Commentary: Crossing the Rubicon—pre-emptive recipient bilateral pneumonectomy and delayed lung transplantation

Central MessageOngoing COVID-19 infection is a contraindication for lung transplantation. Bilateral pneumonectomy and extracorporeal support before lung transplant have been performed for such a patient.See Article page 282.Defying the Roman Senate, Julius Caesar declared “alea iacta est” (“the die is cast”) and crossed the Rubicon River with his army in 49 BCE. The ensuing civil war led to the end of the Roman Republic. By analogy, performing bilateral pneumonectomy in anticipation of later lung transplantation also represents a point of no return. In this issue, Ghodsizad and colleagues1Ghodsizad A. Grant A.A. Mohammed A.N. Navas-Blanco J. Ruhparwar A. Mirsaeidi M. et al.Bilateral pneumonectomy and lung transplant for COVID-19 induced respiratory failure.J Thorac Cardiovasc Surg Tech. 2022; 13: 282-287Scopus (1) Google Scholar present their experience with this strategy for a young patient with active coronavirus disease 2019 (COVID-19) infection and COVID-19–induced end-stage lung disease (COVID-ESLD). After initial bilateral pneumonectomy, a bridge with venous-arterial extracorporeal membrane oxygenation (ECMO) was used before a staged single-lung transplant. This is only the third reported case of pre-emptive pneumonectomy before transplantation, with each case remarkable for a unique ECMO strategy.2Barac Y.D. Bryner B. Bonadonna D. Wolfe C. Reynolds J. Haney J.C. et al.Bilateral pneumonectomy with veno-arterial extracorporeal membrane oxygenation as a bridge to lung transplant.J Heart Lung Transplant. 2019; 38: 1231-1232Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,3Cypel M. Waddell T. Singer L.G. Del Sorbo L. Fan E. Binnie M. et al.Bilateral pneumonectomy to treat uncontrolled sepsis in a patient awaiting lung transplantation.J Thorac Cardiovasc Surg. 2017; 153: e67-e69Abstract Full Text Full Text PDF PubMed Scopus (24) Google ScholarLung transplantation for COVID-ESLD is feasible,4Bharat A. Querrey M. Markov N.S. Kim S. Kurihara C. Garza-Castillon R. et al.Lung transplantation for patients with severe COVID-19.Sci Transl Med. 2020; 12: eabe4282Crossref PubMed Google Scholar,5Yeung J.C. Cypel M. Chaparro C. Keshavjee S. Lung transplantation for acute COVID-19: the Toronto lung transplant program experience.CMAJ. 2021; 193: E1494-E1497Crossref PubMed Scopus (6) Google Scholar with favorable short-term outcomes.6Roach A. Chikwe J. Catarino P. Rampolla R. Noble P.W. Megna D. et al.Lung transplantation for covid-19-related respiratory failure in the United States.N Engl J Med. Jan 26, 2022; ([Epub ahead of print])Crossref Scopus (20) Google Scholar The suggested criteria for lung transplantation in COVID-ESLD are evolving and include age <65 years, isolated and irreversible lung dysfunction, and a negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test.7Schaheen L. Bremner R.M. Walia R. Smith M.A. Lung transplantation for coronavirus disease 2019 (COVID-19): the who, what, where, when, and why.J Thorac Cardiovasc Surg. 2022; 163: 865-868Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,8Cypel M. Keshavjee S. When to consider lung transplantation for COVID-19.Lancet Respir Med. 2020; 8: 944-946Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Despite the emphasis on clearance of virus at the time of transplantation,8Cypel M. Keshavjee S. When to consider lung transplantation for COVID-19.Lancet Respir Med. 2020; 8: 944-946Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar the potential for recurrent infection in lungs transplanted into PCR-positive donors remains unclear. For one, specimens obtained from PCR-positive patients more than 1 week after symptom onset and with cycle threshold values >24 (indicating lower viral load) rarely produce culturable virus in vitro.9Bullard J. Dust K. Funk D. Strong J.E. Alexander D. Garnett L. et al.Predicting infectious severe acute respiratory syndrome coronavirus 2 from diagnostic samples.Clin Infect Dis. 2020; 71: 2663-2666Crossref PubMed Scopus (607) Google Scholar Moreover, there is a report of lung transplantation in a SARS-CoV-2–positive patient (PCR cycle threshold = 33) who avoided recurrent infection.10Lang C. Jaksch P. Hoda M.A. Lang G. Staudinger T. Tschernko E. et al.Lung transplantation for COVID-19-associated acute respiratory distress syndrome in a PCR-positive patient.Lancet Respir Med. 2020; 8: 1057-1060Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Separately, virologic sterilization via pneumonectomy might be impossible since SARS-CoV-2 does not solely replicate in lung tissue.11V'Kovski P. Kratzel A. Steiner S. Stalder H. Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2.Nat Rev Microbiol. 2021; 19: 155-170Crossref PubMed Scopus (946) Google Scholar, 12Wölfel R. Corman V.M. Guggemos W. Seilmaier M. Zange S. Müller M.A. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469Crossref PubMed Scopus (3867) Google Scholar, 13Ziegler C.G.K. Allon S.J. Nyquist S.K. Mbano I.M. Miao V.N. Tzouanas C.N. et al.SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues.Cell. 2020; 181: 1016-1035Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar Evidence of viral replication has been found in lungs, central airways, central nervous system, heart, liver, kidney, and pancreas.13Ziegler C.G.K. Allon S.J. Nyquist S.K. Mbano I.M. Miao V.N. Tzouanas C.N. et al.SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues.Cell. 2020; 181: 1016-1035Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar, 14Bhatnagar J. Gary J. Reagan-Steiner S. Estetter L.B. Tong S. Tao Y. et al.Evidence of severe acute respiratory syndrome coronavirus 2 replication and tropism in the lungs, airways, and vascular endothelium of patients with fatal coronavirus disease 2019: an autopsy case series.J Infect Dis. 2021; 223: 752-764Crossref PubMed Scopus (43) Google Scholar, 15Hou Y.J. Okuda K. Edwards C.E. Martinez D.R. Asakura T. Dinnon III, K.H. et al.SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract.Cell. 2020; 182: 429-446Abstract Full Text Full Text PDF PubMed Scopus (702) Google Scholar Wong and colleagues16Wong L.R. Perlman S. Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses—are we our own worst enemy?.Nat Rev Immunol. 2022; 22: 47-56Crossref Scopus (32) Google Scholar found the COVID-19 PCR test was still positive 3 days postpneumonectomy, suggesting that there were potentially other sources of virus. While pneumonectomy is unlikely to lead to immediate clearance of virus, future investigations should examine whether pneumonectomy instead reduces a source of dysregulated immune response to SARS-CoV-2.16Wong L.R. Perlman S. Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses—are we our own worst enemy?.Nat Rev Immunol. 2022; 22: 47-56Crossref Scopus (32) Google ScholarSupporting a “lung-less” patient requires judicious planning and meticulous execution, which Ghodsizad and colleagues achieved with a novel venous-arterial ECMO circuit. In addition to draining the right atrium, the authors placed an additional drainage cannula in the pulmonary artery to decompress the right heart, prevent blood stasis, reduce right ventricular afterload, and maintain pulsatility. A patent foramen ovale ensured decompression of the left side of the heart. This current approach appears simpler than the other reported solutions for managing the “lung-less” patient as it obviates the need for an additional circuit,3Cypel M. Waddell T. Singer L.G. Del Sorbo L. Fan E. Binnie M. et al.Bilateral pneumonectomy to treat uncontrolled sepsis in a patient awaiting lung transplantation.J Thorac Cardiovasc Surg. 2017; 153: e67-e69Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar theoretically reducing thromboembolic risk, or a vascular anastomosis between the pulmonary artery and veins,2Barac Y.D. Bryner B. Bonadonna D. Wolfe C. Reynolds J. Haney J.C. et al.Bilateral pneumonectomy with veno-arterial extracorporeal membrane oxygenation as a bridge to lung transplant.J Heart Lung Transplant. 2019; 38: 1231-1232Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar reducing complexity of pneumonectomy and subsequent implantation. As most patients do not have a pre-existing patent foramen ovale, the left heart could be decompressed via atrial septostomy, open surgical placement of left ventricular vent, or a catheter-delivered intracardiac pump.17Baldetti L. Gramegna M. Beneduce A. Melillo F. Moroni F. Calvo F. et al.Strategies of left ventricular unloading during VA-ECMO support: a network meta-analysis.Int J Cardiol. 2020; 312: 16-21Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,18Cevasco M. Takayama H. Ando M. Garan A.R. Naka Y. Takeda K. Left ventricular distension and venting strategies for patients on venoarterial extracorporeal membrane oxygenation.J Thorac Dis. 2019; 11: 1676-1683Crossref PubMed Scopus (60) Google ScholarNotwithstanding the clinical and ethical concerns,7Schaheen L. Bremner R.M. Walia R. Smith M.A. Lung transplantation for coronavirus disease 2019 (COVID-19): the who, what, where, when, and why.J Thorac Cardiovasc Surg. 2022; 163: 865-868Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar lung transplantation has been used in a significant number of patients with COVID-ESLD.6Roach A. Chikwe J. Catarino P. Rampolla R. Noble P.W. Megna D. et al.Lung transplantation for covid-19-related respiratory failure in the United States.N Engl J Med. Jan 26, 2022; ([Epub ahead of print])Crossref Scopus (20) Google Scholar While remaining SARS-CoV-2 viral load poses a risk of recurrent infection in lung allografts, this could be mitigated by new targeted antiviral therapies.19Owen D.R. Allerton C.M.N. Anderson A.S. Aschenbrenner L. Avery M. Berritt S. et al.An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19.Science. 2021; 374: 1586-1593Crossref PubMed Scopus (327) Google Scholar Pneumonectomy is unlikely to achieve complete clearance of infection but could help curtail a dysregulated immune response to infection, thus providing a rationale for staged lung transplant, and requires further study. The extracorporeal support of a patient without lungs requires careful preparation and can involve cannulation strategies suggested here by Ghodsizad and colleagues. Ongoing COVID-19 infection is a contraindication for lung transplantation. Bilateral pneumonectomy and extracorporeal support before lung transplant have been performed for such a patient. Ongoing COVID-19 infection is a contraindication for lung transplantation. Bilateral pneumonectomy and extracorporeal support before lung transplant have been performed for such a patient. See Article page 282. See Article page 282. Defying the Roman Senate, Julius Caesar declared “alea iacta est” (“the die is cast”) and crossed the Rubicon River with his army in 49 BCE. The ensuing civil war led to the end of the Roman Republic. By analogy, performing bilateral pneumonectomy in anticipation of later lung transplantation also represents a point of no return. In this issue, Ghodsizad and colleagues1Ghodsizad A. Grant A.A. Mohammed A.N. Navas-Blanco J. Ruhparwar A. Mirsaeidi M. et al.Bilateral pneumonectomy and lung transplant for COVID-19 induced respiratory failure.J Thorac Cardiovasc Surg Tech. 2022; 13: 282-287Scopus (1) Google Scholar present their experience with this strategy for a young patient with active coronavirus disease 2019 (COVID-19) infection and COVID-19–induced end-stage lung disease (COVID-ESLD). After initial bilateral pneumonectomy, a bridge with venous-arterial extracorporeal membrane oxygenation (ECMO) was used before a staged single-lung transplant. This is only the third reported case of pre-emptive pneumonectomy before transplantation, with each case remarkable for a unique ECMO strategy.2Barac Y.D. Bryner B. Bonadonna D. Wolfe C. Reynolds J. Haney J.C. et al.Bilateral pneumonectomy with veno-arterial extracorporeal membrane oxygenation as a bridge to lung transplant.J Heart Lung Transplant. 2019; 38: 1231-1232Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,3Cypel M. Waddell T. Singer L.G. Del Sorbo L. Fan E. Binnie M. et al.Bilateral pneumonectomy to treat uncontrolled sepsis in a patient awaiting lung transplantation.J Thorac Cardiovasc Surg. 2017; 153: e67-e69Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Lung transplantation for COVID-ESLD is feasible,4Bharat A. Querrey M. Markov N.S. Kim S. Kurihara C. Garza-Castillon R. et al.Lung transplantation for patients with severe COVID-19.Sci Transl Med. 2020; 12: eabe4282Crossref PubMed Google Scholar,5Yeung J.C. Cypel M. Chaparro C. Keshavjee S. Lung transplantation for acute COVID-19: the Toronto lung transplant program experience.CMAJ. 2021; 193: E1494-E1497Crossref PubMed Scopus (6) Google Scholar with favorable short-term outcomes.6Roach A. Chikwe J. Catarino P. Rampolla R. Noble P.W. Megna D. et al.Lung transplantation for covid-19-related respiratory failure in the United States.N Engl J Med. Jan 26, 2022; ([Epub ahead of print])Crossref Scopus (20) Google Scholar The suggested criteria for lung transplantation in COVID-ESLD are evolving and include age <65 years, isolated and irreversible lung dysfunction, and a negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test.7Schaheen L. Bremner R.M. Walia R. Smith M.A. Lung transplantation for coronavirus disease 2019 (COVID-19): the who, what, where, when, and why.J Thorac Cardiovasc Surg. 2022; 163: 865-868Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,8Cypel M. Keshavjee S. When to consider lung transplantation for COVID-19.Lancet Respir Med. 2020; 8: 944-946Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Despite the emphasis on clearance of virus at the time of transplantation,8Cypel M. Keshavjee S. When to consider lung transplantation for COVID-19.Lancet Respir Med. 2020; 8: 944-946Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar the potential for recurrent infection in lungs transplanted into PCR-positive donors remains unclear. For one, specimens obtained from PCR-positive patients more than 1 week after symptom onset and with cycle threshold values >24 (indicating lower viral load) rarely produce culturable virus in vitro.9Bullard J. Dust K. Funk D. Strong J.E. Alexander D. Garnett L. et al.Predicting infectious severe acute respiratory syndrome coronavirus 2 from diagnostic samples.Clin Infect Dis. 2020; 71: 2663-2666Crossref PubMed Scopus (607) Google Scholar Moreover, there is a report of lung transplantation in a SARS-CoV-2–positive patient (PCR cycle threshold = 33) who avoided recurrent infection.10Lang C. Jaksch P. Hoda M.A. Lang G. Staudinger T. Tschernko E. et al.Lung transplantation for COVID-19-associated acute respiratory distress syndrome in a PCR-positive patient.Lancet Respir Med. 2020; 8: 1057-1060Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Separately, virologic sterilization via pneumonectomy might be impossible since SARS-CoV-2 does not solely replicate in lung tissue.11V'Kovski P. Kratzel A. Steiner S. Stalder H. Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2.Nat Rev Microbiol. 2021; 19: 155-170Crossref PubMed Scopus (946) Google Scholar, 12Wölfel R. Corman V.M. Guggemos W. Seilmaier M. Zange S. Müller M.A. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469Crossref PubMed Scopus (3867) Google Scholar, 13Ziegler C.G.K. Allon S.J. Nyquist S.K. Mbano I.M. Miao V.N. Tzouanas C.N. et al.SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues.Cell. 2020; 181: 1016-1035Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar Evidence of viral replication has been found in lungs, central airways, central nervous system, heart, liver, kidney, and pancreas.13Ziegler C.G.K. Allon S.J. Nyquist S.K. Mbano I.M. Miao V.N. Tzouanas C.N. et al.SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues.Cell. 2020; 181: 1016-1035Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar, 14Bhatnagar J. Gary J. Reagan-Steiner S. Estetter L.B. Tong S. Tao Y. et al.Evidence of severe acute respiratory syndrome coronavirus 2 replication and tropism in the lungs, airways, and vascular endothelium of patients with fatal coronavirus disease 2019: an autopsy case series.J Infect Dis. 2021; 223: 752-764Crossref PubMed Scopus (43) Google Scholar, 15Hou Y.J. Okuda K. Edwards C.E. Martinez D.R. Asakura T. Dinnon III, K.H. et al.SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract.Cell. 2020; 182: 429-446Abstract Full Text Full Text PDF PubMed Scopus (702) Google Scholar Wong and colleagues16Wong L.R. Perlman S. Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses—are we our own worst enemy?.Nat Rev Immunol. 2022; 22: 47-56Crossref Scopus (32) Google Scholar found the COVID-19 PCR test was still positive 3 days postpneumonectomy, suggesting that there were potentially other sources of virus. While pneumonectomy is unlikely to lead to immediate clearance of virus, future investigations should examine whether pneumonectomy instead reduces a source of dysregulated immune response to SARS-CoV-2.16Wong L.R. Perlman S. Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses—are we our own worst enemy?.Nat Rev Immunol. 2022; 22: 47-56Crossref Scopus (32) Google Scholar Supporting a “lung-less” patient requires judicious planning and meticulous execution, which Ghodsizad and colleagues achieved with a novel venous-arterial ECMO circuit. In addition to draining the right atrium, the authors placed an additional drainage cannula in the pulmonary artery to decompress the right heart, prevent blood stasis, reduce right ventricular afterload, and maintain pulsatility. A patent foramen ovale ensured decompression of the left side of the heart. This current approach appears simpler than the other reported solutions for managing the “lung-less” patient as it obviates the need for an additional circuit,3Cypel M. Waddell T. Singer L.G. Del Sorbo L. Fan E. Binnie M. et al.Bilateral pneumonectomy to treat uncontrolled sepsis in a patient awaiting lung transplantation.J Thorac Cardiovasc Surg. 2017; 153: e67-e69Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar theoretically reducing thromboembolic risk, or a vascular anastomosis between the pulmonary artery and veins,2Barac Y.D. Bryner B. Bonadonna D. Wolfe C. Reynolds J. Haney J.C. et al.Bilateral pneumonectomy with veno-arterial extracorporeal membrane oxygenation as a bridge to lung transplant.J Heart Lung Transplant. 2019; 38: 1231-1232Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar reducing complexity of pneumonectomy and subsequent implantation. As most patients do not have a pre-existing patent foramen ovale, the left heart could be decompressed via atrial septostomy, open surgical placement of left ventricular vent, or a catheter-delivered intracardiac pump.17Baldetti L. Gramegna M. Beneduce A. Melillo F. Moroni F. Calvo F. et al.Strategies of left ventricular unloading during VA-ECMO support: a network meta-analysis.Int J Cardiol. 2020; 312: 16-21Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,18Cevasco M. Takayama H. Ando M. Garan A.R. Naka Y. Takeda K. Left ventricular distension and venting strategies for patients on venoarterial extracorporeal membrane oxygenation.J Thorac Dis. 2019; 11: 1676-1683Crossref PubMed Scopus (60) Google Scholar Notwithstanding the clinical and ethical concerns,7Schaheen L. Bremner R.M. Walia R. Smith M.A. Lung transplantation for coronavirus disease 2019 (COVID-19): the who, what, where, when, and why.J Thorac Cardiovasc Surg. 2022; 163: 865-868Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar lung transplantation has been used in a significant number of patients with COVID-ESLD.6Roach A. Chikwe J. Catarino P. Rampolla R. Noble P.W. Megna D. et al.Lung transplantation for covid-19-related respiratory failure in the United States.N Engl J Med. Jan 26, 2022; ([Epub ahead of print])Crossref Scopus (20) Google Scholar While remaining SARS-CoV-2 viral load poses a risk of recurrent infection in lung allografts, this could be mitigated by new targeted antiviral therapies.19Owen D.R. Allerton C.M.N. Anderson A.S. Aschenbrenner L. Avery M. Berritt S. et al.An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19.Science. 2021; 374: 1586-1593Crossref PubMed Scopus (327) Google Scholar Pneumonectomy is unlikely to achieve complete clearance of infection but could help curtail a dysregulated immune response to infection, thus providing a rationale for staged lung transplant, and requires further study. The extracorporeal support of a patient without lungs requires careful preparation and can involve cannulation strategies suggested here by Ghodsizad and colleagues. Bilateral pneumonectomy and lung transplant for COVID-19–induced respiratory failureJTCVS TechniquesVol. 13PreviewThere are few published descriptions of lung transplant for COVID-19 (Table E1). Here, we describe a COVID-19 polymerase chain reaction (PCR) test-positive patient who underwent bilateral pneumonectomy before lung transplant using a novel cannulation strategy. Institutional review board approval was not required for this case study and the patient provided consent. Full-Text PDF Open Access

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