Biomarker Identification in Fatal Covid-19 and Post-Acute Sequalae of SARS-CoV-2 (PASC) Lungs

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.