key: cord-0709381-inxd8ouz
authors: Menezes, Ritesh G.; Rizwan, Tehlil; Saad Ali, Syed; Hasan, Wardah; Khetpal, Akash; Aqil, Mohammad; Madadin, Mohammed; Jamal Siddiqi, Tariq; Shariq Usman, Muhammad
title: Postmortem findings in COVID-19 fatalities: A systematic review of current evidence
date: 2021-12-07
journal: Leg Med (Tokyo)
DOI: 10.1016/j.legalmed.2021.102001
sha: 80634cee7636b16607354794d0e98873d9915bd9
doc_id: 709381
cord_uid: inxd8ouz

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing pandemic of coronavirus disease 2019 (COVID-19). Almost 17 months after the first COVID-19 case was reported, the exact pathogenesis of the virus is still open to interpretation. Postmortem studies have been relatively scarce due to the high infectivity rate of the virus. We systematically reviewed the literature available for studies that reported gross, histological, microscopic, and immunohistochemical findings in COVID-19 fatalities with the aim of reporting any recurrent findings among different demographics. PubMed and Scopus were searched up till the second of May 2021 and 46 studies with a total of 793 patients were shortlisted after the application of inclusion and exclusion criteria. The selected studies reported gross, histological, microscopic, and immunohistochemical autopsy findings in the lungs, heart, liver, gallbladder, bowels, kidney, spleen, bone marrow, lymph nodes, CNS, pancreas, endocrine/exocrine glands, and a few other miscellaneous locations. The SARS-CoV-2 virus was detected in multiple organs and so was the presence of widespread microthrombi. This finding suggests that the pathogenesis of this highly infectious virus might be linked to some form of coagulopathy. Further studies should focus on analyzing postmortem findings in a larger number of patients from different demographics in order to obtain more generalizable results.

Coronavirus disease 2019 (COVID-19) is a highly contagious infectious disease caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). This disease mainly manifests as fever, dry cough, dyspnea, and myalgias. However, presentations can range from mild flu-like symptoms to severe and fatal respiratory failure.

Furthermore, it is well-established from clinical studies that COVID-19 is not a disease restricted to the lungs and can in fact progress to a systemic disease involving multiple organs [1] . A potential explanation for this phenomenon could be the interaction between SARS-CoV-2 and its receptor -the angiotensin-converting enzyme 2 (ACE2) [2] . ACE2 is a cell surface protein that is expressed not only on type II pneumocytes of the lung but also on myocardial cells, enterocytes, bile duct cells, and vascular endothelium, potentially giving the virus access to all these tissues [3] .

Despite the knowledge that COVID-19 is a multisystemic disease, the exact pathophysiology behind organ damage remains elusive. A primary reason for this is the lack of studies outlining postmortem findings in COVID-19 patients. Autopsy findings can help unravel the mechanisms of disease processes and thus, can provide crucial information to guide therapeutic measures [4] . Most published studies, however, have focused on clinical manifestations of COVID-19, its characteristic radiographic findings, and potential treatments. Postmortem studies have been scarce and often include only a few patients. A major limitation of small-sized autopsy studies is their inability to conclusively demonstrate whether the findings are due to COVID-19 induced damage or due to unrelated comorbidities. This is further complicated by the fact that the majority of patients who die from COVID-19 often suffer from multiple pre-existing comorbidities [5] .

In this study, we systematically reviewed the literature to identify studies reporting gross, histological, microscopic, and immunohistochemical findings on postmortem examination of COVID-19 patients. We postulated that any finding which was a direct consequence of COVID-19 infection would be seen as a recurring theme across multiple studies with different patient demographics. The aim of this systematic review is to highlight the most prominent findings in each organ in a concise and digestible format.

This study adheres to the reporting guidelines established by the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) [6] .

PubMed and Scopus were searched up till the first week of May 2021. The following search string was entered in each database: (COVID-19 OR COVID19 OR coronavirus disease 2019 OR SARS-cov2) AND (histopatholog* OR histolog* OR pathophyiolog* OR postmortem OR autopsy). Additionally, we allowed PubMed to automatically expand the query by searching for MeSH terms as well. The expanded search strategy and number of search results from each database are displayed in Table 1 . All articles retrieved via the search strategy were exported to EndNote Reference Library, where duplicates were identified and removed. The remaining articles were assessed and shortlisted independently by two investigators based on their relevance to the eligibility criteria. Titles and abstracts were reviewed first, after which the fulltext was read. Another two investigators were consulted in case of discrepancies.

The literature search has been summarized in a PRISMA flowchart (Figure 1 ).

Studies were included if they reported postmortem examination findings (gross, histological, microscopic, immunohistochemical) in COVID-19 patients. Studies reporting findings of biopsies of living COVID-19 patients were excluded.

The initial search of electronic databases yielded 1915 results. After the application of inclusion and exclusion criteria, 46 studies on postmortem findings in COVID-19 patients were shortlisted for our qualitative analysis . 793 COVID-19 patients that had undergone postmortem biopsies or autopsies were included in the study.

The studies included mostly elderly patients and the average age ranged from 60-80 years. Characteristics of individual studies have been provided in Table 2 . The key gross findings of each organ system have been summarized in Figure 2 and the key histological, microscopic and immunohistochemical findings have been summarized in Table 3 .

The lungs were evaluated in 36 studies [7] [8] [9] [10] [11] [13] [14] [15] [16] [17] [18] [20] [21] [22] [23] [25] [26] [27] [28] [29] [30] [31] [32] [34] [35] [36] 38, 39, [42] [43] [44] 46, 47, [49] [50] [51] . On macroscopic examination, approximately half of the lungs (212/371; 57.9%) were heavy and congested with a red, maroon-like appearance [7] [8] [9] [10] [11] 14, 15, 17, 23, [26] [27] [28] 32, 35, 38, 43, 44, 47, 51] . The parenchyma was patchy to diffusely edematous and the consistency was firm yet friable in 61.0% (156/247) of the lungs [8, 10, 11, 14, 17, 23, 26, 29, 32, 35, 36, 39, 49] . On the cut surface, 77 out of 189 patients (40.7%) had multiple, bilateral, small pulmonary artery thrombi with multiple areas of hemorrhages grossly visible [10, 14, 15, [27] [28] [29] [34] [35] [36] 39, 42, 44, 47, 49] . Thrombosis of medium or small-sized arteries associated with infarction was found in all the 35/35 (100%) cases [15, 28, [30] [31] [32] 35, 36, 43, 46, 47, 49] . Pulmonary embolism obstructing the main pulmonary artery was found in around 13.5% (29/215) of the patients [9, 25, 27, 29, 30, 32, [34] [35] [36] 43] . Amongst a total of 70 patients, 41 patients (58.6%) had focal to diffuse areas of consolidation with severe and extensive suppurative bronchopneumonic infiltrates [14, 17, 23, 29, 31, [34] [35] [36] 39, 44, 49, 51] .

Histologically, there was evidence of diffuse alveolar damage (DAD). The early exudative phase of DAD is characterized by edema of the bronchial and alveolar lining, capillary congestion, and early hyaline membrane formation without interstitial organization. This finding was found in approximately all of the cases 226/288 (78.4%) [7] [8] [9] [10] [11] [13] [14] [15] 17, 18, 20, 23, [25] [26] [27] [28] [29] [30] [31] [32] [34] [35] [36] 38, 39, 43, 44, 46, 47, [49] [50] [51] . Patients who had a prolonged hospital stay displayed evidence of proliferative phase and early fibrotic phase. These phases are characterized by alveolar hyperplasia, presence of desquamated type II pneumocytes consisting of cytomegaly and nucleomegaly with bright eosinophilic nucleoli in the alveolar spaces. The presence of stromal cells, fibroblasts, and intra alveolar fibrin deposits with thickened intra alveolar septa is consistent with the fibrinous and organizing phase of DAD and was found in 40.3%

(164/406) of hospitalized patients [7, [9] [10] [11] [13] [14] [15] 17, 18, 20, 23, 25, 26, [30] [31] [32] 34, 35, 38, 39, [42] [43] [44] 46, 47, 50] . Interestingly, complete fibrosis was seen in 46 patients, characterized by the complete destruction of pulmonary parenchyma [18, 31, 34, 35, 39, 42, 49] . Intra alveolar neutrophilic infiltration, consistent with bronchopneumonia, ranging from focal to diffuse was also found in small subsets of patients (35%; 68/194) [9, 15, 17, 20] [27, 30, 34, 35, 38, 39, 43, 44, 46, 47, 49, 51] . This finding could be secondary to infection or aspiration [8, 9, 18] .

Pulmonary vasculature was examined in 225 patients. Histological examination of the pulmonary vasculature showed widespread thrombosis and thromboembolism with microangiopathy in 50% of patients [7, 8, 10, 11, [13] [14] [15] 17, 20, 23, 25, 29, 31, 44, 46, 47] . Vessel walls were infiltrated by neutrophils, which were associated with hemorrhagic infarction of lung parenchyma. Fibrinoid necrosis of small vessels was a common finding, seen in 73% of patients [20, 27, 29, 42] .

Immunohistochemistry showed inflammatory cell infiltrates which included the presence of CD3+, CD4+, CD8+, and CD45+ lymphocytes, and CD68+ macrophages in interstitial space, alveolar space, bronchioles, and blood vessels in 70 out of 194 patients (30%) that were examined [7, 8, 10, 11, 14, 15, 18, 25, 26, 28, 29, 32, 35, 44, 46] . However, CD20+ B-lymphocytes were rare [8, 13, 46] . CD4+ and CD8+ lymphocytes varied from scarce in exudative DAD to forming small aggregates in patients with fibroproliferative DAD in 13 out of 26 patients (50%). CD57+ NK cells were also scant [13, 28, 32, 36] . The most striking feature was the presence of CD61+ resident pulmonary megakaryocytes with nuclear hyperchromasia and atypia. Around 69% (123/178) of the patients had formations of platelet-fibrin aggregates in alveolar capillaries leading to thrombi [9] [10] [11] 13, 14, 17, 25, 27, 31, 38, 42, 46, 49] . On DNA stain, pneumocytes with increased RNA in alveolar space showed aggregation [14] .

Ultra-structural examination showed changes in the tissue directly related to viral infection. Viral particles in type I and II pneumocytes showed enveloped, spike like projections and electro-lucent core with peripheral electron-dense granules of the sectioned nucleocapsid [9, 11] . The particles were localized along plasmalemmal membranes and within cytoplasmic vacuoles. The diameter of the particles was 82nm and the projection was about 13nm in length [11] . Platelets and fibrin plugs with entrapped neutrophils were also detected in the lumina of alveolar capillaries in approximately two-thirds of patients (62.6%; 66/106) [10, 11, 28, 49] .

The heart was evaluated postmortem in 19 studies [8] [9] [10] [13] [14] [15] [16] [17] [18] 20, 21, 23, 26, 29, 32, 35, 36, 43, 51] . On gross examination, the findings were mainly due to viral independent pre-existing pathologies and co-morbidities such as hypertension (HTN), diabetes mellitus (DM), and past ischemic injury [13, 20, 23] . The heart was weighed in 53 patients and the weight ranged from 280 grams to 690 grams (normal weight 250g -350g) [14, 15, 32, 35, 43, 51] . There was significant evidence for left, right, or biventricular myocardial hypertrophy and dilatation mainly due to hypertrophic and dilated cardiomyopathy. Moderate to marked atherosclerosis narrowing, scarring of the myocardium post-myocardial infarction, and congestive heart disease (CHD) was also common (33.7%; 58/172 patients) [9, 10, 13, 15, 20, 23, 35, 36, 43] . The cut surface of the heart was firm and red-brown in all patients evaluated (100%; 4/4) [14] .

On histologic examination, enlargement of myocytes with nuclear polymorphism, focal edema and myocardial and interstitial fibrosis were found in around 76% of patients (105/138) with pre-existing hypertension and atherosclerotic cardiovascular disease [9, 10, 13, 15, 16, 20, 29, 32] . 26% of patients had mild to moderate lymphocytic infiltration in the epicardial and myocardial tissues [9, 10, [13] [14] [15] 18, 26] . However, full-fledged epicarditis and myocarditis, as seen in viral infection, was uncommon and noted only in 8 out of 41 patients (19%) [10, 16, 20, 21] . Wichmann et al. and Buja et al. found one case out of a total of 38 patients (5%) that had lymphocytic myocarditis with mononuclear cell infiltration [10, 23] . In patients with ischemic injury and shock, per acute focal necrosis of cardiomyocytes was visible, but there were no large, confluent areas of myocyte necrosis [17, 43, 51] . Lymphocytes were found adjacent to and not surrounding the degenerating myocytes [14, 26, 35] . Senile cardiac amyloidosis was also found in 20% of patients (11/54) [15, 17, 32, 36, 51] . Immunostaining was done in 93 patients. Only 19 patients (19%) showed a predominance of CD4+ lymphocytes over CD8+ lymphocytes, with a lesser number of CD3+ T cells and even rarer CD68+ macrophages [9, 10, 26] .

Evaluation of the vessels showed intimal and medial thickening with luminal narrowing attributed to hypertrophic cardiomyopathy. Accumulation of inflammatory cells associated with endothelium as well as apoptotic bodies in the heart was also seen. Furthermore, there was some evidence of lymphocytic endotheliitis and thrombosis of myocardial veins (16%; 4/24) [13, 15, 21] .

The liver, gallbladder, and bowel were evaluated in 23 studies [8] [9] [10] [13] [14] [15] [16] [17] [18] [20] [21] [22] [23] 26, 29, 30, 32, 33, 35, 39, 42, 51, 52] . Macroscopically, the liver was unremarkable.

However, in 4.7% of patients (4/86) there was evidence of cirrhosis [8, 9, 52] , features including nutmeg congestion with multiple cysts, as reported by Bryce and his colleagues (2/67) [9] .

Amongst a total of 154 patients, 91 were found to have micro and macro vesicular liver steatosis ranging from mild to severe, predominately pericentrally. Periportal steatosis on histological examination was also found, indicating the presence of nonalcoholic fatty liver disease (NAFLD), which was likely a pre-existing condition [8] [9] [10] 13, [15] [16] [17] 20, 22, 26, 29, 32, 35, 42, 52] . About 67.9% of patients (36/53) showed evidence for mild, focal lymphocytic lobular infiltration, centrilobular sinusoidal dilation, ischemic coagulative necrosis with neutrophilic infiltration and venous outflow obstruction leading to chronic hepatic congestion [15, 33, 35, 43, 51, 52] . These findings are very non-specific and are common in terminally ill patients with co-morbidities such as hypertension, diabetes mellitus and shock [9, 13, 17, 20, 22, 23] . Portal changes were also present in 11 patients and included mild to moderate lymphocytic and plasma cells infiltrate and ductal proliferation with signs of fibrosis [10, 15, 18, 35] .

Immunostaining showed increased CD68+ cells in hepatic sinusoids characterized by Kupffer cell activation and proliferation. Most (55.1 %; 16/29), had infrequent CD4+ and few CD8+ lymphocytes in liver lobule and portal areas [13, 15, 22, 52] . CD61+ early organizing thrombi involving portal venules were also found (17/24) [9, 33] .

Furthermore, fibrin microthrombi in liver sinusoids, seen in thirteen out of twentyseven patients, were reported by Duarte-Neto et al and Chaohui Lisa Zhao et al [13, 52] .

Electron microscopic examination identified the presence of typical coronavirus particles characterized by a spike-like structure in the cytoplasm of hepatocytes. A few fragmented virions were also visible. One out of two patients that were evaluated showed SARS-CoV 2 cytopathy as the hepatic mitochondria were swollen, the endoplasmic reticulum was dilated and there were decreased glycogen granules in hepatocytes [22] . Binuclear hepatocytes with apoptotic cells were also observed in all (100%; 4/4) patients [10, 22, 33 ].

The gastrointestinal system was macroscopically unremarkable (20/67) [9] and there were no notable histopathological abnormalities in the esophagus, stomach, small intestine, and colon (28/75) [9, 16] . However, Lax et al. [15] reported the detection of viral RNA on a section obtained from colonic mucosa. Histology of the liver and small intestine endothelium showed endotheliitis of the submucosal vessels and the presence of apoptotic bodies (9/12) [21, 26, 33] .

The kidneys were evaluated in 15 studies [8] [9] [10] [13] [14] [15] [16] [17] [18] [19] 21, 23, 43, 45, 51] . Gross and histopathological findings are mainly attributed to pre-existing conditions and comorbidities such as HTN, DM, and shock. However, in some studies, direct viral injury to the kidneys has also been postulated.

On gross examination, the weight of the kidneys ranged from 80 grams to 270 grams for the right kidney and 35 grams to 305 grams for the left kidney. The macroscopic findings in kidneys are mostly attributed to shock, as seen in almost half of the were filled with proteinaceous masses [15] . The distal tubules and collecting ducts had cellular swelling and edematous expansion. Hemosiderin granules were present in tubular epithelium. Pigmented casts suggestive of rhabdomyolysis, due to increased levels of creatine phosphokinase, were also present in some patients.

Acute pyelonephritis, with foci of bacteria and diffuse polymorphonuclear casts in the tubular lumen, was seen in two out of 26 patients(7%) [19] . Focal and sparse chronic inflammatory infiltrate was found in areas with interstitial fibrosis and tubular atrophy [17] . [9, 10, 13, 17, 19, 45] . One patient had an anemic infarct [17] .Glomerular mesangial expansion and hyalinosis of arterioles were also present [13, 43] . Three patients showed mesangial nodular sclerosis [9, 19, 45] .

Immunostaining showed the expected mix of T and B lymphocytes in areas of scarring with lymphocytic infiltrate. There were some scattered macrophages. 

The immunologic organs were evaluated in 12 studies [8] [9] [10] [13] [14] [15] 17, 18, 23, 24, 42, 51] . On gross examination, the spleen was mostly unremarkable. However, splenomegaly, chronic congestion, and non-specific splenitis were observed in 6% (5/82) of patients [23, 51] . On histological examination, the spleen was enlarged in 24% of patients (13/54) with the expansion of red pulp by congestion and lymphoplasmacytic infiltrate [10, 42, 51] . In 50% of patients (30/61), there was atrophy of the white pulp due to lymphocyte depletion with the absence of marginal zones [10, 13, 15, 24, 42, 51] .

The ratio of red pulp to white pulp was found to be increased with varying degrees [24] .Hemophagocytic histiocytes with preservation of white pulp were observed by

Bryce and his colleagues [9] . Buja immunostaining showed that the quantity of white pulp was normal and the splenic nodules were atrophic. CD68+ stain showed no significant changes in the distribution and quantity of macrophages with more CD68+ cells in the medullary sinuses. Few CD56+ cells were found. Coronavirus particles were found in the cytoplasm of macrophages under electron microscope in 2 out of 10 patients (20%) [24] .

Light microscope examination of a lymph node showed evidence of lymphocyte depletion with a complete absence of germinal centers associated with dilatation of sinuses and vessels in nearly half of the patients (53%;17/32), as well as an increase in reactive plasmablasts consistent with activated immune response seen in 5 out of 9 patients (55%) [15, 17] . Hilar and posterior mediastinal lymph nodes were enlarged in all 11 patients evaluated [15] . Bryce and his colleagues examined thoracic lymph nodes that showed sinus histiocytosis with focal hemophagocytosis in 11 cases out of 67 and multinucleate histiocyte in one case. There was also some evidence of microthrombi in lymph node vessels [9] . Immunohistochemistry showed decreased CD3+ T lymphocytes with no overt loss of B and T lymphocytes. There was a predominance of CD4+ lymphocytes over CD8+ lymphocytes with CD4+ TO CD8+ ratios ranging from approximately 5:1 to 30:1 [9] . Electron microscope examination of a lymph node showed corona-virus induced organelle-like replicative structures consistent with double-membrane vesicles and intracytoplasmic spherical virus particles with a characteristic electron-dense envelope and fine peplomeric projections [9] .

Bone marrow showed normal hematopoiesis with reactive lymphocytic infiltrate in almost all cases [15] . However, reactive left-shifted myelopoiesis and prominent hyperplasia of cytotoxic CD8+ T cells were also seen in 60% (3/5) cases examined by Menter et al [17] . Out of 6 cases examined by Bryce et al., hemophagocytosis was identified in 4 (66%) [9] .

The exocrine and endocrine glands were evaluated in 5 studies [8, 14, 15, 23, 51] . On gross examination, Wichmann and colleagues found normal adrenal glands in 7 patients. However, 4 patients out of 12 (33%) demonstrated micronodular hyperplasia and one patient had an adenoma [23] . Histologic examination was unremarkable except for 55% of patients who had nodular to diffuse adrenocortical hyperplasia mainly in the zona fasciculate [15] . Adrenal glands showed signs of shock in patients examined by Menter and colleagues [17] .

The thyroid was normal in 8 patients out of 11 and the remaining 3(27%) had a nodular goiter [15, 51] . 4 out of 11 deceased patients had focal pancreatitis with pancreatic parenchymal necrosis and calcifications. The submandibular glands showed a mild to moderate degree of lipomatosis in around one-third of patients (36%; 4/11) [15] .

The CNS was evaluated in 9 studies [8, 9, 13, 17, 18, 23, 41, 48, 51] . No visible gross abnormalities were found in the 36 brains that were examined by autopsy [8, 41, 48] .

Microscopically, Bryce and his colleagues found widespread microthrombi in cerebral arteries associated with acute infarction in 30% of their patients. These infarctions showed variable distribution. One case showed a large cerebral artery territory infarct, while others were small and patchy in the deep parenchyma. Interestingly, the vascular congestion was out of proportion as there were acute parenchymal microhemorrhages within the necrotic area of infarction. Two patients had global anoxic injury and 1 had severe hypoxic injury [9, 51] . Duarte-Neto et al. attributed findings in the brain to co-morbidities such as hypertension and direct viral injury to the neuronal tissue. Sixteen patients in his study along with Solomon et al study with (46.4%) had cerebral small vessel disease [13, 48] . 24 out of 31 patients (77.4%) had mild hypoxic injury [17, 48, 51] . However, no inflammatory infiltrate or neuronal necrosis was found on microscopic examination [17] . Focal T-lymphocytes infiltrate suggesting focal emerging encephalitis were also found in 36 out 110 cases (32.7%) [9, 41] . There was no loss of myelin seen on Luxol-Fast-blue/H&E-stained sections.

Menter et al. detected low levels of RNA copy numbers in the brain. However, values in the olfactory bulb were higher than those in the brainstem [17] .

Pharyngeal mucosa was examined in some cases by Wichmann Myositis and necrotic fibers in skeletal muscles were also noted in 20% of patients (2/10) by Duarte-neto et al. [13] . Furthermore, there was some evidence of the presence of viral RNA of SARS-Cov2 in the retina of 3 out of 14 (21%) COVID-19 patients [12] .

This systematic review highlights the fact that the SARS-CoV-2 virus, while primarily a pulmonary pathogen, does not limit itself only to the lungs. This is exemplified by the detection of SARS-CoV-2 in multiple organs, along with damage to these organs. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. -Acute parenchymal microhemorrhages.

-Focal T lymphocytic infiltrate.

Misc. 

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