers considering LTx for COVID-19 induced ARDS should be aware of tedious recovery after the procedure requiring extensive health care ressources. Despite these challenges, LTx for COVID-19 ARDS is feasible and early postoperative outcomes are comparable to other common chronic indications. 

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