Postmortem Findings Associated With SARS-CoV-2: Systematic Review and Meta-analysis

Abstract

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome-associated Coronavirus 2 (SARS-CoV-2), has become a global threat to public health. COVID-19 is more pathogenic and infectious than the prior 2002 pandemic caused by SARS-CoV-1. The pathogenesis of certain disease manifestations in COVID-19 such as diffuse alveolar damage (DAD) are thought to be similar to SARS-CoV-1. However, the exact pathogenesis of COVID-19 related deaths remains poorly understood. The aim of this article was to systematically summarize the rapidly emerging literature regarding COVID-19 autopsies. A meta-analysis was also conducted based on data accrued from preprint and published articles on COVID-19 (n=241 patients) and the results compared with postmortem findings associated with SARS-CoV-1 deaths (n=91 patients). Both autopsy groups included mostly adults of median age 70 years with COVID-19 and 50 years with SARS-CoV-1. Overall, prevalence of DAD was more common in SARS-CoV-1 (100.0%) than COVID-19 (80.9%) autopsies (P=0.001). Extrapulmonary findings among both groups were not statistically significant except for hepatic necrosis (P <0.001), splenic necrosis (P<0.006) and white pulp depletion (P <0.001) that were more common with SARS-CoV-1. Remarkable postmortem findings in association with COVID-19 apart from DAD include pulmonary hemorrhage, viral cytopathic effect within pneumocytes, thromboembolism, brain infarction, endotheliitis, acute renal tubular damage, white pulp depletion of the spleen, cardiac myocyte necrosis, megakaryocyte recruitment, and hemophagocytosis.

FIGURE 1

Right lung shown in the sagittal section from a 68-year-old woman who died of COVID-19 after 3 weeks of ventilation for ARDS showing diffuse hemorrhagic congestion (lung weight=1130 g; normal adult mean weight=300 to 350 g).

FIGURE 2

Forest plot for the prevalence of DAD in reported autopsy studies with COVID-19 versus SARS-CoV-1 (SARS) as the main subgrouping variable. CI indicates confidence interval.

FIGURE 3

DAD associated with COVID-19. Hyaline membranes are present throughout the alveolar spaces in this acute phase of DAD (hematoxylin and eosin).

FIGURE 4

Lung tissue showing diffuse hyaline membrane formation and capillary congestion in early acute DAD from a patient infected with SARS-CoV-1 (hematoxylin and eosin). Note the similarity to Fig. 3. Image courtesy of Jeffrey L. Myers from the University of Michigan, Ann Arbor, MI.

FIGURE 5

Marked alveolar hemorrhage associated with COVID-19. Blood and fibrin expanded alveolar spaces are shown consistent with alveolar hemorrhage (hematoxylin and eosin).

FIGURE 6

Early organizing thrombi are shown in small (A), medium (B), and large (C) vessels in the lung parenchyma of COVID-19 lungs (hematoxylin and eosin).

FIGURE 7

Multinucleated giant cells (arrow) as shown in this image can be detected scattered in alveolar spaces throughout COVID-19 lungs (hematoxylin and eosin).

FIGURE 8

Possible COVID-19 viral cytopathic effect (arrow) within pneumocytes exhibiting enlarged, pink, and smudgy nuclei (hematoxylin and eosin). This finding may be seen in DAD of other causes.

FIGURE 9

In situ hybridization for messenger RNA encoding the SARS-CoV-2 spike protein (S) is visualized as dark brown signals located in the cytoplasm of infected cells (arrows), low power at ×400 (A) and high power at ×1000 (B, C) with some signals showing coalescence into globules (C). The antisense messenger RNA strand of the spike protein is shown (arrows) indicative of active viral replication, low power at ×400 (D).

FIGURE 10

Section of the heart from a patient that died with COVID-19 with lymphocytic myocarditis showing a diffuse lymphocytic infiltrate (hematoxylin and eosin). This patient also had methicillin-sensitive Staphylococcus aureus and influenza A infections. Low-level SARS-CoV-2 RNA was detected within the myocardium.

FIGURE 11

Renal tubular injury. A, Section of a kidney from a deceased patient with COVID-19 showing acute tubular damage with coagulative necrosis of tubules and focal shedding of epithelial cells into the lumen. The interstitium shows edema and a few infiltrating mononuclear inflammatory cells (hematoxylin and eosin). B, Renal tubular injury with vacuolization, mitotic figure (green arrow), and focal interstitial inflammation (hematoxylin and eosin).

FIGURE 12

TEM of SARS-CoV-2 in Vero cells (African green monkey kidney epithelial cells). A, Multiple viral particles along the cell surface are shown displaying a distinct electron-dense surface with radiating peplomeric projections (bar: 0.25 µm). B, Ultrastructural details on a replicating vesicle. Note that the virions are spherical with some pleomorphism and measuring ∼80 to 110 nm in diameter. The surface is covered by an array of projections (peplomers) with the presence of multiple internal electron-dense dots that correspond to cross-sections of the nucleocapsid (bar: 0.2 µm).

FIGURE 13

Neuropathology findings. A, Coronal section of the right cerebral hemisphere in a patient that died of COVID-19 showing acute infarcts (arrows) and thrombosed vessels (arrowhead). B, A brain-blood vessel with a thrombus (arrowhead) is shown occluding the entire lumen. Note the perivascular mononuclear inflammatory cells and towards the bottom of the image (arrow) necrotic cortical brain parenchyma (hematoxylin and eosin). C, Higher magnification showing the organized thrombus within the blood vessel (hematoxylin and eosin). D, Brainstem with acute microhemorrhage (hematoxylin and eosin).

FIGURE 14

Hemophagocytic histiocytes (arrows) in COVID-19 autopsies from the bone marrow (A), subcapsular sinus of a lymph node (B), and spleen (C) (hematoxylin and eosin).