Severe Acute Respiratory Syndrome (SARS)

Back

Practice Essentials

Severe acute respiratory syndrome (SARS) is a serious, potentially life-threatening viral infection caused by a previously unrecognized virus from the Coronaviridae family, the SARS-associated coronavirus (SARS-CoV). Since the 2002-2003 outbreak of SARS, which initially began in the Guangdong province of southern China but eventually involved more than 8000 persons worldwide (see the image below), global efforts have virtually eradicated SARS as a threat. No further cases have been reported.



View Image

World map of severe acute respiratory syndrome (SARS) distribution from the 2002-2003 outbreak infection. The greatest number of past and new cases of....

Signs and symptoms

The clinical course of SARS generally follows a typical pattern. Stage 1 is a flulike prodrome that begins 2-7 days after incubation, lasts 3-7 days, and is characterized by the following:

Less common features include the following[1, 2, 3] :

Stage 2 is the lower respiratory tract phase and is characterized by the following:

See Clinical Presentation for more detail.

Diagnosis

Initial tests in patients suspected of having SARS include the following:

Data from the 2002-2003 outbreak indicate that SARS may be associated with the following laboratory findings[1, 2, 3, 4] :

According to guidelines from the Centers for Disease Control and Prevention (CDC), the laboratory diagnosis of SARS-CoV infection is established on the basis of detection of any of the following with a validated test, with confirmation in a reference laboratory[5, 6] :

Chest radiography results in SARS are as follows:

High-resolution computed tomography (HRCT) scanning is controversial in the evaluation of SARS but may be considered when SARS is a strong clinical possibility despite normal chest radiographs.[9, 10] HRCT findings consistent with SARS include the following:

See Workup for more detail.

Management

No definitive medication protocol specific to SARS has been developed, although various treatment regimens have been tried without proven success.[11, 12] The CDC recommends that patients suspected of or confirmed as having SARS receive the same treatment that would be administered if they had any serious, community-acquired pneumonia.

The following measures may be used:

See Treatment and Medication for more detail.

Pathophysiology

The lungs and gastrointestinal tract have been demonstrated to be the only major organ systems that support SARS-CoV replication.[14, 15]

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.)



View Image

Pathologic slide of pulmonary tissue infected with severe acute respiratory syndrome–associated coronavirus. Diffuse alveolar damage is seen along wit....

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.[16]

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.[17]

Immunologically, SARS is characterized by a phase of cytokine storm, with various chemokines and cytokines being elevated.[15, 18]

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.[19] 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.[20] 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,[21, 22] 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.[21] In 2004, the CDC banned the importation of civets when a SARS-like virus was isolated in animals captured in China.[3]

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.[23]

The surface envelop S protein of SARS-CoV is thought to be a major determinant in establishing infection and cell and tissue tropism.[24] 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.[25, 26]

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.[27]

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).[28, 29, 30, 31]

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).[31]

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.[32, 31]

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.[31, 33]

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.[23, 34]

Middle East respiratory syndrome coronavirus (MERS-CoV)

Middle East respiratory syndrome coronavirus (MERS-CoV; formerly referred to as novel coronavirus [NCoV]), a new virus from the same family as the common cold virus and SARS-CoV, emerged in the Middle East in 2012, with some recent recorded cases in Britain and France among travelers to the Middle East.[35, 36] Although only distantly related to SARS-CoV, MERS-CoV is also apparently of zoonotic origin and causes severe respiratory illness, fever, coughing, and breathing difficulties. Interferons have been shown to efficiently reduce MERS-CoV replication in human airway epithelial cell cultures, suggesting a possible mode of treatment in the event of a large-scale outbreak.

According to the WHO, it is possible for MERS-CoV to be passed between humans, but only after prolonged contact.[37] So far, however, there is no evidence that the virus is able to sustain generalized transmission in communities, a scenario that would raise the specter of a pandemic. Although no specific vaccine or medication is currently available for MERS-CoV, patients have been responding to treatment.

Background

Severe acute respiratory syndrome (SARS) is a serious, potentially life-threatening viral infection caused by a previously unrecognized virus from the Coronaviridae family.[38] 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.)



View Image

Thin-section electron micrograph of the severe acute respiratory syndrome–associated coronavirus isolated in FRhK-4 cells. Courtesy of the Government ....



View Image

Chest radiograph of a 52-year-old symptomatic woman with severe acute respiratory syndrome (March 20, 2003) taken 5 days after presentation. Moderatel....

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.[1, 2, 3, 39, 40] 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.)[41, 42]

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.)[43, 44]

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.)

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).[1, 2] 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.[1, 2, 3, 44]

SARS is thought to be transmitted primarily via close person-to-person contact, through droplet transmission.[45] 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.[46]

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).[43] The map below shows the worldwide distribution of SARS cases during the 2002-03 outbreak.



View Image

World map of severe acute respiratory syndrome (SARS) distribution from the 2002-2003 outbreak infection. The greatest number of past and new cases of....

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[47, 48] :

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.[49]

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.[50] 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.[13]

Morbidity and mortality

SARS can result in significant illness and medical complications that require hospitalization, intensive care treatment, and mechanical ventilation.[51]

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%.

History

SARS initially manifests as a flulike syndrome that may progress to pneumonia, respiratory failure, and, in some cases, death. The mortality rate associated with SARS is significantly higher than that of influenza or other common respiratory tract infections.[1, 2]

Epidemiologic statistics and exposure history are critical to the diagnosis of SARS. The case definition of SARS (see the document below), an essential tool from an epidemiologic perspective, is continually updated by the CDC (see Updated Interim US Case Definition for Severe Acute Respiratory Syndrome).[52]



View Image

Severe acute respiratory syndrome case definition put forth by the US Centers for Disease Control and Prevention (CDC) on April 29, 2003. Courtesy of ....

Exposure history

Research suggests that the major modes of SARS transmission are contact and droplet based. Fecal-oral transmission may also be possible via diarrhea. Evidence indicates that SARS may also be transmitted through airborne, virus-containing aerosols.[45]

Anyone who has had close personal contact with a person with known or suspected SARS within 10 days of symptom onset (eg, healthcare workers, family members, caregivers) is at high risk of SARS-CoV infection.[5]

Close contact is defined as caring for or living with a person known to have SARS or having a high likelihood of direct contact with respiratory secretions or body fluids from a patient known to have SARS. Examples of close contact include kissing, embracing, sharing eating or drinking utensils, conversing closely (< 3 ft [1 m]), performing a physical examination, or sharing any other direct physical contact. Close contact does not include walking by a person or briefly sitting across from a patient with SARS in a waiting room or office.

Traveling to an area where community transmission of SARS has been recently documented or suspected (including visiting an airport) within 10 days of symptom onset in that area is a risk factor.[5, 53]

Disease stages

The clinical course of SARS generally follows a typical pattern. Stage 1 is a flulike prodrome that begins 2-7 days after incubation and is characterized by fever (>100.4°F [38°C]), fatigue, headaches, chills, myalgias, malaise, anorexia, and, in some cases, diarrhea. This stage lasts 3-7 days. This phase is characterized by increasing viral load.

Stage 2 is the lower respiratory tract phase and begins 3 or more days after incubation. Patients experience a dry cough, dyspnea, and, in many cases, progressive hypoxemia. Chest radiography findings may initially be normal, and 7 days or longer may elapse before findings become abnormal. Radiographs may show focal interstitial infiltrates that may progress to a patchier, generalized distribution. Respiratory failure that requires mechanical ventilation may occur.

This phase is thought to be secondary to immunopathologic injury and is characterized by a decreasing viral load.

Physical Examination

Physical examination findings in patients with SARS are consistent with those of a combined mild to severe respiratory tract infection and influenzalike illness.[1, 2, 3, 20] However, from a respiratory standpoint, patients can deteriorate quickly and may require mechanical ventilation during hospitalization.

Moderate respiratory illness is indicated by fever and 1 or more clinical findings of respiratory illness (eg, hypoxia, cough, dyspnea, breathing difficulties).

Severe respiratory illness is indicated by fever, 1 or more clinical findings of respiratory illness (eg, hypoxia, cough, dyspnea, breathing difficulties), and radiographic evidence of pneumonia or respiratory distress syndrome or autopsy findings consistent with pneumonia or respiratory distress syndrome without an identifiable cause. Cough associated with SARS can be mild to severe and tends to be dry and nonproductive.

Chest auscultation results can be unremarkable. If abnormal, findings are more commonly upper respiratory tract in nature as opposed to lower respiratory tract.

Research on patients with SARS found the estimated mean incubation period to be 4.6 days (range of 2-14 d), with the mean time between the development of symptoms and hospitalization ranging from 2-8 days. The major clinical features on presentation included fever, chills/rigor, myalgia, dry cough, headache, malaise, and dyspnea. Sputum production, sore throat, coryza, nausea and vomiting, dizziness, and diarrhea have been found to be less common features.[1, 2, 3]

Hepatitis was a common complication of SARS-CoV infection, with 24% and 69% of patients respectively having increased alanine aminotransferase (ALT) levels on admission and during the subsequent course of the illness. Patients with severe hepatitis had worse clinical outcomes. A severe, acute neurologic syndrome may occasionally accompany SARS.

An atypical presentation, such as malaise, decreased oral intake, fall/fracture, and, in some cases, delirium, without fever, was more likely in older patients.

There was no reported fatality in young children and teenage patients, but SARS in pregnancy carried a significant risk of mortality.

Documentation of a temperature of more than 100.4°F (38°C) is preferred for diagnosis, but clinical judgment is important in the absence of this finding. Features consistent with respiratory illness, such as cough, wheezing, dyspnea, and other breathing difficulties, are noted.

The incidence of asymptomatic infection remains unknown, although 0.1% for the general population and higher rates for healthcare workers have been estimated.[1, 2, 3, 20, 21]

Approach Considerations

Initial tests in patients suspected to have SARS include pulse oximetry, blood cultures, sputum Gram stain and culture, and viral respiratory pathogen tests, notably influenza A and B viruses and respiratory syncytial virus.

Legionella and pneumococcal urinary antigen testing should also be considered. Specimens should also be made available for antibody testing, polymerase chain reaction (PCR) assay, and viral culture/isolation tests.

Acute and convalescent (>28 d after symptom onset) serum samples should be collected. Paired sera and other clinical specimens can be forwarded through state and local health departments for testing at the CDC.

Test results for human metapneumovirus, a virus genetically related to respiratory syncytial virus, have been positive in some patients with SARS.

Histologic findings

Autopsies demonstrated changes mostly confined to pulmonary tissue, with diffuse alveolar damage being the most prominent feature. Multinucleated syncytial giant cells were thought to be characteristic but were rarely seen.[14] SARS-CoV infection causes significant damage to lung tissue, as shown below.



View Image

Thin-section electron micrograph of the severe acute respiratory syndrome–associated coronavirus isolated in FRhK-4 cells. Courtesy of the Government ....

Airport identification

Infrared scanners designed for use by the military for night operations were adapted for airport screening use in various locales (eg, Singapore). These scanners were used to identify potentially febrile passengers by measuring their body heat. False-positive results were common with these scanners. Individuals with positive scanner results were temporarily isolated and brought to a special cubicle, where temperatures were confirmed with an oral thermometer.[5]

Laboratory Findings and Techniques

Data from the 2002-2003 outbreak indicate that SARS may be associated with the following laboratory findings[1, 2, 3, 4] :

Coronavirus antibody testing methods include indirect fluorescent antibody or enzyme-linked immunosorbent assays, which are used to test for specific antibodies after infection. Although these antibodies are found in some patients during the acute phase (ie, within 14 d of onset), a negative test finding using a sample that has been obtained less than 28 days after symptom onset does not exclude the diagnosis of SARS.[54, 55]

Reverse-transcriptase PCR (RT-PCR) assay results can be positive in some patients within the first 10 days of fever. RT-PCR assay can be used to detect SARS-CoV in serum, stool, and nasal secretions. SARS-CoV can also be isolated in viral cultures.

A negative SARS-CoV antibody test finding less than 28 days after symptom onset, a negative PCR assay finding, and a negative viral culture finding do not exclude the diagnosis of SARS. Obtaining convalescent serum for a final antibody determination 28 days or more after symptom onset is critical to the disease’s diagnosis.

Below are the CDC's guidelines for the laboratory diagnosis of SARS-CoV infection.[5] Diagnosis is established based on the detection of any of the following with a validated test, with confirmation in a reference laboratory:

FDA gives emergency approval for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) test

In July 2013, at the request of the CDC, the FDA issued an emergency authorization for a diagnostic test to detect the presence of the Middle East coronavirus (formerly referred to as novel coronavirus). The emergency approval follows the Health and Human Services secretary's determination that MERS-CoV, which has killed at least 40 people, poses a potential public health threat.[56]

Imaging Studies

Initial chest radiography findings were found to be abnormal in approximately 60% of patients. Abnormalities on chest radiographs were observed in serial examinations in nearly all patients by 10-14 days after symptom onset.[8, 9]

Interstitial infiltrates can be observed early in the disease course, although in the early stage, a peripheral, pleural-based opacity (ranging from ground-glass opacification to frank consolidation) may be the only abnormality. High-resolution computed tomography (HRCT) scanning of the chest during this time may reveal an infiltrate in the retrocardiac region. (See the image below.)



View Image

Chest radiograph of a 52-year-old symptomatic woman with severe acute respiratory syndrome (March 20, 2003) taken 5 days after presentation. Moderatel....

As the disease progresses, widespread opacification affects large areas. These changes tend to affect the lower lung fields first. Calcification, cavitation, pleural effusion, and lymphadenopathy are not observed in SARS.

HRCT scanning of the chest

The role of HRCT scanning in the evaluation of SARS is still controversial. Patients with abnormal chest radiographic findings do not need HRCT scanning. However, when SARS is a strong clinical possibility despite a normal chest radiographic finding, the clinician should consider HRCT scanning.[9]

Findings consistent with SARS include ground-glass opacification, with or without thickening of the intralobular or interlobular interstitium, or frank consolidation. Indeed, a combination of ground-glass opacification (with or without thickening of the interstitium) and frank consolidation may be noted.[9]

Approach Considerations

Currently, no definitive medication protocol specific to SARS has been developed, although various treatment regimens have been tried without proven success.[11, 12] The CDC recommends that patients suspected of or confirmed as having SARS receive the same treatment that would be administered if they had any serious, community-acquired pneumonia.

Isolate confirmed or suspected patients and provide aggressive treatment in a hospital setting. Patient care precautions include contact, droplet, and airborne isolation. N95 respirators are preferred to surgical masks.[57] Mechanical ventilation and critical care treatment may be necessary during the illness.[11, 12] No benefit has been shown with prone ventilation.[58] An infectious disease specialist, a pulmonary specialist, and/or a critical care specialist should direct the medical care team. Communication with local and state health agencies, the CDC, and WHO is critical.

Pharmacotherapy

Corticosteroids

Various steroid regimens have been used around the world as part of the initial SARS treatment cocktail. In the initial Hong Kong cohort of patients, corticosteroids were first given (with ribavirin) because of the similarity of the clinical and radiographic findings of SARS to those of bronchiolitis obliterans-organizing pneumonia. Despite anecdotal reports of success, the efficacy of steroids has not been confirmed in a clinical trial.[59, 60]

During phase 2 of the clinical course, intravenous (IV) administration of steroids has been shown to suppress cytokine-induced lung injury. It was also associated with favorable clinical improvement, with resolution of fever and lung opacities within 2 weeks.[60, 61]

However, a retrospective analysis showed an increased risk of 30-day mortality. Carefully designed studies will be needed to clarify the optimal role systemic steroids in the treatment SARS. Findings show that local pulmonary inflammation may be reduced with systemic glucocorticoid therapy.

Antiviral agents

The most widely used of these to date is ribavirin (usually in conjunction with steroids). Despite early anecdotal reports of patients with SARS improving with a combination of ribavirin and steroids, ribavirin does not have proven activity against Coronaviridae. It does have significant adverse effects, including hemolysis. It is unlikely that ribavirin is of any clinical benefit in SARS.

Protease inhibitors

Lopinavir/ritonavir was shown to have in vitro effects against the SARS-CoV. Some synergistic benefits with ribavirin were also demonstrated.[62, 63] However, the outcome of the subgroup that received lopinavir/ritonavir as rescue therapy after receiving pulsed methylprednisolone treatment for worsening respiratory symptoms was not better than that for the matched cohort.[64]

Interferon

Type 1 IFNs inhibit a wide range of RNA and DNA viruses, including SARS-CoV, and these effects have been demonstrated in vitro, as well as in some human and animal cell lines.[65] In experimentally infected cynomolgus macaques, prophylactic treatment with pegylated IFN-alfa significantly reduced viral replication and excretion, viral antigen expression by type 1 pneumocytes, and pulmonary damage.[66] However, the results of post exposure treatment with pegylated IFN-alfa were not as impressive.

In patients, use of IFN-alfacon1 plus corticosteroids was associated with improved oxygenation, more rapid resolution of radiographic lung opacities, and lower levels of creatine phosphokinase (CPK). These findings, although encouraging, need to be supported by further studies.[67]

Monoclonal antibodies

A high-affinity human monoclonal antibody (huMab) to the SARS-CoV S protein, known as 80 R, has potent neutralizing activity in vitro and in vivo. This antibody was shown to neutralize SARS-CoV and inhibit syncytia formation between cells expressing the S protein and those expressing the SARS-CoV receptor ACE2.[68] It reduced replication of SARS-CoV in the lungs of infected ferrets, decreased viral secretion, and prevented macroscopic lung pathology.[69] This may be a useful viral entry inhibitor for the emergency prophylaxis and treatment of SARS.

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) was used in particular in Singapore during the SARS outbreak. However, its use was associated with a hypercoagulable state, and as many as one third of the patients who received IVIG were diagnosed with venous thromboembolism, including some cases of pulmonary embolism.

Pentaglobulin (immunoglobulin-M [IgM]-enriched immunoglobulin) was also used in a small study, with encouraging results, but its use was also complicated by embolic events.[70] The use of convalescent plasma was also attempted in some centers.[71]

Nitric oxide (NO)

Nitric oxide use was associated with improved oxygenation and weaning from ventilator support in a small study.[72]

Glycyrrhizin

In vitro replication of the virus was shown to be inhibited by glycyrrhizin. A study showed that the use of traditional Chinese medicine was more effective than Western medicine in reducing hypoxemia in patients with phase 1 SARS, although it was unclear what components of the traditional medicine contributed to this effect.[73]

Vaccine

Chinese researchers began testing a SARS vaccine in humans in May 2004. The Chinese vaccine trial used an inactivated SARS virus vaccine developed through conventional vaccine technology.

The first US SARS vaccine trial began at the NIH in December 2004. The NIH vaccine is composed of a small, circular piece of deoxyribonucleic acid (DNA) that encodes the viral spike protein.

Vaccine containing recombinant surface Spike (S) protein of SARS-CoV nucleocapsid has been shown to induce high levels of SARS-neutralizing antibody in animal models.[74, 75] However, there was a concern about the safety of these vaccines. Several studies reported that SARS vaccine exacerbated lung eosinophilic immunopathology and paradoxically manifested as a severe disease upon subsequent exposure to SARS-CoV infection.[76, 77] To solve this problem, Honda-Okubo et al proposed a new vaccine design that used recombinant S protein with Delta inulin adjuvants. This design was shown to achieve long-lived immunity and prevented lung eosinophilic immunopathology upon SARS-CoV reexposure.[78]

Currently, SARS DNA vaccine encoding S glycoprotein has been investigated in a phase I clinical trial. Although it was shown to be well tolerated in that study, further studies need to be performed before an optimal yet safe vaccine can be implemented clinically.[79]

Activity and Isolation

The CDC has issued guidelines governing the activity and isolation of patients with SARS, their immediate contacts, and the healthcare professionals who treat SARS.[3, 52]

Patients with SARS pose a risk of transmission to close household contacts and healthcare personnel.[80] In household or residential settings, infection control measures, as described below, are recommended.[81]

Patients with SARS should limit interactions outside the home and should not go to work, school, out-of-home child-care facilities, or other public areas until 10 days after the fever resolves, provided that respiratory symptoms are absent or improving. During this time, infection control precautions should be used to minimize the potential for transmission.

All members of a household of a patient with SARS should carefully follow recommendations for hand hygiene (eg, frequent hand washing, use of alcohol-based hand rubs), particularly after contact with body fluids (eg, respiratory secretions, urine, feces).

Disposable gloves should be used for any direct contact with the body fluids of a patient with SARS. However, gloves are not intended to replace proper hand hygiene. Immediately after activities involving contact with body fluids, gloves should be removed and discarded, and hands should be cleaned. Gloves must never be washed or reused.

Each patient with SARS should be advised to cover his or her mouth and nose with a facial tissue when coughing or sneezing. If possible, patients with SARS should wear surgical masks during close contact with uninfected persons in order to prevent the spread of infectious droplets. If a patient with SARS cannot wear a surgical mask, his or her household members should wear surgical masks when in close contact.

Sharing of eating utensils, towels, and bedding between patients with SARS and others should be avoided, although such items can be used by others after routine cleaning (eg, washing with soap and hot water). Environmental surfaces soiled by body fluids should be cleaned with a household disinfectant according to the manufacturer's instructions; gloves should be worn during this activity.

Household waste soiled with body fluids of patients with SARS, including facial tissues and surgical masks, may be discarded as normal waste.

Precautions by close patient contacts

Household members and other close contacts of patients with SARS should be actively monitored by local health departments.

Household members or other close contacts of patients with SARS should be vigilant for the development of fever or respiratory symptoms and, if these develop, should seek a healthcare evaluation. Prior to the evaluation, healthcare providers should be informed that the individual is a close contact of a patient with SARS so that necessary arrangements can be made to prevent transmission of the disease in the healthcare setting. Household members or other close contacts who have symptoms of SARS should follow the precautions recommended for patients with SARS.

Medication Summary

Currently, no definitive medication protocol specific to SARS has been developed, although various treatment regimens have been tried without proven success.[11, 12] The CDC recommends that patients suspected of or confirmed as having SARS receive the same treatment they would be administered if they had any serious, community-acquired pneumonia.

Because SARS is a viral infection, antibiotics are not indicated. In some of the early cases, antibiotics were administered as part of the treatment regimen, but no positive effect was noted.

Hydrocortisone (Cortef, A-Hydrocort, Solu-Cortef)

Clinical Context:  Hydrocortisone may be beneficial because of its mineralocorticoid activity and glucocorticoid effects.

Class Summary

Various steroid regimens have been used around the world as part of the initial SARS treatment cocktail. In the initial Hong Kong cohort of patients, corticosteroids were first given (with ribavirin) because of the similarity of the clinical and radiographic findings of SARS to those of bronchiolitis obliterans-organizing pneumonia. Despite anecdotal reports of success, the efficacy of steroids has not been confirmed in a clinical trial.[59, 60]

During phase 2 of the clinical course, intravenous (IV) administration of steroids has been shown to suppress cytokine-induced lung injury. It was also associated with favorable clinical improvement, with resolution of fever and lung opacities within 2 weeks.[60, 61]

However, a retrospective analysis showed an increased risk of 30-day mortality. Carefully designed studies will be needed to clarify the optimal role systemic steroids in the treatment SARS. Findings show that local pulmonary inflammation may be reduced with systemic glucocorticoid therapy.

Author

David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS, Associate Professor of Medicine and Pediatrics, Adult and Pediatric Infectious Diseases, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM, Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease, Clinical and Translational Science and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Baxter Medical, Exostat, LiDCO<br/>Received honoraria from LiDCO Ltd for consulting; Received intellectual property rights from iNTELOMED.

Additional Contributors

Faustine Ong, MD, Resident Physician, Department of Internal Medicine, Einstein Medical Center

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Prashant Malhotra, MBBS, FACP, FIDSA, 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

Disclosure: Nothing to disclose.

Sarah Perloff, DO, FACP, Associate Chair for Faculty Affairs, Department of Internal Medicine, Program Director, Infectious Diseases Fellowship, Associate Program Director, Internal Medicine Residency, Einstein Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

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

References

  1. Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003 May 15. 348(20):1986-94. [View Abstract]
  2. Tsang KW, Ho PL, Ooi GC, Yee WK, Wang T, Chan-Yeung M, et al. A cluster of cases of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003 May 15. 348(20):1977-85. [View Abstract]
  3. Centers for Disease Control and Prevention. 2003. Severe Acute Respiratory Syndrome. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/ncidod/sars/. Accessed: January 31, 2019.
  4. Armed Forces Institute of Pathology. Severe Acute Respiratory Syndrome (SARS). Armed Forces Institute of Pathology.;
  5. Centers for Disease Control and Prevention. Clinical Guidance on the Identification and Evaluation of Possible SARS-CoV Disease among Persons Presenting with Community-Acquired Illness, Version 2. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/ncidod/sars/clinicalguidance.htm
  6. Vijay R, Hua X, Meyerholz DK, Miki Y, Yamamoto K, Gelb M, et al. Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection. J Exp Med. 2015 Sep 21. [View Abstract]
  7. Sui J, Li W, Murakami A, Tamin A, Matthews LJ, Wong SK, et al. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci U S A. 2004 Feb 24. 101(8):2536-41. [View Abstract]
  8. Hsu LY, Lee CC, Green JA, Ang B, Paton NI, Lee L, et al. Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts. Emerg Infect Dis. 2003 Jun. 9(6):713-7. [View Abstract]
  9. Nicolaou S, Al-Nakshabandi NA, Müller NL. SARS: imaging of severe acute respiratory syndrome. AJR Am J Roentgenol. 2003 May. 180(5):1247-9. [View Abstract]
  10. Kotani T, Tanabe H, Yusa H, Saito S, Yamazaki K, Ozaki M. Electrical impedance tomography-guided prone positioning in a patient with acute cor pulmonale associated with severe acute respiratory distress syndrome. J Anesth. 2015 Oct 7. [View Abstract]
  11. Ho W. Guideline on management of severe acute respiratory syndrome (SARS). Lancet. 2003 Apr 19. 361(9366):1313-5. [View Abstract]
  12. Lapinsky SE, Hawryluck L. ICU management of severe acute respiratory syndrome. Intensive Care Med. 2003 Jun. 29(6):870-5. [View Abstract]
  13. Tsai LK, Hsieh ST, Chao CC, Chen YC, Lin YH, Chang SC, et al. Neuromuscular disorders in severe acute respiratory syndrome. Arch Neurol. 2004 Nov. 61(11):1669-73. [View Abstract]
  14. Hui DS, Chan PK. Clinical features, pathogenesis and immunobiology of severe acute respiratory syndrome. Curr Opin Pulm Med. 2008 May. 14(3):241-7. [View Abstract]
  15. Lo AW, Tang NL, To KF. How the SARS coronavirus causes disease: host or organism?. J Pathol. 2006 Jan. 208(2):142-51. [View Abstract]
  16. Hui DS, Chan PK. Severe acute respiratory syndrome and coronavirus. Infect Dis Clin North Am. 2010 Sep. 24(3):619-38. [View Abstract]
  17. Tan YJ, Fielding BC, Goh PY, Shen S, Tan TH, Lim SG, et al. Overexpression of 7a, a protein specifically encoded by the severe acute respiratory syndrome coronavirus, induces apoptosis via a caspase-dependent pathway. J Virol. 2004 Dec. 78(24):14043-7. [View Abstract]
  18. Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, Liu J, et al. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am J Respir Crit Care Med. 2005 Apr 15. 171(8):850-7. [View Abstract]
  19. Peiris JS, Lai ST, Poon LL, Guan Y, Yam LY, Lim W, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet. 2003 Apr 19. 361(9366):1319-25. [View Abstract]
  20. Hui DS, Sung JJ. Severe acute respiratory syndrome. Chest. 2003 Jul. 124(1):12-5. [View Abstract]
  21. Wong GW, Hui DS. Severe acute respiratory syndrome (SARS): epidemiology, diagnosis and management. Thorax. 2003 Jul. 58(7):558-60. [View Abstract]
  22. Wang LF, Shi Z, Zhang S, Field H, Daszak P, Eaton BT. Review of bats and SARS. Emerg Infect Dis. 2006 Dec. 12(12):1834-40. [View Abstract]
  23. Rota PA, Oberste MS, Monroe SS, Nix WA, Campagnoli R, Icenogle JP, et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science. 2003 May 30. 300(5624):1394-9. [View Abstract]
  24. Tripet B, Howard MW, Jobling M, Holmes RK, Holmes KV, Hodges RS. Structural characterization of the SARS-coronavirus spike S fusion protein core. J Biol Chem. 2004 May 14. 279(20):20836-49. [View Abstract]
  25. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27. 426(6965):450-4. [View Abstract]
  26. Frieman M, Baric R. Mechanisms of severe acute respiratory syndrome pathogenesis and innate immunomodulation. Microbiol Mol Biol Rev. 2008 Dec. 72(4):672-85, Table of Contents. [View Abstract]
  27. Yang ZY, Huang Y, Ganesh L, Leung K, Kong WP, Schwartz O, et al. pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN. J Virol. 2004 Jun. 78(11):5642-50. [View Abstract]
  28. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev. 2001 Oct. 14(4):778-809, table of contents. [View Abstract]
  29. Stertz S, Reichelt M, Spiegel M, Kuri T, Martínez-Sobrido L, García-Sastre A, et al. The intracellular sites of early replication and budding of SARS-coronavirus. Virology. 2007 May 10. 361(2):304-15. [View Abstract]
  30. Versteeg GA, Bredenbeek PJ, van den Worm SH, Spaan WJ. Group 2 coronaviruses prevent immediate early interferon induction by protection of viral RNA from host cell recognition. Virology. 2007 Apr 25. 361(1):18-26. [View Abstract]
  31. Kuri T, Weber F. Interferon interplay helps tissue cells to cope with SARS-coronavirus infection. Virulence. 2010 Jul-Aug. 1(4):273-5. [View Abstract]
  32. Cervantes-Barragan L, Züst R, Weber F, Spiegel M, Lang KS, Akira S, et al. Control of coronavirus infection through plasmacytoid dendritic-cell-derived type I interferon. Blood. 2007 Feb 1. 109(3):1131-7. [View Abstract]
  33. Cameron MJ, Ran L, Xu L, Danesh A, Bermejo-Martin JF, Cameron CM, et al. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J Virol. 2007 Aug. 81(16):8692-706. [View Abstract]
  34. Fang X, Gao J, Zheng H, Li B, Kong L, Zhang Y, et al. The membrane protein of SARS-CoV suppresses NF-kappaB activation. J Med Virol. 2007 Oct. 79(10):1431-9. [View Abstract]
  35. Kelland K. Deadly New Virus Well-Adapted to Infect Humans. Medscape Medical News. February 19, 2013. Available at http://www.medscape.com/viewarticle/779538. Accessed: February 27, 2013.
  36. Kindler E, Jónsdóttir HR, Muth D, Hamming OJ, et al. Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential. MBio. 2013 Feb 19. 4(1):[View Abstract]
  37. New SARS-like virus can probably pass person-to-person. Medscape Medical News. May 13, 2013.
  38. Fouchier RA, Kuiken T, Schutten M, van Amerongen G, van Doornum GJ, van den Hoogen BG, et al. Aetiology: Koch's postulates fulfilled for SARS virus. Nature. 2003 May 15. 423(6937):240. [View Abstract]
  39. Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003 Jun 4. 289(21):2801-9. [View Abstract]
  40. Severe acute respiratory syndrome (SARS) and coronavirus testing--United States, 2003. MMWR Morb Mortal Wkly Rep. 2003 Apr 11. 52(14):297-302. [View Abstract]
  41. Lim PL, Kurup A, Gopalakrishna G, Chan KP, Wong CW, Ng LC, et al. Laboratory-acquired severe acute respiratory syndrome. N Engl J Med. 2004 Apr 22. 350(17):1740-5. [View Abstract]
  42. Liang G, Chen Q, Xu J, Liu Y, Lim W, Peiris JS, et al. Laboratory diagnosis of four recent sporadic cases of community-acquired SARS, Guangdong Province, China. Emerg Infect Dis. 2004 Oct. 10(10):1774-81. [View Abstract]
  43. World Health Organization. Severe acute respiratory syndrome (SARS): Status of the outbreak and lessons for the immediate future. World Health Organization. Available at http://www.who.int/csr/media/sars_wha.pdf. Accessed: October 2007.
  44. Liang WN, Liu M, Chen Q, Liu ZJ, He X, Pan Y, et al. Assessment of impacts of public health interventions on the SARS epidemic in Beijing in terms of the intervals between its symptom onset, hospital admission, and notification. Biomed Environ Sci. 2005 Jun. 18(3):153-8. [View Abstract]
  45. Yu IT, Li Y, Wong TW, Tam W, Chan AT, Lee JH, et al. Evidence of airborne transmission of the severe acute respiratory syndrome virus. N Engl J Med. 2004 Apr 22. 350(17):1731-9. [View Abstract]
  46. Cyranoski D, Abbott A. Apartment complex holds clues to pandemic potential of SARS. Nature. 2003 May 1. 423(6935):3-4. [View Abstract]
  47. Chan JW, Ng CK, Chan YH, Mok TY, Lee S, Chu SY, et al. Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS). Thorax. 2003 Aug. 58(8):686-9. [View Abstract]
  48. Tansey CM, Louie M, Loeb M, Gold WL, Muller MP, de Jager J, et al. One-year outcomes and health care utilization in survivors of severe acute respiratory syndrome. Arch Intern Med. 2007 Jun 25. 167(12):1312-20. [View Abstract]
  49. Tang NL, Chan PK, Wong CK, To KF, Wu AK, Sung YM, et al. Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome. Clin Chem. 2005 Dec. 51(12):2333-40. [View Abstract]
  50. Hui DS, Wong KT, Ko FW, Tam LS, Chan DP, Woo J, et al. The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors. Chest. 2005 Oct. 128(4):2247-61. [View Abstract]
  51. Tsui PT, Kwok ML, Yuen H, Lai ST. Severe acute respiratory syndrome: clinical outcome and prognostic correlates. Emerg Infect Dis. 2003 Sep. 9(9):1064-9. [View Abstract]
  52. Centers for Disease Control and Prevention. Updated Interim U.S. Case Definition for Severe Acute Respiratory Syndrome (SARS). Centers for Disease Control and Prevention. Available at http://www.cdc.gov/ncidod/sars/casedefinition.htm. Accessed: Oct 26 2011.
  53. World Health Organization. WHO recommended measures for persons undertaking international travel from areas affected by severe acute respiratory syndrome (SARS). Wkly Epidemiol Rec. 2003 Apr 4. 78(14):97-9. [View Abstract]
  54. Ng LF, Wong M, Koh S, Ooi EE, Tang KF, Leong HN, et al. Detection of severe acute respiratory syndrome coronavirus in blood of infected patients. J Clin Microbiol. 2004 Jan. 42(1):347-50. [View Abstract]
  55. Chen X, Zhou B, Li M, Liang X, Wang H, Yang G, et al. Serology of severe acute respiratory syndrome: implications for surveillance and outcome. J Infect Dis. 2004 Apr 1. 189(7):1158-63. [View Abstract]
  56. Reuters. FDA Grants Emergency Approval for Test to Detect MERS. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/807916. Accessed: July 22, 2013.
  57. Offeddu V, Yung CF, Low MSF, Tam CC. Effectiveness of Masks and Respirators Against Respiratory Infections in Healthcare Workers: A Systematic Review and Meta-Analysis. Clin Infect Dis. 2017 Nov 13. 65 (11):1934-1942. [View Abstract]
  58. Taccone P, Pesenti A, Latini R, Polli F, Vagginelli F, Mietto C, et al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2009 Nov 11. 302(18):1977-84. [View Abstract]
  59. Lee N, Allen Chan KC, Hui DS, Ng EK, Wu A, Chiu RW, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol. 2004 Dec. 31(4):304-9. [View Abstract]
  60. Sung JJ, Wu A, Joynt GM, Yuen KY, Lee N, Chan PK, et al. Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. Thorax. 2004 May. 59(5):414-20. [View Abstract]
  61. Ho JC, Ooi GC, Mok TY, Chan JW, Hung I, Lam B, et al. High-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome. Am J Respir Crit Care Med. 2003 Dec 15. 168(12):1449-56. [View Abstract]
  62. Tan EL, Ooi EE, Lin CY, Tan HC, Ling AE, Lim B, et al. Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg Infect Dis. 2004 Apr. 10(4):581-6. [View Abstract]
  63. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004 Mar. 59(3):252-6. [View Abstract]
  64. Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003 Dec. 9(6):399-406. [View Abstract]
  65. Ströher U, DiCaro A, Li Y, Strong JE, Aoki F, Plummer F, et al. Severe acute respiratory syndrome-related coronavirus is inhibited by interferon- alpha. J Infect Dis. 2004 Apr 1. 189(7):1164-7. [View Abstract]
  66. Haagmans BL, Kuiken T, Martina BE, Fouchier RA, Rimmelzwaan GF, van Amerongen G, et al. Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med. 2004 Mar. 10(3):290-3. [View Abstract]
  67. Loutfy MR, Blatt LM, Siminovitch KA, Ward S, Wolff B, Lho H, et al. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. JAMA. 2003 Dec 24. 290(24):3222-8. [View Abstract]
  68. Das D, Kammila S, Suresh MR. Development, characterization, and application of monoclonal antibodies against severe acute respiratory syndrome coronavirus nucleocapsid protein. Clin Vaccine Immunol. 2010 Dec. 17(12):2033-6. [View Abstract]
  69. ter Meulen J, Bakker AB, van den Brink EN, Weverling GJ, Martina BE, Haagmans BL, et al. Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferrets. Lancet. 2004 Jun 26. 363(9427):2139-41. [View Abstract]
  70. Lew TW, Kwek TK, Tai D, Earnest A, Loo S, Singh K, et al. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA. 2003 Jul 16. 290(3):374-80. [View Abstract]
  71. Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005 Jan. 24(1):44-6. [View Abstract]
  72. Chen L, Liu P, Gao H, Sun B, Chao D, Wang F, et al. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin Infect Dis. 2004 Nov 15. 39(10):1531-5. [View Abstract]
  73. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003 Jun 14. 361(9374):2045-6. [View Abstract]
  74. Chen Z, Zhang L, Qin C, Ba L, Yi CE, Zhang F, et al. Recombinant modified vaccinia virus Ankara expressing the spike glycoprotein of severe acute respiratory syndrome coronavirus induces protective neutralizing antibodies primarily targeting the receptor binding region. J Virol. 2005 Mar. 79 (5):2678-88. [View Abstract]
  75. Zhou Z, Post P, Chubet R, Holtz K, McPherson C, Petric M, et al. A recombinant baculovirus-expressed S glycoprotein vaccine elicits high titers of SARS-associated coronavirus (SARS-CoV) neutralizing antibodies in mice. Vaccine. 2006 Apr 24. 24 (17):3624-31. [View Abstract]
  76. Bolles M, Deming D, Long K, Agnihothram S, Whitmore A, Ferris M, et al. A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J Virol. 2011 Dec. 85 (23):12201-15. [View Abstract]
  77. Tseng CT, Sbrana E, Iwata-Yoshikawa N, Newman PC, Garron T, Atmar RL, et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PLoS One. 2012. 7 (4):e35421. [View Abstract]
  78. Honda-Okubo Y, Barnard D, Ong CH, Peng BH, Tseng CT, Petrovsky N. Severe acute respiratory syndrome-associated coronavirus vaccines formulated with delta inulin adjuvants provide enhanced protection while ameliorating lung eosinophilic immunopathology. J Virol. 2015 Mar. 89 (6):2995-3007. [View Abstract]
  79. Martin JE, Louder MK, Holman LA, Gordon IJ, Enama ME, Larkin BD, et al. A SARS DNA vaccine induces neutralizing antibody and cellular immune responses in healthy adults in a Phase I clinical trial. Vaccine. 2008 Nov 25. 26 (50):6338-43. [View Abstract]
  80. Mandavilli A. SARS epidemic unmasks age-old quarantine conundrum. Nat Med. 2003 May. 9 (5):487. [View Abstract]
  81. Yang W. Severe acute respiratory syndrome (SARS): infection control. Lancet. 2003 Apr 19. 361 (9366):1386-7. [View Abstract]

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.

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.

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.

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.

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.

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.

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.

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.