key: cord-0745116-rrr7tvo4
authors: Malik, Preeti; Patel, Karan; Akrmah, Muhammed; Donthi, Deepak; Patel, Urvish; Khader, Samer N.; Asiry, Saeed
title: COVID-19: a Disease with a Potpourri of Histopathologic Findings—a Literature Review and Comparison to the Closely Related SARS and MERS
date: 2021-08-10
journal: SN Compr Clin Med
DOI: 10.1007/s42399-021-01029-5
sha: 811e2d17add624a266e1992e97e918d2ff04d956
doc_id: 745116
cord_uid: rrr7tvo4

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.

The coronavirus disease 2019 (COVID- 19) pandemic has been a global threat since its beginning in Wuhan. It has now spread to over 200 countries and territories worldwide with global cases approaching 1.7 billion and 4 million deaths (as of June 4, 2021) ; it has become a serious public health crisis [1] . The USA has surpassed all countries in the number of COVID-19-positive cases and now stands at over 34 million cases with more than 611,630 deaths as of June 4, 2021 [2] . Other countries with high case rates and disease burden are India (28M), Brazil (16M), France (5.6M), Russia (5.1M), and the UK (4.5M) [1] .

This pandemic has been a challenge for all healthcare professionals as patients are presenting with a variable clinical presentation from asymptomatic to mild symptoms including fever, dry cough, dyspnea, myalgia, sore throat, and headache, to more severe and emergent complications including acute respiratory distress syndrome (ARDS), pneumonia, and multiorgan failure requiring intensive care unit (ICU) admission and mechanical ventilation [3] . Recently, diarrhea, anosmia, and ageusia have also been reported in few studies along with neurologic manifestations [4] . There is an emerging literature on epidemiologic characteristics and diagnostic methods of COVID-19, but insights into disease pathogenesis are still evolving due to a limited number of autopsies.

It has been widely reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the respiratory tract. While there has been a wide array of studies that have reported lung pathologies, the virus has also been known to pathologically affect other organs including the liver, gallbladder, kidney, spleen, heart, and brain. Many overlapping studies have reported a common array of gross and pathological findings in these organs. Some of the most commonly reported pathologic findings include diffuse alveolar damage (DAD), spleen atrophy, and glomerular damage. Given that the SARS-CoV-2 virus has only emerged recently, there has not yet been a consensus as to exactly what pathological changes in each organ system are the result of the virus. Developing a common consensus is made even more difficult by the fact that many patients often have multiple comorbidities further complicating the situation. In this article, we aim to conduct a most up-to-date literature review of the pathological and autopsy findings of COVID-19 patients. In understanding the histopathologic manifestations of the disease, we are hoping to provide a better insight into the pathogenesis of COVID-19.

Lungs It has been well reported that SARS-CoV-2 primarily affects the respiratory system. As a result, many studies have found a wide array of pathologies in the lungs of patients who had contracted the virus. In one of the first studies by Edler et al. where they analyzed autopsies of 80 COVID-19 patients, they found significant pathological changes in the lungs of these patients including signs of ARDS on the lung surface and segmental hyperemia, protein-rich exudate, and purulent pneumonia. Histological findings included DAD with activated type II pneumocytes, fibroblasts, protein-rich exudate, and hyalinization of the membranes [5] . Another study by Tian et al. reported two patients with lung adenocarcinoma and had COVID-19 during hospitalization. Lung biopsies of these patients showed pulmonary edema, hyperplasia of pneumocytes, prominent proteinaceous exudates, vascular congestion, and inflammatory clusters with fibrinoid material and multinucleated giant cells away from the tumor due to COVID-19 (Figs. 1 and 2) [6] . A study of 10 COVID-19 autopsies by Fox et al. reported thrombosis and microangiopathy in small vessels and capillaries (Fig. 3 ) as well as diffuse alveolar damage, hyaline membrane formation, and parenchymal hemorrhage bilaterally (Fig. 4) . Interestingly, they also found that the lungs of these patients were significantly (one standard deviation) heavier than the lungs of non-COVID-19 patients [7] . In the case of a 72-year-old male, Zhang et al. found denudation of alveolar cells, type II pneumocyte hyperplasia, intra-alveolar fibrinous exudates, interstitial loose fibrosis, and intra-alveolar fibrous plugs, all consistent with the findings of DAD [8] . In addition to the previously reported findings, Aguiar et al. found moderate amounts of intraalveolar macrophages and small amounts of polymorphonuclear neutrophils (PMN) and lymphocytes, alongside intraalveolar hemorrhages and bacterial proliferation in the alveolar exudate. No viral inclusions or multinucleated giant cells were noted. The bronchi and bronchioles did not exhibit pathological changes except a small increase in lymphocytes. The interstitial compartment had lympho-monocytic infiltrates and an increase of megakaryocytes [9] . Carsana et al. reported endothelial necrosis, squamous metaplasia with atypia of the bronchi, mural fibrosis, and microcystic honeycombs of lung parenchyma [10] . Copin et al. found cytoplasmic vacuolization of lung endothelial cells, organizing pneumonia within alveolar ducts, and type II pneumocyte hyperplasia [11] . Two case reports found diffusely edematous and firm parenchyma consistent with ARDS [7, 12] . Moreover, Buja et al. described findings of thickened alveolar capillaries with the presence of CD61 + pulmonary megakaryocytes that had nuclear hyperchromasia [12] . In a study reporting autopsy finding on five COVID-19 patients, severe organizing hemorrhagic pneumonitis, injuries of the septal capillaries, and red cell extravasation of alveolar spaces were found [13] . A study done by Conde et al. also found vesicular nuclei with prominent nucleoli suggestive of viral cytopathic effect, and cells with large, hyperchromatic nuclei, similar to smudge cells described in adenovirus-related pneumonitis, were also observed, along with findings similar to DAD [14] . Xu et al. reported histological changes including enlarged pneumocytes in some regions characterized by an enlarged nucleus with granular cytoplasm and prominent nucleoli showing viral cytopathic-like changes, as well as desquamation of pneumocytes in some areas [15] . Menter et al. found that approximately half of the patients in the study developed superimposed bronchopneumonia and that 4/21 patients had pulmonary embolism. They also described bluish-red in color lung parenchyma and severe capillary stasis as part of their most prominent histological findings [16] . Varga et al. found accumulation of mononuclear cells, apoptotic bodies, congestion of small vessels in the lung, and lymphocytic endotheliitis [17] . In addition, Zeng et al. found perivascular inflammatory infiltration, interalveolar multinucleated cells, pneumocyte hyperplasia, and intracytoplasmic viral inclusions in the lung of one patient. Interestingly, they did report finding any of the common lung symptoms including DAD and hyaline membrane damage [18] . Furthermore, Pernazza et al. found prominent and diffuse neutrophil migration in septal vessels, clustering of alveolar macrophages, pneumocyte damage, and interstitial inflammatory infiltrates and diffuse hemorrhage within lung parenchyma [19] . Finally, Yao et al. described finding hyaline thrombus in microvessels, thickening of the alveolar septa, desquamation of proliferative type II AE, and exudative monocytes and macrophages [20] . There was a 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 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 significant overlap within pathological findings of all of the studies that have been included in this review. The most common shared findings among lung-histological sections were DAD including hyaline membrane, edema, type II pneumocyte hyperplasia, increased macrophages, loss of cilia in epithelial cells, accumulation of fibrin deposits [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [20] [21] [22] [23] [24] [25] , and increased lung weight [7, 12, 14] .

Cardiac SARS-CoV-2 is known to cause prominent morphological and pathological changes in the cardiac tissue. A study done on autopsies of 10 African American patients by Fox et al. showed no lesions in the myocardium and no stenosis or acute thrombosis formation on gross examination. The most significant changes found were cardiomegaly and right ventricular dilation which could lead to elevated levels of brain natriuretic peptide. The reported histological findings of this study were rare areas that showed degeneration of myocytes, but the authors could not conclude if this was the result of viral myocarditis since there was no lymphocytic inflammatory infiltrate (Fig. 5) [7] . Another study reporting autopsy finding of three COVID-19 cases by Buja et al. [12] found more cardiac changes in patients who had contracted the virus. In the first case, they found individual cardiomyocytes with degenerated vacuoles and other cardiomyocytes with enlarged hyperchromatic nuclei (Fig. 6) . The histological findings of the second case showed epicardial lymphocytic infiltrates, cardiomyocyte hypertrophy, multifocal interstitial fibrosis, and scattered damaged individual cardiomyocytes, and no myocardial inflammatory foci indicative of myocarditis were seen (Fig. 7) . The third case of the study exhibited multifocal lymphocytic infiltrates in the epicardium, cardiomyocytes with hyperchromatic nuclei and signs of acute injury, thickening of the coronary arteries with luminal narrowing, prominent foci of cardiomyocyte, and capillary disarray primarily in the superior portion of the interventricular septum. Additionally, Conde et al. also found increased left ventricle thickness, dilation of both ventricles, and mild stenosis in the aortic valve [14] . Bryce et al. not only had similar findings as the previous studies including an increase in cardiac mass and left ventricular hypertrophy, but also found hemophagocytosis in an area of inflamed epicardial tissue and epicardial mononuclear infiltrate of CD4/CD8 + T lymphocytes [21] . A study by Menter et al. also reported seeing senile amyloidosis, peracute myocardial necrosis, and acute myocardial infarctions in COVID-19 patients but attributed some of the symptoms to shock [16] . Finally, Suess et al. also noted the presence of nonspecific pericardial inflammatory cell aggregates such as lymphocytes and plasma cells [26] . Because most studies have had relatively small sample sizes, there has not been a set of established pathological findings of SARS-CoV-2, rather there has been a wide array of pathologies that have been reported.

ACE2, the SARS-CoV-2-binding receptor, is highly expressed in liver cells. As a result, studies have found liver injuries marked by an increase in the enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within the first week a patient contracts the virus. However, it is still in question whether the virus is directly responsible for these injuries, or if they occur due to the systemic inflammatory response as a result of SARS-CoV-2 [27] . A study by Tian et al. found pathological changes associated with the liver in four reported cases, which included mild lobular infiltration by small lymphocytes and centrilobular sinusoidal dilation, but all of the patients in this study had underlying liver conditions and many of these changes could be attributed to the presence of liver comorbidities in these patients. In addition, they found glycogen accumulation in hepatocytes and periportal and centrilobular necrosis in one of the four patients [28] . Bryce et al. found significant morphological changes in 22 COVID-19 patients including nutmeg congestion, multiple cysts, venous outflow obstruction, phagocytosed red blood cells, mild to severe steatosis, calcifications in sinusoidal spaces, and stage 3 fibrosis [21] . Menter et al. and Byrce et al. both also reported seeing nonalcoholic fatty liver disease in few of their autopsy findings [16, 21] . Furthermore, Varga et al. noted lymphocytic endotheliosis [17] and Bradley et al. reported centrilobular necrosis most likely sustained from hypoperfusion in a few of their patient tissue samples [29] . In addition, a study conducted by Buja et al. found moderate macrosteatosis (in 2/5 patients) and shrunken hepatocytes (corresponding to apoptosis) as well as lymphoplasmacytic triaditis with portal fibrosis [12] . Histologically, the gallbladder of the patients who had contracted the virus shows inflammatory infiltration and endoluminal obliteration of vessels, atrophic mucosa, hemorrhaging, and an overall hypertrophy of the gallbladder [28] . A study done by Balaphas et al. also found the presence of COVID-19 viral DNA particles in the gallbladder of a few of the analyzed patients [30] .

In their full organ system autopsy report, Zequing et al. found a wide array of pathological changes including splenic nodule atrophy, histiocyte hyperplasia, and lymphocyte reduction. In addition, they found the spleens to be congested, hemorrhagic, and lacking lymphoid follicles. Moreover, they reported seeing interstitial vessels and fibrous tissue hyperplasia in the sinuses [31] . Bryce et al. also found some pathological changes in the spleen of COVID-19 patients, and these included varying degrees of white pulp atrophy and hemophagocytic . 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 nonspecific. 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 

The kidneys are known to be a prominent target for SARS-CoV-2, and as a result, there is a wide array of morphological and pathologic changes in the kidneys of COVID-19 patients. Su et al. reported glomerular changes in patients who have contracted SARS-CoV-2 including nodular mesangial expansion and hyalinosis of arterioles, arteriosclerosis, and ischemic glomeruli. The capillaries around the glomerulus are particularly affected. It has been found that there are aggregations of erythrocytes and regions of segmental fibrin thrombi in the glomerulus areas. Also, ischemic shrinkage of capillaries leading to plasma leakage was identified. Moreover, there were also endothelial changes found around the glomerular loop including endothelial proliferation, swelling, and subendothelial lucent expansion (Fig. 8 ). They also found the presence of viral particles in the podocytes of the glomeruli [33] . This finding is further corroborated by Kral et al. and Sekulic et al. who also found SARS-CoV-2 particles in this region and an increased RNA expression of genes [32, 34] . Other studies have found additional pathologies in COVID patients including minimal change disease, collapsing glomerulopathies, lymphocyte infiltration [35] , and severe podocytopathy [32, 36] . In addition, Kissling et al. also noted finding cases of severe collapsing glomerulopathies, collapse of shrinking capillary loops, and hypertrophic proliferating podocytes [37] .

Although the tubules do not have as many pathological changes as the glomeruli, the few changes that do occur have important clinical relevance. Distal tubules and collecting ducts show occasional swelling and there is edematous expansion of the interstitial space in some patients. The most significant changes are seen in peritubular capillaries. There is often an aggregation of erythrocytes blocking the capillaries, vascular degeneration, loss of brush border cells, dilation of the tubular lumen, acute tubular injuries, and enhanced cb5-9 deposition (Fig. 8 ) [33, 35] . An ACE2 staining also showed an increase in receptors in proximal tubular cells. Coronavirus particles have been found in the renal proximal tubular epithelium and in the distal tubes (less in this region) [33, 35] . In addition, Sekulic et al. [32] also found acute tubular necrosis and an overall increase in kidney mass. Furthermore, Buja et al. also found other pathologies including hyaline arteriolosclerosis with glomerulosclerosis, fibrin platelet thrombus in the renal glomerular capillaries, and rare occurrences of holosclerotic glomeruli necrosis. They also found the presence of viral particles in both glomerular and endothelial cells [12] . Finally, Kissling et al. noted finding intratubular reabsorption vacuoles which they said reflected heavy proteinuria [37] . 

Recent emerging literature has reported headache, anosmia, and confusion as the common symptoms of COVID-19 infection [3, 38] . Solomon et al. performed autopsies of brain specimens from 18 confirmed COVID-19 patients. Some common histological findings among these patients were that their cerebrum and cerebellum showed hypoxic changes and they had loss of neurons in the cerebral cortex, hippocampus, and cerebellar Purkinje layer but no thrombi. Gross inspection showed atherosclerosis in 14/18 brain specimens with no symptoms of acute stroke. The SARS-CoV-2 virus, however, was detected in 6/18 patients' brain tissue samples [39] . This result is further corroborated by a case report published by Paniz-Mondolfi et al. in which they found the presence of SARS-CoV-2 particles in a patient's brain and capillary endothelium ( Fig. 9 ) [40] . Additional findings regarding the pathophysiology of SARS-CoV-2 have also been presented in a case report published by Riechard et al. They found hemorrhaging of white matter ( Fig. 10 ) (through staining for myelin) which they described as having a disseminated encephalomyelitis (ADEM)-like appearance, primarily the result of intraparenchymal blood. Moreover, there was a clustering of macrophages, axonal injuries, and necrosis in microscopic areas of neocortical organizing regions. In addition, they found perivascular cellular infiltrates, graduated myelin loss, terminal hypoxic-ischemic injury characterized by the presence of scattered necrotic neurons in the hippocampus and cerebellum, and varying degrees of axonal injuries scattered throughout the brain (Fig. 11 ) [41] . Furthermore, while most of the brain samples analyzed by Bradley et al. showed no remarkable changes, there were a few samples that showed interesting pathological changes including subarachnoid hemorrhages and microhemorrhages in the brain [29] . The most (6/20) . Only one case showed a large cerebral artery territory infarct, 3 cases showed small and patchy peripheral and deep parenchymal ischemic infarcts, and others were hemorrhagic. They also noticed outof-proportion vascular congestion which was occasionally accompanied by acute parenchymal microhemorrhages, especially within the necrotic area of infarction, suggestive of vascular damage and reperfusion injury [21] .

Skin & A study conducted by Magro et al. reported findings on the skin of five COVID-19 death cases. The most common finding reported was purpuric skin rash found on the buttocks, limbs, and chest which showed pauciinflammatory thrombogenic vasculopathy. Some patients also had inflammation of areas around the skin rashes. There were other rarer findings reported including a superficial vascular ectasia, occlusive arterial thrombus, and extensive vascular deposits of C5b-9, C3d, and C4d throughout the dermis. Additionally, perivascular lymphocytic infiltrates in the superficial dermis and small thrombi venules in the deep dermis were reportedly found in one of the patients [13] . Furthermore, Gianotti et al. described seeing widespread erythema ranging from the chest to the legs that spontaneously disappeared on three separate COVID-19 patients. All three patients had superficial perivascular dermatitis and varying degrees of vessel damage. One of the three patients exhibited more severe pathologies including swollen vessels in the dermis with lymphocyte infiltration and a few necrotic patches of keratinocytes [42] . Finally, Fernandez-Nieto et al. reported finding that some patients with COVID-19 present with various rashes including unspecific maculopapular rash and urticaria [43] .

Usually the tear ducts/eyes are thought of as potential transmission points for viruses. Viruses such as the adenovirus h a v e b e e n k n o w n t o h a v e h i g h l y c o n t a g i o u s keratoconjunctivitis epidemica, and it was thought that this could potentially be a mode of transmission for SARS-CoV-2 as well. Moreover, the eyes could also theoretically allow for an entry point for the virus since they have ACE2 receptors (SARS-CoV-2-binding receptors). However, in a study that analyzed ocular samples from three patients, researchers did not find any trace of the virus or any pathologies that could have been attributed to SARS-CoV-2 [44] . One of the limitations of this study was its small sample size (only 3 patients).

Another study that analyzed 14 patients actually did find the presence of SARS-CoV-2 viral RNA in the retina of 3/14 patient samples; however, they did not analyze or mention the ocular pathologies that could have been associated with the virus [45] . Although conjunctivitis has been found among COVID-19 patients and was reported as a symptom in patients in both above studies [44, 45] , conjunctivitis can be considered one of the presenting symptoms and needs further evaluation in the setting of the COVID-19 pandemic. However, the vast majority of conjunctivitis results from viral infections, and so this symptom should not be a primary factor of evaluation when diagnosing a patient with COVID-19.

One of the first studies that analyzed the effects of SARS-CoV-2 on a placenta found that among the three patients studied there was an overall increase in both fibrin deposit and syncytial nodule size. Two out of the three placentas analyzed showed irregular pathology with one having massive infarction and the other a chronic hemangioma [46] . Although there have only been a few studies on this subject, the findings among them have been fairly consistent. A second study This study also found that there was an increase in circulating nucleated red blood cells [47] . Another study conducted by Baergen that analyzed the placenta of 20 mothers also yielded similar findings: fetal vascular malperfusion and thrombosis as well as an increased intramural fibrin deposits and avascular villi (a rare finding) (Figs. 12, 13, and 14) . This study also brought up the idea that, although it is not commonly seen, SARS-CoV-2 can have a vertical pattern of inheritance [48] . Because of the limited number of studies on this subject and the fact that a lot of the findings have only been considered "low-grade lesions," the true effect of SARS-CoV-2 on pregnant mothers is relatively unknown.

Since SARS-CoV-2 has only recently emerged as a pandemic, there has not been an established set of pathological findings associated with the virus. Pathologists have been working to examine autopsy reports and histological slides of tissues in order to determine the histopathologic features of the virus. However, there have been varying reports in the literature where one study finds one set of pathological changes in an organ and another study finds a completely different set of changes. This is perhaps due to the fact that most studies only analyzed a small number of autopsies (3) (4) (5) due to the risk of pathologists contracting SARS-CoV-2. Hence, it is difficult to see consistent pathological changes. The few significant findings which the literature has reported so far are further complicated by the fact that patients who died due to COVID-19 often have underlying comorbidities that may also have led to these pathological changes. Therefore, in this scenario, the literature review studies looking at the trends as well as the unique findings across an encompassing array of studies can help in understanding the most prevalent and exceptional changes. In our review, we found and reported consistent pathologies associated with some of the organ systems as well as some unique findings (Table 1) . As discussed above, the common pathological changes in the lungs reported by many studies were DAD including hyaline membrane formation, edema, type II pneumocyte hyperplasia, increased macrophages, loss of cilia in epithelial cells, accumulation of fibrin deposits, and increased lung weight. There are many overlapping lung pathologies between SARS-CoV-2 and SARS-CoV and Middle East respiratory syndrome (MERS) patients. Similar to SARS-CoV-2, the pathological findings of SARS include heavy lungs (up to 2100 g), edema, DAD, hyaline membrane damage, increased interstitial lymphocytes, and alveolar macrophages. There has also been RNA of the SARS virus detected through immunofluorescent hybridization in the lungs of patients who had contracted the virus [49] . An autopsy performed by Gu et al. also noted the presence of fluid-filled alveoli, desquamated alveolar bronchial epithelial cells, alveolar epithelial hyperplasia, small vessel vasculitis, edema, and hemorrhaging in the lungs of deceased SARS patients [50] . Furthermore, studies have reported other SARS pathologies including loss of cilia, squamous metaplasia, giant cell infiltrate [51] , acute inflammatory exudates, atypical pneumocytes characterized by eosinophilic nuclei, and a granular amphophilic cytoplasm as well as the formation of granulation tissues in small airways [52] . Finally, Nicholls et al. also reported many similar findings but included seeing fibrin thrombi, giant cell formation in the alveolar lumen, swelling of pulmonary vessels, and diffuse amounts of lung parenchyma [53] . Unlike the low case fatality rate for any type of the SARS-CoV virus (around 2-5%), the case fatality rate for MERS is significantly higher (around 35%). This difference in mortality rates between viruses is striking since MERS also causes many of similar pathologies seen in SARS-CoV and SARS-CoV-2 such as diffuse alveolar damage, necrotizing pneumonia, infections in pneumocytes, epithelial cells, and bronchial submucosal glands [49, 54] . While the autopsy data of SARS and MERS are relatively limited compared to SARS-CoV-2, there is a clear consensus Lung, heart, kidney, liver, and spleen

Case 1: The lungs were heavy but were free of major thromboemboli and hemorrhages Case 2: Extremely congested lungs with multiple bilateral segmental pulmonary thromboemboli and multiple areas of hemorrhage; the heart had 4-chamber hypertrophy and dilatation and patent coronary arteries with minimal atherosclerosis Case 1: early DAD with multiple hyaline membranes accompanied by a focal and mild inflammation with modest numbers of CD3 + lymphocytes and more numerous CD68 + macrophages in some alveolar spaces. The spleen was enlarged. There was expansion of the red pulp not only by congestion but also by a lymphoplasmacytic In the spleen, splenic pulp atrophy, increase in blood leukocyte count, lymphocyte apoptosis, and splenic infarction were noted [28] . The major pathological changes in the spleen included atrophied white pulp, increase in blood leukocyte count, accumulation of white blood cells around the splenic artery, and increase in neutrophil infiltration [31, 32] . SARS-CoV has been known to cause pathologies in the spleen. The virus has been found to cause the spleen to shrink by about 60% due to splenic atrophy of white pulp and necrosis [50, 51] . Like SARS-CoV-2, SARS also causes a reduction of lymphocytes including immune cells of all types and can cause macrophage activation. The presence of SARS viral particles has actually been detected in enlarged macrophages [50] . In the liver, there were glycogen accumulation [28] , nutmeg congestion, cysts, phagocytic red blood cells [21] , nonalcoholic fatty liver disease [16, 28] , lymphocytic endotheliosis [17] , and centrilobular necrosis [29] . Similar to SARS-CoV-2, many studies have shown that patients with SARS infection had elevated ALT and/or AST during the onset of the infection [55] [56] [57] . Additionally, Zhang et al. reported that SARS-CoV infection was found to cause an increase in liver apoptotic cells and a decrease in CD4 + /CD8 + T cells [58] . MERS had also been shown to cause lobular hepatitis in certain groups of patients [54] .

The kidney was affected in two separate regions, namely, the glomeruli where there were severe podocytopathy [32, 36] and collapsing glomerulopathy; and the tubules where there was aggregation of erythrocytes leading to tubular occlusion, acute tubular necrosis, acute tubular injury, and fibrin platelet thrombus [33] . In terms of pathological changes associated with MERS, there have been conflicting reports found in the literature. One study reported finding no prominent changes in the kidneys of MERS patients [59] , while another study by Cha et al. found a wide array of changes including acute Abbreviations: HTN, hypertension; DM, diabetes mellitus; COPD, chronic obstructive pulmonary disease; OSA, obstructive sleep apnea; CKD, chronic kidney disease; CeVD, cerebrovascular disease; CAD, coronary artery disease; MI, myocardial infarction; CLD, chronic liver disease; ESRD, end-stage renal disease; CHD, chronic heart disease; N/A, not available tubular necrosis, proteinaceous cast formation, and acute tubular nephritis in a case study on one patient who had contracted the MERS virus [60] . The brain was marked by hypoxic changes in the cerebrum and cerebellum [39] , hemorrhaging of white matter, axonal injury, perivascular cell infiltrates, myelin loss, microthrombi, acute infarctions [29] , and vascular congestion [21] . While brain impacts of SARS and MERS have not been too widely studied, the SARS-CoV virus has been detected in the hypothalamus and cortex, and autopsies have shown that it causes scattered red degeneration of neurons in these regions [50] . Skin changes were primarily characterized by purpuric rashes, perivascular lymphocytic infiltrates, small thrombi venules, and extensive vascular deposits of C5b-9, C3d, and C4d throughout the dermis [13] . The only major pathological finding in the eyes was conjunctivitis and viral particles were found in the retina of the patients [44, 45] . Finally, the placenta of SARS-CoV-2-infected mothers had basal plates with adherent myometrial fibers, intervillous thrombi, increased perivillous fibrin deposition, and abnormal formation or injury to maternal villi [47, 48] . SARS-CoV-2, SARS, and MERS are all related viruses that show similar pathologic changes. Similar to SARS-CoV-2, both SARS and MERS affect multiple organs. SARS-CoV and MERS have been shown to have overlapping pathologies with SARS-CoV-2 especially in the lungs. SARS-CoV can also lead to DAD, increased lung mass, hyaline damage, increase initial lymphocytes, alveolar macrophages, hemorrhage fibrin thrombi, lung parenchyma, and acute inflammatory exudates, all of which have been found in SARS-CoV-2 patients [49] [50] [51] 53] . Moreover, MERS also causes DAD, in addition to necrotizing pneumonia in epithelial cells, pneumocytes, and bronchial submucosal glands [49, 54] . One of the primary differences between MERS, SARS, and SARS-CoV-2 is that the latter is highly contagious and displays many more pathological changes in a wider array of organ systems. Histological and gross changes for SARS have been limited to the lungs, liver, spleen, and brain, while changes as a result of MERS have been limited to the lungs, liver, and kidneys. In the spleen, SARS has been known to cause white pulp atrophy and a reduction of lymphocytes [50, 51] , while in the liver, it causes an increase in apoptotic cells [58] , decreases in CD4 + and CD8 + T cells [58] , and elevated levels of AST and ALT [55] [56] [57] . In the brain, SARS has been linked to scattered red degeneration of neurons in the hypothalamus and cortex [50] . Meanwhile, MERS causes lobular hepatitis in the liver, acute tubular necrosis/nephritis, and proteinaceous cast formation in the kidneys. The wide array of changes as a result of SARS-CoV-2 compared to SARS and MERS could be attributed to having significantly more studies that have reported on SARS-CoV-2 pathologies.

It is interesting that we found multiple studies reporting the presence of viral particles in various organ systems including the lungs, spleen, kidney, brain, and gallbladder. It has been known that multiorgan failure is the second leading cause of death among coronavirus patients [23] . It may be that as the viral disease progresses, the virus begins to target multiple organs outside of the lungs [61] . Since vaccines/drugs to fight against COVID-19 are still under investigation, it becomes crucial to understand the exact pathology of the disease. This may give us more insights into a personalized treatment approach. As a result, literature reviews such as ours are important to help in creating some better understanding of the disease pathogenesis.

In summary of this literature review, we reported consistent pathological findings associated with some of the organ systems as well as some unique findings in COVID-19 patients. The most common pathological changes were diffuse alveolar damage in the lungs, atrophied white pulp and increase in blood leukocyte count in the spleen, severe podocytopathy and collapsing glomerulopathy in the glomeruli, and acute tubular necrosis, acute tubular injury, and fibrin platelet thrombus in the tubules. The placenta of SARS-CoV-2-infected mothers had basal plates with adherent myometrial fibers, intervillous thrombi, increased perivillous fibrin deposition, and abnormal formation or injury to maternal villi. While vaccines/drugs to combat against COVID-19 are under investigation, it is very important to understand the exact pathology of the disease. Understanding of the COVID-19 pathogenesis will help in setting ground for future research studies into identifying targeted therapies and creating a more personalized treatment approach.

Informed Consent This review article has included already published articles; hence, informed consent was not required. All patient information were de-identified.

The authors declare no competing interests.

Copyright Statement The authors have taken copyright permission to reuse the images of the few studies included in the article. The images and their captions have not been modified from their original content. User license agreement is with the corresponding author and will be made available upon request.

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Ageadjusted risk factors associated with mortality and mechanical ventilation utilization amongst COVID-19 hospitalizations-a systematic review and meta-analysis

Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive

Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans

Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19

Inside the lungs of COVID-19 disease

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study

Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection

The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

Autopsy findings from the first known death from severe acute respiratory syndrome SARS-CoV-2 in Spain

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction

Endothelial cell infection and endotheliitis in COVID-19

Pulmonary pathology of early-phase COVID-19 pneumonia in a patient with a benign lung lesion

Early histologic findings of pulmonary SARS-CoV-2 infection detected in a surgical specimen

Pathological evidence for residual SARS-CoV-2 in pulmonary tissues of a ready-for-discharge patient

Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience

Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore

Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study

Postmortem examination of patients with COVID-19

COVID-19 autopsies

Gross and histopathological pulmonary findings in a COVID-19 associated death during self-isolation

Histopathological findings in a COVID-19 patient affected by ischemic gangrenous cholecystitis

Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series

Covid-19 can mimic acute cholecystitis and is associated with the presence of viral RNA in the gallbladder wall

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes

Molecular detection of SARS-CoV-2 infection in FFPE samples and histopathologic findings in fatal SARS-CoV-2 cases

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Multiorgan and renal tropism of SARS-CoV-2

Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. medRxiv

Spectrum of podocytopathies in new-onset nephrotic syndrome following COVID-19 disease: a report of 2 cases

Collapsing glomerulopathy in a COVID-19 patient

Factors associated with the presence of headache in hospitalized COVID-19 patients and impact on prognosis: a retrospective cohort study

Neuropathological features of COVID-19

Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)

Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology

Cutaneous clinico-pathological findings in three COVID-19-positive patients observed in the metropolitan area of

Comment on: Cutaneous manifestations in COVID-19: a first perspective. Safety concerns of clinical images and skin biopsies

Ocular post-mortem findings in patients having died from COVID-19

Detection of SARS-CoV-2 in human retinal biopsies of deceased COVID-19 patients

Pregnancy with new coronavirus infection: clinical characteristics and placental pathological analysis of three cases

Placental pathology in COVID-19

Placental pathology in Covid-19 positive mothers: preliminary findings

Emerging respiratory infections: the infectious disease pathology of SARS, MERS, pandemic influenza, and Legionella

Multiple organ infection and the pathogenesis of SARS

Severe acute respiratory syndrome: historical, epidemiologic, and clinical features

Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS)

Lung pathology of fatal severe acute respiratory syndrome

Histopathology of Middle East respiratory syndrome coronavirus (MERS-CoV) infection -clinicopathological and ultrastructural study

Liver international : official journal of the International Association for the Study of the Liver

Liver injury in COVID-19: management and challenges

Biomarkers and outcomes of COVID-19 hospitalisations: systematic review and meta-analysis

Detection of cell apoptosis in the pathological tissues of patients with SARS and its significance. Di Yi Jun Yi Da Xue Xue Bao

Hematologic, hepatic, and renal function changes in hospitalized patients with Middle East respiratory syndrome coronavirus

A case report of a Middle East respiratory syndrome survivor with kidney biopsy results

COVID-19 and multiorgan response

Autopsy findings from the first known death from severe acute respiratory syndrome SARS-CoV-2 in Spain. Revista espanola de patologia : publicacion oficial de la Sociedad Espanola de Anatomia Patologica y de la Sociedad Espanola de Citologia

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