SARS: Would You Be Ready?

December 1, 2003
Majid Sadigh, MD

,
Steven I. Aronin, MD

In November 2002, cases of an atypical pneumonia were reported in the Guangdong province of southern China. By the following June, outbreaks of the illness-known as severe acute respiratory syndrome (SARS)-had occurred in Germany, Ireland, the United States, Canada,Hong Kong,Singapore, and Vietnam.

In November 2002, cases of an atypical pneumonia were reported in the Guangdong province of southern China. By the following June, outbreaks of the illness-known as severe acute respiratory syndrome (SARS)-had occurred in Germany, Ireland, the United States, Canada,1 Hong Kong,2 Singapore,3 and Vietnam.4 These outbreaks involved a disproportionate number of health care workers. Altogether, more than 8000 cases of suspected or probable SARS were reported in 29 countries; more than 770 of these were fatal.5

Is SARS likely to return this winter? Here we present the latest thinking on this issue and discuss how to recognize and respond to SARS should it reappear.

WILL SARS RESURFACE?

The genome of the coronavirus associated with SARS (SARS-CoV) is distinctly different from that of other known coronaviruses. Unlike the human coronavirus strains 229E and OC43 (which are responsible for 15% to 30% of cases of the common cold), SARS-CoV infects the lower respiratory tract and can lead to severe respiratory disease and/or death. The entrance of SARS-CoV into the human population was likely the result of mutation of a previously unknown animal coronavirus.6 It has not yet been determined from which animal SARS-CoV originated-although this is an area of active investigation. A small study of 25 market animals from Hong Kong identified a coronavirus essentially identical to SARS-CoV in 6 masked palm civets and a single raccoon dog; antibodies to the virus were detected in a Chinese ferret badger.7 However, more data are required before any conclusions can be drawn.

The primary mode of transmission of SARS-CoV appears to be via droplets from the respiratory secretions of infected persons (eg, through sneezing, coughing, speaking, and exhaling).8 Other modes of transmission (fecal-oral and airborne) are less likely; however, these alternate routes of transmission have been proposed as the mechanism of spread of a cluster of cases associated with a Hong Kong housing estate.9 Occupationally acquired SARS may also occur, as evidenced by the doctoral student in Singapore who became infected in August-most likely through accidental laboratory contamination.10

It is not yet known whether SARS-CoV is shed from the GI and/ or respiratory tract of asymptomatic persons or whether SARS-CoV is or will become established in humans. If SARS-CoV has found a niche in humans, then it will likely circulate itself and produce intermittent, difficult-to-control outbreaks of disease.

On the other hand, if SARS-CoV is a mutant that can no longer exist in its original host and if the virus has not established itself in humans, we may never see SARS again. Future outbreaks could occur, however, if the virus has retained the ability to transmit itself across species, and if humans are re-exposed to the viral reservoir. A factor that may help to determine whether SARS will return is the nature of the viral reservoir, which remains unknown.

For now, keep an open mind when you evaluate patients with suspicious symptoms so that case detection-the first step in an outbreak response-occurs as early as possible.

WHO/CDC CASE DEFINITION

The case definition of SARS developed by the World Health Organization11 and the CDC12 comprises a nonspecific febrile respiratory illness and a consistent epidemiologic history (Box). To determine whether a patient meets the epidemiologic criteria, ask whether, within 10 days of the onset of symptoms, he or she has had close contact with a person known or suspected to have SARS or has traveled to an area with documented or suspected community transmission of the disease. If a patient meets the epidemiologic criteria for SARS, he can be classified as a suspected or a probable case based on the severity of the respiratory illness.

CLINICAL PRESENTATION

The spectrum of disease caused by SARS-CoV may range from asymptomatic infection to respiratory failure and death. Symptomatic infection likely dominates this spectrum. Because the case definition for SARS is broad and because no standardized diagnostic test for SARS-CoV infection exists, it is impossible to determine the accuracy of the clinical descriptions published to date.

SARS has been described as a febrile respiratory illness that develops after an incubation period of approximately 6 days,1,13 and that is indistinguishable from other viral respiratory tract infections. Fever occurs in most patients as a presenting symptom, and it may be accompanied by chills, rigors, malaise, myalgia, headache, and/or diarrhea.1,9,13 After 3 to 7 days-typically in the second week-the illness may progress from the febrile phase to a respiratory phase, which is characterized by a dry cough that may be accompanied by shortness of breath and/or hypoxia.14 Most patients improve spontaneously. However, up to 20% enter a third phase around the third week of illness, characterized by respiratory failure that requires mechanical ventilation; acute respiratory distress syndrome may also develop.14 Patients with SARS may go through 1, 2, or all 3 of these phases; in addition, they may appear to improve clinically before they deteriorate into the next phase.9

The estimated case-fatality rate for patients with SARS is 9.6%,5 and there appears to be a direct relationship between age and mortality.15 In addition to advanced age, other predictors of poor outcome include elevated white blood cell count and elevated lactate dehydrogenase level.16 SARS-CoV may also cause fatal disease in young, previously healthy persons.

DIAGNOSTIC TESTS

Assign the provisional diagnosis of SARS to any febrile patient with a respiratory illness of unknown origin and a consistent epidemiologic history. The initial diagnostic evaluation for patients with suspected SARS includes:

  • Chest radiograph.
  • Pulse oximetry.
  • Blood cultures.
  • Sputum Gram stain and culture.
  • Testing of respiratory tract secretions for viral pathogens, including influenza A and B and respiratory syncytial virus.

Also consider testing the urine for the presence of Legionella and pneumococcal antigen.

Radiographic findings. The chest radiograph may be normal or have only subtle abnormalities in early disease; however, up to 80% of patients with SARS have an abnormal chest radiograph at the onset of fever.1,9,17 The radiographic abnormalities associated with SARS are nonspecific and include a patchy focal peripheral opacity that may progress to unilateral multifocal or bilateral involvement (Figure).17 Cavitation, hilar lymphadenopathy, and pleural effusion are atypical features.17

CT is more sensitive than plain radiography in this setting. CT findings may include lower lobe subpleural focal consolidation with air bronchograms and bilateral airspace ground-glass consolidation, as seen in bronchiolitis obliterans with organizing pneumonia.18

Laboratory features. These include:

  • Normal to low leukocyte count.
  • Lymphopenia (less than 1000/µL).
  • Thrombocytopenia (less than 150,000/µL).
  • Elevated levels of serum aminotransferase, lactate dehydrogenase, creatinine phosphokinase, and D-dimer.1,9,13,19,20

Collect and hold an acute serum sample, and instruct the laboratory to save any available clinical specimens for additional testing until a specific diagnosis is made. If no causative agent is identified on initial testing, the next step is to test clinical specimens for SARS-CoV. Make sure that specimens from patients with suspected SARS are labeled accordingly and that the receiving laboratory is alerted before the samples are sent. Details regarding specimen collection and processing are available from the CDC.21 Currently available specific laboratory tests to detect SARS-CoV infection include:

  • Serology (indirect fluorescent antibody and enzyme-linked immunosorbent assays specific for the antibody produced after SARS infection).
  • Reverse transcriptase polymerase chain reaction (PCR) assay specific for RNA from SARS-CoV.
  • Viral culture.

The currently available PCR assays and viral culture are insensitive means of identifying SARS-CoV; thus, serology is presently the diagnostic test of choice. Seroconversion is defined as a negative antibody test on acute serum followed by a positive antibody test on convalescent serum (at least 28 days after onset of symptoms), or a 4-fold or greater increase in antibody titer between acute- and convalescent-phase sera tested in parallel.

INFECTION CONTROL

If you suspect SARS in an outpatient, provide him with a surgical mask and keep him away from other patients. Next, determine the need for hospital admission. Factors that may influence this decision include disease severity, home environment, and likelihood of compliance with home quarantine.

Given the significant risk of nosocomial transmission of SARS, it is perfectly reasonable (and, in fact, encouraged) to treat select patients with mild disease at home. Instruct such patients to:

  • Wear a surgical mask when in the presence of others.
  • Contain their respiratory secretions.
  • Sanitize their hands frequently.
  • Avoid sharing utensils, towels, and bedding.
  • In addition, instruct close contacts of the patient to:
  • Practice good hand hygiene.
  • Wear disposable gloves when in direct contact with the patient's body fluids.
  • Monitor themselves for the development of fever or respiratory symptoms. If such symptoms occur, they should seek immediate medical evaluation.

The approach to patients who present to the emergency department with suspected SARS is similar. Provide the patient with a surgical mask, keep him away from other patients-preferably in a negative airflow room-and then determine whether he needs to be hospitalized. Keep the number of health care workers who come in contact with the patient to a minimum, and make sure essential personnel wear eye protection and follow strict contact (hand hygiene, gown and gloves) and airborne (properly fitted N-95 respirator) precautions. Although SARS-CoV appears to be transmitted via droplets,8 the virus may also be spread via the fecal-oral and/or airborne route. Thus, the current recommendations are to follow droplet, contact, and airborne precautions.22

Place patients who require hospital admission in a negative airflow room. Keep to a minimum the number of health care workers in contact with them and discourage visitors. Avoid procedures that result in coughing and aerosolization of respiratory secretions. Use an Environmental Protection Agency-registered hospital-grade disinfectant for daily and terminal disinfection, and pay careful attention to fomite surfaces.

TREATMENT

There is no specific therapy for coronavirus infection, including that caused by SARS-CoV. The mainstays of therapy for patients with SARS are supportive care and empiric antibiotics. Because no causative agent is identified in approximately 50% of patients with community-acquired pneumonia-and because the case definition for SARS is nonspecific and testing methods insensitive-it is important to prescribe empiric antibiotics that target the usual community-acquired respiratory pathogens.

Ribavirin and corticosteroids have both been used as empiric therapy for patients with suspected and probable SARS.1,9,13,18,19,23-26 Use of ribavirin is based on assumptions that this agent's broad spectrum of activity includes SARS-CoV, and that the pathogenesis of SARS involves viral replication, which leads to a brisk inflammatory response and cytokine dysregulation with resultant pulmonary injury. Postmortem evaluation of lung tissue from patients with SARS supports the notion that lung damage is primarily mediated by viral replication and tissue exposure.27

However, ribavirin has not been shown to be active in vitro against SARS-CoV. Moreover, patients treated early with ribavirin and corticosteroids have not had better outcomes than those who received only supportive therapy.16 Thus, we find no evidence to date that supports the use of these agents in patients with suspected or confirmed SARS.

References:

REFERENCES:1. Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289:2801-2809.
2. Acute respiratory syndrome-China, Hong Kong Special Administrative Region of China, and Viet Nam. Wkly Epidemiol Rec. 2003;78:73-74.
3. Severe acute respiratory syndrome-Singapore, 2003. MMWR. 2003;52:405-411.
4. Update: outbreak of severe acute respiratory syndrome-worldwide, 2003. MMWR. 2003;52: 269-272.
5. World Health Organization. Summary table of SARS cases by country, November 2002 - 7 August 2003. Available at: http://www.who.int/csr/sars/ country/2003_08_15/en/. Accessed October 13, 2003.
6. Holmes KV. SARS coronavirus: a new challenge for prevention and therapy. J Clin Invest. 2003;111: 1605-1609.
7. Guan Y, Zheng BJ, He YQ, et al. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science. 2003;302:276-278.
8. Seto WH, Tsang D, Yung RWH, et al. Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS). Lancet. 2003; 361:1519-1520.
9. Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361:1767-1772.
10. Della-Porta AJ, Kai CS, Ek LC, et al, for the Review Panel on New SARS Case and Biosafety. Biosafety and SARS incident in Singapore September 2003. Available at: http://www.moh.gov.sg/ sars/pdf/report_SARS_Biosafety.pdf. Accessed November 13, 2003.
11. World Health Organization. Case definition for surveillance of severe acute respiratory syndrome (SARS). Available at: http://www.who.int/csr/sars/ casedefinition/en/. Accessed October 13, 2003.
12. CDC. Updated interim US case definition for severe acute respiratory syndrome (SARS). Available at: http://www.cdc.gov/ncidod/sars/ casedefinition.htm. Accessed October 13, 2003.
13. Lee N, Hui D, Wu A, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003;348:1986-1994.
14. Sampathkumar P, Temesgen Z, Smith TF, Thompson RL. SARS: epidemiology, clinical presentation, management, and infection control measures. Mayo Clin Proc. 2003;78:882-890.
15. WHO Update 49: SARS case fatality ratio, incubation period. May 7, 2003. Available at: http:// www.who.int/csr/sarsarchive/2003_05_07a/en/. Accessed October 13, 2003.
16. Tsui PT, Kwok ML, Yuen H, Lai ST. Severe acute respiratory syndrome: clinical outcome and prognostic correlates. Emerg Infect Dis. 2003;9:1064-1069.
17. Wong KT, Antonio GE, Jui D, et al. Severe acute respiratory syndrome: radiographic appearances and pattern of progression in 138 patients. Radiology.2003;228:401-406.
18. Tsang KW, Ho PL, Ooi GC, et al. A cluster of cases of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003;348:1977-1985.
19. Poutanen SM, Low DE, Henry B, et al. Identification of severe acute respiratory syndrome in Canada. N Engl JMed. 2003;348:1995-2005.
20. Wong RSM, Wu A, To KF, et al. Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis. BMJ. 2003; 326:1358-1362.
21. CDC. Guidelines for collection of specimens from potential cases of SARS. Available at: http:// www.cdc.gov/ncidod/sars/specimen_collection_ sars2.htm. Accessed October 13, 2003.
22. CDC. Updated interim domestic infection control guidance in the health-care and community setting for patients with suspected SARS. Available at: http://www.cdc.gov/ncidod/sars/infectioncontrol. htm. Accessed October 13, 2003.
23. Hsu L, Lee C, Green JA, et al. Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts. Emerg Infect Dis. 2003;9:713-717.
24. Fowler RA, Lapinsky SE, Hallett D, et al. Critically ill patients with severe acute respiratory syndrome. JAMA. 2003;290:367-373.
25. Lew TWK, Kwek T, Tai D, et al. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA. 2003; 290:374-380.
26. So LK, Lau ACW, Yam LYC, et al. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet. 2003;361:1615-1617.
27. Mazzulli T, Farcas GA, Poutanen SM, et al. Severe acute respiratory syndrome-associated coronavirus in lung tissue. Emerg Infect Dis. Published online before print August 21, 2003. Available at: http:// www.cdc.gov/ncidod/EID/vol10no1/03-0404.htm. Accessed October 13, 2003.
28. Hsu LY, Lee CC, Green JA, et al. Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts. Emerg Infect Dis. [serial online]. June 2003;9. Available from: URL:http//www.cdc.gov/ncidod/EID/ vol9no6/03-0264.htm. Accessed October 10, 2003.

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