Severe Acute Respiratory Syndrome (SARS) Lydia Ho & Rui Yang BISC 209 Professor Mary Allen

November 16, 02 Initial cases of SARS appeared in South China February 14, cases & 5 deaths from an unknown acute respiratory syndrome

March 03: New reports of outbreaks came in from Hong Kong, Singapore & Vietnam New syndrome was designated as “severe acute respiratory syndrome,” or SARS

March 17, 03: WHO called for global collaborative research on SARS March 12, 03: WHO issued global alert about SARS

March 24, 03: Scientists in CDC and HK announced isolation of new coronavirus from SARS patients DNA sequencing shows this virus is distinct from all known human pathogens

April 25, 03: Nearly 3000 SARS cases have been identified in China April 20-25, 03: Outbreaks in Hanoi, Hong Kong, China, Singapore & Toronto showed signs of peaking City closed down schools & imposes strict quarantine measures

But the investigation continues… By the end of June, 03: Most countries were removed from the list of areas with recent local transmission of SARS: Singapore, Hong Kong, Beijing, Toronto, Taiwan

The Pathogen behind it all … SARS-CoV Virus

Discovery of the new virus Kochs postulates Discovery of novel coronavirus in patient Isolation of cell culture Reproducible symptom in cell culture Identical isolates produced  Novel coronavirus is the cause of SARS

Coronaviridae A family of large, enveloped, positive- sense single stranded RNA virus Irregular shape Characteristic ‘club- shaped’ surface projections (~20nm)

SARS-CoV Genome 71% of the genome codes for polyproteins Remainder: codes for structural proteins S (spike): receptor binding, cell fusion, major antigen E (envelop): envelop-associated protein M (membrane): transmembrane-budding N (nucleocapsid): genome-associated phosphoprotein

SARS-CoV Genome

SARS-CoV Life Cycle S-protein binds to receptor  initiation of induced endocytosis Translation of viral RNA polymerase Transcription of (+) RNA into genomic and subgenomic mRNA in the cytoplasm N protein synthesized from free ribosome S and M protein synthesized in RER Budding from RER as virion, excretion from cell via Golgi

SARS Case Definition

Clinical Symptoms High fever

Clinical History 10 days before onset of symptoms Close contact with probable/suspected SARS patients Live in / travel to area with transmission of SARS

Transmission of SARS

Transmission of SARS-CoV Highly probable: origination is a cross- species jump from civet cat to human Human-to-human transmission Direct contact Spread in droplets shed from respiratory secretions Possible fecal transmission

Infectiousness of SARS Debatable Most patients are moderately infectious Cases of “superspreaders” reported Factors affecting infectiousness are Viral load of the secretion from index patient Aerosol-generation procedures Distance of the index patient

Methods of Diagnosis

Virus Detection Virus isolation: inoculate suitable cell culture with patient specimens

Antibody Detection When infected by SARS-CoV  antibodies (e.g. IgM and IgG) are produced / change in level Enzyme-linked immunosorbent assay (ELISA)

Antibody Detection Immunofluorescence assay (IFA): Sample: patient serum Method: Fix SARS-CoV-infected cells on microscope’s slide (patient antibodies already bound to viral antigens) Immunofluorescent-labeled 2 º antibodies bind to human IgG/IgM Significance: positive result after 10 days of onset of illness

Clinical Findings Clinical history & observation Chest radiography: important role 70-80% patients have abnormal chest radiographs Normal SARS patient

Method of Cure

Immunomodulatory therapy Corticosteroid Very powerful: affect entire body Anti-inflammatory & immunosuppressive effects Significance: early improvement of fever, better radiographic infiltrates Controversy: ? Effectiveness Adverse side effects

Antiviral Agents Ribavirin: nucleoside analog Most frequently administered Have antiviral activity against many DNA & RNA viruses Criticism: ? Effectiveness Adverse side effects

Antiviral Agents Protease inhibitor: Lopinavir-ritonavir co-formulation: protease inhibitor used to treat HIV infection With ribavirin: block processing of the viral replicase polyprotein  prevent RNA replication

Method of Prevention & Control

Principle of Disease Confinement Principle: to break the chain of transmission from infected to healthy person 3-step protocol of disease confinement Case detection Prompt isolation Contract tracing Daily health check Voluntary home isolation

Epidemic Containment Creation of emergency operating center Institutional support Efficient quarantine measures Legislation International collaboration—WHO Travel alerts and restrictions Coordination for research Agreement of countries on containment protocol

SARS and Beyond… The early management of SARS epidermic may serve as a model for the containment of future epidermics and pandemics

References Cann, A. (January 20, 2004). Severe acute respiratory syndrome (SARS). Retrieved from: Dept. of Communicable Disease Surveillance and Response, WHO. (2003). Consensus document on the epidemiology of severe acute respiratory syndrome (SARS). Kamps, Hoffmann. (October, 2003). SARS Reference. Retrieved from: Shanghai Center for Bioinfomatics Technology. (2004). Life cycle of the SARS virus. Retrieved from: Siddell, S, Wege H., ter Meulen V. The biology of coronaviruses. J. Gen Virol. 1983; 64 (Pt4): Thiel, et al. ( June 19, 2003). Mechanisms and enzymes involved in SARS coronavirus genome expression, Journal of general virology. Retrieved from: Tsang KW, Ho PL, Ooi GC, Yee WK, et al. A Cluster of Cases of Severe Acute Respiratory Syndrome in Hong Kong. N Engl J Med 2003, 348: World Health Organization. (2004). Case Definition. Retrieved from: World Health Organization. (2004). Diagnostic Tests. Retrieved from