Severe acute respiratory syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Severe acute respiratory syndrome is a respiratory disease in humans which is caused by the SARS coronavirus.^[1] There has been one major pandemic to date, between November 2002 and July 2003, with 8,096 known cases of the disease, and 774 deaths (a mortality rate of 9.6%) being listed in the WHO‘s April 21, 2004 concluding report.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Coronaviruses are positive-strand, enveloped RNA viruses that are important pathogens of mammals and birds. This group of viruses cause enteric or respiratory tract infections in a variety of animals including humans, livestock and pets.^[1]

Initial electron microscopic examination in Hong Kong and Germany found viral particles with structures suggesting paramyxovirus in respiratory secretions of SARS patients. Subsequently, in Canada, electron microscopic examination found viral particles with structures suggestive of metapneumovirus (a subtype of paramyxovirus) in respiratory secretions. Chinese researchers also reported that a chlamydia-like disease may be behind SARS. The Pasteur Institute in Paris identified coronavirus in samples taken from six patients, so did the laboratory of Malik Peiris at the University of Hong Kong, which in fact was the first to announce (on March 21, 2003) the discovery of a new coronavirus as the possible cause of SARS after successfully cultivating it from tissue samples and was also amongst the first to develop a test for the presence of the virus. The CDC noted viral particles in affected tissue (finding a virus in tissue rather than secretions suggests that it is actually pathogenic rather than an incidental finding). Upon electron microscopy, these tissue viral inclusions resembled coronaviruses, and comparison of viral genetic material obtained by PCR with existing genetic libraries suggested that the virus was a previously unrecognized coronavirus. Sequencing of the virus genome — which computers at the British Columbia Cancer Agency in Vancouver completed at 4 a.m. Saturday, April 12, 2003 — was the first step toward developing a diagnostic test for the virus, and possibly a vaccine.^[2] A test was developed for antibodies to the virus, and it was found that patients did indeed develop such antibodies over the course of the disease, which is highly suggestive of a causative role.

On April 16, 2003, the WHO issued a press release stating that a coronavirus identified by a number of laboratories was the official cause of SARS.^[3] Scientists at Erasmus University in Rotterdam, the Netherlands demonstrated that the SARS coronavirus fulfilled Koch’s postulates thereby confirming it as the causative agent. In the experiments, macaques infected with the virus developed the same symptoms as human SARS victims.^[4]

An article published in The Lancet identifies a coronavirus as the probable causative agent.

In late May 2003, studies from samples of wild animals sold as food in the local market in Guangdong, China found that the SARS coronavirus could be isolated from civets. This suggests that the SARS virus crossed the xenographic barrier from civets. In 2005, two studies identified a number of SARS-like coronaviruses in Chinese bats.^[5][6] Phylogenetic analysis of these viruses indicated a high probability that SARS coronavirus originated in bats and spread to humans either directly, or through civet cats. The bats did not show any visible signs of disease.

Coronavirus (CoV) genome replication takes place in the cytoplasm in a membrane-protected microenvironment and starts with the translation of the genome to produce the viral replicase. CoV transcription involves a discontinuous RNA synthesis (template switch) during the extension of a negative copy of the subgenomic mRNAs. The requirement for base pairing during transcription has been formally demonstrated in arteriviruses and CoVs. CoV N protein is required for coronavirus RNA synthesis and has RNA chaperone activity that may be involved in template switch. Both viral and cellular proteins are required for replication and transcription. CoVs initiate translation by cap-dependent and cap-independent mechanisms. Cell macromolecular synthesis may be controlled after CoV infection by locating some virus proteins in the host cell nucleus. Infection by different coronaviruses cause in the host alteration in the transcription and translation patterns, in the cell cycle, the cytoskeleton, apoptosis and coagulation pathways, inflammation and immune and stress responses. The balance between genes up- and down-regulated could explain the pathogenesis caused by these viruses. Coronavirus expression systems based on single genome constructed by targeted recombination, or by using infectious cDNAs, have been developed. The possibility of expressing different genes under the control of transcription regulating sequences (TRSs) with programmable strength and engineering tissue and species tropism indicates that CoV vectors are flexible. CoV based vectors have emerged with high potential vaccine development and possibly for gene therapy.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The epidemic of SARS appears to have originated in Guangdong Province, China in November 2002. The first case was reportedly originated from a rural area in Foshan, Guangdong in Nov 2002, and the patient, a farmer, was treated in the First People’s Hospital of Foshan. The patient died soon after, and no definite diagnosis was made on his cause of death. (“Patient #0” — first reported symptoms — has been attributed to Charles Bybelezar of Montreal, Canada) and, despite taking some action to control it, Chinese government officials did not inform the World Health Organization of the outbreak until February 2003, restricting media coverage in order to preserve public confidence. This lack of openness caused delays in efforts to control the epidemic, resulting in criticism of the People’s Republic of China (PRC) from the international community. The PRC has since officially apologized for early slowness in dealing with the SARS epidemic.^[2]

The first clue of the outbreak appears to be November 27, 2002 when Canada’s Global Public Health Intelligence Network (GPHIN), an electronic warning system which is part of the World Health Organization’s (WHO) Global Outbreak and Alert Response Network (GOARN), picked up reports of a “flu outbreak” in China through internet media monitoring and analysis and sent them to the WHO.^{[3] [4]} Subsequently, the WHO requested information from Chinese authorities on December 5 and 11.^[4] Importantly, while GPHIN’s capability had recently been upgraded to enable Arabic, Chinese, English, French, Russian and Spanish translation, the system was limited to English or French in presenting this information. Thus, while the first reports of an unusual outbreak were in Chinese, an English report was not generated until January 21, 2003.^[3]

In early April, there appeared to be a change in official policy when SARS began to receive a much greater prominence in the official media. Some have directly attributed this to the death of American James Earl Salisbury.^[5] However, it was also in early April that accusations emerged regarding the undercounting of cases in Beijing military hospitals. After intense pressure, PRC officials allowed international officials to investigate the situation there. This revealed problems plaguing the aging mainland Chinese healthcare system, including increasing decentralization, red tape, and inadequate communication.

In late April, revelations occurred as the PRC government admitted to underreporting the number of cases of SARS due to the problems inherent in the healthcare system. Dr. Jiang Yanyong exposed the coverup that was occurring in China, at great personal risk. He reported that there were more SARS patients in his hospital alone than were being reported in all of China. A number of PRC officials were fired from their posts, including the health minister and mayor of Beijing, and systems were set up to improve reporting and control in the SARS crisis. Since then, the PRC has taken a much more active and transparent role in combating the SARS epidemic.

The epidemic reached the public spotlight in February 2003, when an American businessman traveling from China became afflicted with pneumonia-like symptoms while on a flight to Singapore. The plane stopped at Hanoi, Vietnam, where the victim died in the French Hospital of Hanoi. Several of the medical staff who treated him soon developed the same disease despite basic hospital procedures. Italian doctor Carlo Urbani identified the threat and communicated it to WHO and the Vietnam government. The severity of the symptoms and the infection of hospital staff alarmed global health authorities fearful of another emergent pneumonia epidemic. On March 12, 2003, the WHO issued a global alert, followed by a health alert by the United States Centers for Disease Control and Prevention (CDC). Local transmission of SARS took place in Toronto, Vancouver, San Francisco, Ulan Bator, Manila, Singapore, Hanoi, Republic of China, Taiwan, the Chinese provinces of Guangdong, Jilin, Hebei, Hubei, Shaanxi, Jiangsu and Shanxi, the Direct-controlled municipality of Tianjin, the Chinese Autonomous Region of Inner Mongolia, and the Chinese Special Administrative Region of Hong Kong.

In Hong Kong the first cohort of affected people were discharged from the hospital on March 29, 2003. The disease spread in Hong Kong from a mainland doctor on the 9th floor of the Metropole Hotel in Kowloon Peninsula, infecting 16 of the hotel visitors. Those visitors traveled to Singapore and Toronto, spreading SARS to those locations. Another, larger, cluster of cases in Hong Kong centered on the Amoy Gardens housing estate. Its spread is suspected to have been facilitated by defects in the sewage system of the estate.

The mortality rates vary across countries and reporting organizations. In early May, for consistency with similar metrics of other diseases, the World Health Organization (WHO) and U.S. Centers for Disease Control and Prevention were quoting 7%, or the number of deaths divided by probable cases, as the SARS mortality rate. Others spoke in favor of a 15% figure, derived from number of deaths divided by the number who recovered, saying it reflects the real situation more accurately. As the outbreak progressed both mortality measures approached 10%.

One reason for the difficulties in plotting a reliable mortality figure is that the number of infections and the number of deaths are increasing at different rates. A possible explanation involves a secondary infection as a causal agent in the disease,^[6] but whatever the cause, the mortality numbers are bound to change.

Mortality by age group as of 8 May 2003 is below 1% for people aged 24 or younger, 6% for those 25 to 44, 15% in those 45 to 64 and more than 50% for those over 65.^[7]

For comparison, the case fatality rate for influenza is usually about 0.6% (primarily among the elderly) but can rise as high as 33% in locally severe epidemics of new strains. The mortality rate of the primary viral pneumonia form is about 70%.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Since severe acute respiratory syndrome is contagious, anyone around a person with severe acute respiratory syndrome is at risk.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The World Health Organization requested that all affected areas screen departing passengers for SARS symptoms. In spite of intensive screening, no SARS cases were detected. SARS has an extremely low prevalence, and the positive predictive value of screening is essentially zero. With the rapid international spread of severe acute respiratory syndrome (SARS) from March through May 2003, Canada introduced various measures to screen airplane passengers at selected airports for symptoms and signs of SARS. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Symptoms usually appear 2–10 days following exposure, but up to 13 days has been reported. In most cases symptoms appear within 2–3 days. About 10–20% of cases require mechanical ventilation.

• Respiratory failure
• Liver failure
• Heart failure

As the first wave of SARS began to subside, the death rate proved to have been about 14 or 15 percent of those diagnosed. In people over age 65, the death rate was higher than 50 percent. Many more were sick enough to require mechanical ventilation, and more still were sick enough to require hospitalization in intensive care units.

Intensive public health policies are proving to be effective in controlling outbreaks. Many nations have stopped the epidemic within their own countries. All nations must be vigilant, however, to keep this disease under control. Viruses in the coronavirus family are known for their ability to change (mutate) in order to better spread among humans.

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