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A. Epidemiology [3]navigator

  1. Initially reported in Guangdong Province, China, in November, 2002
  2. Probably originated in southern China
  3. Caused by a novel human coronavirus [4,5]
  4. Over 8000 patients worldwide infected with probable SARS by May, 2003
  5. Mostly affects adults aged 25-70 previously healthy
  6. Close contacts rarely develop illness
  7. Case fatality rate ~6.5% (range 3-20% depending on area and followup duration) [25]
  8. Outcome mainly affected by age; age >60 associated with poor prognosis [6]
  9. Initial outbreak contained worldwide by June, 2003
  10. Viruses from in Hong Kong, Canada, Vietnam, Singapore are closely linked genetically [28]

B. High Risk Areas [15,16]navigator

  1. Hong Kong Special Administrative Region and Guangdong Province [29]
    1. In 2003, 1755 patients; healthcare workers 23%
    2. About 50% contracted disease in institutional setting
    3. Male:Female 4:5
    4. Mean incubation 4.6 days
    5. Mean time onset to death 23 days
    6. Mean time onset to discharge from hospital 26 days
    7. Elevated lactate dehydrogenase on admission increased risk for death
  2. Peoples' Republic of China
  3. Hanoi
  4. Vietnam
  5. Singapore
  6. Toronto, Canada [18,20]

C. Coronaviruses [4,7] navigator

  1. Coronaviruses typically associated with epidemics in livstock or poultry
    1. Found in 3 serologically unrelated groups
    2. Virion structure with mRNA genome
    3. Viral nucleocapsid with sense RNA form helical nucleocapsid
    4. A "corona" of large spikes in envelope gives virus its name
    5. Spikes are oligomers of spike (S) glycoprotein
    6. Group 2 coronaviruses also have a hemagglutinin-acetylesterase glycoprotein
    7. Unique RNA-dependent RNA polymerase often switches template strands during replication
    8. This error-prone polymerase thus mediates frequent recombination
  2. Human Coronaviruses
    1. Cause up to 30% of human colds
    2. Rarely cause lower respiratory tract infections (LRI) in humans
    3. SARS agent is only distantly related to other other known human or animal coronaviruses or toroviruses
  3. SARS Coronavirus [5,8,9,23]
    1. SARS coronavirus propagated in vitro causes pneumonia in macaques similar to humans
    2. Lack of homology with animal strains means unlikely arose by direct recombination
    3. SARS agent may represent a fourth serological coronavirus group
    4. Virus causes marked cytopathic effects in vitro and in vivo
    5. Complete viral genome was identified within 3 months of first reported cases (May, 2003)
    6. Subtypes of SARS coronavirus have now been sequenced and mutation rates are high [10]
    7. At least two strains of SARS coronavirus have emerged during the epidemic [21]
    8. Viruses from across the globe are genetically very similar, however [27]

D. Clinical Presentation [20,22,25]navigator

  1. Incubation period 2-7 days, up to 10 days
  2. Generally begins with prodrome of fever
    1. Temperatures typically >38.0°C (>100.48F)
    2. Fever occurs in 85-99% of cases
  3. Chills (74%) common; rigors may occur
  4. Cough, typically nonproductive (~70%)
  5. Nonspecific: malaise, myalgia, dyspnea, headache (>50%)
  6. Respiratory Symptoms
    1. Usually mild at beggining of illness
    2. Lower respiratory symptoms begin with dry cough andor dyspnea after 3-7 days
    3. Hypoxemia often follows and is a poor prognostic sign
    4. Acute lung injury / adult respiratory distress syndrome can occur [22]
    5. Intubation and mechanical ventilation required in 10-20% of patients
  7. Children have similar symptoms, generally less severe, with very low mortality rate [11]
  8. Adult case fatility rate ~6.5% in patients with SARS as defined below
    1. Mortality for hospitalized patients overall ~10%
    2. Mortality for patients admitted to intensive care 37% [22]
  9. Immune Dysregulation in SARS [12,13]
    1. SARS is associated with increased macrophages and hemophagocytosis in lungs
    2. Viral load drops in second week of disease but symptoms may increase or recur
    3. These findings suggest that cytokine dysregulation could account for symptom severity
  10. Little evidence for subclinical or mild forms of SARS []

E. Case Definition [2,14] navigator

  1. Measured temperature >38° C ( >100.4 °F)
  2. One or more clinical findings of respiratory illness
    1. Cough
    2. Shortness of breath, difficulty breathing
    3. Hypoxia
    4. Radiographic findings of either pneumonia or acute respiratory distress syndrome (ARDS)
  3. Possible Cases
    1. Travel within 10 days of onset of symptoms to an area with suspected or documented community transmission of SARS OR
    2. Close contact within 10 days of onset of symptoms with either a person with a respiratory illness and travel to a SARS area or a person under investigation or suspected of having SARS
  4. Unclear etiology but likely a virus related to measles

F. Laboratory Testing navigator

  1. Chest Radiography (CXR)
    1. Usually normal during early febrile phase
    2. Respiratory phase with focal interstitial infiltrates
    3. May progress to generalized, patchy interstitial infiltrates
    4. Consolidation may be seen
  2. Overall white blood cell counts (WBC) normal or decreased
  3. Low to low-normal platelet counts (50-150K/µL)
  4. Early respiratory phase may show elevated creatine phosphokinase (CPK) elevations
  5. Hepatic transaminases may be 2-6X normal levels
  6. Renal function generally remains normal

G. Treatmentnavigator

  1. Supportive therapy is given
  2. Standard regimens have been published from Hong Kong group [17]
    1. Glucocorticoids
    2. Ribavirin
    3. Antibiotics for community acquired pneumonia including atypical agents
    4. Consensus interferon (IFN) alpha (Alfacon-1®) has in vitro and in vivo activity [26]
    5. Therapy appears to be effective for children [11] as well as adults [17]
    6. Symptoms may recur as therapy is tapered, possibly due to immunological factors [12]
  3. Glucocorticoids
    1. 21 Day Course
    2. Methylprednisolone (SoluMedrol®) 1mg/kg q8 hrs (3mg/kg daily) IV for 5 days
    3. Then methylprednisolone 1mg/kg q12 h (2mg/kg daily) IV for 5 days
    4. Then prednisolone or prednisone 0.5mg/kg bid (1mg/kg daily) po for 5 days
    5. Then prednisolone or prednisone 0.5mg/kg qd (0.5mg/kg daily) po for 3 days
    6. Then prednisolone or prednisone 0.25mg/kg qd (0.25mg/kg daily) po for 3 days
    7. Then stop
    8. Pulsed methylprednisolone may be given 500mg IV q12 hours for 2 days for worsening
    9. After 2 days pulsed methylprednisolone, return to standard regimen
  4. Ribavirin
    1. 10-14 Day Course
    2. Ribavirin 400mg q8 hours IV for at least 3 days or until stable
    3. Ribavirin 1200mg bid po
  5. Glucocorticoids + IFN alpha [26]
    1. IFN alpha (consensus IFNalpha, Alfacon-1®) has good in vitro anti-SARS activity
    2. Combination IFN alpha with prednisone or methylpresnisolone showed promising superior activity to glucocorticoids alone in probable SARS
    3. Alfacon-1 given 9µg/d SC for at least 2 days, then increase to 15µg/d if no response
    4. Alfacon-1 treatment was continued for one day after steroid tapering
  6. Antibiotics are given to prevent coinfection or treate community acquired pneumonia [17]
    1. Levofloxacin (Levaquin®) 500mg qd IV or po OR
    2. Clarithromycin (Biaxin®) 500mg bid PO
    3. Add amoxicillin/clavulanate (Augmentin®) 375mg po tid for patients <18 years, pregnant, or may have turberuclosids
    4. Azithromycin (Zithromax®) may be used in place of clarithromycin
  7. Ventilation
    1. Supplemental oxygen may be needed
    2. Consider noninvasive ventilation if saturation <96% on 6L per min oxygen nasal canula
    3. Mechanical ventilation may be needed, particularly with acute lung injury [22]
  8. Other Antiviral Agents
    1. IFN ß shows very good in vitro antiviral activity [24]
    2. Oseltamivir - used for influenza A and B
    3. Derivatives of agents which treat common cold under investigation
    4. Additional agents are being tested
  9. The most efficacious treatment is not known

G. Prevention [19]navigator

  1. Masks are most effective at reducing transmission
  2. Gloves and gowns should be considered but unclear if add protection to mask
  3. Likely that droplets are mode of transmission

References navigator

  1. World Health Organization. 2003. MMWR. 52:388
  2. WHO Multicentre Collaborative Network for SARS Diagnosis. 2003. Lancet. 361(9370):1730 abstract
  3. Peiris JSM, Yuen KY, Osterhaus ADME, Stohr K. 2003. NEJM. 349(25):2431 abstract
  4. Holmes KV. 2003. NEJM. 348(20):1948 abstract
  5. Zhong NS, Zheng BJ, Li YM, et al. 2003. Lancet. 362(9393):1353 abstract
  6. Donnelly CA, Ghani AC, Leung GM, et al. 2003. Lancet. 361(9371):1761 abstract
  7. Peiris JSM, Lai ST, Poon LLM, et al. 2003. Lancet. 361(9366):1319 abstract
  8. Ksiazek TG, Erdman D, Goldsmith CS, et al. 2003. NEJM. 348(20):1953 abstract
  9. Drosten C, Gunther S, Preiser W, et al. 2003. NEJM. 348(20):1967 abstract
  10. Ruan Y, Wei CL, Ee LA, et al. 2003. Lancet. 361(9371):1779 abstract
  11. Hon KLE, Leung CW, Cheng WTF, et al. 2003. Lancet. 361(9370):1701 abstract
  12. Peiris JSM, Chu CM, Cheng VCC, et al. 2003. Lancet. 361(9731):1767
  13. Nicholls JM, Pon LLM, Lee KC, et al. 2003. Lancet. 361(9371):1773 abstract
  14. http://www.cdc.gov/ncidod/sars/casedefinition.htm
  15. Tsang KW, Ho PL, Ooi GC, et al. 2003. NEJM. 348(20):1977 abstract
  16. Lee N, Hui D, Wu A, et al. 2003. NEJM. 348(20):1986 abstract
  17. So LKY, Lau ACW, Yam LYC, et al. 2003. Lancet. 361(9359):1615
  18. Poutanen SM, Low DE, Henry B, et al. 2003. NEJM. 348(20):1995 abstract
  19. Seto WH, Tsang D, Yung RWH, et al. 2003. Lancet. 361(9368):1519 abstract
  20. Booth CM, Matukas LM, Tomlinson GA, et al. 2003. NEJM. 289(21):2801 abstract
  21. Tsui SKW, Chim SSC, Lo YMD. 2003. NEJM. 349(2):187 abstract
  22. Lew TWK, Kwek TK, Tai D, et al. 2003. JAMA. 290(3):374 abstract
  23. Kuiken T, Fouchier RAM, Schutten M, et al. 2003. Lancet. 362(9380):263 abstract
  24. Cinatl J, Morgenstern B, Bauer G, et al. 2003. Lancet. 362(9380):293 abstract
  25. Choi KW, Chau TN, Tsang O, et al. 2003. Ann Intern Med. 139(9):715 abstract
  26. Loutfy MR, Blatt LM, Siminovitch KA, et al. 2003. JAMA. 290(24):3222 abstract
  27. Guan Y, Peiris HSM, Zheng B, et al. 2004. Lancet. 363(9403):99 abstract
  28. Rainer TH, Chan PKS, Ip M, et al. 2004. Ann Intern Med. 140(8):614 abstract
  29. Leung GM, Hedley AJ, Ho LM, et al. 2004. Ann Intern Med. 141(9):662 abstract