Pulmonary pathology of ARDS in COVID-19: A pathological review for clinicians

Abstract

COVID-19 has quickly reached pandemic levels since it was first reported in December 2019. The virus responsible for the disease, named SARS-CoV-2, is enveloped positive-stranded RNA viruses. During its replication in the cytoplasm of host cells, the viral genome is transcribed into proteins, such as the structural protein spike domain S1, which is responsible for binding to the cell receptor of the host cells. Infected patients have initially flu-like symptoms, rapidly evolving to severe acute lung injury, known as acute respiratory distress syndrome (ARDS). ARDS is characterized by an acute and diffuse inflammatory damage into the alveolar-capillary barrier associated with a vascular permeability increase and reduced compliance, compromising gas exchange and causing hypoxemia. Histopathologically, this condition is known as diffuse alveolar damage which consists of permanent damage to the alveoli epithelial cells and capillary endothelial cells, with consequent hyaline membrane formation and eventually intracapillary thrombosis. All of these mechanisms associated with COVID-19 involve the phenotypic expression from different proteins transcription modulated by viral infection in specific pulmonary microenvironments. Therefore, this knowledge is fundamentally important for a better pathophysiological understanding and identification of the main molecular pathways associated with the disease evolution. Evidently, clinical findings, signs and symptoms of a patient are the phenotypic expression of these pathophysiological and molecular mechanisms of SARS-CoV-2 infection. Therefore, no findings alone, whether molecular, clinical, radiological or pathological axis are sufficient for an accurate diagnosis. However, their intersection and/or correlation are extremely critical for clinicians establish the diagnosis and new treatment perspectives.

Keywords: COVID-19; DAD; Molecular pathology; Pulmonary pathology; SARS-CoV-2.

Fig. 1

– Scheme of SARS-COV-2 inflammatory response. The host's immune system is activated after SARS-CoV-2 binding to ACE2 receptor on type II pneumocyte surface. A - Recruited monocytes secretes pro-inflammatory cytokines, inducing pneumocytes apoptosis; B - Recruited macrophages releases other cytokines causing capillary permeability increase and consequent neutrophils recruitment; C - Neutrophils migrate into the interstitial/alveolar space and degranulate, culminating in permanent damage to pneumocytes and endothelial cells, resulting in alveolar-capillary barrier disruption; D - Interstitial and alveolar edema due to transmigration of blood proteins.

Fig. 2

– Histopathological findings in COVID-19 lungs by minimally invasive autopsy. Note the virus-induced lung injury are temporal heterogeneity: A - alveolar hyaline membrane (green arrow); B - alveolar-capillary barrier injury with hemorrhage (green arrows); C - acute fibrinous organizing pneumonia (dark blue circle) and organizing pneumonia (dark green circle); and D - pulmonary intravascular thrombotic events. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

– Schematically representation of the two histopathological phases of DAD. A - The first or exudative phase constitutes alveolar edema, neutrophil infiltration in the intra-alveolar space and mainly by hyaline membrane formed by fibrin polymerization contained in the plasma liquid that leaked into the interstitial/alveolar space, being recognized as DAD hallmark; B - The second or proliferative phase is described essentially by an intense fibroblast/myofibroblast recruitment and proliferation, with subsequent extracellular matrix deposition. Over time and together with the fibrotic deposition, there is also the reepithelization by type I and II pneumocytes.