COVID-19: a Disease with a Potpourri of Histopathologic Findings-a Literature Review and Comparison to the Closely Related SARS and MERS

Abstract

Since the coronavirus disease 2019 (COVID-19) pandemic has hit the entire world, there is ample knowledge regarding its clinical course and prognostic biomarkers. Still, the pathophysiology of COVID-19 is poorly understood. Since the first guidelines published in February 2020 for autopsy of both confirmed and suspected COVID-19 cases, there has been an increasing number of autopsies and literature reporting histopathological findings. However, our knowledge about the immunological response of various organ systems to the virus, as well as response patterns, is inadequate but is essential to understand and initiate timely and targeted antiviral, anti-inflammatory, or anticoagulative therapy. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is primarily considered a respiratory virus, current evidence shows that it causes life-threatening complications in almost all organ systems including the heart, brain, kidney, spleen, liver, and eyes. Hence, in this article, we reviewed the published case reports and case series in order to increase our understanding of COVID-19 pathophysiology. The main histopathological findings of the lungs include diffuse alveolar damage with activated type II pneumocytes, fibroblasts, protein-rich exudate, and hyaline membranes. Other significant histopathological findings include cardiomegaly, right ventricular dilation, splenic pulp atrophy, kidneys with severe podocytopathy, and collapsing glomerulopathy, and the brain showed hypoxic changes in the cerebellum and cerebrum. Furthermore, in this review, we also explained different pathological findings of SARS-CoV and MERS and compared them to SARS-CoV-2. This comprehensive review will improve our understanding of COVID-19 pathophysiology and various disease stages, hence promoting the application of targeted therapy.

Keywords: COVID-19; Coronavirus; Diffuse alveolar damage; Pathology; SARS-CoV-2.

Fig. 1

Histologic changes from case 1. (A) Proteinaceous exudates in alveolar spaces, with granules; (B) Scattered large protein globules (arrows); (C) Intra-alveolar fibrin with early organization, mononuclear inflammatory cells, and multinucleated giant cells; (D) Hyperplastic pneumocytes, some with suspected viral inclusions (arrow). Reproduced/adapted from Tian et al., with permission from Elsevier

Fig. 2

Histologic changes of coronavirus disease 2019 pneumonia in case 2. (A) Evident proteinaceous and fibrin exudate; (B) Diffuse expansion of alveolar walls and septa owing to fibroblastic proliferations and type II pneumocyte hyperplasia, consistent with early diffuse alveolar damage pattern; (C) Plugs of proliferating fibroblasts or “fibroblast balls” in the interstitium (arrow); (D) Abundant macrophages infiltrating airspaces and type II pneumocyte hyperplasia. Reproduced/adapted from Tian et al., with permission from Elsevier

Fig. 3

Thrombus in a small pulmonary artery (green arrow), with small thrombus seen in adjacent pulmonary venule (green arrowhead), with H&E present on the left, and CD61 immunostain highlighting platelets within the thrombi on the right. (B) Many megakaryocytes were present within the small vessels and alveolar capillaries (green arrow). (C) CD61 immunostain highlighting additional fibrin and platelet thrombus shown in a small vessel, with megakaryocyte stained below (green arrowhead). Von Willebrand factor immunostain additionally highlighted these vessels. (D) Small, perivascular aggregates of lymphocytes. Also present were small lymphocytic aggregates surrounding airways, which were positive for CD4 immunostain, with only scattered CD8 positive cells present. Reproduced/adapted from Fox et al., with permission from Elsevier

Fig. 4

All patients had extensive diffuse alveolar damage. (A) Green arrows indicate early hyaline membranes in a patient with 1 week of symptomatic illness and no mechanical ventilation (H&E stain). (B) Green arrows indicate extensive hyaline membranes and fibrinous exudate in a patient with 9 days of symptomatic illness, including 6 days of ventilation (H&E stain). (C) Green arrow indicates dense hyaline membranes, with organising fibrosis (green arrowhead), and fibrin thrombi present in small vessels (blue arrows), with a pauci-immune and edematous background in a patient after 32 days of illness, including 25 days on ventilatory support. Extensive hemorrhage was also present (H&E stain). (D) Bronchial respiratory epithelium shown with cilia present, and absence of squamous metaplasia in a patient receiving ventilatory support for 6 days. H&E=hematoxylin and eosin. Reproduced/adapted from Fox et al., with permission from Elsevier

Fig. 5

Patient 2, i: cardiac myocytes, ii: CD4 immunostain, iii: CD8 immunostain. B) Patient 3, i: cardiac myocytes, ii: CD31 immunostain, iii: CD4 immunostain. Cardiac myocytes showing focal, atypical myocyte degeneration (green arrows), H&E stain (sample images from patients aged 44- and 63-years receiving azithromycin but not hydroxychloroquine). Scant lymphocytes were present within the interstitial and endothelial spaces, with slightly more CD4+ than CD8+ cells on visual inspection of immunostains. A CD31 immunostain highlighted endothelial cells, with focal prominence (green arrow) that appeared non-specific. CD4+ lymphocytes were occasionally seen in a non-specific pattern within the coronary artery intima. H&E=hematoxylin and eosin. Reproduced/adapted from Fox et al., with permission from Elsevier

Fig. 6

Houston case One (HC1). (A) Epicardium exhibits a focus with lymphocytic infiltrate indicative of lymphocytic pericarditis. (B) Myocardium is edematous as manifest as separation of the cardiomyocytes (CMC) and capillaries. The CMC in the center shows vacuolar degenerative change (star). No inflammatory cells are present. (C) Liver shows moderate macro-steatosis and altered, shrunken hepatocytes likely representing incipient apoptosis. (D) Renal glomerulus with focally congested capillaries. (A, C and D, Hematoxylin and eosin stains; B, 1-micron section, toluidine blue stain). (Magnification bar: A and C, 100 μm; B and D, 20 μm). Reproduced/adapted from Buja et al., with permission from Elsevier

Fig. 7

Houston case Two (HC2). (A and B) Myocardium is edematous and small blood vessels are congested. The CMC exhibit multifocal vacuolar degenerative changes. No inflammatory cellular infiltrates are present. Note the increased width of these CMC compared to those of HCO (Fig. 6B). The patient's heart weighed 1070 g. (C) The epicardium exhibits a lymphocytic infiltrate adjacent to a vein. (D) Testis with thrombi in peritesticular veins. (A and B, one-micron sections, toluidine blue stain; C and D, hematoxylin and eosin stains). (Magnification bar: A and B, 20 μm; C, 100 μm; D 500 μm). Reproduced/adapted from Buja et al., with permission from Elsevier

Fig. 8

Spectrum of pathologic abnormalities of kidneys from postmortems of patients with coronavirus disease 2019. (a, b) Proximal tubules showed (a) loss of brush border and (b) vacuolar degeneration (arrows), with debris composed of necrotic epithelium in tubular lumens (asterisks). Erythrocyte aggregates obstructing peritubular capillaries were frequently present (arrowheads). (c, d) Some cases showed infiltration of inflammatory cells in (c) tubules and (d) in 1 case, in an arcuate artery (arrows), with multiple foci of bacteria (asterisks) and white blood cell casts (arrowhead). (e, f) Occasional (e) hemosiderin granules and (f) deposits of calcium (arrowheads) were present in tubules with occasional pigmented casts (arrows). (g, h) Segmental fibrin thrombi were present in glomeruli (arrowhead), with ischemic glomerular contraction (arrows) with the accumulation of leaked plasma in Bowman’s space (asterisks). Hematoxylin and eosin. Bars = (f) 50 μm, (a–am) 100 μm, and (d) 250 μm. Reproduced/adapted from Su et al., with permission from Elsevier

Fig. 9

A, Brain capillary endothelial cells showing virus particles within cytoplasmic vacuoles (← arrow). B, Blebbing of viral particles coming in/out of the endothelial cell wall (circles) The relationship of virus particles (arrows←) to the endothelial cells (virus ingress/egress) is depicted. Note the dense inner core and densely stained periphery of viral particles. C, Endothelial neural cell interface showing a cytoplasmic vacuole filled with viral particles in various stages of bud formation (arrow←) adjacent to the basement membrane within the neural cell (frontal lobe). D, Neural intracytoplasmic vesicle showing viral-like particles. Insert: Detail on viral particle exhibiting electron dense centers with distinct stalk-like peplomeric projections. Scale bars are shown at the bottom left/right of each figure. BM, basement membrane; EC, endothelial cells; IV, intracytoplasmic vesicles; NT, neural tissue; RBC, red blood cell. Reproduced/adapted from Mondolfi et al., with permission from John Wiley and Sons

Fig. 10

a–d Microscopic sections of the corpus callosum genu. a H&E section of destructive hemorrhagic white matter lesion. b H&E section with white matter pallor adjacent to hemorrhagic lesion with GFAP immunoreactive reactive astrocytes evenly distributed in the white matter (inset) c CD68 immunostaining highlights a collection of macrophages at the periphery of the hemorrhagic lesion and a macrophage within an area of white matter pallor. d APP immunostain identifies axonal swellings within the hemorrhagic lesion and an absence of damaged axons within adjacent region of demyelination. e, f LFB/PAS stain distinguishes the focal area of myelin loss within the hemorrhagic lesion and adjacent PAS-positive foamy macrophages tracking along blood vessels and (f) higher magnification of the perivascular macrophages. Reproduced/adapted from Reichard et al. (open access article), with permission from Springer Nature

Fig. 11

a) H&E section of subcortical white matter with perivascular pallor. b LFB/PAS stained section demonstrates the perivascular myelin loss within the subcortical white matter lesion. c CD68 immunostain confirms the perivascular distribution of the macrophages. d APP immunostain highlighting some damaged axons present in the region of myelin loss. e LFB/PAS-stained section of middle cerebellar peduncle with a central destructive lesion and radiating graduated myelin loss. f APP immunostained section of middle cerebellar peduncle lesion highlighting the marked axonal injury. Reproduced/adapted from Reichard et al. (open access article), with permission from Springer Nature

Fig. 12

Section of a stem vessel in the placenta showing fetal vascular malperfusion, specifically intramural fibrin deposition where fibrin is deposited in the intima of the vessel. This was the most common type of thrombotic lesion in these placentas. H&E original magnification 200×. Reproduced/adapted from Baergen et al. (open access article), with permission from Sage Publisher

Fig. 13

Section of a chorionic plate vessel showing fetal vascular malperfusion, also with deposition of fibrin in the intimal of the vessel extending into the lumen. H&E original magnification 100×. Reproduced/adapted from Baergen et al., (open access article) with permission from Sage Publisher

Fig. 14

Section of chorionic villi which are avascular. This is another lesion of fetal vascular malperfusion which develops due to thrombosis upstream from the chorionic villi leaving to loss of fetal circulation downstream from the thrombosis. Loss of circulation ultimately leads to loss of fetal vessels with preservation of surface trophoblast. Here, the villi are avascular and the stroma is hyalinized. H&E original magnification 400×. Reproduced/adapted from Baergen et al. (open access article), with permission from Sage Publisher