SARS

This disease burst onto the headlines in 2003. The first cases were described in China but soon new cases occurred in several Asian countries and Toronto, Canada.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
GEOGRAPHY
Update: outbreak of severe acute respiratory syndrome--worldwide, 2003.	MMWR Morb Mortal Wkly Rep. 2003 Apr 4;52(13):269-72. Abstract quote CDC and the World Health Qrganization (WHO) are continuing to investigate the multicountry outbreak of unexplained atypical pneumonia referred to as severe acute respiratory syndrome (SARS). Pending development of confirmatory laboratory testing capacity, CDC's interim suspected SARS case definition is based on clinical criteria and epidemiologic linkage to other SARS cases or areas with community transmission of SARS. This case definition will be updated periodically as new information becomes available. Epidemiologic and laboratory investigations of SARS are ongoing. As of April 2, 2003, a total of 2,223 suspected and/or probable SARS cases have been reported to WHO from 16 countries, including the United States. The reported SARS cases include 78 deaths (case-fatality proportion: 3.5%). This report summarizes SARS cases among U.S. residents and surveillance and prevention activities in the United States.

PATHOGENESIS	CHARACTERIZATION
CORONA VIRUS
Detection of Severe Acute Respiratory Syndrome–Associated Coronavirus in Pneumocytes of the Lung Kuan-Chih Chow, PhD, etal.	Am J Clin Pathol 2004;121:574-580 Abstract quote Previous reports have indicated that patients with severe acute respiratory syndrome (SARS)–associated coronavirus infection could develop atypical pneumonia with fulminant pulmonary edema. However, the target cells of SARS viral infection have not been characterized in detail. We report the pathologic findings of the lung in 3 cases of SARS. Chest radiographs at 2 to 3 weeks of infection revealed an atypical pneumonia with pulmonary consolidation, a clinical characteristic of SARS infection. The presence of the SARS virus was determined by nested reverse transcription–polymerase chain reaction (RT-PCR), and the infected cells were identified by in situ hybridization in open-lung biopsy and postmortem necropsy specimens. Expression of SARS virus–encoded RNA was detected in all 3 cases by RT-PCR, and the SARS viral signal was localized in pneumocytes by using in situ hybridization.
NATURAL KILLER CELLS
The Involvement of Natural Killer Cells in the Pathogenesis of Severe Acute Respiratory Syndrome National Research Project for SARS, Beijing Group	Am J Clin Pathol 121:507-511 Abstract quote By using peripheral blood samples from 221 cases of severe acute respiratory syndrome (SARS), 34 of Mycoplasma pneumoniae infection, and 44 healthy adults, we measured the total number of natural killer (NK) and CD158b+ NK cells (CD158b+ NK) using flow cytometric analysis and calculated the percentage of CD158b+ NK cells. The total number of NK and CD158b+ NK cells and the percentage of CD158b+ NK cells were significantly lower in patients with SARS than in those with M pneumoniae infection (P < .05 for all) and healthy subjects (P < .01, P < .01, P < .05, respectively); in 72 patients with severe SARS than in 149 with mild SARS (P < .05 for all); and in 174 cases of SARS with anti-SARS coronavirus–specific IgG and/or IgM antibodies than in 47 without antibodies (P < .05, P < .01, P < .01, respectively). There were no significant differences for the 3 values among patients with SARS without anti-SARS coronavirus antibody, patients with M pneumoniae infection, and healthy subjects. The number of NK cells and the expression of CD158b on the surface of NK cells changed in patients with SARS and correlated with disease severity and the presence of anti-SARS coronavirus–specific antibodies; SARS differed from M pneumoniae infection in pathogenesis involving NK cells. Monitoring the total number of NK and CD158b+ NK cells and the percentage of CD158b+ NK cells might aid in differentiating SARS from M pneumoniae infection.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. Lew TW, Kwek TK, Tai D, Earnest A, Loo S, Singh K, Kwan KM, Chan Y, Yim CF, Bek SL, Kor AC, Yap WS, Chelliah YR, Lai YC, Goh SK. Department of Anaesthesiology, Tan Tock Seng Hospital, Singapore.	JAMA. 2003 Jul 16;290(3):374-80. Abstract quote CONTEXT: Severe acute respiratory syndrome (SARS) is an emerging infectious disease with a 25% incidence of progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and mortality exceeding 10%. OBJECTIVE: To describe the clinical spectrum and outcomes of ALI/ARDS in patients with SARS-related critical illness. DESIGN, SETTING, AND PATIENTS: Retrospective case series of adult patients with probable SARS admitted to the intensive care unit (ICU) of a hospital in Singapore between March 6 and June 6, 2003. MAIN OUTCOME MEASURES: The primary outcome measure was 28-day mortality after symptom onset. RESULTS: Of 199 patients hospitalized with SARS, 46 (23%) were admitted to the ICU, including 45 who fulfilled criteria for ALI/ARDS. Mortality at 28 days for the entire cohort was 20 (10.1%) of 199 and for ICU patients was 17 (37%) of 46. Intensive care unit mortality at 13 weeks was 24 (52.2%) of 46. Nineteen of 24 ICU deaths occurred late (> or =7 days after ICU admission) and were attributed to complications related to severe ARDS, multiorgan failure, thromboembolic complications, or septicemic shock. ARDS was characterized by ease of derecruitment of alveoli and paucity of airway secretion, bronchospasm, or dynamic hyperinflation. Lower Acute Physiology and Chronic Health Evaluation II scores and higher baseline ratios of PaO2 to fraction of inspired oxygen were associated with earlier recovery. CONCLUSIONS: Critically ill patients with SARS and ALI/ARDS had characteristic clinical findings, high rates of complications; and high mortality. These findings may provide useful information for optimizing supportive care for SARS-related critical illness.
Critically ill patients with severe acute respiratory syndrome. Fowler RA, Lapinsky SE, Hallett D, Detsky AS, Sibbald WJ, Slutsky AS, Stewart TE; Toronto SARS Critical Care Group. Interdepartmental Division of Critical Care Medicine, University of Toronto, Ontario.	JAMA. 2003 Jul 16;290(3):367-73. Abstract quote CONTEXT: Severe acute respiratory syndrome (SARS) is a newly recognized infectious disease capable of causing severe respiratory failure. OBJECTIVE: To determine the epidemiological features, course, and outcomes of patients with SARS-related critical illness. DESIGN, SETTING, AND PATIENTS: Retrospective case series of 38 adult patients with SARS-related critical illness admitted to 13 intensive care units (ICUs) in the Toronto area between the onset of the outbreak and April 15, 2003. Data were collected daily during the first 7 days in the ICUs, and patients were followed up for 28 days. MAIN OUTCOME MEASURES: The primary outcome was mortality at 28 days after ICU admission. Secondary outcomes included rate of SARS-related critical illness, number of tertiary care ICUs and staff placed under quarantine, and number of health care workers (HCWs) contracting SARS secondary to ICU-acquired transmission. RESULTS: Of 196 patients with SARS, 38 (19%) became critically ill, 7 (18%) of whom were HCWs. The median (interquartile range [IQR]) age of the 38 patients was 57.4 (39.0-69.6) years. The median (IQR) duration between initial symptoms and admission to the ICU was 8 (5-10) days. Twenty-nine (76%) required mechanical ventilation and 10 of these (34%) experienced barotrauma. Mortality at 28 days was 13 (34%) of 38 patients and for those requiring mechanical ventilation, mortality was 13 (45%) of 29. Six patients (16%) remained mechanically ventilated at 28 days. Two of these patients had died by 8 weeks' follow-up. Patients who died were more often older, had preexisting diabetes mellitus, and on admission to hospital were more likely to have bilateral radiographic infiltrates. Transmission of SARS in 6 study ICUs led to closure of 73 medical-surgical ICU beds. In 2 university ICUs, 164 HCWs were quarantined and 16 (10%) developed SARS. CONCLUSIONS: Critical illness was common among patients with SARS. Affected patients had primarily single-organ respiratory failure, and half of mechanically ventilated patients died. The SARS outbreak greatly strained regional critical care resources.
Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, Walmsley SL, Mazzulli T, Avendano M, Derkach P, Ephtimios IE, Kitai I, Mederski BD, Shadowitz SB, Gold WL, Hawryluck LA, Rea E, Chenkin JS, Cescon DW, Poutanen SM, Detsky AS. University of Toronto, Mount Sinai Hospital, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.	JAMA. 2003 Jun 4;289(21):2801-9. Abstract quote CONTEXT: Severe acute respiratory syndrome (SARS) is an emerging infectious disease that first manifested in humans in China in November 2002 and has subsequently spread worldwide. OBJECTIVES: To describe the clinical characteristics and short-term outcomes of SARS in the first large group of patients in North America; to describe how these patients were treated and the variables associated with poor outcome. DESIGN, SETTING, AND PATIENTS: Retrospective case series involving 144 adult patients admitted to 10 academic and community hospitals in the greater Toronto, Ontario, area between March 7 and April 10, 2003, with a diagnosis of suspected or probable SARS. Patients were included if they had fever, a known exposure to SARS, and respiratory symptoms or infiltrates observed on chest radiograph. Patients were excluded if an alternative diagnosis was determined. MAIN OUTCOME MEASURES: Location of exposure to SARS; features of the history, physical examination, and laboratory tests at admission to the hospital; and 21-day outcomes such as death or intensive care unit (ICU) admission with or without mechanical ventilation. RESULTS: Of the 144 patients, 111 (77%) were exposed to SARS in the hospital setting. Features of the clinical examination most commonly found in these patients at admission were self-reported fever (99%), documented elevated temperature (85%), nonproductive cough (69%), myalgia (49%), and dyspnea (42%). Common laboratory features included elevated lactate dehydrogenase (87%), hypocalcemia (60%), and lymphopenia (54%). Only 2% of patients had rhinorrhea. A total of 126 patients (88%) were treated with ribavirin, although its use was associated with significant toxicity, including hemolysis (in 76%) and decrease in hemoglobin of 2 g/dL (in 49%). Twenty-nine patients (20%) were admitted to the ICU with or without mechanical ventilation, and 8 patients died (21-day mortality, 6.5%; 95% confidence interval [CI], 1.9%-11.8%). Multivariable analysis showed that the presence of diabetes (relative risk [RR], 3.1; 95% CI, 1.4-7.2; P =.01) or other comorbid conditions (RR, 2.5; 95% CI, 1.1-5.8; P =.03) were independently associated with poor outcome (death, ICU admission, or mechanical ventilation). CONCLUSIONS: The majority of cases in the SARS outbreak in the greater Toronto area were related to hospital exposure. In the event that contact history becomes unreliable, several features of the clinical presentation will be useful in raising the suspicion of SARS. Although SARS is associated with significant morbidity and mortality, especially in patients with diabetes or other comorbid conditions, the vast majority (93.5%) of patients in our cohort survived.
A major outbreak of severe acute respiratory syndrome in Hong Kong. Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, Ahuja A, Yung MY, Leung CB, To KF, Lui SF, Szeto CC, Chung S, Sung JJ. Department of Medicine, Chinese University of Hong Kong, Hong Kong, China.	N Engl J Med. 2003 May 15;348(20):1986-94. Abstract quote BACKGROUND: There has been an outbreak of the severe acute respiratory syndrome (SARS) worldwide. We report the clinical, laboratory, and radiologic features of 138 cases of suspected SARS during a hospital outbreak in Hong Kong. METHODS: From March 11 to 25, 2003, all patients with suspected SARS after exposure to an index patient or ward were admitted to the isolation wards of the Prince of Wales Hospital. Their demographic, clinical, laboratory, and radiologic characteristics were analyzed. Clinical end points included the need for intensive care and death. Univariate and multivariate analyses were performed. RESULTS: There were 66 male patients and 72 female patients in this cohort, 69 of whom were health care workers. The most common symptoms included fever (in 100 percent of the patients); chills, rigors, or both (73.2 percent); and myalgia (60.9 percent). Cough and headache were also reported in more than 50 percent of the patients. Other common findings were lymphopenia (in 69.6 percent), thrombocytopenia (44.8 percent), and elevated lactate dehydrogenase and creatine kinase levels (71.0 percent and 32.1 percent, respectively). Peripheral air-space consolidation was commonly observed on thoracic computed tomographic scanning. A total of 32 patients (23.2 percent) were admitted to the intensive care unit; 5 patients died, all of whom had coexisting conditions. In a multivariate analysis, the independent predictors of an adverse outcome were advanced age (odds ratio per decade of life, 1.80; 95 percent confidence interval, 1.16 to 2.81; P=0.009), a high peak lactate dehydrogenase level (odds ratio per 100 U per liter, 2.09; 95 percent confidence interval, 1.28 to 3.42; P=0.003), and an absolute neutrophil count that exceeded the upper limit of the normal range on presentation (odds ratio, 1.60; 95 percent confidence interval, 1.03 to 2.50; P=0.04). CONCLUSIONS: SARS is a serious respiratory illness that led to significant morbidity and mortality in our cohort.
Identification and containment of an outbreak of SARS in a community hospital. Dwosh HA, Hong HH, Austgarden D, Herman S, Schabas R. Dr. Dwosh is ICU Director, Department of Medicine.	CMAJ. 2003 May 27;168(11):1415-20. Abstract quote BACKGROUND: Severe acute respiratory syndrome (SARS) is continuing to spread around the world. All hospitals must be prepared to care for patients with SARS. Thus, it is important to understand the transmission of this disease in hospitals and to evaluate methods for its containment in health care institutions. We describe how we cared for the first 2 patients with SARS admitted to our 419-bed community hospital in Richmond Hill, Ont., and the response to a SARS outbreak within our institution. METHODS: We collected clinical and epidemiological data about patients and health care workers at our institution who during a 13-day period had a potential unprotected exposure to 2 patients whose signs and symptoms were subsequently identified as meeting the case definition for probable SARS. The index case at our hospital was a patient who was transferred to our intensive care unit (ICU) from a referral hospital on Mar. 16, 2003, where he had been in close proximity to the son of the individual with the first reported case of SARS in Toronto. After 13 days in the ICU, a diagnosis of probable SARS was reached for our index case. Immediately upon diagnosis of our index case, respiratory isolation and barrier precautions were instituted throughout our hospital and maintained for a period of 10 days, which is the estimated maximum incubation period reported for this disease. Aggressive surveillance measures among hospital staff, patients and visitors were also maintained during this time. RESULTS: During the surveillance period, 15 individuals (10 hospital staff, 3 patients and 2 visitors) were identified as meeting the case definition for probable or suspected SARS, in addition to our index case. All but 1 individual had had direct contact with a symptomatic patient with SARS during the period of unprotected exposure. No additional cases were identified after infection control precautions had been implemented for 8 days. No cases of secondary transmission were identified in the 21 days following the implementation of these precautions at our institution. INTERPRETATION: SARS can easily be spread by direct personal contact in the hospital setting. We found that the implementation of aggressive infection control measures is effective in preventing further transmission of this disease.
Identification of severe acute respiratory syndrome in Canada. Poutanen SM, Low DE, Henry B, Finkelstein S, Rose D, Green K, Tellier R, Draker R, Adachi D, Ayers M, Chan AK, Skowronski DM, Salit I, Simor AE, Slutsky AS, Doyle PW, Krajden M, Petric M, Brunham RC, McGeer AJ; National Microbiology Laboratory, Canada; Canadian Severe Acute Respiratory Syndrome Study Team. Toronto Medical Laboratories and Mount Sinai Hospital Department of Microbiology, Toronto, Canada.	N Engl J Med. 2003 May 15;348(20):1995-2005 Abstract quote BACKGROUND: Severe acute respiratory syndrome (SARS) is a condition of unknown cause that has recently been recognized in patients in Asia, North America, and Europe. This report summarizes the initial epidemiologic findings, clinical description, and diagnostic findings that followed the identification of SARS in Canada. METHODS: SARS was first identified in Canada in early March 2003. We collected epidemiologic, clinical, and diagnostic data from each of the first 10 cases prospectively as they were identified. Specimens from all cases were sent to local, provincial, national, and international laboratories for studies to identify an etiologic agent. RESULTS: The patients ranged from 24 to 78 years old; 60 percent were men. Transmission occurred only after close contact. The most common presenting symptoms were fever (in 100 percent of cases) and malaise (in 70 percent), followed by nonproductive cough (in 100 percent) and dyspnea (in 80 percent) associated with infiltrates on chest radiography (in 100 percent). Lymphopenia (in 89 percent of those for whom data were available), elevated lactate dehydrogenase levels (in 80 percent), elevated aspartate aminotransferase levels (in 78 percent), and elevated creatinine kinase levels (in 56 percent) were common. Empirical therapy most commonly included antibiotics, oseltamivir, and intravenous ribavirin. Mechanical ventilation was required in five patients. Three patients died, and five have had clinical improvement. The results of laboratory investigations were negative or not clinically significant except for the amplification of human metapneumovirus from respiratory specimens from five of nine patients and the isolation and amplification of a novel coronavirus from five of nine patients. In four cases both pathogens were isolated. CONCLUSIONS: SARS is a condition associated with substantial morbidity and mortality. It appears to be of viral origin, with patterns suggesting droplet or contact transmission. The role of human metapneumovirus, a novel coronavirus, or both requires further investigation.
A cluster of cases of severe acute respiratory syndrome in Hong Kong. Tsang KW, Ho PL, Ooi GC, Yee WK, Wang T, Chan-Yeung M, Lam WK, Seto WH, Yam LY, Cheung TM, Wong PC, Lam B, Ip MS, Chan J, Yuen KY, Lai KN. University Department of Medicine, University of Hong Kong, Pokfulam, China.	N Engl J Med. 2003 May 15;348(20):1977-85. Abstract quote BACKGROUND: Information on the clinical features of the severe acute respiratory syndrome (SARS) will be of value to physicians caring for patients suspected of having this disorder. METHODS: We abstracted data on the clinical presentation and course of disease in 10 epidemiologically linked Chinese patients (5 men and 5 women 38 to 72 years old) in whom SARS was diagnosed between February 22, 2003, and March 22, 2003, at our hospitals in Hong Kong, China. RESULTS: Exposure between the source patient and subsequent patients ranged from minimal to that between patient and health care provider. The incubation period ranged from 2 to 11 days. All patients presented with fever (temperature, >38 degrees C for over 24 hours), and most presented with rigor, dry cough, dyspnea, malaise, headache, and hypoxemia. Physical examination of the chest revealed crackles and percussion dullness. Lymphopenia was observed in nine patients, and most patients had mildly elevated aminotransferase levels but normal serum creatinine levels. Serial chest radiographs showed progressive air-space disease. Two patients died of progressive respiratory failure; histologic analysis of their lungs showed diffuse alveolar damage. There was no evidence of infection by Mycoplasma pneumoniae, Chlamydia pneumoniae, or Legionella pneumophila. All patients received corticosteroid and ribavirin therapy a mean (+/-SD) of 9.6+/-5.42 days after the onset of symptoms, and eight were treated earlier with a combination of beta-lactams and macrolide for 4+/-1.9 days, with no clinical or radiologic efficacy. CONCLUSIONS: SARS appears to be infectious in origin. Fever followed by rapidly progressive respiratory compromise is the key complex of signs and symptoms from which the syndrome derives its name. The microbiologic origins of SARS remain unclear.

HISTOPATHOLOGY

CHARACTERIZATION

LUNGS

Pulmonary pathology of severe acute respiratory syndrome in Toronto.

Hwang DM, Chamberlain DW, Poutanen SM, Low DE, Asa SL, Butany J.

[1] 1Toronto Medical Laboratories, Toronto, Ontario, Canada [2] 2Department of Pathology, University Health Network, Toronto, Ontario, Canada [3] 3Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada.

Mod Pathol. 2005 Jan;18(1):1-10. Abstract quote The severe acute respiratory syndrome (SARS) pandemic in Toronto resulted in a large number of autopsies on its victims. We describe the pulmonary pathology of patients who died in the 2003 Toronto outbreak. Autopsy material from the lungs of 20 patients who died between March and July 2003 were characterized by histology, molecular biology, and immunohistochemistry for cytokeratins, thyroid transcription factor-1, CD68, Epstein-Barr virus, cytomegalovirus, and human herpes simplex viruses. Matched controls were obtained from patients who died of other causes over the same interval. The mean duration of illness was 27 days (range 5-108 days). Post-mortem lung tissues from 19 of 20 patients with probable SARS were positive for SARS-associated coronavirus by RT-PCR. Histologically, all patients showed varying degrees of exudative and proliferative phase acute lung injury, evidenced in conventional and immunohistochemical stains by edema, inflammatory infiltrate, pneumocyte hyperplasia, fibrinous exudates, and organization. Eight of 20 patients showed predominantly a diffuse alveolar damage pattern of acute lung injury, six showed predominantly an acute fibrinous and organizing pneumonia pattern, and the remainder showed an admixture of the two patterns. Squamous metaplasia and scattered multinucleate giant cells were present in most cases. Vascular fibrin thrombi were a common finding and were often associated with pulmonary infarcts. Special stains demonstrated vascular endothelial damage of both small- and mid-sized pulmonary vessels. Two cases were complicated by invasive fungal disease consistent with Aspergillosis, and another by coinfection with cytomegalovirus. Our findings indicate that the lungs of patients who die of SARS are almost always positive for the SARS-associated coronavirus by RT-PCR, and may show features of both diffuse alveolar damage and acute fibrinous and organizing pneumonia patterns of acute injury. Cases of SARS may be complicated by coexistent infections and therapy-related lung injury.

Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis.

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.

Arch Pathol Lab Med. 2004 Feb;128(2):195-204. Abstract quote

CONTEXT: An outbreak of severe acute respiratory syndrome (SARS), an infectious disease attributed to a novel coronavirus, occurred in Singapore during the first quarter of 2003 and led to 204 patients with diagnosed illnesses and 26 deaths by May 2, 2003. Twenty-one percent of these patients required admission to the medical intensive care unit. During this period, the Center for Forensic Medicine, Health Sciences Authority, Singapore, performed a total of 14 postmortem examinations for probable and suspected SARS. Of these, a total of 8 were later confirmed as SARS infections.

OBJECTIVE: Our series documents the difficulties encountered at autopsy during the initial phases of the SARS epidemic, when the pattern of infection and definitive diagnostic laboratory criteria were yet to be established.

DESIGN: Autopsies were performed by pathologists affiliated with the Center for Forensic Medicine, Health Sciences Authority, Singapore. Tissue was accessed and read at the Tan Tock Seng Hospital, Singapore, and at the Armed Forces Institute of Pathology, Washington, DC. Autopsy tissue was submitted to the Virology Department, Singapore General Hospital, for analysis, and in situ hybridization for the SARS coronavirus was carried out at the National Institute of Infectious Diseases, Tokyo, Japan.

RESULTS: Thirteen of 14 patients showed features of diffuse alveolar damage. In 8 patients, no precipitating etiology was identified, and in all of these patients, we now have laboratory confirmation of coronavirus infection. Two of the 8 patients presented at autopsy as sudden unexpected deaths, while the remaining 6 patients had been hospitalized with varying lengths of stay in the intensive care unit. In 3 patients, including the 2 sudden unexpected deaths, in situ hybridization showed the presence of virally infected cells within the lung. In 4 of the 8 SARS patients, pulmonary thromboemboli were also recognized on gross examination, while one patient had marantic cardiac valvular vegetations.

CONCLUSIONS: It is unfortunate that the term atypical pneumonia has been used in conjunction with SARS. Although nonspecific by itself, the term does not accurately reflect the underlying dangers of viral pneumonia, which may progress rapidly to acute respiratory distress syndrome. We observed that the clinical spectrum of disease as seen in our autopsy series included sudden deaths. This is a worrisome finding that illustrates that viral diseases will have a spectrum of clinical presentations and that the diagnoses made for such patients must incorporate laboratory as well as clinical data.

IMMUNOHISTO-
CHEMISTRY,
SPECIAL STAINS,
ELECTRON MICROSCOPY

Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS). Chan WS, Wu C, Chow SC, Cheung T, To KF, Leung WK, Chan PK, Lee KC, Ng HK, Au DM, Lo AW. 1Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.

Mod Pathol. 2005 Nov;18(11):1432-9. Abstract quote Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease that haunted the world from November 2002 to July 2003. Little is known about the biology and pathophysiology of the novel coronavirus that causes SARS. The tissue and cellular distributions of coronaviral hypothetical and structural proteins in SARS were investigated. Antibodies against the hypothetical (SARS 3a, 3b, 6, 7a and 9b) and structural proteins (envelope, membrane, nucleocapsid and spike) of the coronavirus were generated from predicted antigenic epitopes of each protein. The presence of these proteins were first verified in coronavirus-infected Vero E6 tissue culture model. Immunohistochemical studies on different human tissues, including a cohort of nine autopsies, two liver biopsies and intestinal biopsies of SARS patients, further confirmed the existence of coronaviral hypothetical and structural proteins in the cytoplasm of pneumocytes and small intestinal surface enterocytes in SARS patients. With this vast array of antibodies, no signal was observed in other cell types including those organs in which reverse transcriptase-polymerase chain reactions were reported to be positive. Structural proteins and the functionally undefined hypothetical proteins were expressed in coronavirus-infected cells with distinct expression pattern in different organs in SARS patients. These antipeptide antibodies can be useful for the diagnosis of SARS at the tissue level.

Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan. Shieh WJ, Hsiao CH, Paddock CD, Guarner J, Goldsmith CS, Tatti K, Packard M, Mueller L, Wu MZ, Rollin P, Su IJ, Zaki SR.

Hum Pathol. 2005 Mar;36(3):303-9. Abstract quote Summary This article describes the pathological studies of fatal severe acute respiratory syndrome (SARS) in a 73-year-old man during an outbreak of SARS in Taiwan, 2003. Eight days before onset of symptoms, he visited a municipal hospital that was later identified as the epicenter of a large outbreak of SARS. On admission to National Taiwan University Hospital in Taipei, the patient experienced chest tightness, progressive dyspnea, and low-grade fever. His condition rapidly deteriorated with increasing respiratory difficulty, and he died 7 days after admission. The most prominent histopathologic finding was diffuse alveolar damage of the lung. Immunohistochemical and in situ hybridization assays demonstrated evidence of SARS-associated coronavirus (SARS-CoV) infection in various respiratory epithelial cells, predominantly type II pneumocytes, and in alveolar macrophages in the lung. Electron microscopic examination also revealed coronavirus particles in the pneumocytes, and their identity was confirmed as SARS-CoV by immunogold labeling electron microscopy. This report is the first to describe the cellular localization of SARS-CoV in human lung tissue by using a combination of immunohistochemistry, double-stain immunohistochemistry, in situ hybridization, electron microscopy, and immunogold labeling electron microscopy. These techniques represent valuable laboratory diagnostic modalities and provide insights into the pathogenesis of this emerging infection.

DIFFERENTIAL DIAGNOSIS

KEY DIFFERENTIATING FEATURES

INFLUENZA AVIAN FLU SUBTYPE H5N1

The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1--a review. Ng WF, To KF, Lam WW, Ng TK, Lee KC. Department of Pathology, Princess Margaret Hospital, Kowloon West Cluster Hospitals, Hong Kong Special Administrative Region, China.

Hum Pathol. 2006 Apr;37(4):381-90. Abstract quote The pathology of 2 zoonotic human viral infections that recently emerged, severe acute respiratory syndrome (SARS) due to coronavirus (SARS-CoV) and avian influenza A subtype H5N1, is reviewed and compared based on the literature and the cases examined by the authors. Pneumocytes are the primary target of infection resulting in diffuse alveolar damage. Systemic cytokine activation results in hemophagocytic syndrome, lymphoid depletion, and skeletal muscle fiber necrosis. Severe acute respiratory syndrome induces a more fibrocellular intra-alveolar organization with a "bronchiolitis obliterans organizing pneumonia"-like pattern and presence of multinucleated histiocytes and pneumocytes. H5N1 causes a more fulminant and necrotizing diffuse alveolar damage with patchy and interstitial paucicellular fibrosis. Severe acute respiratory syndrome associated coronavirus persists in the lung up to the second month, whereas H5N1 persists in the lung up to the third week. Severe acute respiratory syndrome associated coronavirus disseminates to blood, urine, feces, gastrointestinal tract, and liver. There is recent report of possible cerebral involvement by H5N1 and its isolation in the blood, gastrointestinal tract, and cerebrospinal fluid. More pathologic studies are urgently needed.

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