key: cord-0711105-ra5bgq58
authors: Wu, Zhonglin; Zhang, Qi; Ye, Guo; Zhang, Hui; Heng, Boon Chin; Fei, Yang; Zhao, Bing; Zhou, Jing
title: Structural and physiological changes of the human body upon SARS-CoV-2 infection
date: 2021-04-16
journal: J Zhejiang Univ Sci B
DOI: 10.1631/jzus.b2000523
sha: 254331aaf942b421c304251e0dfff1bb2e9dd719
doc_id: 711105
cord_uid: ra5bgq58

Since December 2019, the novel Coronavirus (severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2)) has spread to many countries around the world, developing into a global pandemic with increasing numbers of deaths reported worldwide. To data, although some vaccines have been developed, there are no ideal drugs to treat novel coronavirus pneumonia (coronavirus disease 2019 (COVID-19)). By examining the structure of the coronavirus and briefly describing its possible pathogenesis based on recent autopsy reports conducted by various teams worldwide, this review analyzes the possible structural and functional changes of the human body upon infection with SARS-CoV-2. We observed that the most prominent pathological changes in COVID-19 patients are diffuse alveolar damage (DAD) of the lungs and microthrombus formation, resulting in an imbalance of the ventilation/perfusion ratio and respiratory failure. Although direct evidence of viral infection can also be found in other organs and tissues, the viral load is relatively small. The conclusion that the injuries of the extra-pulmonary organs are directly caused by the virus needs further investigation.

The novel coronavirus (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), which belongs to the β-coronavirus family, is the pathogen of novel coronavirus pneumonia (coronavirus disease 2019 ). Since December 2019, when the initial outbreak of COVID-19 occurred in China, a series of effective preventive control and medical treatment measures have been implemented, and have brought the pandemic under control to a certain extent. However, its incidence is still increasing globally. As of Mar. 14, 2021, there were more than 11.92 million COVID-19 patients worldwide, and the cumulative number of deaths had exceeded 2.6 million (https://www. dynamed. com/condition/covid-19-and-cardiovascular-disease-patients). At present, the effects of novel coronavirus infection on the structure and physiology of the human body are still not completely understood, and although the vaccine has been developed, there are currently no ideal specific therapeutic drugs for novel coronavirus pneumonia patients. This paper reviews recent research progress on structural and physiological changes of the human body caused by novel coronavirus infection, so as to provide relevant cues and direction for specific drug research on COVID-19 treatment. 

The coronavirus is circular in shape, with a diameter of about 125 nm (Malik, 2020) . Because its spike glycoprotein protrudes from the surface, the virus displays a "corona" appearance, hence the name coronavirus. There are four genera of coronavirus: α-coronavirus, β-coronavirus, γ-coronavirus, and δ-coronavirus. Mammals are susceptible to α-coronavirus and β-coronavirus, birds to γ -coronavirus, and both mammals and birds to δ-coronavirus (Naqvi et al., 2020) . The novel coronavirus (SARS-CoV-2), which leads to COVID-19, belongs to the β-coronavirus genus. For SARS-CoV-2, next-generation sequencing data have shown 79% and 50% homologies to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), respectively (Malik, 2020) .

The coronavirus genome is constituted of a singlestrand RNA (Wu F et al., 2020) . Their genome is the largest of all RNA viruses, which usually range between 27 and 32 kb (Li, 2016) . The RNA genome of coronavirus is encapsulated by a nucleocapsid protein (N) and is further enclosed within a lipoprotein envelope. There are at least three structural proteins associated with the viral envelope, in which membrane protein (M) and envelope protein (E) are involved in the assembly of the virus, and spike glycoprotein (S) mediates virus entry into host cells (Li, 2016; Shi et al., 2020) . The S protein is committed to adhering the virus to host cells to initiate infection. It consists of three subunits, S1, S2, and S2' (Li, 2016) , which play different roles in the adhesion of the virus to host cells. The S1 subunit can attach the virus to the host cell membrane via interaction with the angiotensin converting enzyme 2 (ACE2) receptor that initiates the infection process (Hoffmann et al., 2020) . As a fusion protein, the S2 subunit contributes to the fusion of viruses with mammalian cell membranes. The S2 subunit functions as a fusion peptide (Naqvi et al., 2020) . In addition to mediating viral entry, spike proteins are the major factors determining the host range and tissue orientation of the virus and are also the main inducers of the host immune response. E proteins contribute to viral assembly and release. E proteins can aggregate on host membranes and form protein-lipid pores which are involved in ion transport and considered to be potential drug targets (Fehr and Perlman, 2015) . M proteins act simultaneously with E, N, and S proteins and are involved in RNA packaging (Tang et al., 2020) .

SARS-CoV-2 uses S proteins on its envelope to bind to ACE2 receptors on the cell membrane and relies on the synergistic activation of transmembrane serine protease 2 (TMPRSS2) (Hoffmann et al., 2020) . Subsequently, the virus enters the host cell through membrane fusion (Offringa et al., 2020) . After entry into the cell, it destroys the endoplasmic reticulum structure, forms a bilayer membrane vesicle structure (double-membrane vesicle (DMV)), and replicates and transcribes within it (Oudshoorn et al., 2017) .

The genome of coronavirus contains a 5' cap structure and a 3' poly(A) tail, similar to eukaryotic messenger RNA (mRNA), so it can be translated just like eukaryotic mRNA (Fehr and Perlman, 2015) . In the overall process of RNA replication, the replicase is translated firstly and then a replicase complex is assembled. Afterwards, RNA replication and subgenomic RNA synthesis are carried out, and finally mature virus particles are formed. After assembly, the virus is transported to the surface of the cell within vesicles and released by exocytosis (Malik, 2020) .

When a virus enters a cell, its antigen presented by the antigen presentation cells (APCs) is then recognized by the cytotoxic T lymphocytes (CTLs), and stimulates humoral and cellular immunity in the human body (Li XW et al., 2020) . Acute respiratory distress syndrome (ARDS) is considered to be the leading cause of death in patients with COVID-19 (Li JZ et al., 2020) . One of the main mechanisms of ARDS is the cytokine storm, which involves upregulation and activation of many inflammatory cytokines in tissue cells (mainly immune cells) after microbial infection of the body, causing ARDS (Song et al., 2020) . Some studies have shown that inflammatory cytokines in serum are significantly increased in most patients with severe COVID-19, including interferon (IFN), interleukin (IL), tumour necrosis factor (TNF), colony-stimulating factor (CSF), IFN-γ-induced protein (IP10), C-reactive protein (CRP), monocyte chemotactic protein-1 (MCP1), and macrophage inflammatory protein 1-α (MIP1α) (Meftahi et al., 2020; Zheng et al., 2020) .

In addition to the direct effects of viral infection and resulting immunopathological damage, immune evasion by the coronavirus is also one of the mechanisms, which promotes disease. Coronavirus has multiple ways to escape immune responses. Viruses are strictly parasitic within cells, thus avoiding the effects of antibodies, the complement system, and drugs. Pattern recognition receptors (PRRs) are mainly expressed on the surface of innate cells and can identify conserved components of exotic microorganisms, namely pathogenassociated molecular patterns (PAMPs). Nevertheless, SARS-CoV and MERS-CoV can induce cells to produce PRR-deficient DMVs and replicate and transcribe within these vesicles, thus avoiding attack by the host immune system (Snijder et al., 2006; Oudshoorn et al., 2017) . Interestingly, SAR-CoV-2 can activate the immune response by PRR. Nuclear factor-κB (NF-κB), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and other pathways can be activated after the cells are infected by SAR-CoV-2 through recognizing PRRs, thus activating the immune response (Catanzaro et al., 2020) . It is believed that SARS-CoV-2 can achieve immune evasion through the coding of 22 N-linked glycosylation sites, the structure of open reading frame 3b (ORF3b), and the methylation of 5' cap of viral RNA (Tan and Tang, 2021) . Antigen presentation is also affected by the coronavirus, for example, by down-regulation of gene expression associated with antigen presentation (Menachery et al., 2018) . ORF8 in SARS-CoV-2 genomes could bind to major histocompatibility complex-1 (MHC-1) to disrupt antigen presentation and initiate immune evasion (Park, 2020) .

After Professor Liang LIU's team of Huazhong University of Science and Technology (Wuhan, China) conducted the first autopsy of a patient who died of COVID-19 in January 2020, other teams and organizations worldwide have also carried out autopsies on deceased COVID-19 patients. We are therefore able to summarize the structural and histological changes caused by SARS-CoV-2 infection observed in these autopsies.

Gross observations: Dark-red bleeding areas and gray-white lesions were observed in cases with severe inflammatory lesions, which exhibited a patchy shape. The lung tissue felt tough and firm as in diffuse edema, and tissue weight was increased (Barton et al., 2020; Sekulic et al., 2020; Suess and Hausmann, 2020) . White mucus or pink foam could be seen within the bronchial lumen; and in the case of inflammatory lesions, a large amount of viscous secretions overflowed from the alveoli and fibrous cords were observed. There could be mild to moderate pleural effusions on both sides (Ducloyer et al., 2020; Fox et al., 2020; Suess and Hausmann, 2020) .

Microscopic observations: In a minimally invasive autopsy performed on patients who died of COVID-19 , diffuse alveolar damage (DAD) was found in the lungs of many patients, but the pathological changes of DAD in different parts of the lung were discordant and often displayed heterogeneity in the same patient (Sekulic et al., 2020) . The pathological features of COVID-19-related DAD were not unique, indicating that there may be similar pathogenesis and etiological factors to other DAD (Konopka et al., 2020) . DAD morphological progress includes three stages: exudation (1-7 d), proliferation (8-20 d), and fibrosis (20 d) (Castro, 2006) . According to available autopsy reports, COVID-19-related DAD was usually at the acute exudation stage or proliferation stage (Polak et al., 2020) , with only a few cases being classified at the fibrosis stage (Fox et al., 2020) .

Acute exudative DAD is mainly characterized by diffuse alveolar exudation, with varying degrees of serous and fibrin exudates in the alveolar cavity which may be accompanied by the formation of hyaline membranes. Reactive hyperplasia of type Ⅱ alveolar epithelial cell (AECⅡ) was observed in many cases (Bradley et al., 2020) . The nuclei of AECⅡ were observed to be large and be deeply stained, with strong pleomorphism, suggesting viral cytopathic changes with diffuse epithelial shedding . Capillary dilation and congestion were seen in the alveolar septum, and hyaline thrombosis and mixed thrombosis within blood vessels were also observed (Polak et al., 2020) . Other findings were inflammatory cell infiltration: predominantly monocytes, macrophages and a few multinucleated giant cells, lymphocytes, eosinophils, and neutrophils (Bradley et al., 2020) . Some areas of interstitial fibrosis occurred in varying degrees, and fibroblast proliferation was seen (Polak et al., 2020) .

A major feature of DAD in the hyperplastic stage is the organization of intra-alveolar exudates and alveolar septal fibrosis, which is more common in patients with long-term illness and hospitalization . Cellulose exudation is seen in the alveolar cavity, and the hyaline membrane is replaced by proliferating fibroblasts, with fibroblast thrombus being formed in some alveolar cavities. In COVID-19 autopsies, the alveolar septal was thickened, with fibrosis and massive fibroblast hyperplasia. Local pulmonary tissue consolidation occurred, with infiltration by a small number of monocytes, macrophages, and small lymphocytes. Notably, secondary infection could overlap with viral infection, resulting in suppurative inflammation. A large number of bacteria and fungi were detected in some cases, suggesting that severe bacterial or fungal infections were secondary to DAD caused by coronavirus (Zhou et al., 2020) .

Coronavirus particles were found in the cytoplasm of tracheal and bronchial mucosal epithelial cells and AECⅡ , as observed under electron microscopy. The quantitative polymerase chain reaction (qPCR) test for SARS-COV-2 on the tissues in some cases was positive in lung tissues .

Extensive alveolar injury, exudation, interstitial inflammatory thickening, and thrombosis are the causes of ventilation disorders. Airway epithelial hyperplasia, shedding, and mucus congestion increase ventilation obstruction. These changes are regarded as the pathological basis of fatal respiratory failure (Bian and The COVID-19 Pathology Team, 2020).

According to autopsy reports from 23 COVID-19 patients provided by five USA research institutions, the major organ damage in COVID-19 patients is not only in the lungs but also in the heart, which aggravates the circulatory system to enter the procoagulant state .

Gross observations: the weight of the heart increased slightly or negligibly. Cardiac enlargement and right ventricular dilatation were found. Under microscopy, scattered individual cardiomyocyte necrosis was observed, but no large or confluent area of cardiomyocyte necrosis was observed. There was no significant inflammatory lymphocytic infiltration . There is little evidence of direct infection and replication of SARS-CoV-2 in cardiac cells (Imazio et al., 2020) . Myocardial tissue damage may involve several potential mechanisms, including coronavirusassociated acute myocarditis, increased cytokine secretion, and hypoxia-induced cardiomyocyte apoptosis. Inflammation may be a potential mechanism of myocardial injury .

Additionally, autopsy reports indicated that blood clots and microangiopathy were present in the small blood vessels and capillaries of the lungs, accompanied by bleeding that caused death (Ackermann et al., 2020). Elevated D-dimer was detected in some patients. This finding may suggest pulmonary vascular endothelial injury. SARS-CoV-2 infects the host through the ACE2 receptor, which is expressed in multiple organs of the human body, including the lung, heart, kidney, and intestine. Endothelial cells also displayed expression of ACE2 receptors. Varga et al. (2020) found the presence of viral inclusion bodies within endothelial cells in patients with COVID-19, and the accumulation of inflammatory cells associated with endothelial cells was also found in various organs. Both direct infection of endothelial cells by the coronavirus and the recruitment of immune cells mediated by the immune system can lead to extensive endothelial dysfunction with apoptosis. Endothelial dysfunction is the main determinant of microvascular dysfunction. It causes vasoconstriction by changing vascular balance, leading to organ ischemia, tissue edema, and inflammation in a coagulation-promoting state .

Histological changes in the liver of COVID-19 patients were limited ; these could manifest as hepatocyte degeneration, punctate necrosis, fragment necrosis, bridging, or massive necrosis with neutrophil infiltration . Lymphocyte infiltration and slight hepatic sinus dilation were observed within the hepatic lobules of deceased COVID-19 patients . The gallbladder was highly filled and the mucosal epithelium was exfoliated . Bile thrombus was seen in the small bile duct (Bradley et al., 2020) . There was moderate microvascular steatosis and some necrotic hepatocytes were seen around the central vein, but no portal vein inflammation was observed (Suess and Hausmann, 2020; Xu et al., 2020) . There is no clear positive evidence that SARS-CoV-2 can cause liver injury directly. Drug-induced liver injury, previous history of chronic liver disease, and COVID-19-associated elevated inflammatory response may also cause liver injury.

Under light microscopy, glomerular segmental hyperplasia or necrosis, swelling of endothelial cells, and a small amount of protein exudate were observed in the balloon cavity (Bian and The COVID-19 Pathology Team, 2020) . The renal tubular lumen was widened, while the renal tubular epithelium was flat, exhibiting interstitial edema, mild inflammatory cell infiltration, and fibrous hyperplasia . Occasionally, hemosiderin granules, protein tube types, and pigmented tube types were found. The proximal tubules were diffusely damaged. The brush border disappeared, and vacuoles were denatured or even necrotic . Transparent tube type was common in distal tubules. There was noticeable red blood cell aggregation blocking the capillary lumen, and a few cases exhibited diffuse intravascular coagulation and small fibrin thrombus in glomerular capillaries, with hyaline thrombus also in evidence .

Microscopic examination showed that spherical virus particles with coronavirus characteristics found within proximal tubule epithelial cells and podocytes may be the cause of acute tubular necrosis and proteinuria in some patients. Viral particles in podocytes may be associated with occasional vacuolation, disappearance of pod processes, and detachment of podocytes . Besides the direct toxicity of SARS-CoV-2, factors leading to acute kidney injury include coagulation abnormalities, systemic hypoxia, and possible drug-or hyperventilation-related rhabdomyolysis.

Immunohistochemical (IHC) staining revealed no specific aggregation of different inflammatory cells, with T and B cells being mixed in non-specific scar tissues infiltrated by lymphocytes and scattered macrophages. CD235a staining confirmed that microvascular obstructions were mainly composed of red blood cells .

Central nervous system complications have been observed to occur in a deceased COVID-19 patient. The autopsy revealed mild brain swelling and hemorrhagic lesions within the white matter of the cerebral hemisphere. There was axonal damage and accumulation of macrophages around the lesion . Cerebral hyperemia and edema, and degeneration and ischemic changes of some neurons were also seen in other cases. Some cases showed neurasthenia, perivascular inflammatory cell infiltration, and focal cerebral infarction. A few cases showed brain hernias (Bian and The COVID-19 Pathology Team, 2020) . A number of studies have also shown that after SARS-CoV-2 infection, patients suffered from disorders of smell, taste, or the respiratory center . The detection of viral copies by SARS-CoV-2specific qPCR showed that the viral load in nerve tissue was relatively low, but the viral load in the olfactory bulb was slightly higher than that in the brain stem, which supported the hypothesis that the virus entered the brain through plates .

Under light microscopy, it was observed that testicular samples of deceased COVID-19 patients exhibited different degrees of spermatogenic cell reduction and injury, obvious damage to the seminiferous tubules, swelling, vacuolation and shedding to the lumen of supporting cells, and decrease of interstitial cells along with interstitial edema and mild inflammation of lymphocytes . In some cases, no virus particles were observed by transmission electron microscope (TEM). No virus was detected within testicular samples by qPCR in a majority of patients . These findings suggest that although testicular parenchyma is significantly impaired, no virus is present in the testes in most cases. Thus, testicular damage may not be directly caused by the viral infection.

Red blood cells, medullary cells, and megakaryocytes decreased in most cases, with a few cases showing obvious hyperplasia (Bian and The COVID-19 Pathology Team, 2020).

Lymphocyte composition of spleen and lymph nodes was observed to decrease in varying degrees , with CD4 + and CD8 + T cells decreasing significantly (Bian and The COVID-19 Pathology Team, 2020) . Within the spleen, splenic nodules underwent atrophy were decreased or became deficient . Additionally, lymphocyte degeneration and necrosis and macrophage proliferation were observed (Bradley et al., 2020) . Hemorrhage and anemia infarction were commonly observed in the spleen. Nevertheless, coronavirus particles were observed in the cytoplasm of macrophages in only a few cases under electron microscopy. qPCR detection of 2019 novel coronavirus viral nucleic acids showed mostly negative results .

COVID-19 infection mainly occurs in the lungs, and the most prominent and important pathological changes are DAD and formation of pulmonary microthrombus, which can easily lead to hypoxia and thus respiratory failure. The disease may also involve various other organs and tissues (Table 1 ). Through qPCR detection of viral nucleic acids, electron microscopy, and IHC staining, SARS-CoV-2 RNA and viral particles have been detected in extrapulmonary tissues such as spleen, heart, liver, gallbladder, kidney, stomach, breast, testis, skin, nasopharynx, and oral mucosa, but the viral load is relatively small and not all COVID-19 patients exhibit direct evidence of viral infection in extrapulmonary tissues. Therefore, the injury of extra-pulmonary tissues may be caused by direct infection of the virus, a serious inflammatory reaction triggered by viral infection, or necrosis of tissue cells caused by hypoxia; or it may arise from the basic medical history of the patient. Elucidation of precise mechanisms requires analysis of more pathological biopsies. This article does not contain any studies with human or animal subjects performed by any of the authors.

Bian and The COVID-19 Pathology Team

Bian and The COVID-19 Pathology Team

Bian and The COVID-19 Pathology Team

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COVID-19 autopsies

Autopsy of COVID-19 patients in China

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ARDS and diffuse alveolar damage: a pathologist's perspective

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

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

COVID-19 pandemic and troponin: indirect myocardial injury, myocardial inflammation or myocarditis? Heart

Diffuse alveolar damage (DAD) resulting from coronavirus disease 2019 infection is morphologically indistinguishable from other causes of DAD

Structure, function, and evolution of coronavirus spike proteins

Clinical features of familial clustering in patients infected with 2019 novel coronavirus in Wuhan, China

Molecular immune pathogenesis and diagnosis of COVID-19

Properties of coronavirus and SARS-CoV-2

The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of "inflame-aging

MERS-CoV and H5N1 influenza virus antagonize antigen presentation by altering the epigenetic landscape

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

Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: structural genomics approach

The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin-angiotensin system

Expression and cleavage of middle east respiratory syndrome coronavirus nsp3-4 polyprotein induce the formation of double-membrane vesicles that mimic those associated with coronaviral RNA replication

Immune evasion via SARS-CoV-2 ORF8 protein

Multisystemic infarctions in COVID-19: focus on the spleen

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An overview of COVID-19

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Coronavirus membrane fusion mechanism offers a potential target for antiviral development

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A new coronavirus associated with human respiratory disease in China

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Pathological findings in the testes of COVID-19 patients: clinical implications

Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou

Bacterial and fungal infections in COVID-19 patients: a matter of concern

This work is supported by the National Key R&D Program of China (No. 2018YFC1105100) and the Zhejiang Provincial Natural Science Foundation of China (No. LY19H090021).

Zhonglin WU, Qi ZHANG, Guo YE, Hui ZHANG, and Boon Chin HENG took the lead in writing the manuscript. Zhonglin WU and Qi ZHANG completed manuscript framework firstly. Yang FEI and Bing ZHAO revised, edited, and checked the final version. Jing ZHOU conceptualized and designed this study. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.

Zhonglin WU, Qi ZHANG, Guo YE, Hui ZHANG, Boon Chin HENG, Yang FEI, Bing ZHAO, and Jing ZHOU declared that they have no conflict of interest.

Organ Lung Heart Liver Gallbladder Kidney Brain Testes Hematopoietic system Spleen Main pathological changes after SARS-CoV-2 infection Inflammatory lesions; different degrees of diffuse alveolar damage Procoagulant state and thrombosis Hepatocyte degeneration and necrosis, neutrophil and lymphocyte infiltration Gallbladder filling and mucosal epithelial exfoliation Glomerular segmental hyperplasia or necrosis; diffuse damage to the proximal tubules; transparent tube type common in distal tubules; inflammatory cell aggregation Different degrees of cerebral congestion and edema; some neurons ischemic, degenerative, and infarcted; inflammatory cell aggregation; disorders of smell, taste, or respiratory center Reduction and injury of parenchymal and stromal cells; mild inflammation Reduction or proliferation of red blood cells, bone marrow cells and megakaryocytes Hemorrhage and anemia infarction; atrophied, shrunk or absent splenic nodules; lymphocyte degeneration and necrosis