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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
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.
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.
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.
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/tissue
Pathology
Number of cases
References
Respiratory tract
Diffuse 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 macrophages
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.
Lymphocyte depletion in spleen and lymph nodes with architectural disruption. Splenic white pulp atrophy. Positive in situ hybridization signals in immune cells
Intestines: no obvious pathological changes/nonspecific changes. Depletion of mucosal lymphoid tissue. Positive in situ hybridization signals in mucosal epithelial cells
Kidneys: acute tubular necrosis, in varying degrees and other nonspecific features. Positive in situ hybridization signals in the epithelial cells of the distal tubules
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.
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of 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.
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.
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
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.
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.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
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.
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 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
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
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.
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.
In addition, atypical enlarged pneumocytes with large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were observed in the majority of SARS patients.
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
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.
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.
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.
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.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
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.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
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.
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
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.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
has also been confirmed by double labeling. We found positive in situ hybridization signals in both fibroblasts and vascular endothelial cells (Figure 1D).
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.
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
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.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS).
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
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.
Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
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
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.
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.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan.
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
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.
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.
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%.
Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.
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