Thesis Clinical, histopathological, and radiological characterization of post-acute sequelae of COVID-19, 2025, Czech

Clinical, histopathological, and radiological characterization of post-acute sequelae of COVID-19

Anna Czech

Abstract
Numerous patients exhibit enduring symptoms following a Coronavirus Disease 2019 (COVID-19) infection, termed Post-Acute Sequelae of COVID-19 (PASC). The typical manifestations of PASC include fatigue, dyspnea on exertion, and cough. The speculated causes encompass the persistence of viral matter, chronic inflammation, or a dysregulated immune response aligning with radiologic abnormalities. The exact cause remains undetermined due to limited data availability. Hence, we have delineated an overview of the histological, radiological, and serological characteristics of PASC.

This cohort comprises 51 patients, averaging 40 years of age, with 43% female. They showcased symptoms an average of 17 weeks post a mild COVID-19 infection, with none requiring hospitalization. This study was conducted before the availability of vaccinations. High-resolution computed Tomography scans (HR-CT), transbronchial biopsies, and comprehensive clinical examinations were performed. Reverse Transcription Polymerase Chain Reaction (RT-PCR) and immunohistochemistry (nucleocapsid/spike/CD3/CD4/CD8) were also executed to detect persistent viral material and T-lymphocyte subtypes. Immunofluorescence multiplex and transmission electron microscopy (TEM) were completed to identify fibrin deposition and related macrophage subtypes. Cytokines in the broncho-alveolar lavage (BAL) fluid were examined using Legendplex immunoassays.

The predominant symptoms within this cohort, dyspnea on exertion, could not be associated with significant spiroergometric or radiologic outcomes. A Forced Expiratory Volume in one second (FEV1) below 80% was seen in 15.7% of patients and a Low Attenuation Volume (LAV) above 5% in 35.5% of this cohort. The oxygen pulse showed improvement over time post-COVID-19 infection, reaching statistical significance (p=0.0009). Residual viral fragments were identified in only one patient. Although this parameter did not reach statistical significance, it's noteworthy that the T-cell concentration within the small airways diminished in the weeks following infection. Histopathological findings characterized PASC with fibrinous alveolitis, organizing pneumonia (OP), and T-cell infiltrates in the small airways. Interstitial fibrin deposition wand pro-fibrotic macrophages (CD68/CD163/S100A9) were identified The H-scores of said macrophages could not be correlated to the severity of disease progression.

The clinical manifestations of PASC varied, yet many patients experienced diminished lung functionality, characterized by decreased FEV1, Forced Vital Capacity (FVC), and airway obstruction resulting in an increased LAV. High levels of IL-1β cytokines and CD4+ lymphocytes in the bronchioles indicate inflammatory processes. Furthermore, subjects exhibited fibrotic tissue remodeling and organizing pneumonia. Despite similarities in symptomatic patterns and HR-CT attributes, the serological criteria for a connective tissue disease-associated interstitial lung disease/IPAF (CTD-ILD/IPAF) diagnosis were unmet. Except for one outlier, the viral matter could not be associated with pathological processes, challenging the hypothesis that unresolved viral presence is the cause of chronic inflammation. The observations suggest that PASC represents a post-viral pathological process driven by bronchiolitis. The histological, serological, and radiological results within this PASC cohort align with the criteria of bronchiolitis following a mild COVID-19 infection. Given the proven fibrotic deposition via transmission electron microscopy, profibrotic macrophages, and IL-1β cytokines in BAL fluid, it is concluded that continuous monitoring of PASC patients is imperative to observe the progression of pulmonary fibrosis.

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