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Pathology and Pathogenesis of Severe Acute Respiratory Syndrome

  • Jiang Gu
    Correspondence
    Address reprint requests to Jiang Gu, M.D., Ph.D., Professor and Chairman, Department of Pathology, Dean, School of Medical Sciences, Director, Infectious Disease Center, Peking (Beijing) University, 38 Xueyuan Rd., 100083 Beijing, China
    Affiliations
    Department of Pathology and Infectious Disease Center, School of Basic Medical Sciences, Peking (Beijing) University, Beijing, China
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  • Christine Korteweg
    Affiliations
    Department of Pathology and Infectious Disease Center, School of Basic Medical Sciences, Peking (Beijing) University, Beijing, China
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      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).
      A novel coronavirus was identified as the etiological agent of SARS.
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      This virus (SARS-CoV) belongs to a family of large, positive, single-stranded RNA viruses.
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      Nevertheless, genomic characterization showed that the SARS-CoV is only moderately related to other known coronaviruses.
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      • van der Werf S
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      • Becker S
      • Rabenau H
      • Panning M
      • Kolesnikova L
      • Fouchier RA
      • Berger A
      • Burguiere AM
      • Cinatl J
      • Eickmann M
      • Escriou N
      • Grywna K
      • Kramme S
      • Manuguerra JC
      • Muller S
      • Rickerts V
      • Sturmer M
      • Vieth S
      • Klenk HD
      • Osterhaus AD
      • Schmitz H
      • Doerr HW
      Identification of a novel coronavirus in patients with severe acute respiratory syndrome.
      • Marra MA
      • Jones SJ
      • Astell CR
      • Holt RA
      • Brooks-Wilson A
      • Butterfield YS
      • Khattra J
      • Asano JK
      • Barber SA
      • Chan SY
      • Cloutier A
      • Coughlin SM
      • Freeman D
      • Girn N
      • Griffith OL
      • Leach SR
      • Mayo M
      • McDonald H
      • Montgomery SB
      • Pandoh PK
      • Petrescu AS
      • Robertson AG
      • Schein JE
      • Siddiqui A
      • Smailus DE
      • Stott JM
      • Yang GS
      • Plummer F
      • Andonov A
      • Artsob H
      • Bastien N
      • Bernard K
      • Booth TF
      • Bowness D
      • Czub M
      • Drebot M
      • Fernando L
      • Flick R
      • Garbutt M
      • Gray M
      • Grolla A
      • Jones S
      • Feldmann H
      • Meyers A
      • Kabani A
      • Li Y
      • Normand S
      • Stroher U
      • Tipples GA
      • Tyler S
      • Vogrig R
      • Ward D
      • Watson B
      • Brunham RC
      • Krajden M
      • Petric M
      • Skowronski DM
      • Upton C
      • Roper RL
      The genome sequence of the SARS-associated coronavirus.
      In contrast with previously described coronaviruses, SARS-CoV infection typically causes severe symptoms related to the lower respiratory tract. 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.
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      Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China.
      Recently, certain bat species have been reported as potential natural reservoirs.
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      Bats are natural reservoirs of SARS-like coronavirus.
      SARS is transmitted to and among humans by direct contact, droplet, and airborne routes.
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      The severe acute respiratory syndrome.
      Viral isolation from fecal and urinary samples suggests additional routes of transmission.
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      The severe acute respiratory syndrome.
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      Detection of SARS coronavirus in patients with suspected SARS.
      SARS has a characteristic clinical course. Patients present with flu-like symptoms including fever, chills, cough, and malaise.
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      Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong.
      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.
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      The severe acute respiratory syndrome.
      Approximately 20 to 30% of patients require intensive care treatment including mechanical ventilation.
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      The severe acute respiratory syndrome.
      Increased alanine aminotransferase, lactate dehydrogenase, thrombocytopenia, and lymphopenia have all been frequently detected in SARS patients.
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      The severe acute respiratory syndrome.
      • Donnelly CA
      • Chani AC
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      • Ferguson NM
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      Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong.
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      Retrospective analysis of liver function derangement in severe acute respiratory syndrome.
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      Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets.
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      In patients younger than 60 years of age the estimated fatality rate amounts to 6.8% and in older patients attains an estimated 43%.
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      Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong.
      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.

      Pathology

      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 Tissue
      Organs/tissuePathologyNumber of casesReferences
      Respiratory 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 macrophages63
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      Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS).
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      Multiple organ infection and the pathogenesis of SARS.
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      Lung pathology of fatal severe acute respiratory syndrome.
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      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
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      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.
      Spleen and lymph nodesLymphocyte depletion in spleen and lymph nodes with architectural disruption. Splenic white pulp atrophy. Positive in situ hybridization signals in immune cells25
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      Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis.
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      Multiple organ infection and the pathogenesis of SARS.
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      Lung pathology of fatal severe acute respiratory syndrome.
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      Digestive tractIntestines: no obvious pathological changes/nonspecific changes. Depletion of mucosal lymphoid tissue. Positive in situ hybridization signals in mucosal epithelial cells19
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      Retrospective analysis of liver function derangement in severe acute respiratory syndrome.
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      Urogenital tractKidneys: acute tubular necrosis, in varying degrees and other nonspecific features. Positive in situ hybridization signals in the epithelial cells of the distal tubules21
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      The clinical pathology of severe acute respiratory syndrome (SARS): a report from China.
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      Central nervous systemEdema and degeneration of neurons, several neurons in situ hybridization-positive12
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      • 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.
      ,
      • Xu J
      • Zhong S
      • Liu J
      • Li L
      • Li Y
      • Wu X
      • Li Z
      • Deng P
      • Zhang J
      • Zhong N
      • Ding Y
      • Jiang Y
      Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis.
      Bone marrowIn some cases, reactive hemophagocytosis9
      • Chan 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.
      ,
      • Ding 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.
      ,
      • Hsueh PR
      • Chen PJ
      • Hsiao CH
      • Yeh SH
      • Cheng WC
      • Wang JL
      • Chiang BL
      • Chang SC
      • Chang FY
      • Wong WW
      • Kao CL
      • Yang PC
      • SARS Research Group of National Taiwan University College of Medicine and National Taiwan University Hospital
      Patient data, early SARS epidemic, Taiwan.
      Skeletal MusclesMyofiber necrosis and atrophy, few regenerative myofibers13
      • Ding 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.
      ,
      • Wu 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.
      ,
      • Leung 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.
      Adrenal glandNecrosis and infiltration of monocytes and lymphocytes14
      • Ding 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.
      ,
      • Lang 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).
      ,
      • Gu 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.
      Thyroid glandDestruction of follicular epithelial cells, several apoptotic cells5
      • Wei 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.
      TestesGerm cell destruction, apoptotic spermatogenetic cells7
      • Xu J
      • Qi L
      • Chi X
      • Yang J
      • Wei X
      • Gong E
      • Peh S
      • Gu J
      Orchitis: a complication of severe acute respiratory syndrome (SARS).
      HeartEdema and atrophy of myocardial fibers22
      • Ding 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.
      ,
      • Lang 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).
      ,
      • Gu 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.
      ,
      • Chong 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.
      Table 2Results of Ancillary Tests, Used to Confirm SARS-CoV Infection in Lung and Intestinal Tissue
      Additional 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/intestines
      RT-PCR47/5512/23
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      ,
      • Franks 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.
      ,
      • Nakajima 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.
      ,
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Chong 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.
      ,
      • Farcas GA
      • Poutanen SM
      • Mazzulli T
      • Willey BM
      • Butany J
      • Asa SL
      • Faure P
      • Akhavan P
      • Low DE
      • Kain KC
      Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus.
      51 days
      • Farcas GA
      • Poutanen SM
      • Mazzulli T
      • Willey BM
      • Butany J
      • Asa SL
      • Faure P
      • Akhavan P
      • Low DE
      • Kain KC
      Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus.
      /43 days
      • Farcas GA
      • Poutanen SM
      • Mazzulli T
      • Willey BM
      • Butany J
      • Asa SL
      • Faure P
      • Akhavan P
      • Low DE
      • Kain KC
      Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus.
      In situ hybridization31/67
      In 63 SARS cases, the findings on general histopathology have been reported, whereas in 67 cases, the results of in situ hybridization have been reported. This difference is attributable to the fact that some recently published studies have only described in situ hybridization results without reporting general pathology.
      18/24
      • Lang 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).
      ,
      • Gu 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.
      ,
      • Chong 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.
      ,
      • Nakajima 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.
      ,
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      ,
      • Chan WS
      • Wu C
      • Chow SC
      • Cheung T
      • To KF
      • Leung WK
      • Chan PK
      • Lee KC
      • Ng HK
      • Au DM
      • Lo AW
      Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
      ,
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      (23),
      These results have been published in two different journals.
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      ,
      • Chow KC
      • Hsiao CH
      • Lin TY
      • Chen CL
      • Chiou SH
      Detection of severe acute respiratory syndrome-associated coronavirus in pneumocytes of the lung.
      • Chan WS
      • Wu C
      • Chow SC
      • Cheung T
      • To KF
      • Leung WK
      • Chan PK
      • Lee KC
      • Ng HK
      • Au DM
      • Lo AW
      Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
      ,
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      (23),
      These results have been published in two different journals.
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      ,
      • Shi 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.
      62 days
      • Gu 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.
      /45 days
      • Shi 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.
      IHC12/479/11
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      ,
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      ,
      • Chan WS
      • Wu C
      • Chow SC
      • Cheung T
      • To KF
      • Leung WK
      • Chan PK
      • Lee KC
      • Ng HK
      • Au DM
      • Lo AW
      Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
      ,
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      (23)
      These results have been published in two different journals.
      • Chan WS
      • Wu C
      • Chow SC
      • Cheung T
      • To KF
      • Leung WK
      • Chan PK
      • Lee KC
      • Ng HK
      • Au DM
      • Lo AW
      Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
      ,
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      (23)
      These results have been published in two different journals.
      20 days
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      /20 days
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      EM26/3812/20
      • Ding 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.
      ,
      • Tse 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).
      (29),
      These results have been published in two different journals.
      • Gu 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.
      ,
      • Nicholls 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.
      ,
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      ,
      • Nakajima 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.
      ,
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Chan WS
      • Wu C
      • Chow SC
      • Cheung T
      • To KF
      • Leung WK
      • Chan PK
      • Lee KC
      • Ng HK
      • Au DM
      • Lo AW
      Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
      ,
      • Shi 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.
      ,
      • Leung 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.
      46 days
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      /21 days
      • Shi 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.
      Viral culture10/2315/27
      • Tse 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).
      (29),
      These results have been published in two different journals.
      • Chong 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.
      ,
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      • Tse 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).
      (29),
      These results have been published in two different journals.
      • Chong 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.
      ,
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      ,
      • Leung 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.
      20 days
      • Nicholls 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.
      /16 days
      • Tse 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).
      For each test, the number of positive cases and the total number of cases are listed.
      * In 63 SARS cases, the findings on general histopathology have been reported, whereas in 67 cases, the results of in situ hybridization have been reported. This difference is attributable to the fact that some recently published studies have only described in situ hybridization results without reporting general pathology.
      These results have been published in two different journals.

      Respiratory Tract

      The pathological findings in the lungs of more than 60 autopsies of SARS cases have been reported. On gross examination, the lungs were edematous and increased in weight.
      • Ding 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.
      • Lang 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).
      • Tse 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).
      • Gu 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.
      • Nicholls 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.
      • Chong 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.
      In most cases, they showed extensive consolidation.
      • Ding 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.
      • Tse 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).
      • Gu 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.
      • Nicholls 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.
      • Chong 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.
      Histopathologically, the lungs in SARS characteristically show DAD. During the first phase of the disease (7 to 10 days), SARS lungs display the following features of acute exudative DAD
      • Ding 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.
      • Lang 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).
      • Nicholls 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.
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      • Franks 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.
      • Hsiao CH
      • Wu MZ
      • Chen CL
      • Hsueh PR
      • Hsieh SW
      • Yang PC
      • Su IJ
      Evolution of pulmonary pathology in severe acute respiratory syndrome.
      • Nakajima 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.
      • He 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.
      (Figure 1A): 1) extensive edema, 2) hyaline membrane formation, 3) collapse of alveoli, 4) desquamation of alveolar epithelial cells, and 5) fibrous tissue in alveolar spaces. In cases of longer disease duration, features of fibrous organization of DAD appear after ∼10 to 14 days, such as interstitial and airspace fibrosis and pneumocytic hyperplasia.
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      • Franks 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.
      • Hsiao CH
      • Wu MZ
      • Chen CL
      • Hsueh PR
      • Hsieh SW
      • Yang PC
      • Su IJ
      Evolution of pulmonary pathology in severe acute respiratory syndrome.
      • He 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.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      The longer the disease, the more extensive becomes the fibrous organization of the lung tissue.
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      • Franks 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.
      In SARS cases lasting more than 2 to 3 weeks, dense septal and alveolar fibrosis were demonstrated, in addition to organizing features.
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      • Hsiao CH
      • Wu MZ
      • Chen CL
      • Hsueh PR
      • Hsieh SW
      • Yang PC
      • Su IJ
      Evolution of pulmonary pathology in severe acute respiratory syndrome.
      • He 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.
      A direct correlation has been found between the extent of fibrosis and the duration of the illness.
      • Tse 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).
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      Pathological changes suggesting active pulmonary injury have been observed up to 108 days after the onset of disease.
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      Hwang and colleagues
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      have established a specific pathological pattern in SARS autopsies, characterized by a combination of fibrin balls within airspaces and features of an organizing pneumonia.
      Figure thumbnail gr1
      Figure 1Pathology in the lungs, brain, and spleen. A: Lung tissue of a SARS autopsy showing severe damage, hyaline membrane formation, edema, fibrin exudation, and some inflammatory cells (H&E staining). Sample from a 50-year-old male SARS patient who died 33 days after disease onset. B: Multinucleated cells (arrows) in the lungs of a SARS patient (H&E staining). Sample from a 51-year-old male SARS patient who died on day 45. C: Double labeling combining in situ hybridization (ISH) of SARS viral genomic sequence and IHC with antibodies to cytokeratin (AE1/AE3) showing both brownish red (cytokeratin) and purplish blue signals for viral genome in the same cells, identifying the infected cells as pneumocytes (arrow 1). Arrow 2 points to an ISH-positive and cytokeratin-negative cell (purplish blue signal only), representing an inflammatory cell that is infected by SARS virus. Arrow 3 points to an in situ hybridization-negative pneumocyte (cytokeratin-positive, brownish red signal only) that is not infected by SARS virus. Sample from a 58-year-old male patient with SARS who died 58 days after disease onset. D: SARS-CoV genomic sequence in various cells in the lungs. Both a dark blue in situ hybridization signal and a brownish red IHC (CD3) signal are present in the same cell (arrow 1), suggesting the infection of T lymphocytes. There are also some uninfected CD3-positive cells (arrow 2, brownish red signal only). Arrow 3 points to in situ hybridization-positive mononuclear cell (purplish blue signal only). A spindle-shaped pneumocyte with a positive in situ hybridization signal is also shown (arrow 4, purplish blue signal only). Arrow 5 points to an in situ hybridization-positive cell morphologically resembling a vascular endothelial cell (purplish blue signal only). Sample from a 24-year-old male SARS patient who died on day 21. E: Spleen tissue showing depletion of lymphocytes. Sample from same patient as in C. F: Positive in situ hybridization signals in the cytoplasm of many neurons (arrows) in brain tissue of a SARS patient. Sample from a 49-year-old female SARS patient who died on day 32. In C, D, and F, in situ hybridization was performed with a 154-nucleotide cRNA probe directed against fragments of the polymerase gene (R1ab) of SARS-CoV. The probe was labeled with digoxigenin, and a NBT/BCIP substrate chromogen kit (Promega Corp., Madison, WI) was used to visualize in situ hybridization signals, resulting in a purplish blue color. In C and D, IHC with antibodies to cytokeratin (AE1/AE3) and CD3 was performed. IHC signals were detected with the HRP reaction kit AEC, which gives a brownish red color. Scale bars: 50 μm (A); 25 μm (B, C, E, F); 20 μm (D).
      In many cases, cellular infiltration has been observed. Immunohistochemical staining has shown that these inflammatory cells predominantly consist of macrophages
      • Lang 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).
      • Chong 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.
      • Nakajima 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.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Hsueh PR
      • Chen PJ
      • Hsiao CH
      • Yeh SH
      • Cheng WC
      • Wang JL
      • Chiang BL
      • Chang SC
      • Chang FY
      • Wong WW
      • Kao CL
      • Yang PC
      • SARS Research Group of National Taiwan University College of Medicine and National Taiwan University Hospital
      Patient data, early SARS epidemic, Taiwan.
      or a combination of macrophages and lymphocytes with or without neutrophils.
      • Ding 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.
      • Tse 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).
      • Gu 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.
      • Nicholls 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.
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      • He 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.
      • Yen YT
      • Liao F
      • Hsiao CH
      • Kao CL
      • Chen YC
      • Wu-Hsieh BA
      Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro.
      In other cases, however, a disproportionate scarcity of inflammatory cells has been noted.
      • Tse 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).
      • Gu 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.
      Large multinucleated cells have frequently been observed in the lungs of SARS patients (Figure 1B).
      • Ding 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.
      • Tse 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).
      • Gu 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.
      • Nicholls 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.
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      • Franks 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.
      • He 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.
      IHC has identified these cells as macrophages and pneumocytes.
      • Tse 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).
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      • Franks 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.
      In addition, atypical enlarged pneumocytes with large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were observed in the majority of SARS patients.
      • Tse 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).
      • Nicholls 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.
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      • Franks 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.
      It should be noted, however, that multinucleated cells in the lungs may be the result of many viral or bacterial infections, whereas atypical pneumocytes often appear as a reaction to alveolar damage. Therefore, neither the presence of multinucleated cells or atypical enlarged pneumocytes can be regarded as a unique characteristic of SARS-related pathology.
      Additional pathological features include: 1) squamous metaplasia of bronchial and alveolar epithelial cells
      • Nicholls 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.
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      • Franks 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.
      ; 2) subpleural proliferation of fibrogranulative tissue in small airways and airspaces
      • Tse 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).
      ; 3) loss of cilia of bronchiolar epithelial cells
      • Nicholls 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.
      ; 4) hemophagocytosis in mononuclear cells residing in pulmonary tissue
      • Nicholls 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.
      ; 5) apoptosis in epithelial cells, monocytes/macrophages, lymphocytes, and pneumocytes
      • He 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.
      ; and 6) vascular injury. Vascular injury consists of edema of the walls of pulmonary vessels and fibrous thrombi with or without pulmonary infarction.
      • Ding 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.
      • Lang 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).
      • Nicholls 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.
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      • Franks 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.
      In a number of SARS cases, co-infections have been reported.
      • Chong 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.
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      These include infections by Aspergillus species, Mucor species, Pseudomonas aeruginosa, Klebsiella species, methicillin-resistant Staphylococcus aureus, α-hemolytic Streptococcus species, and cytomegolavirus. These co-infections are probably related to longer disease durations and/or treatment with high doses of corticosteroids.
      • Hwang DM
      • Chamberlain DW
      • Poutanen SM
      • Low DE
      • Asa SL
      • Butany J
      Pulmonary pathology of severe acute respiratory syndrome in Toronto.
      Certain studies have compared the pulmonary pathology of SARS cases with non-SARS cases showing SARS-like symptoms.
      • Gu 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.
      • Chong 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.
      • Franks 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.
      Thirty-six of 36 SARS autopsies showed DAD, contrasting with only 19 of 40 of such non-SARS cases. Apart from prominent vascular injury, which was more frequently observed in the SARS cases than in the non-SARS cases, no significant differences in terms of morphology and extent of alveolar damage were established. It is therefore of noticeable interest that SARS-related pathology lacks specific characteristics. It seems to be impossible to distinguish DAD caused by SARS from DAD caused by, for instance, trauma, aspiration, oxygen toxicity, or infectious microorganisms. Therefore, additional tests such as in situ hybridization, IHC, viral isolation, or RT-PCR are necessary to confirm the diagnosis.
      Both sense and anti-sense probes with specificity for several viral proteins have been used for in situ hybridization.
      • Lang 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).
      • Gu 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.
      • Nakajima 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.
      • He 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.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Zhan 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.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Chan WS
      • Wu C
      • Chow SC
      • Cheung T
      • To KF
      • Leung WK
      • Chan PK
      • Lee KC
      • Ng HK
      • Au DM
      • Lo AW
      Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      • Chow KC
      • Hsiao CH
      • Lin TY
      • Chen CL
      • Chiou SH
      Detection of severe acute respiratory syndrome-associated coronavirus in pneumocytes of the lung.
      • Ye J
      • Zhang B
      • Xu J
      • Chang Q
      • McNutt MA
      • Korteweg C
      • Gong E
      • Gu J
      Molecular pathology in the lungs of severe acute respiratory syndrome patients.
      In situ hybridization has been performed on lung tissue of 67 SARS cases, of which 31 showed positive staining of epithelial cells. After double-labeling with cytokeratin/anti-epithelial membrane antigen (Figure 1C) and surfactant protein A, these cells were identified as type II pneumocytes.
      • Gu 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.
      • Nakajima 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.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Zhan 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.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      • Chow KC
      • Hsiao CH
      • Lin TY
      • Chen CL
      • Chiou SH
      Detection of severe acute respiratory syndrome-associated coronavirus in pneumocytes of the lung.
      • Ye J
      • Zhang B
      • Xu J
      • Chang Q
      • McNutt MA
      • Korteweg C
      • Gong E
      • Gu J
      Molecular pathology in the lungs of severe acute respiratory syndrome patients.
      Some studies also found positive in situ hybridization signals in epithelial cells of bronchi, bronchioles, trachea, and multinucleated cells.
      • Gu 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.
      • Nakajima 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.
      • He 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.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      In addition, infection of alveolar macrophages
      • Gu 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.
      • Nakajima 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.
      • He 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.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Zhan 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.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Ye J
      • Zhang B
      • Xu J
      • Chang Q
      • McNutt MA
      • Korteweg C
      • Gong E
      • Gu J
      Molecular pathology in the lungs of severe acute respiratory syndrome patients.
      and lymphocytes (Figure 1D)
      • Gu 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.
      • Ye J
      • Zhang B
      • Xu J
      • Chang Q
      • McNutt MA
      • Korteweg C
      • Gong E
      • Gu J
      Molecular pathology in the lungs of severe acute respiratory syndrome patients.
      has also been confirmed by double labeling. We found positive in situ hybridization signals in both fibroblasts and vascular endothelial cells (Figure 1D).
      • Ye J
      • Zhang B
      • Xu J
      • Chang Q
      • McNutt MA
      • Korteweg C
      • Gong E
      • Gu J
      Molecular pathology in the lungs of severe acute respiratory syndrome patients.
      Up to 62 days after onset of disease, in situ hybridization has detected viral sequences in lung tissue.
      • Gu 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.
      Three research groups have used immunofluorescence and fluorescence in situ hybridization with several cell markers and have found infected pneumocytes, bronchiolar epithelial cells, and macrophages.
      • Nakajima 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.
      • Chan WS
      • Wu C
      • Chow SC
      • Cheung T
      • To KF
      • Leung WK
      • Chan PK
      • Lee KC
      • Ng HK
      • Au DM
      • Lo AW
      Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      IHC with antibodies against SARS-CoV nucleocapsid (N) protein, spike (S) protein, and nonstructural protein 3a has been performed in 47 SARS cases.
      • He 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.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Yen YT
      • Liao F
      • Hsiao CH
      • Kao CL
      • Chen YC
      • Wu-Hsieh BA
      Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Chan WS
      • Wu C
      • Chow SC
      • Cheung T
      • To KF
      • Leung WK
      • Chan PK
      • Lee KC
      • Ng HK
      • Au DM
      • Lo AW
      Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      Positive staining of alveolar epithelial cells and macrophages was observed in 12 of 47 cases.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Yen YT
      • Liao F
      • Hsiao CH
      • Kao CL
      • Chen YC
      • Wu-Hsieh BA
      Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Chan WS
      • Wu C
      • Chow SC
      • Cheung T
      • To KF
      • Leung WK
      • Chan PK
      • Lee KC
      • Ng HK
      • Au DM
      • Lo AW
      Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      Limited staining of bronchiolar epithelium has also been reported.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      Positive IHC has not been established in cases with a disease duration exceeding 20 days.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      Specific immunohistochemical staining with antibodies to P-selectin, dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN), and interferon-inducible protein-10 (IP-10) has been performed in a number of cases.
      • Yen YT
      • Liao F
      • Hsiao CH
      • Kao CL
      • Chen YC
      • Wu-Hsieh BA
      Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro.
      • Jiang Y
      • Xu J
      • Zhou C
      • Wu Z
      • Zhong S
      • Liu J
      • Luo W
      • Chen T
      • Qin Q
      • Deng P
      Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome.
      • Tang NL
      • Chan PK
      • Wong CK
      • To KF
      • Wu AK
      • Sung YM
      • Hui DS
      • Sung JJ
      • Lam CW
      Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome.
      Increased expression of DC-SIGN, P-selectin, and IP-10 in both pneumocytes and macrophages was demonstrated.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Jiang Y
      • Xu J
      • Zhou C
      • Wu Z
      • Zhong S
      • Liu J
      • Luo W
      • Chen T
      • Qin Q
      • Deng P
      Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome.
      • Tang NL
      • Chan PK
      • Wong CK
      • To KF
      • Wu AK
      • Sung YM
      • Hui DS
      • Sung JJ
      • Lam CW
      Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome.
      The results of immunostaining with antibodies directed against monocyte chemoattractant protein 1, transforming growth factor-β1, tumor necrosis factor-α, interleukin-1, and interleukin-6 in SARS patients have recently been reported by He and colleagues
      • He 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.
      Strong expression of such proinflammatory cytokines was found in angiotensin-converting enzyme 2 (ACE2)-positive cells infected with SARS-CoV.
      • He 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.
      Ultrastructurally, SARS-CoV infection of cultured cells has shown features similar to those of previously described coronaviruses.
      • Goldsmith CS
      • Tatti KM
      • Ksiazek TG
      • Rollin PE
      • Comer JA
      • Lee WW
      • Rota PA
      • Bankamp B
      • Bellini WJ
      • Zaki SR
      Ultrastructural characterization of SARS coronavirus.
      SARS-specific characteristics include large granular cytoplasmic areas, nucleocapsid inclusions, and typical double-membrane vesicles.
      • Goldsmith CS
      • Tatti KM
      • Ksiazek TG
      • Rollin PE
      • Comer JA
      • Lee WW
      • Rota PA
      • Bankamp B
      • Bellini WJ
      • Zaki SR
      Ultrastructural characterization of SARS coronavirus.
      In some SARS autopsies, EM examination has revealed cytoplasmic viral particles in pneumocytes.
      • Ding 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.
      • Tse 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).
      • Nakajima 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.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      The majority of these viral particles were within membrane-bound vesicles. Viral particles have also been observed in macrophages in lung tissue.
      • Nakajima 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.
      In addition, the presence of viral inclusion bodies has been reported.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      In some studies the viral origin of the identified particles and inclusion bodies has been confirmed by immunogold labeling.
      • Gu 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.
      • Shieh WJ
      • Hsiao CH
      • Paddock CD
      • Guarner J
      • Goldsmith CS
      • Tatti K
      • Packard M
      • Mueller L
      • Wu MZ
      • Rollin P
      • Su IJ
      • Zaki SR
      Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
      SARS-CoV was successfully isolated from lung tissue in 10 of 23 cases, including cases with a duration of illness of up to 20 days.
      • Tse 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).
      • Chong 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.
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      By RT-PCR, genomic sequences were found in the lungs of 47 of 55 SARS autopsies.
      • Nicholls 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.
      • Cheung OY
      • Chan JW
      • Ng CK
      • Koo CK
      The spectrum of pathological changes in severe acute respiratory syndrome (SARS).
      • Nakajima 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.
      • Nicholls JM
      • Butany J
      • Poon LL
      • Chan KH
      • Beh SL
      • Poutanen S
      • Peiris JS
      • Wong M
      Time course and cellular localization of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS.
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      Quantitative RT-PCR has detected viral sequences in lung tissues up to 51 days after onset of symptoms.
      • Farcas GA
      • Poutanen SM
      • Mazzulli T
      • Willey BM
      • Butany J
      • Asa SL
      • Faure P
      • Akhavan P
      • Low DE
      • Kain KC
      Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus.
      Similar to SARS, avian influenza A (H5N1) is an emerging viral infectious disease that targets the lungs. Both diseases often result in respiratory distress, with a high fatality rate. Certain pathological similarities and differences between the two diseases have been described in a comparative review.
      • Ng WF
      • To KF
      • Lam WW
      • Ng TK
      • Lee KC
      The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1—a review.
      DAD in H5N1 influenza cases shows a more fulminant progression, compared with that in SARS, with marked hemorrhage and necrosis.
      • Ng WF
      • To KF
      • Lam WW
      • Ng TK
      • Lee KC
      The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1—a review.
      Multinucleated cells were readily noticeable in SARS cases, whereas the presence of such cells has thus far not been reported in H5N1 influenza cases. The organizing phase of H5N1 influenza seems to be characterized by paucicellular fibrosis, without the BOOP-like pattern as found in SARS autopsies. With respect to extrapulmonary manifestations, SARS is less often associated with a reactive hemophagocytic syndrome.

      Immune System

      In most SARS autopsies, both extensive necrosis of the spleen and atrophy of the white pulp with severe lymphocyte depletion have been found.
      • Wong 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.
      • Ding 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.
      • Lang 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).
      • Tse 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).
      • Chong 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.
      • Zhan 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.
      Zhan and colleagues
      • Zhan 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.
      have demonstrated a sharp decrease in the number of periarterial sheaths in the spleen (Figure 1E).
      • Zhan 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.
      Quantification of the various immune cells residing in the spleen including CD4+ lymphocytes, CD8+ lymphocytes, CD20+ lymphocytes, dendritic cells, macrophages, and natural killer cells showed a decrease of 78, 83, 90, 80, 39, and 48%, respectively. The average size of macrophages was found to be increased by more than 100%.
      • Zhan 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.
      Some studies have failed to detect any positive viral signal in splenic cells
      • Ding YQ
      • He L
      • Zhang QL
      • Huang ZX
      • Che XY
      • Hou JL
      • Wang HJ
      • Shen H
      • Qiu LW
      • Li ZG
      • Geng J
      • Cai JJ
      • Han HX
      • Li X
      • Kang W
      • Weng DS
      • Liang P
      • Jiang SB
      Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      • Chow KC
      • Hsiao CH
      • Lin TY
      • Chen CL
      • Chiou SH
      Detection of severe acute respiratory syndrome-associated coronavirus in pneumocytes of the lung.
      or to isolate virus from cultures of splenic tissue.
      • Wong 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.
      • Tse 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).
      • To KF
      • Tong JH
      • Chan PK
      • Au FW
      • Chim SS
      • Chan KC
      • Cheung JL
      • Liu EY
      • Tse GM
      • Lo AW
      • Lo YM
      • Ng HK
      Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases.
      In contrast, others have detected infection of T lymphocytes and macrophages in the spleen
      • Gu 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.
      • Zhan 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.