Pathology and Pathogenesis of Severe Acute Respiratory Syndrome
2007; Elsevier BV; Volume: 170; Issue: 4 Linguagem: Inglês
10.2353/ajpath.2007.061088
ISSN1525-2191
Autores Tópico(s)Long-Term Effects of COVID-19
ResumoSevere acute respiratory syndrome (SARS) is an emerging infectious viral disease characterized by severe clinical manifestations of the lower respiratory tract. The pathogenesis of SARS is highly complex, with multiple factors leading to severe injury in the lungs and dissemination of the virus to several other organs. The SARS coronavirus targets the epithelial cells of the respiratory tract, resulting in diffuse alveolar damage. Several organs/cell types may be infected in the course of the illness, including mucosal cells of the intestines, tubular epithelial cells of the kidneys, neurons of the brain, and several types of immune cells, and certain organs may suffer from indirect injury. Extensive studies have provided a basic understanding of the pathogenesis of this disease. In this review we describe the most significant pathological features of SARS, explore the etiological factors causing these pathological changes, and discuss the major pathogenetic mechanisms. The latter include dysregulation of cytokines/chemokines, deficiencies in the innate immune response, direct infection of immune cells, direct viral cytopathic effects, down-regulation of lung protective angiotensin converting enzyme 2, autoimmunity, and genetic factors. It seems that both abnormal immune responses and injury to immune cells may be key factors in the pathogenesis of this new disease. Severe acute respiratory syndrome (SARS) is an emerging infectious viral disease characterized by severe clinical manifestations of the lower respiratory tract. The pathogenesis of SARS is highly complex, with multiple factors leading to severe injury in the lungs and dissemination of the virus to several other organs. The SARS coronavirus targets the epithelial cells of the respiratory tract, resulting in diffuse alveolar damage. Several organs/cell types may be infected in the course of the illness, including mucosal cells of the intestines, tubular epithelial cells of the kidneys, neurons of the brain, and several types of immune cells, and certain organs may suffer from indirect injury. Extensive studies have provided a basic understanding of the pathogenesis of this disease. In this review we describe the most significant pathological features of SARS, explore the etiological factors causing these pathological changes, and discuss the major pathogenetic mechanisms. The latter include dysregulation of cytokines/chemokines, deficiencies in the innate immune response, direct infection of immune cells, direct viral cytopathic effects, down-regulation of lung protective angiotensin converting enzyme 2, autoimmunity, and genetic factors. It seems that both abnormal immune responses and injury to immune cells may be key factors in the pathogenesis of this new disease. Severe acute respiratory syndrome (SARS) first emerged in China's Guangdong Province in November 2002. During the following 3 months, it spread rapidly across the world, infecting individuals in several countries and thus resulting in the first human pandemic of the 21st century. At the end of the initial epidemic in August 2003, 8096 probable SARS cases had been reported, with a fatality rate of ∼10% (World Health Organization: http://www.who.int/csr/sars/country/table 2004_04_21/en/). Additional sporadic cases occurred in the period between the winter of 2003 and early spring of 2004 (World Health Organization: http://www.who.int/csr/don/archive/disease/severe_acute_respiratory_syndrome/en/index.html). 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The virus has been isolated from several animals, including civet cats and raccoon dogs, although neither of these animals is regarded as the true source.4Guan Y Zheng BJ He YQ Liu XL Zhuang ZX Cheung CL Luo SW Li PH Zhang LJ Guan YJ Butt KM Wong KL Chan KW Lim W Shortridge KF Yuen KY Peiris JS Poon LL Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China.Science. 2003; 302: 276-278Crossref PubMed Scopus (1832) Google Scholar Recently, certain bat species have been reported as potential natural reservoirs.5Li W Shi Z Yu M Ren W Smith C Epstein JH Wang H Crameri G Hu Z Zhang H Zhang J McEachern J Field H Daszak P Eaton BT Zhang S Wang LF Bats are natural reservoirs of SARS-like coronavirus.Science. 2005; 310: 676-679Crossref PubMed Scopus (1875) Google Scholar SARS is transmitted to and among humans by direct contact, droplet, and airborne routes.6Peiris JS Yuen KY Osterhaus AD Stohr K The severe acute respiratory syndrome.N Engl J Med. 2003; 349: 2431-2441Crossref PubMed Scopus (1029) Google Scholar Viral isolation from fecal and urinary samples suggests additional routes of transmission.6Peiris JS Yuen KY Osterhaus AD Stohr K The severe acute respiratory syndrome.N Engl J Med. 2003; 349: 2431-2441Crossref PubMed Scopus (1029) Google Scholar, 7Chan KH Poon LL Cheng VC Guan Y Hung IF Kong J Yam LY Seto WH Yuen KY Peiris JS Detection of SARS coronavirus in patients with suspected SARS.Emerg Infect Dis. 2004; 10: 294-299Crossref PubMed Scopus (261) Google Scholar SARS has a characteristic clinical course. Patients present with flu-like symptoms including fever, chills, cough, and malaise.8Donnelly CA Chani AC Leung GM Hedley AJ Fraser C Riley S Abu-Raddad LJ Ho LM Thach TQ Chau P Chan KP Lam TH Tse LY Tsang T Liu SH Kong JH Lau EM Ferguson NM Anderson RM Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong.Lancet. 2003; 361: 1761-1766Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar Approximately 70% of the patients subsequently suffer from shortness of breath and recurrent or persistent fever, whereas the remaining 30% show clinical improvement after the first week.6Peiris JS Yuen KY Osterhaus AD Stohr K The severe acute respiratory syndrome.N Engl J Med. 2003; 349: 2431-2441Crossref PubMed Scopus (1029) Google Scholar Approximately 20 to 30% of patients require intensive care treatment including mechanical ventilation.6Peiris JS Yuen KY Osterhaus AD Stohr K The severe acute respiratory syndrome.N Engl J Med. 2003; 349: 2431-2441Crossref PubMed Scopus (1029) Google Scholar Increased alanine aminotransferase, lactate dehydrogenase, thrombocytopenia, and lymphopenia have all been frequently detected in SARS patients.6Peiris JS Yuen KY Osterhaus AD Stohr K The severe acute respiratory syndrome.N Engl J Med. 2003; 349: 2431-2441Crossref PubMed Scopus (1029) Google Scholar, 8Donnelly CA Chani AC Leung GM Hedley AJ Fraser C Riley S Abu-Raddad LJ Ho LM Thach TQ Chau P Chan KP Lam TH Tse LY Tsang T Liu SH Kong JH Lau EM Ferguson NM Anderson RM Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong.Lancet. 2003; 361: 1761-1766Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar, 9Chan HLY Leung WK To KF Chan PKS Lee N Wu A Tam JSL Sung JJY Retrospective analysis of liver function derangement in severe acute respiratory syndrome.Am J Med. 2004; 116: 566-567Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 10He Z Zhao C Dong Q Zhuang H Song S Peng G Dwyer DE Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets.Int J Infect Dis. 2005; 9: 323-330Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 11Wong RSM Wu A To KF Lee N Lam CWK Wong CK Chan PKS Margaret HLN Yu LM Hui DS Tam JS Cheng G Sung JJY Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis.BMJ. 2003; 326: 1358-1362Crossref PubMed Scopus (468) Google Scholar In patients younger than 60 years of age the estimated fatality rate amounts to 6.8% and in older patients attains an estimated 43%.8Donnelly CA Chani AC Leung GM Hedley AJ Fraser C Riley S Abu-Raddad LJ Ho LM Thach TQ Chau P Chan KP Lam TH Tse LY Tsang T Liu SH Kong JH Lau EM Ferguson NM Anderson RM Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong.Lancet. 2003; 361: 1761-1766Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar A number of complete and partial autopsies of SARS patients have been reported since the first outbreak in 2003. The predominant pathological finding in these cases was diffuse alveolar damage (DAD). This severe pulmonary injury of SARS patients is caused both by direct viral effects and immunopathogenetic factors. Many important aspects of the pathology and pathogenesis of SARS have not yet been fully clarified. Here, we offer a comprehensive overview of the morphological and histopathological findings present in different organs and cells. In addition, we summarize the most important mechanisms that may play a role in the seemingly complex pathogenesis of this new disease. Certain organs of SARS victims, such as the lungs and intestines, have been extensively studied, and the pathological lesions of SARS in these organs are fairly well known. By contrast, the pathology of other organs is incompletely described, and imperfectly known. For ease of reference, the major pathological findings for each organ are summarized in Table 1. Table 2 lists the results of ancillary tests that have been used to confirm the diagnosis, including in situ hybridization, immunohistochemistry (IHC) with antibodies against viral antigens, reverse transcriptase-polymerase chain reaction (RT-PCR), electron microscopic (EM) examination, and viral culture.Table 1Major Pathological Findings in Various Organs and TissueOrgans/tissuePathologyNumber of casesReferencesRespiratory tractDiffuse alveolar damage with varying degrees of acute exudative features including edema and hyaline membranes, organization, and fibrosis. Macrophagic or mixed cellular infiltration, multinuclear giant cells, atypical reactive pneumocytes, and vascular injury. Positive in situ hybridization signals in pneumocytes, lymphocytes, and macrophages6312Ding YQ Wang HJ Shen H Li ZG Geng J Han HX Cai JJ Li X Kang W Weng DS Lu YD Wu DH He L Yao KT The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.J Pathol. 2003; 200: 282-289Crossref PubMed Scopus (628) Google Scholar, 13Lang ZW Zhang LJ Zhang SJ Meng X Li JQ Song CZ Sun L Zhou YS Dwyer DE A clinicopathological study of three cases of severe acute respiratory syndrome (SARS).Pathology. 2003; 35: 526-531Crossref PubMed Scopus (91) Google Scholar, 14Tse GMK To KF Chan PKS Lo AWI Ng KC Wu A Lee N Wong HC Mak SM Chan KF Hui DSC Sung JJY Ng HK Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS).J Clin Pathol. 2004; 57: 260-265Crossref PubMed Scopus (181) Google Scholar, 15Gu J Gong EC Zhang B Zheng J Gao ZF Zhong YF Zou WZ Zhan J Wang SL Xie ZG Zhuang H Wu BQ Zhong HH Shao HQ Fang WG Gao DX Pei F Li XW He ZP Xu DZ Shi XY Anderson VM Leong ASY Multiple organ infection and the pathogenesis of SARS.J Exp Med. 2005; 202: 415-424Crossref PubMed Scopus (1079) Google Scholar, 16Nicholls JM Poon LL Lee KC Ng WF Lai ST Leung CY Chu CM Hui PK Mak KL Lim W Yan KW Chan KH Tsang NC Guan Y Yuen KY Peiris JS Lung pathology of fatal severe acute respiratory syndrome.Lancet. 2003; 361: 1773-1778Abstract Full Text Full Text PDF PubMed Scopus (915) Google Scholar, 18Cheung OY Chan JW Ng CK Koo CK The spectrum of pathological changes in severe acute respiratory syndrome (SARS).Histopathology. 2004; 45: 119-124Crossref PubMed Scopus (72) Google Scholar, 19Hwang DM Chamberlain DW Poutanen SM Low DE Asa SL Butany J Pulmonary pathology of severe acute respiratory syndrome in Toronto.Mod Pathol. 2005; 18: 1-10Crossref PubMed Scopus (268) Google Scholar, 20Franks TJ Chong PY Chui P Galvin JR Lourens RM Reid AH Selbs E McEvoy CPL Hayden CDL Fukuoka J Taubenberger JK Travis WD Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore.Hum Pathol. 2003; 34: 743-748Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 21Hsiao CH Wu MZ Chen CL Hsueh PR Hsieh SW Yang PC Su IJ Evolution of pulmonary pathology in severe acute respiratory syndrome.J Formos Med Assoc. 2005; 104: 75-81PubMed Google Scholar, 22Nakajima N Asahi-Ozaki Y Nagata N Yko S Dizon F Paladin FJ Olveda RM Odagiri T Masato T Sata T SARS coronavirus-infected cells in lung detected by new in situ hybridization technique.Jpn J Infect Dis. 2003; 56: 139-141PubMed Google Scholar, 23He L Ding Y Zhang Q Che X He Y Shen H Wang H Li Z Zhao L Geng J Deng Y Yang L Li J Cai J Qiu L Wen K Xu X Jiang S Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2(+) cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS.J Pathol. 2006; 210: 288-297Crossref PubMed Scopus (331) Google ScholarSpleen and lymph nodesLymphocyte depletion in spleen and lymph nodes with architectural disruption. Splenic white pulp atrophy. Positive in situ hybridization signals in immune cells2511Wong RSM Wu A To KF Lee N Lam CWK Wong CK Chan PKS Margaret HLN Yu LM Hui DS Tam JS Cheng G Sung JJY Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis.BMJ. 2003; 326: 1358-1362Crossref PubMed Scopus (468) Google Scholar, 12Ding YQ Wang HJ Shen H Li ZG Geng J Han HX Cai JJ Li X Kang W Weng DS Lu YD Wu DH He L Yao KT The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.J Pathol. 2003; 200: 282-289Crossref PubMed Scopus (628) Google Scholar, 13Lang ZW Zhang LJ Zhang SJ Meng X Li JQ Song CZ Sun L Zhou YS Dwyer DE A clinicopathological study of three cases of severe acute respiratory syndrome (SARS).Pathology. 2003; 35: 526-531Crossref PubMed Scopus (91) Google Scholar, 15Gu J Gong EC Zhang B Zheng J Gao ZF Zhong YF Zou WZ Zhan J Wang SL Xie ZG Zhuang H Wu BQ Zhong HH Shao HQ Fang WG Gao DX Pei F Li XW He ZP Xu DZ Shi XY Anderson VM Leong ASY Multiple organ infection and the pathogenesis of SARS.J Exp Med. 2005; 202: 415-424Crossref PubMed Scopus (1079) Google Scholar, 16Nicholls JM Poon LL Lee KC Ng WF Lai ST Leung CY Chu CM Hui PK Mak KL Lim W Yan KW Chan KH Tsang NC Guan Y Yuen KY Peiris JS Lung pathology of fatal severe acute respiratory syndrome.Lancet. 2003; 361: 1773-1778Abstract Full Text Full Text PDF PubMed Scopus (915) Google Scholar, 17Chong PY Chui P Ling AE Franks TJ Tai DY Leo YS Kaw GJ Wansaicheong G Chan KP Ean Oon LL Teo ES Tan KB Nakajima N Sata T Travis WD Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis.Arch Pathol Lab Med. 2004; 128: 195-204PubMed Google Scholar, 27Zhan J Deng R Tang J Zhang B Tang Y Wang JK Li F Anderson VM McNutt MA Gu J The spleen as a target in severe acute respiratory syndrome.FASEB J. 2006; 20: 2321-2328Crossref PubMed Scopus (31) Google ScholarDigestive tractIntestines: no obvious pathological changes/nonspecific changes. Depletion of mucosal lymphoid tissue. Positive in situ hybridization signals in mucosal epithelial cells1912Ding YQ Wang HJ Shen H Li ZG Geng J Han HX Cai JJ Li X Kang W Weng DS Lu YD Wu DH He L Yao KT The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.J Pathol. 2003; 200: 282-289Crossref PubMed Scopus (628) Google Scholar, 13Lang ZW Zhang LJ Zhang SJ Meng X Li JQ Song CZ Sun L Zhou YS Dwyer DE A clinicopathological study of three cases of severe acute respiratory syndrome (SARS).Pathology. 2003; 35: 526-531Crossref PubMed Scopus (91) Google Scholar, 39Shi X Gong E Gao D Zhang B Zheng J Gao Z Zhong Y Zou W Wu B Fang W Liao S Wang S Xie Z Lu M Hou L Zhong H Shao H Li N Liu C Pei F Yang J Wang Y Han Z Shi X Zhang Q You J Zhu X Gu J Severe acute respiratory syndrome associated coronavirus is detected in intestinal tissues of fatal cases.Am J Gastroenterol. 2005; 100: 169-176Crossref PubMed Scopus (83) Google Scholar, 46Leung WK To KF Chan PK Chan HL Wu AK Lee N Yuen KY Sung JJ Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection.Gastroenterology. 2003; 125: 1011-1017Abstract Full Text Full Text PDF PubMed Scopus (550) Google ScholarLiver: no specific pathological changes. In some cases, necrosis and evidence of apoptosis209Chan HLY Leung WK To KF Chan PKS Lee N Wu A Tam JSL Sung JJY Retrospective analysis of liver function derangement in severe acute respiratory syndrome.Am J Med. 2004; 116: 566-567Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 12Ding YQ Wang HJ Shen H Li ZG Geng J Han HX Cai JJ Li X Kang W Weng DS Lu YD Wu DH He L Yao KT The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.J Pathol. 2003; 200: 282-289Crossref PubMed Scopus (628) Google Scholar, 13Lang ZW Zhang LJ Zhang SJ Meng X Li JQ Song CZ Sun L Zhou YS Dwyer DE A clinicopathological study of three cases of severe acute respiratory syndrome (SARS).Pathology. 2003; 35: 526-531Crossref PubMed Scopus (91) Google Scholar, 17Chong PY Chui P Ling AE Franks TJ Tai DY Leo YS Kaw GJ Wansaicheong G Chan KP Ean Oon LL Teo ES Tan KB Nakajima N Sata T Travis WD Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis.Arch Pathol Lab Med. 2004; 128: 195-204PubMed Google Scholar, 39Shi X Gong E Gao D Zhang B Zheng J Gao Z Zhong Y Zou W Wu B Fang W Liao S Wang S Xie Z Lu M Hou L Zhong H Shao H Li N Liu C Pei F Yang J Wang Y Han Z Shi X Zhang Q You J Zhu X Gu J Severe acute respiratory syndrome associated coronavirus is detected in intestinal tissues of fatal cases.Am J Gastroenterol. 2005; 100: 169-176Crossref PubMed Scopus (83) Google Scholar, 48Chau TN Lee KC Yao H Tsang TY Chow TC Yeung YC Choi KW Tso YK Lau T Lai ST Lai CL SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases.Hepatology. 2004; 39: 302-310Crossref PubMed Scopus (329) Google ScholarUrogenital tractKidneys: acute tubular necrosis, in varying degrees and other nonspecific features. Positive in situ hybridization signals in the epithelial cells of the distal tubules2112Ding YQ Wang HJ Shen H Li ZG Geng J Han HX Cai JJ Li X Kang W Weng DS Lu YD Wu DH He L Yao KT The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.J Pathol. 2003; 200: 282-289Crossref PubMed Scopus (628) Google Scholar, 13Lang ZW Zhang LJ Zhang SJ Meng X Li JQ Song CZ Sun L Zhou YS Dwyer DE A clinicopathological study of three cases of severe acute respiratory syndrome (SARS).Pathology. 2003; 35: 526-531Crossref PubMed Scopus (91) Google Scholar, 15Gu J Gong EC Zhang B Zheng J Gao ZF Zhong YF Zou WZ Zhan J Wang SL Xie ZG Zhuang H Wu BQ Zhong HH Shao HQ Fang WG Gao DX Pei F Li XW He ZP Xu DZ Shi XY Anderson VM Leong ASY Multiple organ infection and the pathogenesis of SARS.J Exp Med. 2005; 202: 415-424Crossref PubMed Scopus (1079) Google Scholar, 17Chong PY Chui P Ling AE Franks TJ Tai DY Leo YS Kaw GJ Wansaicheong G Chan KP Ean Oon LL Teo ES Tan KB Nakajima N Sata T Travis WD Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis.Arch Pathol Lab Med. 2004; 128: 195-204PubMed Google Scholar, 43Chu KH Tsang WK Tang CS Lam MF Lai FM To KF Fung KS Tang HL Yan WW Chan HW Lai TS Tong KL Lai KN Acute renal impairment in coronavirus-associated severe acute respiratory syndrome.Kidney Int. 2005; 67: 698-705Crossref PubMed Scopus (356) Google Scholar, 44Wu VC Hsueh PR Lin WC Huang JW Tsai HB Chen YM Wu KD the SARS Research Group of the National Taiwan Acute renal failure in SARS patients: more than rhabdomyolysis.Nephrol Dial Transplant. 2004; 19: 3180-3182Crossref PubMed Scopus (24) Google ScholarCentral nervous systemEdema and degeneration of neurons, several neurons in situ hybridization-positive1212Ding YQ Wang HJ Shen H Li ZG Geng J Han HX Cai JJ Li X Kang W Weng DS Lu YD Wu DH He L Yao KT The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.J Pathol. 2003; 200: 282-289Crossref PubMed Scopus (628) Google Scholar, 15Gu J Gong EC Zhang B Zheng J Gao ZF Zhong YF Zou WZ Zhan J Wang SL Xie ZG Zhuang H Wu BQ Zhong HH Shao HQ Fang WG Gao DX Pei F Li XW He ZP Xu DZ Shi XY Anderson VM Leong ASY Multiple organ infection and the pathogenesis of SARS.J Exp Med. 2005; 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10: 489-493Crossref PubMed Scopus (65) Google ScholarSkeletal MusclesMyofiber necrosis and atrophy, few regenerative myofibers1312Ding YQ Wang HJ Shen H Li ZG Geng J Han HX Cai JJ Li X Kang W Weng DS Lu YD Wu DH He L Yao KT The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.J Pathol. 2003; 200: 282-289Crossref PubMed Scopus (628) Google Scholar, 44Wu VC Hsueh PR Lin WC Huang JW Tsai HB Chen YM Wu KD the SARS Research Group of the National Taiwan Acute renal failure in SARS patients: more than rhabdomyolysis.Nephrol Dial Transplant. 2004; 19: 3180-3182Crossref PubMed Scopus (24) Google Scholar, 46Leung WK To KF Chan PK Chan HL Wu AK Lee N Yuen KY Sung JJ Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection.Gastroenterology. 2003; 125: 1011-1017Abstract Full Text Full Text PDF PubMed Scopus (550) Google ScholarAdrenal glandNecrosis and infiltration of monocytes and lymphocytes1412Ding YQ Wang HJ Shen H Li ZG Geng J Han HX Cai JJ Li X Kang W Weng DS Lu YD Wu DH He L Yao KT The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.J Pathol. 2003; 200: 282-289Crossref PubMed Scopus (628) Google Scholar, 13Lang ZW Zhang LJ Zhang SJ Meng X Li JQ Song CZ Sun L Zhou YS Dwyer DE A clinicopathological study of three cases of severe acute respiratory syndrome (SARS).Pathology. 2003; 35: 526-531Crossref PubMed Scopus (91) Google Scholar, 15Gu J Gong EC Zhang B Zheng J Gao ZF Zhong YF Zou WZ Zhan J Wang SL Xie ZG Zhuang H Wu BQ Zhong HH Shao HQ Fang WG Gao DX Pei F Li XW He ZP Xu DZ Shi XY Anderson VM Leong ASY Multiple organ infection and the pathogenesis of SARS.J Exp Med. 2005; 202: 415-424Crossref PubMed Scopus (1079) Google ScholarThyroid glandDestruction of follicular epithelial cells, several apoptotic cells549Wei L Sun S Xu CH Zhang J Xu Y Zhu H Peh SC Korteweg C McNutt MA Gu J Pathology of the thyroid in severe acute respiratory syndrome.Hum Pathol. 2007; 38: 95-102Abstract Full Text Full Text PDF PubMed Scopus (163) Google ScholarTestesGerm cell destruction, apoptotic spermatogenetic cells745Xu J Qi L Chi X Yang J Wei X Gong E Peh S Gu J Orchitis: a complication of severe acute respiratory syndrome (SARS).Biol Reprod. 2006; 74: 410-416Crossref PubMed Scopus (332) Google ScholarHeartEdema and atrophy of myocardial fibers2212Ding YQ Wang HJ Shen H Li ZG Geng J Han HX Cai JJ Li X Kang W Weng DS Lu YD Wu DH He L Yao KT The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.J Pathol. 2003; 200: 282-289Crossref PubMed Scopus (628) Google Scholar, 13Lang ZW Zhang LJ Zhang SJ Meng X Li JQ Song CZ Sun L Zhou YS Dwyer DE A clinicopathological study of three cases of severe acute respiratory syndrome (SARS).Pathology. 2003; 35: 526-531Crossref PubMed Scopus (91) Google Scholar, 15Gu J Gong EC Zhang B Zheng J Gao ZF Zhong YF Zou WZ Zhan J Wang SL Xie ZG Zhuang H Wu BQ Zhong HH Shao HQ Fang WG Gao DX Pei F Li XW He ZP Xu DZ Shi XY Anderson VM Leong ASY Multiple organ infection and the pathogenesis of SARS.J Exp Med. 2005; 202: 415-424Crossref PubMed Scopus (1079) Google Scholar, 17Chong PY Chui P Ling AE Franks TJ Tai DY Leo YS Kaw GJ Wansaicheong G Chan KP Ean Oon LL Teo ES Tan KB Nakajima N Sata T Travis WD Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis.Arch Pathol Lab Med. 2004; 128: 195-204PubMed Google Scholar Open table in a new tab Table 2Results of Ancillary Tests, Used to Confirm SARS-CoV Infection in Lung and Intestinal TissueAdditional testPositive test results/total tests (lung tissue)Positive test results/total tests (intestinal tissue)References (lungs)References (intestines)Longest duration reported with positive test results in lungs/intestinesRT-PCR47/5512/2318Cheung OY Chan JW Ng CK Koo CK The spectrum of pathological changes in severe acute respiratory syndrome (SARS).Histopathology. 2004; 45: 119-124Crossref PubMed Scopus (72) Google Scholar, 20Franks TJ Chong PY Chui P Galvin JR Lourens RM Reid AH Selbs E McEvoy CPL Hayden CDL Fukuoka J Taubenberger JK Travis WD Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore.Hum Pathol. 2003; 34: 743-748Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 22Nakajima N Asahi-Ozaki Y Nagata N Yko S Dizon F Paladin FJ Olveda RM Odagiri T Masato T Sata T SARS coronavirus-infected cells in lung detected by new in situ hybridization technique.Jpn J Infect Dis. 2003; 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