Severe Acute Respiratory Syndrome (SARS) 

  • Author: Manish N Trivedi, MD; Chief Editor: Michael R Pinsky, MD, CM, FCCP, FCCM   more...
 
Updated: Nov 8, 2011
 

Background

Severe acute respiratory syndrome (SARS) is a serious, potentially life-threatening viral infection caused by a previously unrecognized virus from the Coronaviridae family.[1] This virus has been named the SARS-associated coronavirus (SARS-CoV). Previously, Coronaviridae was best known as the second-most-frequent cause of the common cold. (See the images below.)

Thin-section electron micrograph of the severe acuThin-section electron micrograph of the severe acute respiratory syndrome–associated coronavirus isolated in FRhK-4 cells. Courtesy of the Government Virus Unit, Department of Health, Hong Kong SAR, China. Chest radiograph of a 52-year-old symptomatic womaChest radiograph of a 52-year-old symptomatic woman with severe acute respiratory syndrome (March 20, 2003) taken 5 days after presentation. Moderately severe-to-severe ground-glass and consolidative bilateral changes are noted in the lung fields and are somewhat worse on the left side. Courtesy of Michael E. Katz, MD.

The SARS-CoV strain is believed to have originated in Guangdong province in southern China prior to its spread to Hong Kong, neighboring countries in Asia, and Canada and the United States during the 2002-2003 outbreak.[2, 3, 4, 5, 6] In early 2004, several new cases of SARS were investigated in Beijing and in the Anhui province of China. The most recent outbreak was believed to have been successfully contained without spread into the general population. There have subsequently been three instances of laboratory-acquired infection, and one reintroduction from animals in Guangdong Province, China. (See Epidemiology.)[7, 8]

Despite concerns that new cases of SARS would emerge in the region, no new human-to-human transmission has been reported. The reasons for this maybe (1) a very high prevalence of serious illness, making identification of cases and transmission easier and (2) a low risk of transmission before the development of severe illness.

The World Health Organization’s (WHO’s) timely updates on where SARS cases were occurring, the clinical and epidemiologic features of infection, laboratory methods, strategies to control the disease’s spread, and the intensive collaborative global response to SARS were also responsible for the effective prevention of a global pandemic. (See Epidemiology, Workup, and Treatment.)[9, 10]

Global efforts to acknowledge and research the CoV have virtually eradicated SARS as a threat. Although much has already been learned about the virus, ongoing efforts are being made to better understand it in hopes of developing medications and vaccinations to maintain its suppression. Global organizations, including WHO, the Centers for Disease Control and Prevention (CDC), and the National Institutes of Health (NIH) are still facilitating research on the virus and its family. (See Etiology, Workup and Treatment.)

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Pathophysiology

The lungs and gastrointestinal tract have been demonstrated to be the only major organ systems that support SARS-CoV replication.[11, 12]

After establishment of infection, SARS-CoV causes tissue damage by (1) direct lytic effects on host cells and (2) indirect consequences resulting from the host immune response. Autopsies demonstrated changes that were confined mostly to pulmonary tissue, where diffuse alveolar damage was the most prominent feature. (See the image below.)

Pathologic slide of pulmonary tissue infected withPathologic slide of pulmonary tissue infected with severe acute respiratory syndrome–associated coronavirus. Diffuse alveolar damage is seen along with a multinucleated giant cell with no conspicuous viral inclusions. Courtesy of the US Centers for Disease Control and Prevention.

Multinucleated syncytial giant cells were thought to be characteristic of SARS but were rarely seen. Angiotensin-converting enzyme-2 (ACE-2), being a negative regulator of the local rennin-angiotensin system, was thought to be a major contributor to the development of this damage.[13]

The other mechanism was thought to be the induction of apoptosis. The SARS-CoV–3a and –7a proteins have been demonstrated to be inducers of apoptosis in various cell lines.[14]

Immunologically, SARS is characterized by a phase of cytokine storm, with various chemokines and cytokines being elevated.[12, 15]

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Etiology

Sources

Coronaviruses (CoVs) are found in a wide range of animal species, including in cats, dogs, pigs, rabbits, cattle, mice, rats, chickens, pheasants, turkeys, and whales, as well as in humans.[16] They cause numerous veterinary diseases (eg, feline infectious peritonitis, avian infectious bronchitis); they can also cause upper and, more commonly, lower respiratory tract illness in humans (group 1 [human CoV 229E] and group 2 [human CoV OC43]).

The near absence of SARS-CoV antibodies in persons who did not have SARS demonstrated that SARS-CoV had not circulated to any significant extent in humans before 2003 and was introduced into humans from animals.[17] Preliminary data after the outbreak started suggested that animals in the markets of Guangdong province in China may have been the source of human infection. However SARS-CoV ̶ like viruses were not found in animals prior to arrival in the markets.

A wide range of other coronaviruses in bats has been found,[18, 19] suggesting that bats are the most likely animal reservoir for the SARS outbreak. SARS infection in animals before arrival in the markets was uncommon, and these animals were probably not the original reservoir of the outbreak, although they may have acted as amplifying hosts. The proximity in which humans and livestock live in rural southern China may have led to the transmission of the virus to humans.[18]

Cellular binding

Single-stranded ribonucleic acid (RNA) viruses such as the SARS-CoV have no inherent proofreading mechanism during replication. Accordingly, mutations in the RNA sequence replication of coronaviruses are relatively common. Such mutations can cause the resulting new virus to be either less or more virulent.[20]

The surface envelop S protein of SARS-CoV is thought to be a major determinant in establishing infection and cell and tissue tropism.[21] This protein, after binding to its receptor—which is thought to be angiotensin-converting enzyme 2 (ACE-2) and is expressed in a variety of tissues, including pulmonary, intestinal, and renal—undergoes conformational change and cathepsin L–mediated proteolysis within the endosome.[22, 23]

The binding of SARS-CoV to DC-SIGN (dendritic cell–specific intercellular adhesion molecule–grabbing nonintegrin), which recognizes a variety of microorganisms, does not lead to entry of the virus into dendritic cells. It instead facilitates the transfer and dissemination within the infected host.[24]

Immune response

The type I interferon (IFN-alfa/beta) system represents a powerful part of the innate immune system and has potent antiviral activity. However, SARS-CoV discourages attack by the IFN system. Replication of the virus occurs in cytoplasmic compartments surrounded by a double membrane layer. Such concealment within cells probably causes a spatial separation of the viral pathogen-associated molecular patterns (PAMPs) and the cellular cytoplasmic pattern recognition receptors (PRRs).[25, 26, 27, 28]

In addition, the activation of IFN regulatory factor–3 (IRF-3) is actively inhibited by SARS-CoV, with IRF-3 being targeted by 5 known SARS-CoV proteins in order to prevent IFN-system activation. IFN induction can also be affected by unspecific degradation of host messenger RNA (mRNA).[28]

These defensive measures prevent tissue cells from mounting an antiviral IFN attack following SARS-CoV infection. Ultimately, however, an IFN immune response can occur. Plasmacytoid dendritic cells (pDCs) use Toll-like receptors (TLRs) to recognize pathogen structures and use IRF-7 to induce IFN transcription. Large amounts of IFN are thus produced by the pDCs following infection with SARS-CoV.[29, 28]

In a study that examined 40 clinically well-defined human SARS cases, high levels of IFN were found in the infection’s early stages, except in more severe cases, and early production of IFN correlated with a beneficial outcome for the infected individuals.[28, 30]

Nuclear factor

SARS-CoV membrane protein, most likely by interacting directly with IkappaB kinase (IKK), also suppresses nuclear factor-kappaB (NF-kappaB) activity and reduces cyclooxygenase-2 (COX-2) expression. These disturbances may aid SARS pathogenesis.[20, 31]

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Epidemiology

In November 2002, an unusual epidemic of severe pneumonia of unknown origin in Guangdong Province in southern China was noted. There was a high rate of transmission to health care workers (HCWs).[2, 3] Some of these patients were positive for SARS-CoV in the nasopharyngeal aspirates(NPA), whereas 87% patients had positive antibodies to SARS-CoV in their convalescent sera. Genetic analysis showed that the SARS-CoV isolates from Guangzhou had the same origin as those in other countries, with a phylogenetic pathway that matched the spread of SARS to other parts of the world.

The 2002-2003 SARS outbreak predominantly affected mainland China, Hong Kong, Singapore, and Taiwan. In Canada, a significant outbreak occurred in the area around Toronto, Ontario. In the United States, 8 individuals contracted laboratory-confirmed SARS. All patients had traveled to areas where active SARS-CoV transmission had been documented.[2, 3, 4, 10]

SARS is thought to be transmitted primarily via close person-to-person contact, through droplet transmission.[32] Most cases have involved persons who lived with or cared for a person with SARS or who had exposure to contaminated secretions from a patient with SARS. Some affected patients may have acquired SARS-CoV infection after their skin, respiratory system, or mucous membranes came into contact with infectious droplets propelled into the air by a coughing or sneezing patient with SARS.

Leaky, backed-up sewage pipes; fans; and a faulty ventilation system were likely responsible for a severe outbreak of SARS in the Amoy Gardens residential complex in Hong Kong. Transmission may have occurred within the complex via airborne, virus-laden aerosols.[33]

The worldwide number of SARS cases from the original outbreak (November 2002 through July 31, 2003) reached more than 8000 persons, including 1706 healthcare workers. Of those cases, 774 resulted in death, with a case fatality ratio of 9.6% deaths, and 7295 recoveries. The majority of these cases occurred in mainland China (5327 cases, 349 deaths), Hong Kong (1755 cases, 299 deaths), with Taiwan (346 cases, 37 deaths), and Singapore (238 cases, 33 deaths).

In North America, there were 251 cases, with 43 resulting in death (all in Canada).[9] The map below shows the worldwide distribution of SARS cases during the 2002-03 outbreak.

World map of severe acute respiratory syndrome (SAWorld map of severe acute respiratory syndrome (SARS) distribution from the 2002-2003 outbreak infection. The greatest number of past and new cases of SARS are in mainland China, Hong Kong, Taiwan, and Singapore (red). Canada, more specifically Toronto, Ontario (yellow), is the fifth-ranked area, although community transmission of SARS now appears to be contained, according to the US Centers for Disease Control and Prevention. Green represents the other countries reporting SARS cases.
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Prognosis

WHO data indicate that mortality from SARS is highly variable. The mortality rate has been found to range from less than 1% in patients below age 24 years to more than 50% in patients aged 65 and older. Certain risk factors, including the following, have been associated with a poorer prognosis[34, 35] :

  • Older age
  • Chronic hepatitis B infection
  • Laboratory features - Including marked lymphopenia and leukocytosis, elevated lactate dehydrogenase level, hepatitis, high SARS-CoV viral load, and comorbidities such as diabetes mellitus

Elevated levels of interferon-inducible protein 10 (IP-10), monokine induced by IFN-gamma (MIG), and interleukin 8 (IL-8) during the first week, as well as an increase of MIG during the second week, have also been associated with a poor prognosis.[36]

A study of SARS survivors found that most of these had significant improvement clinically, radiographically, and in their pulmonary function studies. However, 27.8% of patients still exhibited abnormal radiographs at 12 months. Significant reductions in the diffusing capacity of carbon monoxide and in exercise ability (6-min walking distance) were also documented at 12 months.[37] Polyneuropathy and myopathy associated with critical illness, avascular necrosis (possibly steroid induced), steroid toxicity, and psychosis were some of the other long-term sequel observed in the SARS survivors.[38]

Morbidity and mortality

SARS can result in significant illness and medical complications that require hospitalization, intensive care treatment, and mechanical ventilation.[39]

Morbidity and mortality rates were observed to be greater in elderly patients. The overall mortality rate of SARS has been approximately 10%. According to the CDC and WHO, the death rate among individuals older than age 65 years exceeds 50%.

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Contributor Information and Disclosures
Author

Manish N Trivedi, MD  Fellow in Infectious Diseases, North Shore-Long Island Jewish Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Prashant Malhotra, MBBS  Assistant Professor of Medicine, Division of Infectious Diseases, Department of Medicine, LIJ School of Medicine at Hofstra University; Attending Physician, Division of Infectious Diseases, Department of Internal Medicine, North Shore-Long Island Jewish Health System

Prashant Malhotra, MBBS is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, FCCP, FCCM  Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine

Michael R Pinsky, MD, CM, FCCP, FCCM is a member of the following medical societies: American College of Chest Physicians, American College of Critical Care Medicine, American Heart Association, American Thoracic Society, Association of University Anesthetists, European Society of Intensive Care Medicine, Shock Society, and Society of Critical Care Medicine

Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; Edwards Lifesciences Honoraria Consulting; Applied Physiology, Ltd Honoraria Consulting; Cheetah Medical Consulting fee Consulting

Additional Contributors

Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Asim A Jani, MD, MPH, FACP Clinician-Educator and Epidemiologist, Consultant and Senior Physician, Florida Department of Health; Diplomate, Infectious Diseases, Internal Medicine and Preventive Medicine

Asim A Jani, MD, MPH, FACP is a member of the following medical societies: American Association of Public Health Physicians, American College of Physicians, American College of Preventive Medicine, American Medical Association, American Public Health Association, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Richard Oehler, MD Associate Professor, Department of Internal Medicine, Division of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Director of Clinical Education, Division of Infectious Diseases, Tampa Veterans Affairs Medical Center

Richard Oehler, MD is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America, and Society for Healthcare Epidemiology of America

Disclosure: Nothing to disclose.

Charles V Sanders, MD Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center

Charles V Sanders, MD is a member of the following medical societies: Alliance for the Prudent Use of Antibiotics, Alpha Omega Alpha, American Association for the Advancement of Science, American Association of University Professors, American Clinical and Climatological Association, American College of Physician Executives, American College of Physicians, American Federation for Medical Research, American Foundation for AIDS Research, American GeriatricsSociety, American Lung Association, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal Disease Association, Association for Professionals in Infection Control and Epidemiology, Association of American Medical Colleges, Association of American Physicians, Association of Professors of Medicine, Infectious Disease Society for Obstetrics and Gynecology, Infectious Diseases Societyof America, Louisiana State Medical Society, Orleans Parish Medical Society, Royal Society of Medicine, Sigma Xi, Society of General Internal Medicine, Southeastern Clinical Club, Southern Medical Association, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology

Disclosure: Nothing to disclose.

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

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Thin-section electron micrograph of the severe acute respiratory syndrome–associated coronavirus isolated in FRhK-4 cells. Courtesy of the Government Virus Unit, Department of Health, Hong Kong SAR, China.
World map of severe acute respiratory syndrome (SARS) distribution from the 2002-2003 outbreak infection. The greatest number of past and new cases of SARS are in mainland China, Hong Kong, Taiwan, and Singapore (red). Canada, more specifically Toronto, Ontario (yellow), is the fifth-ranked area, although community transmission of SARS now appears to be contained, according to the US Centers for Disease Control and Prevention. Green represents the other countries reporting SARS cases.
Pathologic slide of pulmonary tissue infected with severe acute respiratory syndrome–associated coronavirus. Diffuse alveolar damage is seen along with a multinucleated giant cell with no conspicuous viral inclusions. Courtesy of the US Centers for Disease Control and Prevention.
Severe acute respiratory syndrome case definition put forth by the US Centers for Disease Control and Prevention (CDC) on April 29, 2003. Courtesy of the CDC.
Clinical and laboratory criteria for severe acute respiratory syndrome cases and infection per the US Centers for Disease Control and Prevention (CDC) on April 29, 2003. Courtesy of the CDC.
Chest radiograph of a 52-year-old symptomatic woman with severe acute respiratory syndrome (March 20, 2003) taken 5 days after presentation. Moderately severe-to-severe ground-glass and consolidative bilateral changes are noted in the lung fields and are somewhat worse on the left side. Courtesy of Michael E. Katz, MD.
 
 
 
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