Amit Banga Md, FCCP

As of September 2021, over 222 million people worldwide (WHO, 2021) and 40 million Americans (CDC, 2021) have been infected with the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The total number of infections in the United States began climbing again this summer with the persistence of vaccine reluctance among a significant proportion of the population and the emergence of the much more infectious B.1.617.2 (Delta) variant. While the clinical illness caused by the SARS-CoV-2 virus, referred to as the Coronavirus disease 2019 (COVID-19), is mostly mild, approximately 10% of cases develop acute respiratory distress syndrome (ARDS) (Remuzzi A, et al. Lancet. 2020;395[10231]:1225-8). A small but substantial proportion of patients with COVID-19 ARDS fails to respond to the various supportive measures and requires extracorporeal membrane oxygenation (ECMO) support. The overarching goal of the different support strategies, including ECMO, is to provide time for the lungs to recover from ARDS. ECMO has the theoretical advantage over other strategies in facilitating recovery by allowing the injured lungs to ‘rest’ as the oxygenation and ventilation needs are met in an extracorporeal fashion. Regardless, a small number of patients with COVID-19 ARDS will not recover enough pulmonary function to allow them to be weaned from the various respiratory support strategies.

For patients with irreversible lung injury, lung transplantation (LT) is a potential consideration. Earlier in the pandemic, older patients with significant comorbid illnesses were more vulnerable to severe COVID-19, often precluding consideration for transplantation. However, the emergence of the Delta variant may have altered this dynamic via a substantial increase in the incidence of COVID-19 ARDS among younger and healthier patients. A handful of patients with COVID-19 ARDS have already had successful transplantation. However, the overall number is still small (Bharat A, et al. Sci Translat Med. 2020 Dec 16;12[574]:eabe4282. doi: 10.1126/scitranslmed.abe4282. Epub 2020 Nov 30; and Hawkins R, et al. Transplantation. 2021;6:1381-7), and there is a lack of long-term outcomes data among these patients.

There is currently little guidance regarding criteria for patient selection and consideration for LT among patients with COVID-19 ARDS. Given that the SARS-CoV-2 virus is a novel pathogen that leads to an illness that is unique from other forms of viral pneumonia, specific considerations regarding LT should be made among these patients. In the current article, we discuss some of the pertinent issues related to the consideration of LT among patients with COVID-19 ARDS.

The timing for considering LT is one of the most important aspects. First, patients with COVID-19 ARDS must not be actively infected at the time of transplantation consideration. It has been suggested that LT should only be considered in patients with two separate negative polymerase chain reaction (PCR) test results for SARS-CoV-2 from bronchoalveolar lavage fluid 24 hours apart and at least 4 weeks after the onset of COVID-19 symptoms (Bharat A, et al. Sci Translat Med. 2020 Dec 16;12[574]:eabe4282. doi: 10.1126/scitranslmed.abe4282. Epub 2020 Nov 30). Among patients with persistently positive SARS-CoV-2 PCR 4 to 6 weeks after symptom onset, a negative viral culture from a bronchoalveolar lavage (BAL) can be used to confirm viral inactivity (Lang C, et al. Lancet Respir Med. 2020;8[10]:1057-60).

Despite the sparse data in this domain, there seems to be a consensus in the literature that LT could be considered once 4 to 6 weeks have elapsed since the onset of the respiratory failure (Cypel M, et al. Lancet Respir Med. 2020;8[10]:944-6). This timeline is felt to be long enough to alleviate the concerns regarding ongoing inflammatory processes that may be reversible while not so long to risk the development of non-pulmonary complications or severe debility that may become significant barriers to transplant candidacy. An exception may be made in patients with medically unmanageable complications such as recalcitrant bronchopleural fistulae in the background of fibrotic changes or right ventricular failure from severe pulmonary hypertension. Regardless, this timeline is borrowed from the approach to irreversible ARDS from other forms of viral pneumonia. It is not clear if it is appropriate to extrapolate past experience to COVID-19, which is a disease unlike any other seen during the LT era: a profound inflammatory phase mediated by a cytokine storm as the etiologic basis for the organ dysfunction, activation of coagulation pathways in pulmonary circulation leading to immunothrombosis contributing to the refractory hypoxemia, favorable effects of anticoagulants, diverse pulmonary physiologic phenotypes of ARDS, an increased risk of pleural complications, and utilization of novel anti-inflammatory therapies with consequent risks ofsecondary infections are all unique to COVID-19. A recent study found that patients requiring ECMO for COVID-19 ARDS took longer to recover lung function but had similar survival rates to patients on ECMO with other virus-induced ARDS (Raff LA, et al. Am J Surg. 2021;S0002-9610[21]00233-6. doi: 10.1016/j.amjsurg.2021.04.004. Online ahead of print).These data support pursuing a more conservative timeline for consideration of LT.

Determining the reversibility of pulmonary impairment in COVID-19 ARDS is another challenge. The nature of the pulmonary opacities should be assessed on CT scan imaging as close as possible to the time of LT consideration. Differentiating the extent of irreversible parenchymal scarring vs salvageability during acute illness can be challenging. The presence of extensive architectural distortion with or without bullous changes, while being the best indicator of irreversibility, may not be sensitive enough. The standard of care in such situations remains serial assessments, often weekly, by a dedicated multidisciplinary group. We have found it useful to augment the imaging data with pulmonary physiologic assessments, including the extent of ventilator and ECMO support as well as dynamic and static compliance trends. Improvement in physiologic data often precedes radiologic improvement. Nonetheless, an important area of future research is to identify objective markers for determining reversibility, which could include novel biomarkers in serum or bronchoalveolar lavage fluid.

When a determination is made regarding the irreversibility of pulmonary impairment, the LT evaluation should begin promptly. Pre-transplant deconditioning and debility is associated with worse post-transplant outcomes. In this regard, patients managed using an ambulatory ECMO strategy may have superior rehabilitation potential. Furthermore, an attempt should be made during the evaluation to wean sedation in order to facilitate discussions regarding the rigors of LT with the patient alongside present family members. An additional consideration, given the use of immunomodulatory medications for COVID-19 and prolonged intubation, is the dramatically increased risk of multi-drug resistant infections in this population; these must be aggressively managed for patients to remain eligible for LT.

The degree of pulmonary impairment and frequent colonization of the airways will likely dictate bilateral LT as the preferred strategy, although surgical feasibility may, at times, be the overriding determinant. Regardless of the type of transplant, certain unique aspects should be anticipated. The inflammatory responses during COVID-19 that often spill outside the confines of the pulmonary parenchyma, along with potentially frequent thoracic interventions prior to transplant, create significant technical challenges during the operation. Native pneumonectomy can take longer than usual leading to prolonged ischemic time, increased need for intra-operative blood products, and raised risk for primary graft dysfunction. All of these factors have a significant impact on early and late outcomes. Finally, the long-term immunologic consequences of severe infection from a novel virus remain unknown, and it is unclear if COVID-19 ARDS patients bridged to transplant will enjoy comparable survival. It is pertinent to acknowledge that the high-risk nature of such transplants is substantially accentuated due to several unique characteristics of the illness related to COVID-19.

The emergence of the COVID-19 pandemic has led to an increase in the number of urgent inpatient lung transplant consultations for refractory ARDS. While the basic principles of LT candidate selection should continue to guide us, the unique characteristics of this illness merit using a customized approach. There are few validated predictors to guide decision-making, and longitudinal assessments by a dedicated multidisciplinary group remain the best strategy. Finally, in the absence of systemic studies and lack of longitudinal outcomes data, there is an emergent need to establish consensus guidelines regarding the approach to LT consideration in these patients.
 

Dr. Quinn and Dr. Banga are with the Lung Transplant Program, Divisions of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas.

As of September 2021, over 222 million people worldwide (WHO, 2021) and 40 million Americans (CDC, 2021) have been infected with the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The total number of infections in the United States began climbing again this summer with the persistence of vaccine reluctance among a significant proportion of the population and the emergence of the much more infectious B.1.617.2 (Delta) variant. While the clinical illness caused by the SARS-CoV-2 virus, referred to as the Coronavirus disease 2019 (COVID-19), is mostly mild, approximately 10% of cases develop acute respiratory distress syndrome (ARDS) (Remuzzi A, et al. Lancet. 2020;395[10231]:1225-8). A small but substantial proportion of patients with COVID-19 ARDS fails to respond to the various supportive measures and requires extracorporeal membrane oxygenation (ECMO) support. The overarching goal of the different support strategies, including ECMO, is to provide time for the lungs to recover from ARDS. ECMO has the theoretical advantage over other strategies in facilitating recovery by allowing the injured lungs to ‘rest’ as the oxygenation and ventilation needs are met in an extracorporeal fashion. Regardless, a small number of patients with COVID-19 ARDS will not recover enough pulmonary function to allow them to be weaned from the various respiratory support strategies.

For patients with irreversible lung injury, lung transplantation (LT) is a potential consideration. Earlier in the pandemic, older patients with significant comorbid illnesses were more vulnerable to severe COVID-19, often precluding consideration for transplantation. However, the emergence of the Delta variant may have altered this dynamic via a substantial increase in the incidence of COVID-19 ARDS among younger and healthier patients. A handful of patients with COVID-19 ARDS have already had successful transplantation. However, the overall number is still small (Bharat A, et al. Sci Translat Med. 2020 Dec 16;12[574]:eabe4282. doi: 10.1126/scitranslmed.abe4282. Epub 2020 Nov 30; and Hawkins R, et al. Transplantation. 2021;6:1381-7), and there is a lack of long-term outcomes data among these patients.

There is currently little guidance regarding criteria for patient selection and consideration for LT among patients with COVID-19 ARDS. Given that the SARS-CoV-2 virus is a novel pathogen that leads to an illness that is unique from other forms of viral pneumonia, specific considerations regarding LT should be made among these patients. In the current article, we discuss some of the pertinent issues related to the consideration of LT among patients with COVID-19 ARDS.

The timing for considering LT is one of the most important aspects. First, patients with COVID-19 ARDS must not be actively infected at the time of transplantation consideration. It has been suggested that LT should only be considered in patients with two separate negative polymerase chain reaction (PCR) test results for SARS-CoV-2 from bronchoalveolar lavage fluid 24 hours apart and at least 4 weeks after the onset of COVID-19 symptoms (Bharat A, et al. Sci Translat Med. 2020 Dec 16;12[574]:eabe4282. doi: 10.1126/scitranslmed.abe4282. Epub 2020 Nov 30). Among patients with persistently positive SARS-CoV-2 PCR 4 to 6 weeks after symptom onset, a negative viral culture from a bronchoalveolar lavage (BAL) can be used to confirm viral inactivity (Lang C, et al. Lancet Respir Med. 2020;8[10]:1057-60).

Despite the sparse data in this domain, there seems to be a consensus in the literature that LT could be considered once 4 to 6 weeks have elapsed since the onset of the respiratory failure (Cypel M, et al. Lancet Respir Med. 2020;8[10]:944-6). This timeline is felt to be long enough to alleviate the concerns regarding ongoing inflammatory processes that may be reversible while not so long to risk the development of non-pulmonary complications or severe debility that may become significant barriers to transplant candidacy. An exception may be made in patients with medically unmanageable complications such as recalcitrant bronchopleural fistulae in the background of fibrotic changes or right ventricular failure from severe pulmonary hypertension. Regardless, this timeline is borrowed from the approach to irreversible ARDS from other forms of viral pneumonia. It is not clear if it is appropriate to extrapolate past experience to COVID-19, which is a disease unlike any other seen during the LT era: a profound inflammatory phase mediated by a cytokine storm as the etiologic basis for the organ dysfunction, activation of coagulation pathways in pulmonary circulation leading to immunothrombosis contributing to the refractory hypoxemia, favorable effects of anticoagulants, diverse pulmonary physiologic phenotypes of ARDS, an increased risk of pleural complications, and utilization of novel anti-inflammatory therapies with consequent risks ofsecondary infections are all unique to COVID-19. A recent study found that patients requiring ECMO for COVID-19 ARDS took longer to recover lung function but had similar survival rates to patients on ECMO with other virus-induced ARDS (Raff LA, et al. Am J Surg. 2021;S0002-9610[21]00233-6. doi: 10.1016/j.amjsurg.2021.04.004. Online ahead of print).These data support pursuing a more conservative timeline for consideration of LT.

Determining the reversibility of pulmonary impairment in COVID-19 ARDS is another challenge. The nature of the pulmonary opacities should be assessed on CT scan imaging as close as possible to the time of LT consideration. Differentiating the extent of irreversible parenchymal scarring vs salvageability during acute illness can be challenging. The presence of extensive architectural distortion with or without bullous changes, while being the best indicator of irreversibility, may not be sensitive enough. The standard of care in such situations remains serial assessments, often weekly, by a dedicated multidisciplinary group. We have found it useful to augment the imaging data with pulmonary physiologic assessments, including the extent of ventilator and ECMO support as well as dynamic and static compliance trends. Improvement in physiologic data often precedes radiologic improvement. Nonetheless, an important area of future research is to identify objective markers for determining reversibility, which could include novel biomarkers in serum or bronchoalveolar lavage fluid.

When a determination is made regarding the irreversibility of pulmonary impairment, the LT evaluation should begin promptly. Pre-transplant deconditioning and debility is associated with worse post-transplant outcomes. In this regard, patients managed using an ambulatory ECMO strategy may have superior rehabilitation potential. Furthermore, an attempt should be made during the evaluation to wean sedation in order to facilitate discussions regarding the rigors of LT with the patient alongside present family members. An additional consideration, given the use of immunomodulatory medications for COVID-19 and prolonged intubation, is the dramatically increased risk of multi-drug resistant infections in this population; these must be aggressively managed for patients to remain eligible for LT.

The degree of pulmonary impairment and frequent colonization of the airways will likely dictate bilateral LT as the preferred strategy, although surgical feasibility may, at times, be the overriding determinant. Regardless of the type of transplant, certain unique aspects should be anticipated. The inflammatory responses during COVID-19 that often spill outside the confines of the pulmonary parenchyma, along with potentially frequent thoracic interventions prior to transplant, create significant technical challenges during the operation. Native pneumonectomy can take longer than usual leading to prolonged ischemic time, increased need for intra-operative blood products, and raised risk for primary graft dysfunction. All of these factors have a significant impact on early and late outcomes. Finally, the long-term immunologic consequences of severe infection from a novel virus remain unknown, and it is unclear if COVID-19 ARDS patients bridged to transplant will enjoy comparable survival. It is pertinent to acknowledge that the high-risk nature of such transplants is substantially accentuated due to several unique characteristics of the illness related to COVID-19.

The emergence of the COVID-19 pandemic has led to an increase in the number of urgent inpatient lung transplant consultations for refractory ARDS. While the basic principles of LT candidate selection should continue to guide us, the unique characteristics of this illness merit using a customized approach. There are few validated predictors to guide decision-making, and longitudinal assessments by a dedicated multidisciplinary group remain the best strategy. Finally, in the absence of systemic studies and lack of longitudinal outcomes data, there is an emergent need to establish consensus guidelines regarding the approach to LT consideration in these patients.
 

Dr. Quinn and Dr. Banga are with the Lung Transplant Program, Divisions of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas.

As of September 2021, over 222 million people worldwide (WHO, 2021) and 40 million Americans (CDC, 2021) have been infected with the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The total number of infections in the United States began climbing again this summer with the persistence of vaccine reluctance among a significant proportion of the population and the emergence of the much more infectious B.1.617.2 (Delta) variant. While the clinical illness caused by the SARS-CoV-2 virus, referred to as the Coronavirus disease 2019 (COVID-19), is mostly mild, approximately 10% of cases develop acute respiratory distress syndrome (ARDS) (Remuzzi A, et al. Lancet. 2020;395[10231]:1225-8). A small but substantial proportion of patients with COVID-19 ARDS fails to respond to the various supportive measures and requires extracorporeal membrane oxygenation (ECMO) support. The overarching goal of the different support strategies, including ECMO, is to provide time for the lungs to recover from ARDS. ECMO has the theoretical advantage over other strategies in facilitating recovery by allowing the injured lungs to ‘rest’ as the oxygenation and ventilation needs are met in an extracorporeal fashion. Regardless, a small number of patients with COVID-19 ARDS will not recover enough pulmonary function to allow them to be weaned from the various respiratory support strategies.

For patients with irreversible lung injury, lung transplantation (LT) is a potential consideration. Earlier in the pandemic, older patients with significant comorbid illnesses were more vulnerable to severe COVID-19, often precluding consideration for transplantation. However, the emergence of the Delta variant may have altered this dynamic via a substantial increase in the incidence of COVID-19 ARDS among younger and healthier patients. A handful of patients with COVID-19 ARDS have already had successful transplantation. However, the overall number is still small (Bharat A, et al. Sci Translat Med. 2020 Dec 16;12[574]:eabe4282. doi: 10.1126/scitranslmed.abe4282. Epub 2020 Nov 30; and Hawkins R, et al. Transplantation. 2021;6:1381-7), and there is a lack of long-term outcomes data among these patients.

There is currently little guidance regarding criteria for patient selection and consideration for LT among patients with COVID-19 ARDS. Given that the SARS-CoV-2 virus is a novel pathogen that leads to an illness that is unique from other forms of viral pneumonia, specific considerations regarding LT should be made among these patients. In the current article, we discuss some of the pertinent issues related to the consideration of LT among patients with COVID-19 ARDS.

The timing for considering LT is one of the most important aspects. First, patients with COVID-19 ARDS must not be actively infected at the time of transplantation consideration. It has been suggested that LT should only be considered in patients with two separate negative polymerase chain reaction (PCR) test results for SARS-CoV-2 from bronchoalveolar lavage fluid 24 hours apart and at least 4 weeks after the onset of COVID-19 symptoms (Bharat A, et al. Sci Translat Med. 2020 Dec 16;12[574]:eabe4282. doi: 10.1126/scitranslmed.abe4282. Epub 2020 Nov 30). Among patients with persistently positive SARS-CoV-2 PCR 4 to 6 weeks after symptom onset, a negative viral culture from a bronchoalveolar lavage (BAL) can be used to confirm viral inactivity (Lang C, et al. Lancet Respir Med. 2020;8[10]:1057-60).

Despite the sparse data in this domain, there seems to be a consensus in the literature that LT could be considered once 4 to 6 weeks have elapsed since the onset of the respiratory failure (Cypel M, et al. Lancet Respir Med. 2020;8[10]:944-6). This timeline is felt to be long enough to alleviate the concerns regarding ongoing inflammatory processes that may be reversible while not so long to risk the development of non-pulmonary complications or severe debility that may become significant barriers to transplant candidacy. An exception may be made in patients with medically unmanageable complications such as recalcitrant bronchopleural fistulae in the background of fibrotic changes or right ventricular failure from severe pulmonary hypertension. Regardless, this timeline is borrowed from the approach to irreversible ARDS from other forms of viral pneumonia. It is not clear if it is appropriate to extrapolate past experience to COVID-19, which is a disease unlike any other seen during the LT era: a profound inflammatory phase mediated by a cytokine storm as the etiologic basis for the organ dysfunction, activation of coagulation pathways in pulmonary circulation leading to immunothrombosis contributing to the refractory hypoxemia, favorable effects of anticoagulants, diverse pulmonary physiologic phenotypes of ARDS, an increased risk of pleural complications, and utilization of novel anti-inflammatory therapies with consequent risks ofsecondary infections are all unique to COVID-19. A recent study found that patients requiring ECMO for COVID-19 ARDS took longer to recover lung function but had similar survival rates to patients on ECMO with other virus-induced ARDS (Raff LA, et al. Am J Surg. 2021;S0002-9610[21]00233-6. doi: 10.1016/j.amjsurg.2021.04.004. Online ahead of print).These data support pursuing a more conservative timeline for consideration of LT.

Determining the reversibility of pulmonary impairment in COVID-19 ARDS is another challenge. The nature of the pulmonary opacities should be assessed on CT scan imaging as close as possible to the time of LT consideration. Differentiating the extent of irreversible parenchymal scarring vs salvageability during acute illness can be challenging. The presence of extensive architectural distortion with or without bullous changes, while being the best indicator of irreversibility, may not be sensitive enough. The standard of care in such situations remains serial assessments, often weekly, by a dedicated multidisciplinary group. We have found it useful to augment the imaging data with pulmonary physiologic assessments, including the extent of ventilator and ECMO support as well as dynamic and static compliance trends. Improvement in physiologic data often precedes radiologic improvement. Nonetheless, an important area of future research is to identify objective markers for determining reversibility, which could include novel biomarkers in serum or bronchoalveolar lavage fluid.

When a determination is made regarding the irreversibility of pulmonary impairment, the LT evaluation should begin promptly. Pre-transplant deconditioning and debility is associated with worse post-transplant outcomes. In this regard, patients managed using an ambulatory ECMO strategy may have superior rehabilitation potential. Furthermore, an attempt should be made during the evaluation to wean sedation in order to facilitate discussions regarding the rigors of LT with the patient alongside present family members. An additional consideration, given the use of immunomodulatory medications for COVID-19 and prolonged intubation, is the dramatically increased risk of multi-drug resistant infections in this population; these must be aggressively managed for patients to remain eligible for LT.

The degree of pulmonary impairment and frequent colonization of the airways will likely dictate bilateral LT as the preferred strategy, although surgical feasibility may, at times, be the overriding determinant. Regardless of the type of transplant, certain unique aspects should be anticipated. The inflammatory responses during COVID-19 that often spill outside the confines of the pulmonary parenchyma, along with potentially frequent thoracic interventions prior to transplant, create significant technical challenges during the operation. Native pneumonectomy can take longer than usual leading to prolonged ischemic time, increased need for intra-operative blood products, and raised risk for primary graft dysfunction. All of these factors have a significant impact on early and late outcomes. Finally, the long-term immunologic consequences of severe infection from a novel virus remain unknown, and it is unclear if COVID-19 ARDS patients bridged to transplant will enjoy comparable survival. It is pertinent to acknowledge that the high-risk nature of such transplants is substantially accentuated due to several unique characteristics of the illness related to COVID-19.

The emergence of the COVID-19 pandemic has led to an increase in the number of urgent inpatient lung transplant consultations for refractory ARDS. While the basic principles of LT candidate selection should continue to guide us, the unique characteristics of this illness merit using a customized approach. There are few validated predictors to guide decision-making, and longitudinal assessments by a dedicated multidisciplinary group remain the best strategy. Finally, in the absence of systemic studies and lack of longitudinal outcomes data, there is an emergent need to establish consensus guidelines regarding the approach to LT consideration in these patients.
 

Dr. Quinn and Dr. Banga are with the Lung Transplant Program, Divisions of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas.