ASA September 2003 Newsletter

Late last November, while the World Health Organization (WHO) was holding its annual flu vaccine conference in Beijing, China, it began hearing reports of an illness that was causing severe respiratory problems and deaths in the southern Chinese province of Guangdong. WHO requested tissue samples for testing but found them to contain only common flu strains. In retrospect, this was the early stage of an outbreak of a yet unknown disease later labeled severe acute respiratory syndrome (SARS) with a previously unknown human pathogen (SARS-related coronavirus, or SARS-CoV).

It would not be until mid-February, after several missed opportunities, that WHO had sufficient evidence of the unusual outbreak to begin questioning the Chinese government. During the remainder of February and early March, WHO and the Centers for Disease Control and Prevention (CDC) sent teams to China and attempted to obtain more data. The Chinese government did not allow them access to the necessary people or data, however. Then on February 21, a physician from Guangdong province checked into the Metropole Hotel in Hong Kong. He became ill with SARS and was hospitalized in Hong Kong but not before 10 other guests from the United States, Canada, Singapore, Ireland and Vietnam were exposed.

And so began the worldwide spread of the SARS virus. WHO issued a global alert on March 12, but the imminence of the war with Iraq overshadowed this news. A more emphatic alert was issued on March 15 when it became apparent that the disease had broken out of China and the epidemic was spreading to other countries.¹ A dramatic pictorial representation of the explosive spread of SARS can be found on the CDC Web site at <www.cdc.gov/mmwr/preview/mmwrhtml/mm5218a1.htm#fig1>. Six months into the epidemic, there have been 7,864 cases of SARS in 28 countries with 643 deaths.²

The case definition for SARS [Table 1] is based on clinical and epidemiological factors. This is a result of our current knowledge deficit on the duration of viremia and viral shedding during which time a direct viral test could be used for confirmation of the disease. It is also not known when sera can be tested for an acute or chronic phase antibody response. A negative laboratory test should not be used to rule out SARS-CoV infection until further data on viral testing is available.

Table 1 (Click to enlarge)

SARS-CoV
There are currently three identified groups of corona-viruses. Groups I and II are known to cause human illness but generally fairly mild upper-respiratory diseases. Group III is only known to cause animal disease.⁴ Based on recent sequencing data, SARS-CoV does not fit clearly into any of these three groups. In addition, it does not show evidence of being a recombinant of other known viruses. It is an enveloped, single-stranded RNA virus containing 29,727 nucleotides and is approximately 100-150 nanometers in size.^5-9 Transmission is known to occur by close contact and large droplets but also may have airborne as well as fecal-oral spread. Symptoms begin from two to 10 days (importantly, not a firm outer limit) after exposure, with fever (100 percent), chills/rigors (73-90 percent), headache (20-70 percent), myalgia (20-83 percent) and malaise. This progresses in another three to seven days to respiratory symptoms (nonproductive cough and dyspnea) and is often accompanied by leukopenia, lymphopenia, increased creatine phosphokinase (CPK) and transaminases. Infiltrates on a chest X-ray (CXR) may not be present initially but generally begin as focal, become interstitial and then progress to involve multiple lobes. The period of infectivity is currently believed to start with the onset of symptoms and end within 10 days of the resolution of fever with the caveat that respiratory symptoms are resolving. This outer limit of infectivity may not be accurate when steroids have been used in treatment or if the patient is immunocompromised for other reasons.⁴

Workup of patients suspected of having SARS should include a CXR, blood and sputum cultures, oxygen saturation measurements and tests for other viral pathogens as well as legionella and streptococcus pneumonia. Reverse transcriptase polymerase chain reaction (RT-PCR) can be done to test for the presence of viral antigens in specimens. The virus has been found in nasopharyngeal aspirates, blood, stool and urine. The timing of testing for the presence of the antigen in various sample types is still to be delineated [Table 2]. Therefore, a RT-PCR test does not rule out the presence of the disease. A positive test is a true positive as long as there has been no contamination during the conduct of the test.⁴

Table 2 (Click to Enlarge)

Antibody to SARS-CoV may be identified using one of three tests: immunoflorescent antibody (IFA), enzyme-linked immunosorbent antibody (ELISA) or a neutralization test. A serum specimen obtained greater than 21 days after onset of the illness should be used to test the convalescent serum for evidence of an IgG response to SARS-CoV. Based on testing of greater than 1,000 individuals who have not had SARS, there is no evidence of immunity in the general population (consistent with a totally new disease); therefore, a positive antibody test is confirmatory of having had the disease. The CDC is now making the reagents for these tests available to many laboratories around the country, but until more is known about the optimal timing, sensitivity and specificity of these tests, the case definition of the disease will be based on clinical and epidemiological factors. Local and state health departments should be notified of any suspect or probable cases.^{4, 10}

Current recommendations for treatment are predominantly supportive. Testing for the efficacy of many antiviral agents as well as drugs that are immune modulators is ongoing. There are no data at this time to recommend any particular drug therapy.⁴

Factors associated with severity of disease and fatality are under investigation. Age, coexisting disease and possible pregnancy¹¹ are adversely associated with outcome. The current estimates of fatality from SARS are subject to error for various reasons. If the method of taking the number of fatalities divided by the total number of reported cases is used, the number may be significantly inaccurate because there are thousands of patients who currently have the disease, but we do not yet know their outcome. Some of the mortality estimates only include the subset of patients who were admitted to a hospital. It is unknown at this time whether exposure, followed by conversion to antibody positivity, can occur without the development of disease symptoms. If so, the denominator may be much larger. Another factor affecting the varying mortality rates from different countries is that in places where there have been relatively small numbers of cases, the affected population is not necessarily a random cross section of the population. In addition, all the data are not yet known from China where the vast majority of the cases have occurred to date.¹²

Infection Control
The principles for control of the spread of SARS are based on the known (contact, droplet) and suspected/possible (airborne, fecal-oral) mechanisms of transmission. Precautions include isolation, use of personal protective equipment, handwashing and disinfection of environmental surfaces.

Isolation
Whenever possible, patients should have a private, negative-pressure room with at least six to 12 air exchanges per hour. If this is unavailable, they should have a room with a high-efficiency particulate air (HEPA) filter. A designated nursing unit for SARS patients would be the third choice option. Doors and windows must be kept closed for the measures to be effective.^13-16

Personal Protective Equipment
Respirators: Disposable, National Institute for Occupational Safety and Health-approved, fit tested N-95 or greater respirators should be used when in contact with patients. A surgical mask placed over the nose and mouth of the patient is sufficient to trap the large particles generated through coughing or sneezing. However, they are incapable of filtering the virus once the expectorated material dries and the virus becomes airborne as a droplet nucleus. N-95 masks attain a 95-percent filtration efficiency through mechanisms such as electrostatic filtration, sedimentation and diffusion.^13-17

Eye protection, gowns, gloves: Goggles, disposable gowns and gloves should be worn when entering a patient’s room and during patient contact. When leaving the patient’s room, gowns should be removed prior to gloves as one would do when scrubbing out of a surgical procedure to avoid self-contamination.^13-16

Handwashing: Hands should be washed with soap (antimicrobial or plain) and water after patient contact regardless of whether gloves have been worn. Alcohol-based hand rubs may be used if there has been no visible soiling.^13-16

Patient Care Equipment and Environmental Surfaces
When possible, patient care equipment should be left in the patient’s room. Equipment and environmental surfaces should be disinfected with an Environmental Protection Agency-approved agent (such as a quaternary ammonium or phenolic compound) that is recommended for the particular item. Seventy-five percent ethanol, 2 percent phenol, hypochlorite (500 ppm available chlorine) and household detergent all have been shown to be effective disinfectants.^{13-16,
18}

Recommendations for Practice
Patient triage: Any patient suspected to have SARS is advised to contact the health care facility prior to their arrival. Patients should put on surgical masks and be isolated from other individuals at the earliest opportunity.

Patient transfer: SARS patients should only be outside their room for required medical procedures. Elective procedures should be postponed until the patient is no longer deemed to be infectious. While outside their room, patients should wear surgical masks. Transport personnel should use full barrier protection.

Operating room: When surgery is required, efforts should be made to limit exposure of personnel and other patients. This may be accomplished by performing the procedure when the least number of people are present in the operating room (O.R.) and limiting those in the patient’s O.R. to only those who are essential for the procedure. Operating rooms generally have positive pressure in relation to the outside hallways in order to decrease surgical infection risk. If available, O.R.s with antechambers are preferable for cases where the patient may expose personnel to infection risk. All unnecessary equipment should be removed from the room to prevent contamination. Patients should be transferred directly to the O.R. in which the surgery will be performed. Everyone in the O.R. should use full precautions discussed earlier. Bacterial/viral filters should be used on both the inspiratory and expiratory limbs of the anesthesia machine. There are no recommendations on anesthetic technique. Care should be taken to avoid contamination of the anesthesia machine and cart, which may be accomplished by double-gloving and changing the outer pair of gloves after each patient contact. After the procedure, the patient must be recovered in isolation. This may require that recovery occur in the O.R. itself or the patient’s isolation room. All personal protective equipment (PPE) should be removed prior to leaving the O.R. as it may be contaminated. New PPE should be put on for transport of the patient when leaving the O.R. There is controversy as to whether the N-95 masks should be reused. If adequate supplies are available, it is preferable to dispose of the masks after use as they are potential fomites for the transfer of infection. If there is a shortage of masks, one recommendation is to wear a surgical mask over the N-95 mask (not under the mask as this defeats the purpose of a tight seal that only allows filtered air inside the mask), thus decreasing gross soiling of the mask. The O.R. should remain vacant for a sufficient period of time to allow for 99.9 percent air turnover. For a room with five air changes per hour (ACH), 83 minutes would be required. At 10 ACH, this drops to 41 minutes and only 28 minutes for 15 ACH. All surfaces should be disinfected with an EPA-approved agent.¹⁹ The circuit and gas sampling line should be disposed. All trash should be properly bagged and disposed of per standard O.R. requirements. The tragically high infection rates of health care workers at the early stages of the epidemic makes it clear that these recommendations must be strictly adhered to in order to protect oneself and other health care workers.^{13-16,
18}

Ongoing Areas of Investigation
Mechanisms of transmission:
• Does transmission of SARS occur by an airborne mechanism?
• Does transmission of SARS occur by a fecal-oral mechanism?
• How long does SARS remain viable on environmental surfaces?²⁰
• What is the infectious period?

Reservoirs:
• Is there an animal reservoir for SARS? The New York Times recently reported that a coronavirus nearly identical to SARS-CoV has been identified in three species of animals sold in the markets where SARS is thought to have originated. The animals include the palm civet, raccoon dog and badger.²¹ It is not known whether the infected animals were farmed or wild. There have been unverified reports of the virus in other species as well. A reservoir of the virus in undomesticated animals would pose a far greater challenge to eradication.

• Can individuals be asymptomatic but transmit the disease?

• Will this virus be eliminated or become endemic?

Natural history:
• How will this virus mutate over time? Will it become more or less virulent?

• Will there be seasonal outbreaks as with the flu?

• Will people develop long-term immunity after exposure?

Treatment:
• What is the most effective treatment?

• Will there be an effective vaccine against the disease?

Resources:
Centers for Disease Control and Prevention Web site <www.cdc.gov/>.
World Health Organization Web site <www.who.int/en/>.

References:

1. McNeil Jr DG, Altman LK. As SARS outbreak took shape, health agency took fast action. New York Times. 2003:1,6.

2. World Health Organization: Cumulative number of reported probable cases of SARS. <www.who.int/csr/sars/country/2003_07_11/en/>.

3. World Health Organization: Case definitions for surveillance of severe acute respiratory syndrome (SARS). <www.who.int/csr/sars/casedefinition/en/>.

4. Jernigan J, Erdman D, Chiarello L. Increasing Clinician Preparedness for Severe Acute Respiratory Syndrome (SARS). Atlanta: Centers for Disease Control and Prevention; 2003.

5. Drosten C, Günther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med. 2003; 348:1-10.

6. Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003; 348:1953-1966.

7. Falsey AR, EE W. Novel coronavirus and severe acute respiratory syndrome (commentary). Lancet. 2003; 361:1312-1313.

8. Peiris JSM, Lai ST, Poon LLM, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet. 2003; 361:1319-1325.

9. Rota PA, Oberste MS, Monroe SS, et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science. 2003; 300:1394-1399.

10. Centers for Disease Control and Prevention: Severe Acute Respiratory Syndrome (SARS) and Coronavirus Testing — United States, 2003. MMWR Weekly. 2003; 52:297-302. [Erratum: April 18, 2003; 52(15):345].

11. Ngan Kee WD, TN L: Severe acute respiratory syndrome (SARS). Int J Ob Anesth. 2003; 12:(in press).

12. CDC Media Relations: CDC update on severe acute respiratory syndrome (SARS). CDC Media Relations <www.cdc.gov/od/oc/media/transcripts/t030508.htm>.

13. American Society of Anesthesiologists: Recommendations for Infection Control for the Practice of Anesthesiology. 2nd ed. 1998.

14. World Health Organization: Hospital infection control guidance for severe acute respiratory syndrome (SARS). WHO <www.who.int/csr/sars/infectioncontrol/en/>. 2003.

15. Centers for Disease Control and Prevention: Part II. Recommendations for isolation precautions in hospitals. CDC <www.cdc.gov/ncidod/hip/ISOLAT/isopart2.htm>. 2003.

16. Bonta D, California Department of Health Services: Severe acute respiratoroy syndrome (SARS) — infection control recommendatiolns, update of April 7. 2003.

17. Kolata G: Now that SARS has arrived, will it ever leave? New York Times. New York, 2003, pp 1,14.

18. World Health Organization: Severe Acute Respiratory Syndrome (SARS). Communicable Disease Surveillance & Response (CSR), <www.who.int/csr/sars/en/index.html>. 2003.

19. OSHA: Occupational Exposure to Tuberculosis: Proposed Rule. Federal Register. 1997; 29 CFR, Part 1910.

20. World Health Organization: Meeting on SARS virus detection and survival in food and water, Madrid, 8-9 May 2003. <www.who.int/csr/sars/guidelines/madridmeeting/en/>.

21. Bradsher K, Altman LK. Strain of SARS is found in 3 animal species in Asia. New York Times. 2003.

Robin A. Stackhouse, M.D., is Associate Professor of Anesthesia, University of California-San Francisco, San Francisco, California.

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