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Lung transplantation for patients with severe COVID-19

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Science Translational Medicine  16 Dec 2020:
Vol. 12, Issue 574, eabe4282
DOI: 10.1126/scitranslmed.abe4282
  • Fig. 1 Radiographic and intraoperative findings in lung transplant recipients with severe COVID-19.

    (A to C) Radiographic and intraoperative findings for case 1 with severe COVID-19 who underwent lung transplantation. (A) Pretransplant chest radiograph (day 38 after onset of ARDS) for case 1, revealing opacification of the right lung and a left lower lobe necrotic cavity attributed to pneumonia caused by Serratia marcascens. A tube thoracostomy was required to treat right spontaneous hemothorax and peumothoraces. In addition, the image shows ECMO cannulas (inflow cannula carrying oxygenated blood to the patient is indicated by the white arrow, and outflow cannula carrying deoxygenated blood from the patient to the ECMO machine is indicated by the black arrow). (B) Severe ARDS and lower lung lobe necrosis in case 1 were confirmed by cross-sectional computed tomography imaging. (C) Shown is an intraoperative image revealing contrasting features between the diseased native right lung (d) and the newly transplanted left lung (n). The photograph was taken immediately after the transplant of the left lung and before proceeding onto right lung transplantation. The pericardial sac (white arrow) containing the heart was opened to gain access to the aorta and place the outflow cannula of the venoarterial ECMO. (D to F) Radiographic and intraoperative findings for case 2 with severe COVID-19 who underwent lung transplantation. (D) Pretransplant chest radiograph (at day 98 after onset of ARDS) for case 2 revealing bilateral lung opacifications and a necrotic cavity in the right lung attributed to pneumonia caused by Pseudomonas aeruginosa. A chest tube to treat bronchopleural fistula is visible. The dual lumen ECMO cannula is indicated by the black arrow. (E) Computed tomography imaging indicates severe ARDS and development of a necrotic cavity in the right lung. (F) Freshly explanted right lung of case 2 with extensive pleural inflammation and loss of identifiable anatomical planes. (G) Formalin-fixed explanted right lung of case 1 demonstrating the development of lung cavities. (H to J) Radiographic and intraoperative findings for case 3 with severe COVID-19 who underwent lung transplantation. (H) Pretransplant chest radiograph (day 86 after onset of severe ARDS) for case 3, revealing extensive consolidation (lack of air) with right fibrothorax. In addition, the image shows ECMO cannulas (inflow cannula carrying oxygenated blood to the patient is indicated by the white arrow, and the outflow cannula carrying deoxygenated blood from the patient to the ECMO machine is indicated by the black arrow). (I) Posttransplant day 1 chest radiograph for case 3 demonstrating the expected appearance of new lung allografts after bilateral lung transplantation. (J) Intraoperative photograph after implantation of the left lung and explantation of the right lung revealing the right hemithorax. Diffuse pleuritis with severe thickening of parietal pleura and neoangiogenesis (white arrows) were noted as in the other two cases.

  • Fig. 2 Common histological features of lung explants.

    Shown are common histological features of lung explants from three patients with severe COVID-19 who underwent lung transplantation. (A to C) Gross pathology images of explanted lungs from case 1 (A), case 2 (B), and case 3 (C). Cystic structures are evident on the lung surface and in the lung parenchyma (white arrows) along with diffuse fibrosis. Purulent secretions in the airways suggestive of bronchopneumonia are indicated by white diamond arrows. (D to R) Remaining images show sections of the explanted lung from cases 1, 2, and 3 stained with hematoxylin and eosin, except for image (O), which was stained with Prussian blue to detect iron deposition. (D) Image shows lung alveoli in the explanted lung from case 1 demonstrating hemorrhage, interstitial fibrosis, and prominent reactive pneumocytes (100×). (E) Bronchiolitis and bronchiolar fibrosis with microscopic honeycombing were observed for the explanted lung from case 2 (200×). (F) Organizing areas of alveolar hemorrhage are visible on this image of explanted lung from case 3 (100×). (G) Microscopic honeycombing adjacent to an area of more dense fibrosis with interstitial expansion and inflammatory infiltrates is visible on this image of explanted lung from case 2 (100×). (H) Bronchiolitis and fibrosis (black diamond arrow) are visible on this image of explanted lung from case 2 (200×). (I) An area of organizing pneumonia showing whorls of fibroblasts in the airways and interstitial expansion is observed on this image of explanted lung from case 2 (200×). (J) Interstitial fibrosis and bronchiolar fibrosis (black arrows) are visible in this image of explanted lung from case 2 (100×). (K) Enlarged inset from (J) reveals a bronchiole surrounded by interstitial fibrosis and cuboidal epithelia. (L) Area of interstitial fibrosis and microscopic honeycombing with multinucleated giant cells in the airspaces is visible on this image of explanted lung from case 1 (200×). (M) A medium-size blood vessel with an organizing thrombus and recannulation can be observed in this image of explanted lung from case 2 (100×). (N) Interstitial inflammation and expansion with alveoli filled with pigmented macrophages are visible in this image of explanted lung from case 1 (100×). (O) Staining for iron revealed alveolar macrophages laden with hemosiderin (blue) in this image of explanted lung from case 1 (100×). (P) This image of explanted lung from case 1 shows formation of cystic airspaces with neutrophilic inflammatory infiltrates (200×). (Q) This image of explanted lung from case 1 reveals cystic airspaces lined by histiocytes and hyperplastic epithelia (100×), and (R) this image reveals a mature cyst (black arrow) near an area of airway fibrosis (40×).

  • Fig. 3 smFISH and matrix imaging in cleared lung sections from patients with severe COVID-19.

    (A to D) RNAScope and immunohistochemistry of lung autopsy tissue from a patient who declined interventions for COVID-19–induced respiratory failure (palliative COVID-19). Nuclear staining (blue), positive strand SARS-CoV-2 RNA (yellow), negative strand SARS-CoV-2 RNA (cyan), and CD206 (magenta). Positive strand SARS-CoV-2 RNA (yellow) was detected in cells with morphological features suggestive of epithelial cells (white arrows); negative strand SARS-CoV-2 RNA was also detected (cyan; circular arrow). (E and F) RNAScope images of the explanted lung from case 1 who underwent lung transplantation. There is yellow autofluorescence but no staining for SARS-CoV-2 positive or negative strand RNA in either left (E) or right (F) explanted lung. (G and H) RNAScope images of the explanted lung of case 2 who underwent lung transplantation, showing no evidence of SARS-CoV-2 RNA. (I) RNAScope image of a postmortem lung biopsy from a patient who died of COVID-19 (PMB1), showing no evidence of SARS-CoV-2 RNA. (J to O) Cleared lung tissue allowing visualization of the collagen structure and matrix of lung tissue (cyan); ×20 magnification. (J) Normal lung from a patient who died of pulmonary embolism. (K) An explanted lung from case 1 who underwent lung transplantation. (L and M) Shown are postmortem lung biopsies from two patients who died of COVID-19 (PMB1 and PMB2). (N and O) Shown are lung explants from two patients with idiopathic pulmonary fibrosis (IPF1 and IPF2) who underwent lung transplantation.

  • Fig. 4 Single-cell RNA sequencing of lung tissue from patients with severe COVID-19.

    (A, C, and E) Uniform Manifold Approximation and Projection (UMAP) plots showing individual populations of epithelial cells (A), macrophages (C), and mesenchymal cells (E). (B, D, and F) Heatmaps illustrating expression of select marker genes in epithelial cells (B), macrophages (D), and mesenchymal cells (F). Gene expression for the pulmonary fibrosis dataset of Habermann et al. (16) is shown as an average per condition; gene expression for the end-stage COVID-19 dataset is shown per individual patient. Labels on heatmaps (B, D, and F) correspond to the following samples: Control (H), healthy controls; IPF, idiopathic pulmonary fibrosis samples; Other PF, samples from patients with other forms of pulmonary fibrosis, all from the Habermann et al. dataset. Donor 1, Donor 2, control donor lungs; Case 1, lung transplant case 1; PMB1, PMB2, postmortem lung biopsies from two patients with COVID-19, all from the end-stage COVID-19 dataset. (G) Immunofluorescence microscopy revealed KRT17 staining (magenta) of flat epithelial cells resembling alveolar type 1 cells in nonfibrotic lung tissue from a patient who died of COVID-19 (palliative COVID-19). (H and I) Immunofluorescence microscopy revealed KRT17 staining (magenta) of distal explanted lung tissue from a patient with COVID-19 undergoing lung transplantation (H) and lung tissue from a patient (PMB1) who died from late-stage severe COVID-19 (I). Normal lung architecture is lacking, and solitary KRT17-positive cells (magenta) can be observed close to COL1A1-positive cells (green). Scale bars, 20 um.

  • Table 1 Clinical characteristics of lung transplant recipients.

    Continuous data are shown as means ± SD. BMI, body mass index; VA ECMO, veno-arterial extracorporeal membrane oxygenation; ICU, intensive care unit.

    VariablePatients with COVID-19 (3)
    Age, years44.3 ± 13.9
    Female1 (33.3%)
    BMI, kg/m225.2 ± 4.5
    Operating time (hours)9.5 ± 1.0
    Intraoperative blood transfusion
      packed red blood cells10.6 ± 4.1
      fresh frozen plasma5.3 ± 2.4
      platelets2.6 ± 1.2
    Intraoperative VA ECMO use3 (100%)
    Intraoperative VA ECMO time
    (hours)
    2.8 ± 0.3
    Ischemic time (hours)5.1 ± 0.1
    ICU stay (days)13.3 ± 7.0
    Posttransplant ventilator (days)12.6 ± 8.3
    Pleural drainage (days)20.3 ± 4.4

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/scitranslmed.abe4282/DC1

    Fig. S1. Common histological features of warm lung autopsies.

    Fig. S2. Single-cell RNA-seq identifies similarities between end-stage pulmonary fibrosis and organizing pneumonia resulting from COVID-19.

    Table S1. Description of the specimens used in this study.

    Table S2. Marker genes for epithelial cell, macrophage, and mesenchymal cell clusters.

    Table S3. Differentially expressed genes in COVID-19 and IPF lung samples for each epithelial cell cluster.

    Table S4. Differentially expressed genes in COVID-19 and IPF lung samples for each macrophage cluster.

    Table S5. Differentially expressed genes in COVID-19 and IPF lung samples for each mesenchymal cell cluster.

    Movie S1. Three-dimensional matrix imaging of COVID-19 and non–COVID-19 lung tissue.

  • The PDF file includes:

    • Figure S1. Common histological features of warm lung autopsies.
    • Figure S2. Single cell RNA sequencing identifies similarities between end-stage pulmonary fibrosis and organizing pneumonia resulting from COVID-19.
    • Table S1. Description of the specimens used in this study.

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Table S2. Marker genes for epithelial cell, macrophage and mesenchymal cell clusters.
    • Table S3. Differentially expressed genes in COVID-19 and IPF lung samples for each epithelial cell cluster.
    • Table S4. Differentially expressed genes in COVID-19 and IPF lung samples for each macrophage cluster.
    • Table S5. Differentially expressed genes in COVID-19 and IPF lung samples for each mesenchymal cell cluster.
    • Movie S1. Three-dimensional matrix imaging of COVID-19 and non-COVID-19 lung tissue.

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