Severe Acute Respiratory Syndrome (SARS)

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.)

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.

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]

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.

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.)

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.

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.)

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.

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.

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] :

• 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.[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%.

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]

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.

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 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]

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.

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.

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]

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

• Modest lymphopenia, leukopenia, and thrombocytopenia - Series have shown white blood cell (WBC) counts of less than 3.5 x 109/L and lymphopenia of less than approximately 1 x 109/L

• Mild hyponatremia and hypokalemia

• Elevated levels of lactate dehydrogenase, alanine aminotransferase, and hepatic transaminase

• Elevated creatine kinase level

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:

• Serum antibodies to SARS-CoV in a single serum specimen

• A 4-fold or greater increase in SARS-CoV antibody titer between acute- and convalescent-phase serum specimens tested in parallel

• Negative SARS-CoV antibody test result on acute-phase serum and positive SARS-CoV antibody test result on convalescent-phase serum tested in parallel

• Isolation in cell culture of SARS-CoV from a clinical specimen, with confirmation using a test validated by the CDC

• Detection of SARS-CoV RNA via RT-PCR assay validated by the CDC, with confirmation in a reference laboratory, from (1) two clinical specimens from different sources or (2) two clinical specimens collected from the same source on 2 different days[7]

  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.

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]

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.)

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.

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]

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.

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]

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]

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.

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.

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.

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

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