Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantation.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) can lead to the development of acute respiratory distress syndrome (ARDS). In some patients with non-resolvable (NR) COVID-19, lung injury can progress rapidly to the point that lung transplantation is the only viable option for survival. This fatal progression of lung injury involves a rapid fibroproliferative response and takes on average 15 weeks from initial symptom presentation. Little is known about the mechanisms that lead to this fulminant lung fibrosis (FLF) in NR-COVID-19. METHODS: Using a pre-designed unbiased PCR array for fibrotic markers, we analyzed the fibrotic signature in a subset of NR-COVID-19 lungs. We compared the expression profile against control lungs (donor lungs discarded for transplantation), and explanted tissue from patients with idiopathic pulmonary fibrosis (IPF). Subsequently, RT-qPCR, Western blots and immunohistochemistry were conducted to validate and localize selected pro-fibrotic targets. A total of 23 NR-COVID-19 lungs were used for RT-qPCR validation. FINDINGS: We revealed a unique fibrotic gene signature in NR-COVID-19 that is dominated by a hyper-expression of pro-fibrotic genes, including collagens and periostin. Our results also show a significantly increased expression of Collagen Triple Helix Repeat Containing 1(CTHRC1) which co-localized in areas rich in alpha smooth muscle expression, denoting myofibroblasts. We also show a significant increase in cytokeratin (KRT) 5 and 8 expressing cells adjacent to fibroblastic areas and in areas of apparent epithelial bronchiolization. INTERPRETATION: Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19. FUNDING: National Institute of Health (NIH) Grants R01HL154720, R01DK122796, R01DK109574, R01HL133900, and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100, DoD Grant W81XWH-19-1-0007, and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association: 19CDA34660279, American Lung Association: CA-622265, Parker B. Francis Fellowship, 1UL1TR003167-01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y.

Post-Lung Transplantation Outcomes and Ex Vivo Histopathological Findings in Severe Post-Covid-19 Pulmonary Disease-A Single-Center Experience.

Background: A significant proportion of patients with severe and persistent coronavirus disease 2019 (COVID-19) require continuous ventilatory support and occasional extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS). Lung transplantation is a treatment option for patients who develop severe ARDS. Methods: Our lung transplant database was retrospectively reviewed for patients who underwent lung transplantation for COVID-19 pulmonary disease at Memorial Hermann Hospital, Texas Medical Center, Houston, Texas, from January 2020 to March 2022. We evaluated outcomes of patients who were followed in our clinic at least 6 months post-transplant. Pretransplant patient characteristics, COVID-19-related treatment, histopathology results, and postdischarge course were evaluated. Results: Among a total of 13 lung transplant recipients, 6 consecutive patients were identified who had a minimum of 6 months of follow-up post-lung transplantation. The average age of patients was 55 years, with a male predominance. The median time to transplantation was 111 days. All 6 patients had significant postinfectious complications due to COVID-19 before transplant. Histopathological findings from explanted lungs showed a predominance of fibrotic change. There were no reported cases of rejection or graft dysfunction. 5 patients had minimal to no post-transplant infectious complications. One patient died 218 days post-transplant from infectious complications. Conclusions: Five out of six lung transplant recipients at our institution have demonstrated excellent long-term outcomes after index hospitalization, for a mean follow-up of 13 months post-lung transplantation. Lung transplantation for lung fibrosis due to COVID-19 is an acceptable salvage treatment option. Larger studies are warranted to confirm these findings.

Post–Lung Transplantation Outcomes and Ex Vivo Histopathological Findings in Severe Post-Covid-19 Pulmonary Disease—A Single-Center Experience

Background A significant proportion of patients with severe and persistent coronavirus disease 2019 (COVID-19) require continuous ventilatory support and occasional extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS). Lung transplantation is a treatment option for patients who develop severe ARDS. Methods Our lung transplant database was retrospectively reviewed for patients who underwent lung transplantation for COVID-19 pulmonary disease at Memorial Hermann Hospital, Texas Medical Center, Houston, Texas, from January 2020 to March 2022. We evaluated outcomes of patients who were followed in our clinic at least 6 months post-transplant. Pretransplant patient characteristics, COVID-19-related treatment, histopathology results, and postdischarge course were evaluated. Results Among a total of 13 lung transplant recipients, 6 consecutive patients were identified who had a minimum of 6 months of follow-up post–lung transplantation. The average age of patients was 55 years, with a male predominance. The median time to transplantation was 111 days. All 6 patients had significant postinfectious complications due to COVID-19 before transplant. Histopathological findings from explanted lungs showed a predominance of fibrotic change. There were no reported cases of rejection or graft dysfunction. 5 patients had minimal to no post-transplant infectious complications. One patient died 218 days post-transplant from infectious complications. Conclusions Five out of six lung transplant recipients at our institution have demonstrated excellent long-term outcomes after index hospitalization, for a mean follow-up of 13 months post–lung transplantation. Lung transplantation for lung fibrosis due to COVID-19 is an acceptable salvage treatment option. Larger studies are warranted to confirm these findings. Lung transplantation for lung fibrosis due to COVID-19 can be considered a safe salvage treatment option with relatively low infectious post-transplant complications despite significant infectious complications before lung transplantation. Larger studies are warranted to confirm the findings.

Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections.

Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibited heterogeneous rheological behaviors, with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observed increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factor-stimulated gene-6 staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicated that increases in HA and DNA in COVID-19 respiratory secretion samples correlated with enhanced inflammatory burden and suggested that DNA and HA may be viable therapeutic targets in COVID-19 infection.

A Postmortem Portrait of the Coronavirus Disease 2019 (COVID-19) Pandemic: A Large Multi-institutional Autopsy Survey Study.

CONTEXT.­: This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting. OBJECTIVE.­: To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy. DESIGN.­: Comprehensive data from 135 autopsy evaluations of COVID-19-positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple-choice and open-ended survey responses. RESULTS.­: Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than 1 preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited. CONCLUSIONS.­: Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic.

Morphoproteomics and Etiopathogenic Features of Pulmonary COVID-19 with Therapeutic Implications: A Case Study.

OBJECTIVE: The COVID-19 pandemic has challenged the world economically and medically. Understanding and defining the biology of this specific coronavirus infection may lead to targeted therapies to lessen its virulence and expand the host resistance. This study's objective was to apply morphoproteomics to pulmonary lung sections from a forensic autopsy of an untreated COVID-19 victim, so that we may better define its biology from the perspective of its interaction with the host and provide options for therapeutic targets. DESIGN: Morphoproteomic analysis from a case study of this COVID-19 pulmonary infection included immunohistochemical probes to detect phosphorylated p-STAT3 (Tyr 705), as part of the interleukin (IL)-6 pathway; cyclooxygenase (COX)-2, CD8+ cytotoxic lymphocytes, Programmed Death (PD)-1 receptor+ lymphoid cells, CD56+ NK lymphoid cells, CD163+ (M2 polarized monocytes/macrophages), and programmed death-ligand 1 (PD-L1) expression as part of the host response to interaction with the COVID-19 virus. RESULTS: Representative sections of the COVID-19 victim's lung showed: nuclear expression of p-STAT3 (Tyr 705) in many of the alveolar pneumocytes and in occasional endothelial cells; COX-2 expression in the alveolar pneumocytes; a relative paucity of CD8+ cytotoxic lymphocytes; absence of CD56+ NK lymphoid cells; abundance of intra-alveolar and alveolar interstitial CD163+ macrophages/monocytes; PD-L1 expression on occasional macrophages, focally on collections of alveolar pneumocytes, and on cells in the alveolar interstitium; and rare PD-1+ lymphocytes in similar regions as CD8+ lymphocytes. CONCLUSION: Morphoproteomics and microanatomical features coincide with the etiopathogenic features of pulmonary coronavirus infection and the host response. This suggests that a targeted therapy could address the biology of COVID-19 pneumonia, enhance the host immune response and prevent its progression to a life-threatening, ventilator-dependent clinical situation.

EMERGING SPECTRUM OF CARDIOPULMONARY PATHOLOGY OF THE CORONAVIRUS DISEASE 2019 (COVID-19): REPORT OF THREE AUTOPSIES FROM HOUSTON, TEXAS AND REVIEW OF AUTOPSY FINDINGS FROM OTHER UNITED STATES CITIES

This paper collates the pathological findings from initial published autopsy reports on 23 patients with Coronavirus Disease 2019 (COVID-19) from 5 centers in the United States of America, including 3 cases from Houston, Texas. Findings confirm that COVID-19 is a systemic disease with major involvement of the lungs and heart. Acute COVID-19 pneumonia has features of a distinctive acute interstitial pneumonia with: a diffuse alveolar damage (DAD) component, coupled with microvascular involvement with intra- and extra-vascular fibrin deposition and intravascular trapping of neutrophils, and, frequently, with formation of microthombi in arterioles. Major pulmonary thromboemboli with pulmonary infarcts and/or hemorrhage occurred in 5 of the 23 patients. Two of the Houston cases had interstitial pneumonia with DAD pattern. One of the Houston cases had multiple bilateral segmental pulmonary thromboemboli with infarcts and hemorrhages coupled with, in non-hemorrhagic areas, a distinctive interstitial lymphocytic pneumonitis with intra-alveolar fibrin deposits and no hyaline membranes, possibly representing a transition form to acute fibrinous and organizing pneumonia (AFOP). Multifocal acute injury of cardiac myocytes was frequently observed. Lymphocytic myocarditis was reported in 1 case. In addition to major pulmonary pathology, the three Houston cases had evidence of lymphocytic pericarditis, multifocal acute injury of cardiomyocytes without inflammatory cellular infiltrates, depletion of splenic white pulp, focal hepatocellular degeneration and rare glomerular capillary thrombosis. Each had evidence of chronic cardiac disease: hypertensive left ventricular hypertrophy (420 gram heart), dilated cardiomyopathy (1070 gram heart), and hypertrophic cardiomyopathy (670 gram heart). All three subjects were obese (BMIs of 33.8, 51.65 and 35.2 Kg/m2). Overall, the autopsy findings support the concept that the pathogenesis of severe COVID-19 disease involves direct viral-induced injury of multiple organs, including heart and lungs, coupled with the consequences of a procoagulant state with coagulopathy.