Lung Transplant In COVID – Why, When & How ?

1. Lung Transplant In COVID – Why, When & How ? Dr. Kamran Ali Consultant Lung Transplant & Thoracic Surgery

3. “The only gift is a portion of thyself” Ralph Waldo Emerson

4. Holy grail ?

5. Why ?

8. Early data demonstrated that SARS-CoV-2 infection progressed to severe respiratory failure and ARDS in up to 42% of patients • Despite optimized supportive care, mortality rates of patients with COVID-19 requiring mechanical ventilation are between 20% and 40% • Several early studies reported a mortality rate of up to 60% in patients with severe COVID-19-associated ARDS ( vs 30% to 45% mortality rate reported with other causes of ARDS)

9. In both of these situations, treatment teams often inquire about the possibility of lung transplantation • In fact, lung transplantation has been successfully employed for both CARDS and post-COVID fibrosis in a limited number of patients worldwide

10. CARDS: • Inability to conduct proper psychosocial evaluation and pre-transplantation education • Marked deconditioning from critical illness • Infectious concerns regarding viral reactivation • Post-COVID fibrosis: • Limited knowledge about the natural history of recovery after COVID-19 infection • Must weigh the risks and benefits of LuTx differently in a post-COVID fibrosis patient who is likely to remain stable or gradually improve • in comparison with a patient with a known (pfILD)

11. ECMO for ARDS • VV ECMO has historically been considered a last-line therapy for patients with refractory hypoxemia or hypercapnia when conventional management has failed • ECMO has progressed remarkably over recent years: • advancements in circuit design • single-site cannulation • awake status and patient mobilization • Remarkable improvement in outcomes observed when ECMO is used to treat patients with severe ARDS

12. ECMO in COVID-19 • Preliminary results from studies indicated dismal outcomes with 84–100% mortality of patients who had COVID-19 and were treated with ECMO Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395: 1054–62 Henry BM, Lippi G. Poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): pooled analysis of early reports. J Crit Care 2020; 58: 27–28

14. Mortality for ECMO in ARDS COVID-19 ARDS ARDS ECMO in the EOLIA trial (35% at day 60), post-hoc Bayesian analysis LIFEGARD registry (39% at day 180) • Sorbonne University, Paris (31% at day-60), COVID-19

15. Unfortunately, some patients with ARDS will progress to the fibrotic phase, preventing them from successful separation from ECMO and leaving them with irreversible ESLD

16. Time course of ARDS After seven to ten days, a proliferative phase may develop, with marked interstitial inflammation, fibrosis, and disordered healing

17. ECMO in ARDS • Uncertainty of long-term outcome • Lack of clarity on the intended treatment direction: Bridge to recovery (BTR) or Bridge to transplant (BTT) ???? • Optimal duration of support remain an evolving challenge

18. Ichikadoand colleagues • presence of extensive fibroproliferative changes seen on CT images ~ independent predictor of poor prognosis in patients with ARDS • Chung and colleagues • CT findings of >80% of lung involvement, a right atrium to left atrium ratio >1, and varicoid bronchiectasis portended the highest risk of mortality • Findings of extensive honeycombing, reticular opacities, and traction bronchiectasis may help to identify patients who have a lower chance of recovery and should be considered for LuTx

19. Clinical availability of biomarkers is limited • KRT17+KRT5− basaloid cells or profibrotic alveolar macrophages in bronchoscopic biopsies as markers of irreversible lung disease  • Assessment of lung recoverability requires careful evaluation of pulmonary physiology • Radiology • Histology (when available) • Medical course and complications • Response to therapies • Many other clinical factors by an experienced multidisciplinary care team

20. Current status of LuTx for COVID-19 respiratory failure

21. LuTx for COVID-19 • Tremendous number of potential candidates for LuTx • Significant interest and enthusiasm for use of LuTx as a salvage option • Actual number of LuTx performed worldwide is fairly small • Although the exact number of transplants is not known, the available data give us some sense of the scope of LuTx for COVID-19

22. August 1, 2020, and September 30, 2021 • United Network for Organ Sharing (UNOS) registry • Of 3039 lung transplantations: • 214 (7.0%) were performed for Covid-19–related respiratory failure • 140 (4.6%) for ARDS • 74 (2.4%) for pulmonary fibrosis

27. ISHLT 2021 Consensus statement

28. European data • As of April 23, 2021 • Eurotransplant consortium (responsible for organ allocation in Austria, Belgium, Croatia, Germany, Hungary, Luxemburg, the Netherlands, and Slovenia) • 21patients undergoing transplantation for a diagnosis of COVID-19 (Personal communication, Juergen Behr, April 2021)

29. When ?

30. Too early vs Too Late

32. Time window for native Lung recovery

33. How ?

34. How ?

35. How ?

36. Is the Patient’s Lung Injury Irreversible? • Particularly difficult question to answer and requires the best judgment of the lung transplant team • Patients should receive appropriate standard-of- care medical therapy for their COVID-19 infection to optimize the chances for recovery with adequate time allowed for lung recovery

37. Is the Patient’s Lung Injury Irreversible? • 4 weeks is considered an absolute minimum, and more often wait for 8 weeks before seriously considering transplantation • Review of CT imaging may be helpful: • Findings suggestive of irreversible change include traction bronchiectasis and subpleural fibrosis. • On the other end of the spectrum, ground-glass infiltrates are commonly encountered early on and are typically due to an alveolar-filling process and hence regarded as potentially reversible

38. How ?

39. Has the Patient Cleared Their COVID-19 Infection? • Potential impact of lingering active virus • Even a small inoculum of residual viable virus could have potentially devastating consequences, especially in the context of profound immunosuppression typically employed in the early post-transplantation period • With unbridled viral proliferation, COVID-19 could result in acute lung injury • mimicking and perhaps being misdiagnosed as PGD, and thus jeopardizing the patient’s outcome

40. Has the Patient Cleared Their COVID-19 Infection? • The diagnosis of COVID-19 is most commonly established with rt-PCR testing to detect COVID-19 RNA • Testing is generally performed on URT samples, although LRT samples have a higher viral load and are less likely to yield a false negative result • Having a positive rt-PCR result does not necessarily translate into having actively replicating virus, because RNA from viral fragments may still yield a positive rt- PCR

41. Has the Patient Cleared Their COVID-19 Infection? • Unfortunately no test aside from viral culture can establish the presence of active virus • However, performance of viral culture is not widely available and presents infection control issues • Data suggest that immunocompetent patients affected with severe or critical disease do not have replication-competent virus 20 days after symptom onset • however, severely immunocompromised patients may continue to harbor active virus for significantly longer periods

42. Has the Patient Cleared Their COVID-19 Infection? • Bharat and colleagues advocate for two negative rt-PCR tests, obtained at least 24 hours apart, from BAL samples in intubated patients before proceeding with LuTx • For patients with no tracheostomy or endotracheal tube, two negative upper respiratory tract rt-PCR tests obtained at least 24 hours apart would be the minimum threshold the authors would require to proceed with LuTx

43. How ?

44. Is the Patient Physically Conditioned Enough for Transplantation? • Most patients with critical COVID-19 will have: • prolonged hospitalization and immobilization • compromised nutritional status from critical illness, and treatment with corticosteroids and neuromuscular blockade • All of which predispose to critical illness polyneuropathy/myopathy and marked deconditioning

45. Is the Patient Physically Conditioned Enough for Transplantation? • Before transplantation, every effort should be made: • to optimize nutritional status • achieve a wakeful, interactive state in which patients can participate meaningfully in the transplantation process and rehabilitation • ECMO support may be required to achieve these goals • In exceptional circumstances, a patient with a normal baseline functional status and good potential for recovery post-LTx whose pulmonary status precludes rehabilitation before transplantation could be considered

46. Is the Patient Physically Conditioned Enough for Transplantation? • Whether rehabilitation potential and frailty present a contraindication to LuTx must be interpreted in the context of the patient’s global clinical picture • In addition to their physical functional ability, their mental resilience is equally important in withstanding the acute psychological stress of transplantation, as well as the long-term commitment to a strict medical regimen • This is especially difficult for patients who were well before their COVID-19 infection and who have not had the time to accept or adapt psychologically to their new reality

47. How ? – Surgical • The operation need not be performed in a negative-pressure environment • Given that the LTx recipient will be tested for and proven clear of COVID-19 infection before transplantation • Surgical teams may consider wearing N-95 or equivalent masks and eye protection in addition to standard gown and gloves

48. How ? – Surgical Double Single

49. How ? – Surgical • Bilateral LuTxshould be performed in appropriate candidates: • Due to the underlying pulmonary hypertension • Additionally, explants from COVID-19 LuTx recipients revealed cavitary areas of pneumonia that could serve as a nidus of infection if a single-lung transplantation was performed

50. How ? – Surgical