SEVERE ACUTE RESPIRATORY SYNDROME (SARS) CORONAVIRUS (SARS-CoV / SCoV / SCV)ref1, ref2

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Table of contents :


  • Epidemiology
  • Genomics
  • Proteomics
  • Transmission
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Therapy
  • Prognosis
  • Prevention
  • Web resources


  • Epidemiology : 8422 people has sickened in 29 countries, with 918 deaths (CFR ~ 10.9 %) and 7442 recovered. The last known case of the February 2003 outbreak was detected and isolated in Taiwan on June 15 : successively 2 laboratoy-related infections have been reported on September in Singapore and December in Taiwan (see above) and some cases in China. In the outbreak in Guangdong reported in February 2003, the proportion of SARS cases in health care workers was approximately 30% : in the final analysis of the global outbreak, approximately 21% of SARS cases reported in 2003 were in health care workers, with a high of 43% reported in Canada. Most patients have been previously healthy adults aged 25-70 years. Very few and milder suspected cases of SARS have been reported among children (< 15 years) : the immaturity of kids' immune systems could protect them from the virus and make immune-mediated damage milder, as occurs for HAV and HHV-3 / VZV. The CFR, among those admitted to hospital, in patients > 60 years of age is estimated to be far higher (43.3%) than in those < 60 (13.2%) : additional infections in the community that do not lead to hospitalisation or death would lower this CFR estimateref. According to the final analyses, the age-specific CFRs reported in China were 0.9% for those 20-29 years of age, 3.0% for 30-39 years, and 5.0% for 40-49 years. Some outbreaks have reassuring features. A high awareness of SARS symptoms among travellers and the medical and nursing professions has often resulted in good management of imported cases – prompt isolation of patients and management according to strict procedures of infection control. As a result, many countries having only a single or a few imported cases have experienced no further spread to hospital staff, families of patients and hospital visitors, or the community at large
    Genomics :
    The virus, 29,727-29,751 bpref, 11 ORFs, diverges by 50–60% from the 3 known groups of coronavirusref, but that is typical of the variation between coronavirus groups : the origin is completely unclear because no other coronavirus is closely relatedref. Scientists in the Netherlands were able to switch the host of a coronavirus just by swapping one of their genesref. A few nucleotide differences among individual genomes were detected as the virus is expected to mutate very fast. Here is the list of shared mutations : When the S-gene sequences of 4 animal viruses [3 Himalayan palm civet and one raccoon dog] were compared with 11 human SCoV viruses [HKU65806, Urbani, Tor 2, HKU 39849, HKU 66078, CUHK-W1, HKU 36871, GZ50, GZ01, GZ60 and GZ43], 38 nucleotide polymorphisms were noted, with 26 of them being non-synonymous changes. The S genes among the 4 animal viruses had 8 nucleotide differences, whereas there were 20 nucleotide differences among 11 human viruses. Thus the animal viruses, though isolated from the same market, are no less divergent than the human viruses isolated from Hong Kong, Guangdong, Canada, and Vietnam. However, whereas 14 (70%) of the 20 polymorphisms among the human viruses were non-synonymous mutations, only 2 (25%) of the 8 nucleotide substitutions within the animal viruses were. An amino acid deletion (nucleotide positions: 21690-21692) was observed in 2 of the human viruses (GZ43 and GZ60). Of the 38 polymorphisms, there were 11 consistent nucleotide signatures that appeared to distinguish animal and human viruses. Phylogenetic analysis showed that the human and animal viruses form distinct clusters, which makes it highly unlikely that the isolation of SCoV-like viruses in these wild animals is due to the transmission of SCoV from human to animalsref. Despite the recent onset of the SARS epidemic, genetic signatures are emerging that partition the worldwide SARS viral isolates into groups on the basis of contact source history and geography. 2 isolates (BJ01 and BJ03) come from the same individual : they share 4 mutations but each isolate has 3 additional unshared mutations (all 3 in orf1ab for BJ01; 2 in E2 and 1 in orf1ab for BJ03). In addition, a common variant associated with a non-conservative amino acid change in the S1 region of the spike protein suggests that immunological pressures might be starting to influence the evolution of the SARS virus in human populationsref. Phylogenetic analysis of SARS-CoV spike protein :


    Molecular characterization of the SARS coronavirus has revealed genetic diversity among isolates. The spike (S) glycoprotein, the major target for vaccine and immune therapy, shows up to 17 substitutions in its 1,255-aa sequence. The functional effects of S mutations have been determined by analyzing their affinity for a viral receptor, human angiotensin-converting enzyme 2 (ACE2), and their sensitivity to Ab neutralization with viral pseudotypes. Although minor differences among 8 strains transmitted during human outbreaks in early 2003 were found, substantial functional changes were detected in S derived from a case in late 2003 from Guangdong province [S(GD03T0013)] and from 2 palm civets, S(SZ3) and S(SZ16). S(GD03T0013) depended less on the hACE-2 receptor and was markedly resistant to Ab inhibition. Antibodies collected from mice injected with S protein from a SARS virus taken from a human patient infected in early 2003 were unable to attack S protein from a different strain of SARS, isolated from a patient infected in late 2003. Unexpectedly, Abs that neutralized most human S glycoproteins enhanced entry mediated by the civet virus S glycoproteins. The mechanism of antibody-dependent enhancement (ADE) involved the interaction of Abs with conformational epitopes in the hACE-2-binding domain. Finally, improved immunogens and mAbs that minimize this complication have been defined. The virus changes over time, so that a strain that crops up in one outbreak might be quite different from that in a later outbreak. This raises the prospect that a vaccine against one strain of SARS virus could prove ineffective against others. Worse, a jab against one strain might even aggravate an infection with SARS virus from civets or another speciesref.
    Some (opportunistic ?) co-infections have been associated with the disease : Proteomics : Receptor : Transmission : the presence of the virus has been demonstrated in some mammals ... SARS-CoV GVU6109 can survive for 4 days in diarrheal stool samples with an alkaline pH, and it can remain infectious in respiratory specimens for >7 days at room temperature. Even at a relatively high concentration (104 tissue culture infective doses/mL), the virus could not be recovered after drying of a paper request form, and its infectivity was shown to last longer on the disposable gown than on the cotton gown. All disinfectants tested were shown to be able to reduce the virus load by >3 log within 5 minref.
    Susceptibility : HLA-B*4601 (in about 10-15% of Taiwan's and other southern Asians populations, including people from China's Guangdong and Fujian provinces, and people from Hong Kong, Singapore and parts of Vietnam, where people have maintained close genetic connections over the past 400 years. Taiwan's Aborigines, as well as Caucasians and African people, do not have the SARS-prone HLA-B46 gene)
    Resistance : HLA-B13. 1.2-2.9% of healthy individuals tested in Guangdong are seropositive for SARS-associated coronavirus
    Pathogenesis : the largest series of fatal cases of SARS with autopsy material to date was collected by merging the pathological material from two regions involved in the 2003 worldwide SARS outbreak in Hong Kong, China, and Toronto, Canada. A mAb against the SARS-CoV nucleoprotein was used together with in situ hybridization (ISH) to analyze the autopsy lung tissues of 32 patients with SARS from Hong Kong and Toronto. The results of these assays were compared with the pulmonary pathologies and the clinical course of illness for each patient. SARS-CoV nucleoprotein and RNA were detected by immunohistochemistry and ISH, respectively, primarily in alveolar pneumocytes and, less frequently, in macrophages. Such localization was detected in 4 of the 7 patients who died within 2 weeks of illness onset, and in 0 of the 25 patients who died > 2 weeks after symptom onset. The pulmonary alveolar epithelium is the chief target of SARS-CoV, with macrophages infected subsequently. Viral replication appears to be limited to the first 2 weeks after symptom onset, with little evidence of continued widespread replication after this period. If antiviral therapy is considered for future treatment, it should be focused on this 2-week period of acute clinical diseaseref. Severe SARS is associated with a more robust IgG responseref. Analyses of T cell repertoires in health care workers who survived SARS-CoV infection during the 2003 outbreak revealed that their effector memory Vg9Vd2 T cell populations were selectively expanded ~3 months after the onset of disease. No such expansion of their alpha beta T cell pools was detected. The expansion of the Vg9Vd2 T cell population was associated with higher anti-SARS-CoV IgG titers. In addition, in vitro experiments demonstrated that stimulated Vg9Vd2 T cells display an IFN-g-dependent anti-SARS-CoV activity and are able to directly kill SARS-CoV-infected target cells. These findings are compatible with the possibility that Vg9Vd2 T cells play a protective role during SARSref. Deletion allele (D allele) of ACE gene is associated with hypoxemia in SARS patients. Moreover, the ACE D allele has been shown to be more prevalent in patients suffering from adult respiratory distress syndrome (ARDS) in a previous study. Anyway the ACE I/D polymorphism is not directly related to increased susceptibility to SARS-coronavirus infection and is not associated with poor outcomes after SARS-coronavirus infectionref.
    Analyses of T cell repertoires in health care workers who survived SARS-CoV infection during the 2003 outbreak revealed that their effector memory Vg9Vd2 T cell populations were selectively expanded ~3 months after the onset of disease. No such expansion of their abT cell pools was detected. The expansion of the Vg9Vd2 T cell population was associated with higher anti-SARS-CoV IgG titers. In addition, in vitro experiments demonstrated that stimulated Vg9Vd2 T cells display an IFN-g-dependent anti-SARS-CoV activity and are able to directly kill SARS-CoV-infected target cells. These findings are compatible with the possibility that Vg9Vd2 T cells play a protective role during SARSref
    Incubation period : 2-10 days, allowing the infectious agent to be transported, unsuspected and undetected, in a symptomless air traveller from one city in the world to any other city having an international airport
    => severe acute respiratory syndrome (SARS) : it was initially believed to be due to influenzavirus A H5N1 subtype as Guangdong lies between Hong Kong and Fujian province. SARS-CoV infection was diagnosed in 75% (329 of 436) of postmortem samples from patients fitting the case definition of SARSRef, compared with 0% for a control group of healthy individuals or those with unrelated illnesses. SARS-CoV-infected macaques excreted SARS-CoV from nose, mouth, and pharynx from 2 days after infection : 3 of 4 macaques developed diffuse alveolar damage, similar to that in SARS patients, and characterised by epithelial necrosis, serosanguineous exudate, formation of hyaline membranes, type 2 pneumocyte hyperplasia, and the presence of syncytia. SARS-CoV was detected in pneumonic areas by virus isolation and RT-PCR, and was localised to alveolar epithelial cells and syncytia by immunohistochemistry and transmission electron microscopy.
    Symptoms & signs : prodrome of fever > 38°C sometimes associated with chills, rigors, headache, malaise, myalgias, and sometimes mild respiratory symptoms and diarrhea (2-7%; 60% in residents in Amoy Gardens => possible transmission via the sewage system). Myocarditis has also been described. After 3-7 days, a lower respiratory phase begins with the onset of a dry, non-productive cough or dyspnea that may be accompanied by or progress to hypoxemia via ARDS. Hematological changes are common and include lymphopenia, thrombocytopenia and occasionally leukopenia. A significant decrease was also observed in peripheral CD4+ and CD8 T lymphocyte subsets and it was related to onset of SARS. A number of potential mechanisms may be involved. The development of auto-immune antibodies or immune complexes triggered by viral infection may play a major role in inducing lymphopenia and thrombocytopenia. Moreover, SARS-CoV may also directly infect hematopoietic stem/progenitor cells via CD13 or CD66a inducing their growth inhibition and apoptosis. The receptor for group I and III CoV is CD13 / aminopeptidase N. CD13 has been identified in human bone marrow CD34+ cells, platelets, megakaryocytes, myeloid cells, and erythroid cells, but not in lymphocytes. The common receptor for group II CoV is CEACAM1a / CD66a. CD66a is an adhesion molecule expressed on bone marrow CD34+ cells, platelets, granulocytes and activated lymphocytes. In addition, glucocorticoids could induce lymphopenia and the use of steroids may account for the decrease of lymphocytes in some SARS patients. The increased consumption of platelets and/or the decreased production of platelets in the damaged lungs are a potential alternative but often overlooked mechanism that can contribute to thrombocytopenia in severe critical pulmonary conditionsref
    Laboratory examinations : Therapy : The following criteria are considered prior to making a decision regarding discharge from hospital regarding a convalescent case who is medically fit for discharge : Discharged convalescent patients should be asked to monitor and record their temperature twice daily. If they have an elevated temperature > 38°C on 2 consecutive occasions they should report to the health care facility from which they were discharged. Follow up is recommended at 1 week at which time they should have a repeat chest x-ray, full blood count and any other blood tests that were previously abnormal. The patient should be followed up by the health care facility from which they were discharged. In addition, the clinician may decide that the patient needs to be followed up before 1 week. Subsequent follow-ups are recommended until the chest x-ray and patient’s health returns to normal. As part of the follow-up we ask that convalescent serology is taken at 3 weeks after the date of the presenting symptoms and provided to the health care facility from which they were discharged. Until more is known about the aetiological agent, and the potential for continued carriage (and hence the risk of continuing transmission) a cautious approach is warranted. Therefore, we advise that following discharge from hospital convalescent cases should be advised to wait for a minimum of 14 days (twice the known maximum incubation period), before considering returning to work/school/college. During this period they should stay indoors, keeping contact with others to a minimum. Clear instructions should be given to convalescent cases to return to the health care facility from which they were discharged if their condition deteriorates and any further symptoms develop.
    Prognosis : plasma CXCL10 / IP-10 concentration (but not CXCL9 / MIG, CCL2 / MCP-1, CCL5 / RANTES, and CXCL8 / IL-8) at the first week is an independent prognostic factor, with an odds ratio for adverse outcome of 1.52 (95% confidence interval, 1.05-2.55) per fold increase in plasma IP-10 concentration above the median. During the second week, chemokines provided little independent prognostic information. IP-10 was increased in lung tissue from patients who died of SARSref
    Prevention : Web resources :
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