Severe Acute Respiratory Syndrome (SARS)

Special Report by Michele Barry, MD

Sources: MMWR Morb Mortal Wkly Rep. 2003;52(11):226-228; MMWR Morb Mortal Wkly Rep. 2003;52(12):241-248; MMWR Morb Mortal Wkly Rep. 2003;52(14):299-302; WHO: www.who.int; CDC: www.cdc.gov/ncidod/sars; Promed: www.promedmail.org; Health Canada: www.sars.gc.ca.

Since late February 2003, the CDC and WHO have been investigating a multicountry outbreak of an atypical pneumonia manifested by an illness referred to as severe acute respiratory syndrome (SARS). These initial reports in MMWR describe the scope of the outbreak, case definition, and interim infection control guidance for the United States. Continuous daily updates can be obtained from these web sites: www.cdc.gov/ncidod/sars and www.who.int.

Epidemiology and Transmission

The first case of SARS was reported outside China on February 26, 2003. By April 9—in less than 2 months—the number of probable cases from 16 countries had reached 2722 with 106 deaths (3.9%). Initially, some 60-70% of infected people were health care professionals who treated SARS-infected people, and the remaining 30-40% were family members and other close contacts of infected people. However, a recent report from Hong Kong documented spread of the disease within nonrelated tenants of an apartment complex with faulty sewage facilities. The current working hypothesis is SARS is transmitted via large droplets (sneezes, coughs, or bodily fluids). This concept does not account for all the epidemiologic evidence including the people in one Hong Kong housing complex and on one floor of a Hong Kong hotel raising the idea of "super-spreaders" or an undiscovered environmental mode of transmission.

Etiologic Agent

Although the etiologic agent had not been confirmed initially, laboratory data indicate that a coronavirus is most probably the culprit. Coronaviruses are enveloped, single-stranded RNA viruses that infect both humans and animals and have a halo or crown-like corona appearance under electron microscopy. The known human coronaviruses are common causes of mild-to-moderate upper respiratory tract infections and are responsible for approximately one-third of common colds. However, they can cause serious infections of the lower respiratory tract in children and adults and are associated with necrotizing enterocolitis in newborns. Coronaviruses can survive on environmental surfaces for up to 3 hours and can be transmitted person-to-person via droplets, hand contamination, formites, and small particle aerosols.1,2 The SARS-associated coronavirus was isolated in Vero E6 cells from clinical specimens of 2 patients in Thailand and Hong Kong with suspected SARS. Electron microscopy identified the isolate as a coronavirus and its identity was confirmed by immunostaining, indirect immunofluorescence assays, and RT-PCR and sequencing of a segment of the polymerase gene. Serology performed on paired convalescent and sera confirm antibody responses to the suspected agent. Sequence microarray analysis suggests this new coronavirus is distinct from other coronaviruses and that it may have begun its current course as an animal pathogen.

Table

CDC Updated Interim Case Definition for Severe Acute Respiratory Syndrome (SARS)*

Suspected case†

Respiratory illness of unknown etiology with onset since February 1, 2003, and the following criteria:
  • Measured temperature > 100.4°F (> 38.0°C)
  • One or more clinical findings of respiratory illness (eg, cough, shortness of breath, difficulty breathing, hypoxia, or radiographic findings of either pneumonia or acute respiratory distress syndrome)
  • Travel within 10 days of onset of symptoms to an area with suspected or documented community transmission of SARS,§ (excluding areas with secondary cases limited to health-care workers or direct household contacts) or
  • 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

* As of March 22, 2003

† Suspected cases with either radiographic evidence of pneumonia or respiratory distress syndrome, or evidence of unexplained respiratory distress syndrome by autopsy, are designated "probable" cases by the World Health Organization case definition

§ Hong Kong Special Administrative Region and Guangdong province, China; Hanoi, Vietnam; and Singapore.

†† Close contact is defined as having cared for, having lived with, or having had direct contact with respiratory secretions and/or body fluids of a patient suspected of having SARS.

Clinical Description of SARS

The incubation period for SARS is typically 2-7 days; however, isolated reports have suggested an incubation period as long as 10 days and reports even up to 15 days in recent isolated cases. The illness generally begins with a prodrome of fever (> 100.4°F or > 38.0°C). Fever is often quite high, sometimes is associated with chills and rigors, and might be accompanied by other symptoms, including headache, malaise, and myalgia. At the onset of illness, some persons have mild respiratory symptoms. Typically, rash and neurologic or gastrointestinal findings are absent; however, some patients have reported diarrhea during the febrile prodrome.

After 3-7 days, a lower respiratory phase begins with the onset of a dry, nonproductive cough or dyspnea, which might be accompanied by or progress to hypoxemia. In 10-20% of cases, the respiratory illness has been severe enough to require intubation and mechanical ventilation. The case-fatality rate among persons with illness meeting the current WHO case definition of SARS is approximately 4%. Chest radiographs might be normal during the febrile prodrome and throughout the course of illness. However, in a substantial proportion of patients, the respiratory phase is characterized by early focal infiltrates progressing to more generalized, patchy, interstitial infiltrates. Some chest radiographs from patients in the late stages of SARS also have shown areas of consolidation.

Early in the course of disease, the absolute lymphocyte count is often decreased. Overall white blood cell counts have generally been normal or decreased. At the peak of the respiratory illness, approximately 60% of patients have leukopenia and thrombocytopenia or low-normal platelet counts (50,000-150,000/µL). Early in the respiratory phase, elevated creatine phosphokinase levels (< 3000 IU/L) and hepatic transaminases (ALT 2-6 times the upper limits of normal) have been noted. In the majority of patients, renal function has remained normal. The severity of illness may be highly variable, ranging from mild illness to death. Although most close contacts of patients with SARS have remained well, other close contacts have reported a mild, febrile illness without respiratory signs or symptoms, suggesting the illness might not always progress to the respiratory phase.

Treatment

Treatment regimens have included several antibiotics to presumptively treat known bacterial agents of atypical pneumonia. Therapy also has included antiviral agents such as oseltamivir or ribavirin. Steroids have also been administered orally or intravenously to patients developing acute respiratory distress syndrome. At present, the most efficacious treatment regime, if any, is unknown, and supportive therapy is recommended by CDC. In Hong Kong and Canada, intravenous ribavirin had been recommended in presumed SARS cases in dosages of 33 mg/kg (max 2 g) IV loading dose following by 16 mg/kg (max 1 g) every 6 hours for 4 days then 8 mg/kg (max 0.5 g) every 8 hours for 3-6 days depending on clinical response. The CDC has not officially recommended use of ribavirin or steroids but does recommend use of antibiotics for community-acquired atypical pneumonia until the agent is definitely documented.

In the United States, clinicians who suspect cases of SARS are requested to report such cases to their state health departments. CDC requests that reports of suspected cases from state health departments, international airlines, cruise ships, or cargo carriers be directed to the SARS Investigative Team at the CDC Emergency Operations Center (telephone, [770] 488-7100).

Clinicians evaluating suspected cases should use standard precautions (eg, hand hygiene) together with airborne prevention (N95 or higher efficiency particle prevention respirator) and contact precautions (gowns and gloves). Until mode of transmission has been defined more precisely, eye protection should also be worn. CDC infection control guidelines for SARS in the inpatient and outpatient setting can be found on the following web site: www.cdc.gov/ncidod/sars/infectioncontrol.htm.

Travel Advisories

At this writing, there are no travel restrictions directly related to SARS; however, a CDC travel advisory recommends that individuals who are planning nonessential or elective travel to mainland China, Hong Kong, Vietnam or Singapore may wish to postpone their trip (for updates see www.cdc.gov/travel). Canada has had a cluster of cases in Toronto but has not been added to the CDC list as of this printing. All Canadian cases have been linked to foreign travel or exposed health care workers.

Specific guidelines for airline crew and flight personnel of commercial flights have been developed (www.cdc.gov/ncidod/sars/flight_crew_guidelines.htm) as well as for air evacuation aircraft www.cdc.gov/ncidod/sars/airtransport-sarspatients.htm). CDC’s Division of Global Migration and Quarantine has sent quarantine officials to provide health alert notices (25,000 daily) to returning travelers on airplanes, cargo ships or cruise ships from infected areas and board airplanes or ships to assess ill travelers. Fact sheets for travelers can be obtained from the CDC web page. (www.cdc.gov/ncidod/sars) Each country is handling travel and case contacts in their particular fashion and travelers should check web sites before leaving as quarantines and mask requirements may occur at airports. For WHO to issue global travel warnings for specific geographical areas is unprecedented even during the years of the smallpox eradication campaign. Daily advisories and press releases are posted on www.who.int.

Table 2

Cumulative Number of Reported Cases of Severe Acute Respiratory Syndrome (SARS)

From: Nov 1, 20021 to: April 3, 2003

Country

Cumulative number of case(s) Number of deaths Local chain(s) of transmission2
Australia  1  0  None
Belgium  1 0 None
Brazil  1 0 None

Canada 

62 6 Yes
China  1190 46 Yes
China, Hong Kong - - -
Special Administrative Region  734 17* Yes
China, Taiwan  14 0 Yes
France  3 0 None
Germany  5 0 None
Italy  3 0 None
Republic of Ireland  2 0 None
Romania  1 0 None
Singapore  98 4 Yes
Switzerland  2 0 None
Thailand  7 2 None
United Kingdom 3 0 None
United States   85 0 Being determined
Vietnam  59 4 Yes
TOTAL  2270  79 -

Notes:

Cumulative number of cases includes number of deaths.

As SARS is a diagnosis of exclusion, the status of a reported case may change over time. This means that previously reported cases may be discarded after further investigation and follow-up.
1. The start of the period of surveillance has been changed to November 1, 2002, to capture cases of atypical pneumonia in China that are now recognized as being cases of SARS.
2. National public health authorities report to WHO on the areas in which local chain(s) of transmission is/are occurring. These areas are provided on the list of affected areas.
A§ Due to differences in the case definitions being used at a national level, probable cases are reported by all countries except the United States of America, which is reporting suspect cases under investigation.
* One death attributed to Hong Kong Special Administrative Region of China occurred in a case medically transferred from Vietnam.

Comment by Michele Barry, MD, FACP

Readers should note the mortality rate of 3-4% may understate actual rate for SARS because many patients who have been infected are healthy, relatively young, health care workers with case detection occurring in the context of a closely watched epidemic and health care setting. Should SARS continue its spread, older and sicker patients with comorbid diseases may contract the disease, treatment resources may fall, and mortality rates could increase. In less than 2 weeks due to amazing global collaboration, the virus has been identified, the genome has been sequenced and diagnostic tests have been developed. In the coming weeks, it will be crucial to develop and use diagnostic tests to apply quickly in hospitals and possibly airports.

Key questions and developments to watch:

  • The transmissibility of SARS during the incubation period before symptoms occur. Is transmissibility large or small droplets, airborne, or by fecal-water contamination?
  • Are there super-spreaders—and what makes one a super-spreader?—more virulent strain, higher inoculum, etc.
  • Do ribavirin or steroids have an effect on mortality or morbidity?
  • Will public health authorities impose travel bans or strict quarantines?
  • Can a vaccine be developed by next winter?

References

1. Sizun J, et al. J Hosp Infect. 2000;46:55-60.

2. Ijaz MK, et al. J Gen Virol. 1985;66:2743-2748.

Dr. Barry is Professor of Medicine; Co-Director, Tropical Medicine and International Travelers' Clinic, Yale University School of Medicine.