Severe acute respiratory syndrome: an overview.

Abstract: Severe acute respiratory syndrome (SARS) is a severe pulmonary infection that has been identified in multiple outbreaks around the world after emerging from mainland China in early 2003. The syndrome is caused by SARS-associated coronavirus, a novel human infection. SARS-associated coronavirus is spread by multiple mechanisms, including direct contact and large-droplet aerosolization, and may be spread by droplet nuclei as well. Clinical disease is characterized by fever, dry cough, interstitial infiltrates, and variable progression to respiratory failure. No treatment has clearly been shown to be effective. Aggressive infection control measures to prevent viral spread are key to outbreak management.

Key Words: coronavirus, epidemic, infection control, pneumonia, severe acute respiratory syndrome

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In November 2002, several hundred cases of a severe respiratory illness in the Guandong Province in the People's Republic of China were described. Although it was initially localized to Asia, the infection spread globally by late February 2003 through defined transmission links of infected individuals. The World Health Organization (WHO) subsequently designated this emerging infectious disease as severe acute respiratory syndrome (SARS). In March 2003, the cause of SARS was identified as a coronavirus (SARS-associated coronavirus, or SARS-CoV). By April 2003, this virus was genetically sequenced and found to be a novel coronavirus not closely related to any of the previously described coronaviruses that infect humans and animals. This review focuses on the epidemiology, clinical features, diagnosis, and treatment of SARS on the basis of the limited data that have emerged to date.

What Is SARS-associated Coronavirus?

SARS-CoV is a novel virus within the coronavirus family. These enveloped viruses replicate in the cytoplasm of host cells. SARS-CoV is a large, single-stranded, plus sense RNA virus that is loosely related to the three known groups of coronaviruses that are described. Although other coronaviruses can induce mild human disease and severe domestic animal disease, SARS-CoV is clearly new and pathogenic to humans. The virus contains viral membrane proteins that are likely to be involved in its pathogenesis. The large S (ie, spike) protein that forms part of the viral corona, or crown, is visible on electron microscopy and may be necessary fur viral membrane fusion. Recent studies in China detected several coronaviruses closely related to SARS-CoV in animals obtained from markets, including the raccoon-dog and the masked palm civet. (1) These viruses were virtually identical genetically to SARS-CoV, with the exception of some additional sequence in the animal coronaviruses. It has been speculated that the virus may have successfully achieved a cross-species "jump" in Asia and subsequently spread.

Where Is SARS Being Identified?

SARS has been identified across the globe, with more than 8,400 probable cases reported by late June 2003. Mainland China, Taiwan, Singapore, and Canada have reported the greatest number of cases, with sporadic reporting in at least 29 countries worldwide. (2) Cases in general have declined globally, although a resurgence of cases in Toronto, ON, Canada after initial control has highlighted the need for strict infection control practices. (3) The United States had reported approximately 409 cases (334 suspected and 75 probable cases) in 42 states and Puerto Rico as of late June 2003. (2)

How Is SARS Transmitted?

Although the potential modes of transmission have not been delineated completely, large-droplet aerosolization and direct contact with infected individuals are likely the primary mechanisms of viral transmission. Epidemiologic data suggest, however, that airborne transmission of droplet nuclei (<10 [micro]m diameter) may also occur with SARS-CoV, as has been observed in measles, tuberculosis, and influenza outbreaks. Documented cases of transmission have occurred in the setting of aerosol-generating procedures such as nebulization, intubation, continuous positive airway pressure, and bimodal positive airway pressure. (4) Spread by contact and fecal-oral transmission also may occur, with several investigators reporting that SARS-CoV may remain viable on environmental surfaces for 1 to 2 days. These observations have not been confirmed to date. Transmission dynamics models have suggested that, in general, one case will lead to three secondary cases without infection control mechanisms in place. (5,6) In several countries, large clusters of cases were associated with single infected individuals, who have been designated superspreaders. (7) Notably, nosocomial transmission to health care workers has accounted for a large number of secondary cases. (8)

What Are the Clinical Manifestations of SARS Infection?

After an incubation period of 2 to 7 days, patients infected with SARS-CoV typically develop fever (>100.4[degrees]F [38[degrees]C]), rigors, headache, malaise, and myalgias (Table 1). Respiratory symptoms most often do not begin until 3 to 7 days after the onset of symptoms. Dry cough and dyspnea are most common, but coryzal symptoms are unusual. Diarrhea may be seen in a substantial proportion of patients. The illness can progress slowly, and severe illness usually does not occur until the second week of the illness. Most patients have rales or rhonchi evident on physical examination, and hypoxia is common.

The white blood cell count is generally normal or slightly low. Lymphopenia and elevation in lactate dehydrogenase is present in most patients, and low-normal platelet counts and elevations in creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase levels also may be seen. (9-11) In one study, advanced age, a high neutrophil count, and a high lactate dehydrogenase level were independent predictors of an adverse outcome. (12)

More than 80% of patients develop radiographic findings, typically on Days 5 to 7 of illness. The infiltrates are usually interstitial and may initially be focal in 50 to 75% of cases. This often progresses to involve multiple lobes, (12) and as many as 10 to 20% of patients progress to respiratory failure. WHO estimates suggest a worldwide mortality rate of approximately 9.5%. (2) Mortality varies inversely with age, with case fatality rates among the elderly being greater than 40%. The major findings at autopsy are generally limited to the lungs, with the primary histopathologic finding being diffuse alveolar damage.

How Is SARS Diagnosed?

At this time, tests for SARS-CoV are still being refined; the sensitivity and specificity are uncertain and are still being evaluated. It is also not known which tests perform best at given time points after the onset of a patient's illness. Several types of newly developed tests are being used to test for SARS-CoV: (13,14)

1. Serum antibody tests that measure SARS-CoV-specific total immunoglobulin G, immunoglobulin M, and immunoglobulin A antibodies, including both enzyme-linked immunosorbent assay and indirect fluorescent antibody formats, have been developed. At this time, the Centers for Disease Control and Prevention (CDC) is interpreting positive test results to indicate previous infection with SARS-CoV. Some patients do not test positive until more than 21 days after onset of illness, however, and as such, a negative test result can be considered a true-negative only if the specimen was collected more than 21 days after the onset of the patient's illness. (13)

2. Reverse transcriptase polymerase chain reaction testing can detect SARS-CoV RNA in serum, stool, and nasal secretions.

3. Viral isolation for SARS-CoV has been done. In these studies, clinical specimens from SARS patients are co-cultured with well-characterized cell lines, and SARS-CoV replication is detected by cytopathic effect.

CDC has made reagents for SARS-CoV antibody testing available to state public health laboratories and reagents for SARS-CoV nucleic acid testing available to the Laboratory Response Network laboratories. Clinicians are encouraged to obtain informed consent before collecting such specimens if possible and to contact their state's public health laboratory for additional information on submitting specimens. The CDC has developed specific clinical, epidemiologic, and laboratory criteria for defining a case of SARS. (14)

What Treatments Are Available for SARS?

The optimal treatment for SARS is unknown. Empiric treatment regimens usually include several antibiotics targeting the bacterial agents of typical and atypical pneumonia (eg, a fluoroquinolone or a combination of a [beta]-lactam and a macrolide), as well as antiviral agents such as ribavirin and oseltamivir. These antiviral drugs seem to lack in vitro activity against SARS-CoV, although they may be effective clinically.

Although the pathogenesis of SARS remains poorly understood, some investigators have hypothesized that the disease process may be at least in part immune-mediated. This possibility has led to the hypothesis that immunomodulatory agents such as corticosteroids may have a role in treatment, (9) but no controlled studies have been conducted, and the efficacy of this approach is unknown. Some investigators have hypothesized that SARS-CoV-specific immunoglobulin may be of benefit. In certain animal coronavirus infections, however, antibody responses may produce an antibody-dependent enhancement of disease. Controlled trials designed to evaluate treatment regimens are needed.

Alpha and [beta] interferons may have some in vitro activity against SARS-CoV, but the endogenous cytokine response in SARS is poorly understood, and it remains unclear whether the administration of exogenous interferons would be beneficial. A 3C proteinase is necessary for viral processing in most coronaviruses, and 3C proteinase inhibitors have shown promising in vitro activity. There are no licensed 3C proteinase inhibitors currently available for human use, however.

What Infection Control Measures Are Necessary if a Patient Is Infected with SARS?

On the basis of the limited data available regarding the transmission of SARS-CoV, patients with suspected SARS should be placed in isolation according to strict infection control guidelines (Table 2). Infection control personnel should be notified immediately, and infection control measures should include standard precautions such as hand hygiene as well as contact and airborne particle precautions. These precautions involve wearing gown and gloves during contact with infected patients and their environment, as well as using a negative-pressure isolation room, N-95-filtering disposable respirators, and eye protection. (4) Because viral spread can be limited effectively with infection control measures, early triage of patients with SARS and prompt application of infection control guidelines are critical to preventing further transmission. Guidelines for the management of people exposed to SARS can be found on the Internet at http:// www.cdc.gov/ncidod/sars/ic.htm

What Web Sites Are Available for Information on SARS?

Both the CDC and the WHO have web sites dedicated to SARS information. The CDC's SARS web site can be found at http://www.cdc.gov/ncidod/sars/. The WHO's SARS web site can be found at http://www.who.int/csr/sars/en/. The nucleotide sequence of SARS-CoV can be found at http://www. cdc.gov/ncidod/sars/sequence.htm

Conclusions

SARS is a novel coronavirus infection characterized by severe pulmonary illness with significant associated morbidity and mortality. New diagnostic techniques have been developed, and treatment options are currently being studied. Aggressive infection control measures are necessary to prevent further spread of this viral infection. Physicians should be aware of the clinical manifestations of this infection and notify public health authorities about potential cases immediately.

Key Points

* Severe acute respiratory syndrome is a severe pulmonary syndrome presenting as an atypical pneumonia that is caused by a novel coronavirus.

* There is as yet no clearly efficacious treatment regimen for severe acute respiratory syndrome infection.

* Strict infection control measures must be instituted to prevent the spread of this viral infection, including contact and droplet and airborne precautions.

Table 1. Clinical manifestations of severe acute
respiratory syndrome (a)

Symptom         Range (%)

Fever              100
Cough             57-100
Dyspnea           20-100
Chills/rigor      73-90
Myalgias          20-83
Headache          20-70
Diarrhea          10-67

(a) Adapted from references 9-12.

Table 2. Severe acute respiratory syndrome infection
control measures

Contact precautions
  Gowns
  Gloves
Airborne particle precautions
  N-95 respirators with fit testing by infection control
  Negative-pressure room
Eye protection
Hand hygiene
Avoid aerosol-producing procedures

References

(1.) World Health Organization. Communicable Disease Surveillance & Response (CSR): Severe Acute Respiratory Syndrome (SARS)--WHO guidelines/recommendations/descriptions. Available at: http://www. who.int/csr/sars/guidelines/en/. Accessed July 15, 2003.

(2.) Centers for Disease Control and Prevention. Update: Severe acute respiratory syndrome---United States, June 18, 2003. MMWR Morb Mortal Wkly Rep 2003;52(24):570.

(3.) Centers for Disease Control and Prevention. Update: Severe acute respiratory syndrome--Toronto, Canada, 2003. MMWR Morb Mortal Wkly Rep 2003;52(23):547-550.

(4.) Centers for Disease Control and Prevention. Cluster of severe acute respiratory syndrome eases among protected health-care workers: Toronto, Canada, April 2003. MMWR Moth Mortal Wkly Rep 2003;52(19): 433-436.

(5.) Riley S, Fraser C, Donnelly CA, et al. Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions. Science 2003 ;300:1961-1966.

(6.) Dye C, Gay N, Epidemiology: Modeling the SARS epidemic. Science 2003;300:1884-1885 (comment).

(7.) Centers for Disease Control and Prevention. Severe acute respiratory syndrome: Singapore, 2003. MMWR Morb Mortal Wkly Rep 2003;52(18):405-411.

(8.) Centers for Disease Control and Prevention. Severe acute respiratory syndrome: Taiwan, 2003. MMWR Morb Mortal Wkly Rep 2003;52(20): 461-466.

(9.) 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.

(10.) Peiris JS, Chu CM, Cheng VC, et al; HKU/UCH SARS Study Group. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study. Lancet 2003: 361:1767-1772.

(11.) 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.

(12.) 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.

(13.) Centers for Disease Control and Prevention. Severe acute respiratory syndrome (SARS) and coronavirus testing: United States. 2003. MMWR Morb Mortal Wkly Rep 2003;52(14):297-302.

(14.) Centers for Disease Control and Prevention. Updated interim surveillance case definition for severe acute respiratory syndrome (SARS): United States, April 29, 2003. MA4WR Moth Mortal Wkly Rep 2003; 52(17):391-393.

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Southern Medical Journal Featured CME Topic: Severe Acute Respiratory Syndrome

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Purpose and Objectives

Severe acute respiratory syndrome (SARS) has been the locus of numerous infection control measures since its emergence from China in early 2003. The etiology of this syndrome was identified as SARS-associated corona-virus (SARS-CoV), which was soon thereafter genetically sequenced and found to be a virus not closely related to any of those that normally infect humans and animals. Following an incubation period of 2 to 7 days, those infected with SARS typically develop fever, dry cough, interstitial infiltrates and variable progression to respiratory failure. After reading the following article, physicians will better understand the epidemiology, clinical manifestations, diagnosis, treatment and prevention of SARS.

Disclosure

In publishing this section in Southern Medical Journal, the Southern Medical Association recognizes educational needs of physicians in all specialties, especially those in primary care, for current information regarding SARS. In this section, authors may have included discussions about drug interventions, whether approved or unapproved by the U.S. Food and Drug Administration. Therefore, it is incumbent on physicians reading this section to be aware of these factors in interpreting the contents and evaluating recommendations. Moreover, views of authors do not necessarily reflect the opinions of the Southern Medical Association. Every effort has been made to encourage the author to disclose any commercial relationships or personal benefit that may be associated with this section. If the author disclosed a relationship, it is indicated below. This disclosure in no way implies that the information presented is biased or of lesser quality, but allows participants to make informed judgments regarding program content.

Disclaimer

The primary purpose of this section in the Journal is education. Information presented and techniques discussed are intended to inform physicians of medical knowledge, clinical procedures, and experiences of physicians willing to share such information with colleagues. It is recognized that a diversity of professional opinions exists in the contemporary practice of medicine that influences the selection of methods and procedures. The views and approaches of authors are offered solely for educational purposes. The Southern Medical Association disclaims any and all liability for injury or other damages to any individual reading this section and for all claims that may result from the use of techniques and procedures presented in it.

Fares J. Khater, MD, and Jonathan P. Moorman, MD

Grant/Research Support:

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Other Support:

From the Medical Service, James H. Quillen VAMC, and the Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Reprint requests to Jonathan P. Moorman, MD, Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, Box 70622, Johnson City, TN 37614. Email: [e-mail]

Accepted July 29. 2003.