DOI: http://dx.doi.org/10.18203/2320-6012.ijrms20221501

Diverse immunopathological manifestations and immunogenomic predispositions in COVID-19: summarizing the evidence

Shramana Deb, Ritwick Mondal, Durjoy Lahiri, Upasana Ganguly, Gourav Shome

Abstract


The COVID-19 pandemic has caused immense damage to most nations of the world, both in terms of loss of human lives, as well as, socio-economic attributes. The immunopathogenesis of the responsible pathogen, SARS-CoV-2, has been a focal point and researchers have succeeded in deciphering the multi-organ tropism of the virus along with its different routes of infection. The hallmark feature of the SARS-CoV-2 disease pathogenesis is the high rates of transmission and the susceptibility of a vulnerable group with systemic co-morbidities. Also, genetic components of the host, as well as mutant variants of the virus have further complicated the development of appropriate treatment strategies and preventive measures. The virus is aptly able to modulate the host immune system and mediate immune-dysregulation in terms of cytokine or chemokine production leading to a heightened inflammatory response. In the current review, we have summarized the present research on SARS-CoV-2 from the angles of host genetic polymorphism, genetic variants of the virus, and how these affect the high transmission, disease susceptibility, and tissue tropism in multiple organs of the human body.


Keywords


COVID-19, Immunopathology, ACE2, Phylo-immunogenomics, Hypercytokinemia, Hypercomplementemia

Full Text:

PDF

References


Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265-9.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020;395(10223):497-506.

Mondal R, Lahiri D, Deb S, Bandyopadhyay D, Shome G, Sarkar S et al. COVID-19: Are we dealing with a multisystem vasculopathy in disguise of a viral infection? J Thromb Thrombolysis. 2020;50(3):567-79.

Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm' in COVID-19, J Infect. 2020;80(6):607-13.

Presti ML, Beck DB, Duggal P, Cummings DAT, Solomon BD. The Role of Host Genetic Factors in Coronavirus Susceptibility: Review of Animal and Systematic Review of Human Literature. Am J Hum Genet. 2020;107(3):381-402.

Bhaskar S, Sinha A, Banach M, Mittoo S, Weissert R, Kass JS et al.Cytokine storm in COVID-19—Immunopathological mechanisms, clinical considerations, and therapeutic approaches: The REPROGRAM Consortium position paper. Front in Immunology. 2020;11:1648.

Kimura H, Yoshizumi M, Ishii H, Oishi K, Ryo A. Cytokine production and signaling pathways in respiratory virus infection. Front Microbiol. 2013;4:276.

Mogensen TH, Paludan SR, Molecular pathways in virus-induced cytokine production. Microbiol Mol Biol Rev. 2001;65(1):131-50.

Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res. 2020;43(7):648-54.

Song W, Wang Y, Wang N, Wang D, Guo J, Fu L, Shi X. Identification of residues on human receptor DPP4 critical for MERS-CoV binding and entry. Virology. 2014;471-3.

Tang NL, Chan PK, Wong CK. Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome. Clin Chem. 2005;51(12):2333-40.

Chien JY, Hsueh PR, Cheng WC, Yu CJ, Yang PC, Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology. 2006;11(6):715-22.

Wong CK, Lam CW, Wu AK. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome, Clin Exp Immunol. 2004;136(1):95-103.

Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, Liu J et al. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome, Am J Respir Crit Care Med. 2005;171(8):850-7.

Huang KJ, Su IJ, Theron M, et al, An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. 2005;75(2):185-94.

Kim ES, Choe PG, Park WB. Clinical Progression and Cytokine Profiles of Middle East Respiratory Syndrome Coronavirus Infection. J Korean Med Sci. 2016;31(11):1717-25.

Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine. 2018;104:8-13.

Zhou J, Chu H, Li C. Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis. J Infect Dis. 2014;209(9):1331-42.

Chen G, Wu D, Guo W. Clinical and immunological features of severe and moderate coronavirus disease 2019, J Clin Invest. 2020;130(5):2620-9.

Qin C, Zhou L, Hu Z. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China, Clin Infect Dis. 2020;71(15):762-8.

Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181(5):1036-45.

Liu J, Zheng X, Tong Q. Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV. J Med Virol. 2020;92(5):491-4.

Chu H, Zhou J, Wong BH. Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response. Virology. 2014;454-5.

Johnson BS, Laloraya M. A cytokine super cyclone in COVID-19 patients with risk factors: the therapeutic potential of BCG immunization. Cytokine Growth Factor Rev. 2020;54:32-42.

Cheemarla NR, Brito AF, Fauver JR, Alpert T, Vogels CB, Omer SB et al. Host response-based screening to identify undiagnosed cases of COVID-19 and expand testing capacity. medRxiv. 2020.

Liu B, Li M, Zhou Z, Guan X, Xiang Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020;111:102452.

Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy. 2020;8(8):959-70.

Cameron MJ, Ran L, Xu L. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J Virol. 2007;81(16):8692-706.

Vaninov N. In the eye of the COVID-19 cytokine storm, Nat Rev Immunol. 2020;20:277.

Polak SB, Van Gool IC, Cohen D. A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression, Mod Pathol. 2020.

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S et al, Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z et al, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, The Lancet. 2020.

Barton LM, Duval EJ, Stroberg E, Ghosh S, Mukhopadhyay S. Covid-19 autopsies, Oklahoma, USA. American Journal of Clinical Pathology. 2020;153(6):725-33.

Ong EZ, Chan YFZ, Leong WY, Lee NMY, Kalimuddin S, Mohideen SM et al. A Dynamic Immune Response Shapes COVID-19 Progression. Cell Host Microbe. 2020.

Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39(5):529-39.

Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention, Nat Rev Immunol. 2020;20:363-74.

Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J et al. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing. Allergy and Immunology. 2020.

Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369(6504):718-24.

Varga Z. Endothelial cell infection and endothelitis in COVID-19. Lancet. 2020;395:1417-8.

Shi Z, Fu W. Diagnosis and treatment recommendation for novel coronavirus pneumonia related isolated distal deep vein thrombosis. Shanghai Medical Journal. 2020.

Han H, Yang L, Liu R. Prominent changes in blood coagulation of patients with SARS-COV_2 infection. Clin Chem Lab Med. 2020.

Xie Y, Wang X, Yang P, Zhang S. COVID-19 complicated by acute pulmonary embolism. Radiology. 2020;2(2):e200067.

Alvi RM, Frigault MJ, Fradley MG. Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T). J Am Coll Cardiol. 2020;74 (25):3099-108.

Mukandala G, Tynan R, Lanigan S, O’Connor JJ. The Effects of Hypoxia and Inflammation on Synaptic Signaling in the CNS. Brain Sci. 2016;6.

Xu X, Han M, Li T. Effective treatment of severe COVID-19 patients with Tocilizumab. 2020.

Rizzo P, Vieceli Dalla Sega F, Fortini F, Marracino L, Rapezzi C, Ferrari R. COVID-19 in the heart and the lungs: could we "Notch" the inflammatory storm? Basic Res Cardiol. 2020;115(3):31.

Tremblay ME, Madore C, Bordeleau M, Tian L, Verkhratsky A. Neuropathobiology of COVID-19: The Role for Glia. Front Cell Neurosci. 2020;14:592214.

Garg RK. Spectrum of Neurological Manifestations in Covid-19: A Review. Neurol India. 2020;68:560-72.

Virani A, Rabold E, Hanson T. Guillain-Barré Syndrome associated with SARS-CoV-2 infection. ID Cases. 2020;20:e00771.

Finsterer J, Scorza FA, Ghosh R. COVID-19 polyradiculitis in 24 patients without SARS-CoV-2 in the cerebro-spinal fluid. J Med Virol. 2020.

Yuki N. Guillain-Barré syndrome and anti-ganglioside antibodies: a clinician-scientist's journey. Proc Jpn Acad Ser B Phys Biol Sci. 2020;88(7):299-326.

Panariello A, Bassetti R, Radice A. Anti-NMDA receptor encephalitis in a psychiatric Covid-19 patient: A case report, Brain Behav Immun. 2020;87:179-81.

Pilotto A, Odolini S, Masciocchi S, Comelli A, Volonghi I, Gazzina S et al. Steroid-Responsive Encephalitis in Coronavirus Disease 2019. Ann Neurol. 2020.88(2):423-7.

Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: Imaging Features. Radiology. 2020;296(2):E119-20.

Mondal R, Deb S, Shome G, Ganguly U, Lahiri D, Leon JB. Spectrum of spinal cord involvement in COVID-19: A systematic review medRxiv. 2020.

Butler M, Pollak TA, Rooney AG, Michael BD, Nicholson TR. Neuropsychiatric complications of covid-19. BMJ. 2020;371:m3871.

Ferini-Strambi L, Salsone M. COVID-19 and neurological disorders: are neurodegenerative or neuroimmunological diseases more vulnerable? J Neurol. 2020;1-11.

Campbell IL. Trans-signaling is a dominant mechanism for the patho-genic actions of interleukin-6 in the brain. J Neurosci. 2014;34:2503-13.

Lindqvist D, Janelidze S, Hagell P. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry. 2009;66(3):287-92.

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.

Wang S, Cheng Q, Malik S, Yang J. Interleukin-1β inhibits γ-aminobutyricacid type A [GABA(A)] receptor current in cultured hippocampal neurons. J Pharm Exp Ther. 2000;292:497-504.

Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC. Cytokine effects on glutamate uptake by human astrocytes, Neuroimmunomodulation. 2000;7:153-9.

Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T. Clinical risk factors in SUDEP: a nationwide population-based case-control study. Neurology. 2000;94:e419-29.

Chaudhri I, Moffitt R, Taub E, Annadi RR, Hoai M, Bolotova O et al. Association of Proteinuria and Hematuria with Acute Kidney Injury and Mortality in Hospitalized Patients with COVID-19. Kidney Blood Press Res. 2020;45:1018-32.

Richardson S, Hirsch JS, Narasimhan M. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020;323(20):2052-9.

Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829-38.

Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020;98(1):219-27.

Gross O, Moerer O, Weber M, Huber TB, Scheithauer S. COVID-19-associated nephritis: early warning for disease severity and complications? Lancet. 2020;395(10236):e87-8.

Gaillard F, Ismael S, Sannier A, Tarhini H, Volpe T, Greze C et al. Tubuloreticular inclusions in COVID-19-related collapsing glomerulopathy. Kidney international. 2020;98(1):241.

Diao B, Wang C, Wang R, Feng Z, Tan Y, Wang H et al. Human Kidney is a target for novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. medRxiv. 2020.

van den Berg JG, Weening JJ. Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome, Clin Sci (Lond). 2004;107(2):125-36.

Siligato R, Cernaro V, Nardi C. Emerging therapeutic strategies for minimal change disease and focal and segmental glomerulosclerosis, Expert Opin Investig Drugs. 2018;27(11):839-79.

Angeletti A, Drovandi S, Sanguineri F, Santaniello M, Ferrando G, Forno R et al. COVID-19 in Children with Nephrotic Syndrome on Anti-CD20 Chronic Immunosuppression. Clin J Am Soc Nephrol. 2019;15(10):1494-5.

Chua HR, MacLaren G, Choong LH, Chionh CY, Khoo BZE, Yeo SC et al. Ensuring Sustainability of Continuous Kidney Replacement Therapy in the Face of Extraordinary Demand: Lessons From the COVID-19 Pandemic. Am J Kidney Dis. 2020;76(3):392-400.

Velez J, Caza T, Larsen CP. COVAN is the new HIVAN: the re-emergence of collapsing glomerulopathy with COVID-19. Nature reviews. Nephrology. 2020;16(10):565-7.

Pal R, Banerjee M. COVID-19 and the endocrine system: exploring the unexplored. J Endocrinol Invest. 2020;43(7):1027-31.

Liu F, Long X, Zou W, Fang M, Wu W, Li W, et al. Highly ACE2 expression in pancreas may cause pancreas damage after SARS-CoV-2 infection. medRxiv. 2020.

Jaeckel E, Manns M, Herrath M. Viruses and diabetes. Ann N Y Acad Sci. 2006;958:7-25.

Alsadhan I, Alruwashid S, Alhamad M, Alajmi S, Alshehri S, Alfadhli E et al. Diabetic ketoacidosis precipitated by Coronavirus disease 2019 infection: Case series. Curr Ther Res Clin Exp. 2000;93:100609.

Brancatella A, Ricci D, Viola N, Sgrò D, Santini F, Latrofa F. Subacute Thyroiditis After Sars-COV-2 Infection, J Clin Endocrinol Metab. 2000;105(7).

Wheatland R. Molecular mimicry of ACTH in SARS—implications for corticosteroid treatment and prophylaxis, Med Hypotheses. 2008;63:855-62.

Chen M, Zhou W, Xu W. Thyroid Function Analysis in 50 Patients with COVID-19: A Retrospective Study. Thyroid. 2020.

Scappaticcio L, Pitoia F, Esposito K, Piccardo A, Trimboli P. Impact of COVID-19 on the thyroid gland: an update. Rev Endocr Metab Disord. 2020;1-13.

Stasiak M, Tymoniuk B, Michalak R, Stasiak B, Kowalski ML, Lewiński A. Subacute Thyroiditis is Associated with HLA-B*18:01, -DRB1*01 and -C*04:01-The Significance of the New Molecular Background. J Clin Med. 2020;9(2):534.

Mateu-Salat M, Urgell E, Chico A. SARS-COV-2 as a trigger for autoimmune disease: report of two cases of Graves' disease after COVID-19. J Endocrinol Invest. 2020;43(10)1527-8.

Leow MK, Kwek DS, Ng AW, Ong KC, Kaw GJ, Lee LS. Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clin Endocrinol (Oxf). 2002;63(2):197-202.

Vardas K, Apostolou K, Briassouli E, Goukos D, Psarra K, Botoula E et al. Early Response Roles for Prolactin Cortisol and Circulating and Cellular Levels of Heat Shock Proteins 72 and 90α in Severe Sepsis and SIRS. BioMed Research International. 2014.

Somasundaram NP, Ranathunga I, Ratnasamy V, Wijewickrama PAV, Dissanayake HA, Yogendranathan N et al. The Impact of SARS-Cov-2 Virus Infection on the Endocrine System. Journal of the Endocrine Society. 2020;4(8).

Criado PR, Abdalla BMZ, de Assis IC, van Blarcum de Graaff Mello C, Caputo GC, Vieira IC. Are the cutaneous manifestations during or due to SARS-CoV-2 infection/COVID-19 frequent or not? Revision of possible pathophysiologic mechanisms. Inflamm Res. 2020;69(8):745-56.

Wollina U, Karadağ AS, Rowland-Payne C, Chiriac A, Lotti T. Cutaneous signs in COVID-19 patients: A review, Dermatol Ther. 2020;e13549.

Sachdeva M, Gianotti R, Shah M. Cutaneous manifestations of COVID-19: Report of three cases and a review of literature. J Dermatol Sci. 2021;98(2):75-81.

Gisondi P, PIaserico S, Bordin C, Alaibac M, Girolomoni G, Naldi L. Cutaneous manifestations of SARS-CoV-2 infection: a clinical update. J Eur Acad Dermatol Venereol. 2020.

Galvan-Casas C, Catala A, Carretero-Hernandez G. Five common skin manifestations of COVID-19 identified, Br J Dermatol. 2020;183(1):e16.

Bomhof G, Mutsaers PGNJ, Leebeek FWG. COVID-19-associated immune thrombocytopenia. Br J Haematol. 2020;190(2):e61-4.

Zhang Y, Xiao M, Zhang S. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020;382(17):e38.

Raut S, Roy Chowdhoury S, Bhakta S, Sarkar M, Nandi M. Incomplete Kawasaki Disease as Presentation of COVID-19 Infection in an Infant: A Case Report. Journal of Tropical Pediatrics. 2020;fmaa047.

Jones VG, Mills M, Suarez D. COVID-19 and Kawasaki Disease: Novel Virus and Novel Case. Hosp Pediatr. 2020;10(6).

Dominguez-Santas M, Diaz-Guimaraens B, Abellas GP, Real MGC, Burgos-Blasco P, Suarez-Valle A. Cutaneous small-vessel vasculitis associated with novel 2019 coronavirus SARS-CoV-2 infection (COVID-19). J Eur Acad Dermatol Venereol. 2020.

Chen N, Zhou M, Dong X. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507-13.

Guan W-Jie, Ni Z-yi, Hu Y. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020.

Wang D, Hu B, Hu C. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061.

Lin L, Jiang X, Zhang Z. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut. 2020;69:997-1001.

Parasa S, Desai M, Thoguluva Chandrasekar V. Prevalence of Gastrointestinal Symptoms and Fecal Viral Shedding in Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020;3(6):e2011335.

Lamers MM, Beumer J, Van Der Vaart J, Knoops K, Puschhof J, Breugem TI et al. SARS-CoV-2 productively infects human gut enterocytes. Science. 2020;eabc1669.

Lin L, Jiang X, Zhang Z. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut. 2020;69:997-1001.

Effenberger M, Grabherr F, Mayr L. Faecal calprotectin indicates intestinal inflammation in COVID-19. Gut. 2020;69:1543-44.

Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203-9.

Bostancıklıoğlu M. Temporal Correlation Between Neurological and Gastrointestinal Symptoms of SARS-CoV-2. Inflammatory Bowel Diseases. 2020;izaa131.

Available at: https://psychscenehub.com/psychinsights/covid-19-and-the-brain-pathogenesis-and-neuropsychiatric-manifestations-of-sars-cov-2-cns-involvement/. Accessed on 10 January 2021.

Esposito G, Pesce M, Seguella L, Sanseverino W, Lu J, Sarnelli G. Can the enteric nervous system be an alternative entrance door in SARS-CoV2 neuroinvasion? Brain, Behavior and Immunity. 2020;87.

Chai X, Hu L, Zhang H, Han W, Lu Z, Ke A et al. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV. Infection bioRxiv. 2020.02.03.931766.

Jothimani D, Venugopal R, Abedin MF, Kaliamoorthy I, Rela M. COVID-19 and the liver. J Hepatol. 2020;73(5):1231-40.

Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol. 2020;5(5):428-30.

Fix OK, Hameed B, Fontana RJ, Kwok RM, McGuire BM, Mulligan DC et al. Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement, Hepatology. 2020;72(1):287-304.

Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2022;8(4):420-2.

Tian S, Xiong Y, Liu H, Niu H, Guo J, Liao M. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol. 2020;33(6):1007-14.

Goldsmith CS, Tatti KM, Ksiazek TG, Rollin PE, Comer JA, Lee WW et al. Ultrastructural characterization of SARS coronavirus. Emerging infectious diseases. 2020;10(2):320.

Xu X, Chang XN, Pan HX. Pathological changes of the spleen in ten patients with coronavirus disease 2019(COVID-19) by postmortem needle autopsy. Zhonghua Bing li xue za zhi Chinese Journal of Pathology. 2020;49(6):576-82.