What is SARS

Severe Acute Respiratory Syndrome (SARS) is an acute respiratory illness caused by infection with the SARS virus. Fever followed by a rapidly progressive respiratory compromise is the key complex of signs and symptoms, which also include chills, muscular aches, headache and loss of appetite. 　Mortality, initially believed to be around 3 %, may well be as high as 15 %. The WHO estimates that the case fatality ratio of SARS ranges from 0% to 50% depending on the age group affected: less than 1% in persons aged 24 years or younger; 6% in persons aged 25 to 44 years; 15% in persons aged 45 to 64 years; and greater than 50% in persons aged 65 years and older. 　The etiologic agent of SARS is a coronavirus which was identified in March 2003. The initial clusters of cases in hotel and apartment buildings in Hong Kong have shown that transmission of the SARS virus can be extremely efficient. Attack rates in excess of 50% have been reported. The virus is predominantly spread by droplets or by direct and indirect contact. Shedding in feces and urine also occurs. Medical personnel, physicians, nurses, and hospital workers are among those commonly infected.

Fig:Electron micrograph of SARS

　In the absence of effective drugs or a vaccine for SARS, control of this disease relies on the rapid identification of cases and their appropriate management, including the isolation of suspect and probable cases and the management of their close contacts. In the great majority of countries, these measures have prevented imported cases from spreading the disease to others.
At present, the most efficacious treatment regimen for SARS is still subject to debate. For patients with progressive deterioration, intensive and supportive care is of primary importance. Immunomodulation by steroid treatment may be important.

Virology

The severe acute respiratory syndrome (SARS) is due to an infection with a novel coronavirus which was first identified by researchers in Hong Kong, the United States, and Germany. The virus was provisionally termed SARS-associated coronavirus (SARS-CoV). Coronaviridae 　The coronaviruses (order Nidovirales, family Coronaviridae, genus Coronavirus) are members of a family of large, enveloped, positive-sense single-stranded RNA viruses that replicate in the cytoplasm of animal host cells. 　The genomes of coronaviruses range in length from 27 to 32 kb, the largest of any of the RNA viruses. The virions measure between about 100 and 140 nanometers in diameter. Most but not all viral particles show the characteristic appearance of surface projections, giving rise to the virus’ name (corona, Latin = crown). These spikes extend a further 20 nanometers from the surface.

Fig:SARS viron

　The Coronaviridae family has been divided up into three groups, originally on the basis of serological cross-reactivity, but more recently on the basis of genomic sequence homology (see online database ICTVdB). Groups 1 (canine, feline infectious peritonitis, porcine transmissible gastroenteritis and porcine respiratory viruses, human coronavirus 229E) and 2 (bovine, murine hepatitis, rat sialodacryoadenitis viruses, human coronavirus OC43) contain mammalian viruses, while group 3 contains only avian viruses (avian infectious bronchitis, turkey coronavirus).
　In animals, coronaviruses can lead to highly virulent respiratory, enteric, and neurological diseases, as well as hepatitis, causing epizootics of respiratory diseases and/or gastroenteritis with short incubation periods (2-7 days), such as those found in SARS (Holmes). Coronaviruses are generally highly species-specific. In immunocompetent hosts, infection elicits neutralizing antibodies and cell-mediated immune responses that kill infected cells.
SARS Co-V Genome Sequence
　The genome sequence data of SARS Co-V reveal that the novel agent does not belong to any of the known groups of coronaviruses, including two human coronaviruses, HCoV-OC43 and HCoV-229E (Drosten, Peiris, Marra, Rota), to which it is only moderately related. The SARS-CoV genome appears to be equidistant from those of all known coronaviruses. Its closest relatives are the murine, bovine, porcine, and human coronaviruses in group 2 and avian coronavirus IBV in group 1. For links to the most recent sequence data and publications, see the NCBI web page http://www.ncbi.nlm.nih.gov/genomes/SARS/S ARS.html.
　It has been proposed that the new virus defines a fourth lineage of coronavirus. The sequence analysis of SARS-CoV seems to be consistent with the hypothesis that it is an animal virus for which the normal host is still unknown and that has recently either developed the ability to productively infect humans or has been able to cross the species barrier. The genome shows that SARS-CoV is neither a mutant of a known coronavirus, nor a recombinant between known coronaviruses.
　As the virus passes through human beings, SARS-CoV is apparently maintaining its consensus genotype and seems thus well-adapted to the human host. However, genetic analysis is able to distinguish between different strains of SARS-CoV, which is of great value for epidemiological studies and may also have clinical implications.
Morphology
　Negative-stain transmission electron microscopy of patient samples and of cell culture supernatants reveals pleomorphic, enveloped coronavirus-like particles with diameters of between 60 and 130 nm..
　Examination of infected cells by thin-section electron microscopy shows coronavirus-like particles within cytoplasmic membrane-bound vacuoles and the cisternae of the rough endoplasmic reticulum. Extracellular particles accumulate in large clusters, and are frequently seen lining the surface of the plasma membrane (MMWR 2003; 52: 241-248).
Organization
　The SARS-CoV genome contains five major open reading frames (ORFs) that encode the replicase polyprotein; the spike (S), envelope (E), and membrane (M) glycoproteins; and the nucleocapsid protein (N).
　The main function of the S protein is to bind to species-specific host cell receptors and to trigger a fusion event between the viral envelope and a cellular membrane. Much of the species specificity of the initial infection depends upon specific receptor interactions. In addition, the spike protein has been shown to be a virulence factor in many different coronaviruses. Finally, the S protein is the principal viral antigen that elicits neutralizing antibody on behalf of the host.
　The M protein is the major component of the virion envelope. It is the major determinant of virion morphogenesis, selecting S protein for incorporation into virions during viral assembly. There is evidence that suggests that the M protein also selects the genome for incorporation into the virion.
　One remarkable feature about coronavirus RNA synthesis is the very high rate of RNA-RNA recombination.
Stability and Resistance
　Preliminary results, obtained by members of the WHO multicenter collaborative network on SARS diagnosis (see: http://www.who.int/csr/sars/sur vival_2003_05_04/en/index.html), show that the virus is stable in feces and urine at room temperature for at least 1-2 days. The stability seems to be higher in stools from patients with diarrhea (the pH of which is higher than that of normal stool).
　In supernatants of infected cell cultures, there is only a minimal reduction in the concentration of the virus after 21 days at 4°C and -80°C. After 48 hours at room temperature, the concentration of the virus is reduced by one log only, indicating that the virus is more stable than the other known human coronaviruses under these conditions. However, heating to 56°C inactivates SARS-CoV relatively quickly. Furthermore, the agent loses its infectivity after exposure to different commonly-used disinfectants and fixatives.
Natural Host

Research teams in Hong Kong and Shenzhen detected several coronaviruses that were closely related genetically to the SARS coronavirus in animals taken from a southern Chinese market that was selling wild animals for human consumption. They found the virus in masked palm civets (Paguma larvata) as well as some other species. All six of the civets included in the study were found to harbor SARS coronavirus, which was isolated in cell culture or detected by a PCR molecular technique. Serum from these animals also inhibited the growth of SARS coronavirus isolated from humans. Vice versa, human serum from SARS patients inhibited the growth of SARS isolates from these animals. Sequencing of viruses isolated from these animals demonstrated that, with the exception of a small additional sequence, the viruses are identical to the human SARS virus (Cyranoski; Enserink 2003b).

Fig: masked palm civets-one of the natural host of SARS

　The study provides a first indication that the SARS virus exists outside a human host. However, at present, no evidence exists to suggest that these wild animal species play a significant role in the epidemiology of SARS outbreaks. The civets sold on Chinese markets are born in the wild and then captured and raised on farms. They could therefore have acquired the virus from a wild animal or from other animals or even humans during captivity. More research is needed before any firm conclusions can be reached (WHO Update 64, 23 May).
Transmission
　The SARS coronavirus (SARS Co-V) is predominantly spread in droplets that are shed from the respiratory secretions of infected persons. Fecal or airborne transmission seem to be less frequent.
　In some instances, however, so-called "superspreader" patients are able to transmit the SARS virus to a large number of individuals. Superspreaders and nosocomial amplification were the driving factors behind the early 2003 outbreaks.

Epidemiology
　The epidemiological observation that SARS was first detected in the Guangdong province in November 2002 and took three months to spread even to the immediately neighboring Hong Kong, despite easy exchange of family members between the two areas, does suggest, fortunately, a virus with a low infectiousness.
　Outbreaks to date have been restricted to families, often living in high-density accommodation, and to hotels and hospitals. This limited spread is the hallmark of a virus with low communicability.
　A truly global respiratory virus like influenza rather quickly emerged to infect millions of persons worldwide. Given the remarkable extent of air travel today, the SARS virus is not spreading rapidly, at least to date.
　Two major epidemiological studies have been published on the possible consequences of introduction of the SARS virus into a susceptible population. Both calculate that the "basic case reproduction number" - the fundamental epidemiological quantity that determines the potential for disease spread - is of the order of 2 to 4 for the Hong Kong epidemic. They draw the conclusion that the SARS coronavirus, if uncontrolled, would infect the majority of people wherever it was introduced, but that it is not so contagious as to be uncontrollable with good, basic public health measures: improved control measures in hospitals, quarantine of contacts of cases, and voluntary reduction in contacts in the population.
Riley et al. estimate that in Hong Kong, 2.7 secondary infections were generated on average per case at the start of the epidemic, with a substantial contribution from hospital transmission. Transmission rates fell during the epidemic, primarily due toreductions in population contact rates improved hospital infection control more rapid hospital attendance by symptomatic individuals.

Prevention

SARS, in contrast to diseases like flu or rubella, is only moderately transmissible. The number of secondary SARS cases per index case, ranging in one epidemiologic study from 2.2 to 3.6, are considerably lower than those estimated for most other diseases with respiratory transmission. This indicates that a combination of control measures, including shortening the time from symptom onset to isolation of patients, effective contact tracing and quarantine of exposed persons, can be effective in containing SARS. Indeed, such measures have been successful and have contributed to the prevention of major outbreaks in other countries. On the other hand, in the absence of such effective measures, SARS has the potential to spread widely. 　In the absence of a vaccine, the most effective way to control a new viral disease such as SARS is to break the chain of transmission from infected to healthy persons. In almost all documented cases, SARS is spread through close face-to-face contact with infected droplets when a patient sneezes or coughs (WHO, WER 20/2003).

Fig:prevension of SARS

　For SARS, three activities - case detection, patient isolation and contact tracing - can reduce the number of people exposed to each infectious case and eventually break the chain of transmission (WHO, WER 20/2003):Case detection aims to identify SARS cases as soon after the onset of illness as possible.
　Once cases are identified, the next step is to ensure their prompt isolation in a properly equipped facility, and management according to strict infection control procedures.
　The third activity - the detective work - involves the identification of all close contacts of each case and assurance of their careful follow-up, including daily health checks and possible voluntary home isolation.
　Together, these activities limit the daily number of contacts possible for each potentially infectious case. They also work to shorten the amount of time that lapses between the onset of illness and isolation of the patient, thus reducing the opportunities for the virus to spread to other patients (WHO WER 20/2003).

SARS Treatment
　The treatment of coronavirus-associated SARS has been evolving and so far there is no consensus on an optimal regimen. This chapter reviews the diverse treatment experience and controversies to date, and aims to consolidate our current knowledge and prepare for a possible resurgence of the disease.
Treatment strategies for SARS were first developed on theoretical bases and from clinical observations and inferences. Prospective randomized controlled treatment trials were understandably lacking during the first epidemic of this novel disease. The mainstream therapeutic interventions for SARS involve broad-spectrum antibiotics and supportive care, as well as antiviral agents and immunomodulatory therapy. Assisted ventilation in a non-invasive or invasive form would be instituted in SARS patients complicated by respiratory failure.
　Anti-bacterial agents are routinely prescribed for SARS because its presenting features are non-specific and rapid laboratory tests that can reliably diagnose the SARS-CoV virus in the first few days of infection are not yet available. Appropriate empirical antibiotics are thus necessary to cover against common respiratory pathogens as per national or local treatment guidelines for community-acquired or nosocomial pneumonia (Niederman et al 2001). Upon exclusion of other pathogens, antibiotic therapy can be withdrawn.
　In addition to their antibacterial effects, some antibiotics are known to have immunomodulatory properties, notably the quinolones (Dalhoff & Shalit 2003) and macrolides (Labro & Abdelghaffar 2001). Their effect on the course of SARS is undetermined.
　SARS can present with a spectrum of disease severity. A minority of patients with a mild illness recover either without any specific form of treatment or on antibiotic therapy alone (Li G et al 2003; So et al 2003).

　Various antiviral agents were prescribed empirically from the outset of the epidemic and their use was continued despite lack of evidence about their effectiveness. With the discovery of the SARS-CoV as the etiologic agent, scientific institutions worldwide have been vigorously identifying or developing an efficacious antiviral agent. Intensive in vitro susceptibility tests are underway.

Reference:
http://www.sarsreference.com/sarsref/virol.htm
http://www.sarsreference.com/sarsref/virol.htm
http://www.sarsreference.com/sarsref/epidem.htm
http://www.sarsreference.com/sarsref/prevent.htm
http://www.sarsreference.com/sarsref/treat.htm