Analysis of Deaths During the Severe Acute Respiratory Syndrome (SARS) Epidemic in Singapore: Challenges in Determining a SARS Diagnosis

Abstract

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.

Studies of Severe Acute Respiratory Syndrome Coronavirus Pathology in Human Cases and Animal Models

“…Cellular infiltration by macrophages has been observed, as has a combination of macrophages and lymphocytes, with or without neutrophils. 6,8,17 –19,48,58,69 Large multinucleated cells identified as macrophages and pneumocytes by immunohistochemistry are frequently observed in the lungs of SARS patients. Bronchiolitis obliterans organizing pneumonia, 48 hemophagocytosis in the mononuclear cells residing in pulmonary tissues, 48 and apoptosis of epithelial cells, monocytes/macrophages, lymphocytes and pneumocytes 17 are also seen.…”

“…In some cases, coinfections by Aspergillus sp, Mucor sp, Pseudomonas aeruginosa, Klebsiella sp, methicillin-resistant Staphylococcus aureus , α-hemolytic Streptococcus sp, and cytomegalovirus have been reported. 6,19 In situ hybridization and immunohistochemistry studies have identified viral nucleic acid and/or antigen in epithelial cells from bronchi, bronchioles, trachea, and alveoli and in multinucleated cells and alveolar macrophages. 16,17,47,58,66,75 Investigation of the cytokine and chemokine profiles of SARS patients has suggested that severe SARS-related lung injury might be attributed to an excessive host immune response—particularly, the deregulation of proinflammatory cytokine production.…”

“…Human lungs infected with SARS-CoV show evidence of DAD characterized by desquamation of epithelial cells, fibrin and collagen deposition in the alveolar space, hyperplasia of type II pneumocytes, increased infiltration of the interstitium by mononuclear cells, and, in some cases, the presence of multinucleated syncytial cells. 6,10,50 The detection of antigen-positive cells in human tissues is usually related to the duration of illness. In fatal cases of short duration, viral antigens were detected in pneumocytes and, occasionally, macrophages within the intra-alveolar necrotic debris in the alveolar septal walls and, rarely, in bronchial epithelial cells.…”

Incidence of Deep Venous Thrombosis in Patients With COVID‐19 and Pulmonary Embolism

“…An increase of PE has been reported in intensive care unit patients with COVID‐19 7–13 . Previous outbreaks of SARS‐CoV‐1 and Middle Eastern respiratory syndrome have been associated with an increased risk of thrombosis 14,15 . Despite previous experience with these coronaviruses, the pathophysiologic characteristics of PE in SARS‐CoV‐2 infection are not well documented.…”

Immunothrombosis in Acute Respiratory Dysfunction of COVID-19

“…SARS-CoV-1 infection has been associated with hematological abnormalities, including thrombocytosis (49%), elevated D-dimer (45.0%), thrombocytopenia (55%), and prolonged activated partial thromboplastin time (aPTT) (63%) (55,56). Chong et al also reported that 20.5% of patients infected with SARS-CoV-1 had deep vein thrombosis, and 11.4% of these patients showed clinical evidence of pulmonary embolism (57). Furthermore, in a SARS-CoV-1-infected patient, edema and fibrin thrombi were identified in the pulmonary vasculature (58).…”