ABSTRACT
Rationale: SARS-CoV-2 has affected millions worldwide. Among those individuals infected with this coronavirus, most recover without hospitalization. However, COVID-19 is characterized by chronic lung failure and death in a significant number of hospitalized patients. Indeed, there is growing evidence that SARS-CoV-2 causes ARDS leading to lung fibrosis that shares similarities with interstitial lung diseases (ILDs) including idiopathic pulmonary fibrosis (IPF). Herein, we addressed the hypothesis that fatal COVID-19, PASC, and ILDs share key biomarkers of interest in lung fibrosis. Methods: This study included 9 fatal COVID-19 and 13 PASC cases, who received lung transplants due COVID-19 associated lung failure. Clinical characteristics such as duration of mechanical ventilation, length of hospitalization, age, sex, and BMI were evaluated in each patient. Autopsy and explanted lung samples were subjected to histopathological and/or immunohistochemical (IHC) analysis for key biomarkers of interest in lung fibrosis including bromodomain-containing protein-4(BRD4), interferon alpha 2(IFNα2), interleukin-1(IL-11), growth differentiation factor 15(GDF15), and keratin 8(KRT8). COVID-19 and PASC lung samples were also compared with lung samples from fatal ARDS due to other causes (i.e., non-COVID-19 ARDS).Results: In the fatal COVID-19 patient group, the mean age was 60.6(50-71) years-old and included 6 males and 3 females. In the transplanted-PASC patient group, the mean age was 46(31-71) years-old and included 12 males and 2 females. The average BMI was 28.3(21-35.5) for fatal COVID-19 and 25.2(19-29.5) for PASC. In fatal COVID-19, comorbidities included hypertension(22%), diabetes(44%), immunocompromised status(11%). The mean duration of mechanical ventilation was 23(8-65) days while hospitalization was 25(8-67) days. Conversely, PASC patients averaged 168(71-539) days from diagnosis to transplant date. The SARS-CoV-2 ARDS survivors that developed chronic lung failure had diffuse interstitial fibrosis frequently with organization into a non-specific interstitial fibrosis (NSIP) pattern. Key IHC findings in fatal COVID-19 and in PASC lung samples included BRD4, IFNalpha2, and IL-11 receptor alpha (IL-11RA) protein expression, which were markedly increased in several cell types most notably macrophages or myeloid cells localized in the alveolar space in COVID-19 lung samples. Although these markers were detected in non-COVID-19 ARDS the levels of each were markedly lower than that detected in the COVID-19 lung samples.Conclusions: These data suggest that key profibrotic pathways in the lung are shared among COVID-19 and chronic fibrotic ILDs. The identification of these pathways provides the impetus to further explore treatment strategies which might survival benefit to chronically ventilated COVID-19 patients and mitigate the need from lung transplantation in PASC patients.
ABSTRACT
Rationale: Recent advancements in sequencing technologies have led to a substantial increase in the scale and resolution of transcriptomic data. Despite this progress, accessibility to this data, particularly among those who are coming from non-computational backgrounds is limited. To facilitate improved access and exploration of our single-cell RNA sequencing data, we generated several data sharing, mining and dissemination portals to accompany our idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and lung endothelial cells (Lung EC) cell atlases. Descriptions and links of each website can be found here: https://medicine.yale.edu/lab/kaminski/research/atlas/. Methods: Each interactive data mining website is coded in the R language using the Shiny package and is hosted by Shinyapps.io. Percell expression data for each website is stored on a MySQL database hosted by Amazon Web Services (AWS). Time-associated website engagement statistics and gene query information is collected for each website using a combination of Google Analytics and a gene search table stored on our MySQL database. User exploration of available data is facilitated through several easy-touse visualization tools available on each website. Results: Website usage statistics since the publication of each website shows that 9,772 unique users from 56 countries and five continents have accessed at least one of the three websites. At the time of writing, 300,748 total queries have been made for 15,627 unique genes across the websites. The top five searched genes for the IPF Cell Atlas are CD14, ACE2, ACTA2, IL11 and MUC5B while for the COPD Cell Atlas they are FAM13A, MIRLET7BHG, HHIP, ISM1 and DDT. Finally, the top searched genes for the Lung Endothelial Cell Atlas are BMPR2, PECAM1, EDNRB, APLNR and PROX1. Of note, interaction with the IPF Cell Atlas increased dramatically at the start of the COVID-19 pandemic, with queries for the ACE2 gene, the putative binding receptor for the SARS-CoV-2 virus, increasing substantially at the pandemic's onset in the United States. Conclusions: Usage statistics, gene query information and feedback from users, both within academia and industry, have shown broad engagement with our websites by individuals across computational and non-computational backgrounds. We envision widespread adoption of web-based portals similar to ours will facilitate novel discoveries within these complex datasets and new scientific collaborations.