Lung transplantation for patients with severe COVID-19

Abstract

Lung transplantation can potentially be a life-saving treatment for patients with non-resolving COVID-19-associated respiratory failure. Concerns limiting lung transplantation include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and the potential risk for allograft infection by pathogens causing ventilator-associated pneumonia in the native lung. Importantly, the native lung might recover, resulting in long-term outcomes preferable to those of transplant. Here, we report the results of lung transplantation in three patients with non-resolving COVID-19-associated respiratory failure. We performed single molecule fluorescent in situ hybridization (smFISH) to detect both positive and negative strands of SARS-CoV-2 RNA in explanted lung tissue from the three patients and in additional control lung tissue samples. We conducted extracellular matrix imaging and single cell RNA sequencing on explanted lung tissue from the three patients who underwent transplantation and on warm post-mortem lung biopsies from two patients who had died from COVID-19-associated pneumonia. Lungs from these five patients with prolonged COVID-19 disease were free of SARS-CoV-2 as detected by smFISH, but pathology showed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis. Using machine learning, we compared single cell RNA sequencing data from the lungs of patients with late stage COVID-19 to that from the lungs of patients with pulmonary fibrosis and identified similarities in gene expression across cell lineages. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is their only option for survival.

Post-acute COVID-19 syndrome

“…This fibrotic state may be provoked by cytokines such as interleukin-6 (IL-6) and transforming growth factor-β, which have been implicated in the development of pulmonary fibrosis 6,[56][57][58] and may predispose to bacterial colonization and subsequent infection [59][60][61] . Analysis of lung tissue from five cases with severe COVID-19-associated pneumonia, including two autopsy specimens and three specimens from explanted lungs of recipients of lung transplantation, showed histopathologic and single-cell RNA expression patterns similar to end-stage pulmonary fibrosis without persistent SARS-CoV-2 infection, suggesting that some individuals develop accelerated lung fibrosis after resolution of the active infection 62 .…”

Fatal COVID-19 and non-COVID-19 Acute Respiratory Distress Syndrome is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State Without Fibrosis

“…The transitional cells in fibrosis may be senescent (13, 18, 19). Similarly, recent case reports identified transitional cells in the fibrosis that develops after months of nonresolving COVID-19, so-called “fibroproliferative ARDS” (20, 21). In these cases, transitional cells existed in the milieu of extensive matrix deposition and architectural distortion that was deemed irreversible, necessitating lung transplantation.…”

“…Persistence of the transitional state with ineffectual AEC1 differentiation has previously been observed in humans only in the setting of fibrosis, an irreversible condition causing chronic respiratory failure (13, 14, 16–21). It is unknown whether transitional cells are inevitably associated with and/or cause fibrosis and therefore whether fibrosis may be the cause of acute respiratory failure in COVID-19 ARDS (20, 21). In mouse models of physiologic regeneration (e.g., lipopolysaccharide and pneumonectomy), transitional cells appear transiently then differentiate into AEC1s to restore normal alveolar architecture without fibrosis (13, 15, 16).…”

“…In these cases, transitional cells existed in the milieu of extensive matrix deposition and architectural distortion that was deemed irreversible, necessitating lung transplantation. In fact, the presence of transitional cells on biopsy was proposed as a potential biomarker of irreversible fibrosis (20). However, it is unknown whether transitional cells arise in early ARDS and whether ineffectual AEC1 differentiation from transitional cells without fibrosis may be pathogenic in acute respiratory failure.…”

Three platforms: Ways to pivot in a pandemic

“…That's outside my scope as a surgeon,” he says. Instead, he developed a surgical solution for patients with severe COVID‐19 3 …”