key: cord-339009-wcoch07b authors: File, Thomas M.; Tsang, Kenneth W. T. title: Severe Acute Respiratory Syndrome: Pertinent Clinical Characteristics and Therapy date: 2012-08-23 journal: Treat Respir Med DOI: 10.2165/00151829-200504020-00003 sha: doc_id: 339009 cord_uid: wcoch07b Severe acute respiratory syndrome (SARS) is a newly emerged infection that is caused by a previously unrecognized virus–a novel coronavirus designated as SARS-associated coronavirus (SARS-CoV). From November 2002 to July 2003 the cumulative number of worldwide cases was >8000, with a mortality rate of close to 10%. The mortality has been higher in older patients and those with co-morbidities. SARS has been defined using clinical and epidemiological criteria and cases are considered laboratory-confirmed if SARS coronavirus is isolated, if antibody to SARS coronavirus is detected, or a polymerase chain reaction test by appropriate criteria is positive. At the time of writing (24 May 2004), no specific therapy has been recommended. A variety of treatments have been attempted, but there are no controlled data. Most patients have been treated throughout the illness with broad-spectrum antimicrobials, supplemental oxygen, intravenous fluids, and other supportive measures. Transmission of SARS is facilitated by close contact with patients with symptomatic infection. The majority of cases have been reported among healthcare providers and family members of SARS patients. Since SARS-CoV is contagious, measures for prevention center on avoidance of exposure, and infection control strategies for suspected cases and contacts. This includes standard precautions (hand hygiene), contact precautions (gowns, goggles, gloves) and airborne precautions (negative pressure rooms and high efficiency masks). In light of reports of new cases identified during the winter of 2003–4 in China, it seems possible that SARS will be an important cause of pneumonia in the future, and the screening of outpatients at risk for SARS may become part of the pneumonia evaluation. Severe acute respiratory syndrome (SARS) was first recog-1. Definition nized in the Guangdong Province in Southeast China in late 2002, For surveillance purposes and before the availability of laboraand it subsequently spread globally rapidly during the early tory tests to detect the causative agent, SARS was originally months of 2003. [1, 2] SARS captured worldwide attention as a defined using clinical and epidemiologic criteria from suspect or highly infectious disease with high mortality and as an occupationprobable cases. [3, 4] A suspect case included a respiratory illness of al hazard among healthcare providers. The impact of SARS was unknown etiology and with the following criteria: extensive from both a sociological and economical consequence -• measured temperature >100.4ºF (>38.0ºC) particularly in Asia. Because the causative agent of SARS is • one or more clinical findings of respiratory illness (e.g. cough, contagious, preventative measures focus on avoidance of exposhortness of breath, difficulty in breathing, or hypoxia) sure, and infection control strategies for suspected patients and • travel within 10 days of onset of symptoms to an area with contacts. The emergence of SARS illustrates the need for global suspected or documented community transmission of SARS cooperation of healthcare systems to ensure the public health of (excluding areas with secondary cases limited to healthcare local regions, and the need to be prepared to rapidly institute workers or direct household contacts and close contact within policies to respond to newly emerging infectious threats. 10 days of onset of symptoms with either a person with a respiratory illness or a person under investigation or suspected recombination event between mammalian-like and avian-like parof having SARS). ent viruses which may have been responsible for the switch of host of the SARS-CoV from animals to humans. A probable case was defined as a suspect case with either radiographic evidence of pneumonia or respiratory distress syndrome, or autopsy findings consistent with respiratory distress 3. Epidemiology syndrome without an identifiable cause. [4] Once the virus was identified and laboratory tests became As of July 2003 the cumulative number of worldwide SARS available for detection, the surveillance case definition for SARS cases was 8437, with a mortality of 9.6%. [12] Of the reported cases was updated to include laboratory criteria for evidence of infection 64% were from China, 19% from Hong Kong, 8% from Taiwan, with the SARS-associated coronavirus (SARS-CoV). Initially, 3% from Canada, and 2% from Singapore. The US has been since it was unclear whether SARS infection could be present in relatively spared from the clinical impact of SARS. At July 2003, people who were asymptomatic, the definition included the possi-27 probable cases had been reported, of which only eight had bility of asymptomatic ('subclinical') infection. However, subselaboratory confirmation of acute coronavirus infection. [13] quent investigations suggest that asymptomatic infection is very The initial cases reported in Hong Kong were linked to an index uncommon. [1] As a consequence, the latest surveillance case defipatient, a medical doctor from the Guangdong province of China nition for SARS by the US Center for Disease Control and who traveled to Hong Kong to attend a wedding in late February Prevention (CDC) has been updated to include clinical criteria for 2003. [14] He had previously treated patients with 'atypical' pneuearly illness, mild-to-moderate illness, and severe respiratory illmonia in Guangdong. Subsequently several guests who had stayed ness, which are then characterized by epidemiological and laboraat the same hotel became ill with SARS. These patients subsetory criteria (table I) . [5] quently infected numerous healthcare workers and family members or became index cases in other countries (Canada, Vietnam, Singapore, etc.) [ figure 1 ]. The mortality has been higher in older patients and those with co-morbidities. The syndrome has been observed primarily in Soon after the recognition of the clinical syndrome of SARS, adults aged 25-70 years, and children have been relatively spared. several different laboratories identified a novel coronavirus, desig-There appears to be no significant underlying predisposing condinated SARS-CoV, in Vero E6 cell cultures inoculated with respirtion for the development of SARS, however the elderly and atory secretions and lung tissue of infected patients. [6, 7] Other patients with underlying conditions are at greater risk for mortalitechniques, including electron microscopy, reverse transcriptionty. In one study from Hong Kong the mortality for those >60 years polymerase chain reaction (RT-PCR), and serovonversion, have of age was 43%. [15] In another study, multivariate analysis showed also pointed to this as the causative agent. Sero-epidemiological that age >60 years, presence of diabetes mellitus or heart disease, data indicate the SARS-CoV was not previously found in and the presence of other co-morbid conditions were independenthumans. [8] Preliminary reports of detection of the SARS ly associated with mortality. [16] Early in the evaluation of this coronavirus in Himalayan palm civet cats and a number of other syndrome, most of the descriptions were of patients who required species are suggestive of interspecies transmission of this new hospitalization. However, as more cases were identified, particuvirus. Investigators from Hong Kong reported a coronavirus relarly in the Western countries, the majority of patients have not sembling SARS virus isolated from several Himalayan palm civet required hospitalization. cats and a raccoon dog obtained in a market in the Guangdong province (such animals are considered as food delicacies in that SARS appears to be transmitted by close contact with patients region. [9] ) They also reported that several of the handlers at the who have illness due to SARS virus. [1, 2] The greatest risk of market had antibody to the SARS virus. Studies of the genetic transmission is most probably via direct contact with respiratory sequence of the two viruses show a similar pattern, suggesting a secretions. There is no evidence of spread from patients before species jump from wild animals to humans. Furthermore, experi-they develop symptoms. The majority of cases have been reported mental infection of macaques with SARS-CoV produced a pneu-among healthcare workers and family members of affected permonia that was pathologically similar to SARS in humans. [10] sons. However, evidence of community spread of the disease is Stavrinides and Guttman compared the SARS-CoV genome with emerging, suggesting that other modes of transmission, such as related coronaviruses and found about half the DNA resembled airborne or direct contact, may also have a role. [1] Clusters of cases coronavirus sequences from mammals, while the other half looked in community settings such as hotels and apartment buildings like virus found in birds. [11] These data suggest a possible past demonstrate that transmission can be efficient. Many household [5] Clinical criteria Presence of two or more of the following features: fever (might be subjective), chills, rigors, myalgia, headache, diarrhea, sore throat, or rhinorrhea Temperature >100.4°F (>38°C), and One or more clinical findings of lower respiratory illness (e.g. cough, shortness of breath, or difficulty breathing) Meets clinical criteria of mild-to-moderate respiratory illness, and One of more of the following findings: radiographic evidence of pneumonia, or acute respiratory distress syndrome, or autopsy findings consistent with pneumonia or acute respiratory distress syndrome without an identifiable cause One or more of the following exposures in the 10 days before onset of symptoms: travel to a foreign or domestic location with documented or suspected recent transmission of SARS-CoV, or close contact with a person with mild-to-moderate or severe respiratory illness and history of travel in the 10 days before onset of symptoms to a foreign or domestic location with documented or suspected recent transmission of SARS-CoV One or more of the following exposures in the 10 days before onset of symptoms: close contact with a person with confirmed SARS-CoV disease, or close contact with a person with mild-to-moderate or severe respiratory illness for whom a chain of transmission can be linked to a confirmed case of SARS-CoV disease in the 10 days before onset of symptoms Detection of serum antibody to SARS-CoV by a test validated by CDC (e.g. enzyme immunoassay), or Isolation in cell culture of SARS-CoV from a clinical specimen, or Detection of SARS-CoV RNA by a RT-PCR test validated by CDC and with subsequent confirmation in a reference laboratory (e.g. CDC) Case classification b Probable case of SARS-CoV disease: meets the clinical criteria for severe respiratory illness and the epidemiologic criteria for likely exposure to SARS-CoV Confirmed case of SARS-CoV disease: clinically compatible illness (i.e. early, mild-to-moderate, or severe) that is laboratory confirmed a Tests to detect SARS-CoV are being refined and, therefore, criteria for laboratory diagnosis of SARS-CoV are changing. b Asymptomatic infection or clinical manifestations other than respiratory illness may be identified in future as more is learned about SARS-CoV. CDC = Center for Disease Control; RT-PCR = reverse transcription polymerase chain reaction; SARS-CoV = SARS-associated coronavirus. contacts have become ill. Epidemiologic evidence indicates that quired SARS via contact with a fomite. Of still unexplained significance, a few patients have been involved in the transmission the transmission of SARS is facilitated by face-to-face contact, of an unusually large number of secondary cases -so-called superand this still appears to be the most common mode of spread in the spreading events. form of droplet transmission. [1] However, airborne or fecal transmission may have a role in some settings, and it could account for Peiris et al. [17] studied the viral load of SARS-CoV over time in the extensive spread within buildings and other confined areas that respiratory secretions from 14 SARS patients and found the load in has been observed in some places in Asia. Transmission via casual nasopharyngeal aspirates increased to a peak on the tenth day after contact is uncommon, but has been documented on an airplane or onset of symptoms, then decreased gradually. Notwithstanding the in a taxi. [1] Some healthcare workers also appeared to have ac-small sample size and the effects of concomitant administration of ribavirin and corticosteroid, this suggests that SARS patients of Virology in Beijing. The virus was apparently transmitted to the student's mother and a nurse caring for the student (all three had might be most contagious in the second week of illness. laboratory-confirmed cases). At the time of writing, a total of nine After the termination of the initial outbreak of SARS in July possible cases of SARS have been identified and the health author-2003, there were two further cases of SARS-CoV infection which ities were involved in active surveillance to identify other possible were likely acquired in a laboratory setting, one case in late August cases. [20] and the other in December. [18] This reinforces the necessity for careful laboratory practices when working with this virus. It 4. Clinical Manifestations appears there was no evidence of secondary transmission associated with either case, despite the active social activities undertaken The initial descriptions of the clinical manifestations of SARS by these two scientists after their exposure to SARS-CoV. An have come from reports of patients who have required hospitalizaadditional four community-acquired cases from the Guangdong tion. [8, [21] [22] [23] [24] In such patients the disease is often reported as a bi-Province of China were subsequently diagnosed from December phasic or tri-phasic illness with an initial acute febrile phase 2003 through January 2004. Of interest, no close contacts of these followed by a lower respiratory illness phase then progression in cases was found to have fever or respiratory symptoms after home approximately 20-30% of patients to a phase characterized by quarantine to date. [19] More recently, in April 2004, the Chinese acute respiratory distress syndrome (ARDS) necessitating ventilator support. Ministry of Health reported additional cases of SARS which seemed to be initially associated with an index case of a 26-year-It is imperative to appreciate that individual patients do not old female graduate student who worked at the National Institute necessarily display these 'phases', which could be highly individ- Peiris et al. [17] (n = 50) Lee et al. [23] (n = 138) Poutanen et al. [22] (n = 10) Tsang et al. [21] (n = 10) ualized, from hyperacute to indolent presentation in time course. festations as the patients described above (figure 2). Although the At the time of writing, the mortality of probable SARS cases was majority of patients developed symptoms of respiratory tract inapproximately 10%, but was much higher in older individuals and fection during admission, only a minority of patients had sympthose with significant co-morbidities. toms at the time of admission to the hospital. Diarrhea was present The mean incubation period of SARS is estimated to be 6 days, in only 10% at the time of admission, but 50% developed this with a usual range up to approximately 10 days after exposymptom while in the hospital. These investigators also observed sure. [1, 2, 15, 25] The illness generally begins with a prodrome of fever, the duration of time from the onset of illness until the evolution of often associated with chills, rigors and myalgia. Headache and various endpoints of their disease: fever, 0.3 days; admission to the severe malaise may accompany this phase; rash has been absent in most cases. In one outbreak within an apartment complex in Hong Kong, diarrhea was found in 66% of cases. [1] After a typical period of 3-7 days, a lower respiratory phase may begin with the onset of non-productive cough and progressive pneumonia. In the initial reports of cases, 20-30% of patients required intensive care unit management and mechanical ventilation. The presenting symptoms of patients admitted to the hospital from four published series are listed in table II. [8, [21] [22] [23] Most patients were admitted to the hospital several days after the onset of symptoms. The most common complaints were fever and chills or rigors. Upper respiratory tract symptoms such as rhinorrhea and sore throat were less common. At the time of examination, abnormal auscultatory findings were present in about one-third of patients. Although fever and progressive respiratory manifestations are a hallmark of most cases of SARS, patients with more indolent characteristics (including absence of fever) have been describedespecially in elderly or immunocompromised patients. [1, 26] The first report of a complete outbreak of SARS (from beginning of the outbreak until declaration of containment) was recently published by Vu et al. [27] They report a cohort of patients, all of whom required hospitalization, who presented with similar mani- hospital, 4.3 days; onset of radiographic change, 4.4 days; onset of multivariate analysis, the only factors that were predictive of an respiratory symptoms, 4.5 days; onset to maximal radiographic adverse outcome were advanced age, a high peak lactate change, 10 days; onset to intubation, 10.5 days; onset to end of dehydrogenase level, and a higher absolute neutrophil count. fever, 12.7 days; and onset to death, 18.8 days. [27] 5. Diagnosis Chest x-ray abnormalities are usually absent during the initial phase of illness but become progressively abnormal during the The initial manifestations of SARS are not specific and cannot phase of lower respiratory illness. Initially this is characterized by easily be distinguished from those of other respiratory infections. early focal interstitial infiltrates, usually seen as ground glass The first clinical definition developed by the WHO (see section 1) opacity, and progressing to bilateral disease (figure 3). A typical was found to be only 29% sensitive and approximately 70% ARDS picture has emerged in many very seriously ill patients. In specific for identifying laboratory documented cases. [30] Clinicians these patients, high-resolution computed tomography (HRCT) is should conduct thorough diagnostic testing to rule out other etiolomore sensitive in early disease when the chest x-ray could be gies in patients suspected of having SARS. Initial recommended normal or only showing inconclusive consolidation. Characteristidiagnostic testing procedures include chest radiograph and pulse cally, HRCT shows peripheral and, most commonly, lower lobe oximetry. Since SARS often progresses rapidly, repeated chest xconsolidation. [28, 29] Although non-diagnostic and closely mimickrays within the first or second day, sometimes twice daily, may be ing the appearance of bronchiolitis obliterans with organizing helpful in documenting the course of disease. Indiscriminate use of pneumonia, HRCT is also helpful for showing no evidence of HRCT to detect 'radiographically occult disease' is to be discourpleural effusion or intrathoracic lymphadenopathy, which are very aged in view of infection control issues, and the rapidly progresrarely seen in SARS. [2, 21, 28, 29] Spontaneous pneumomediastinum sive nature of SARS, thus making it likely that radiographic also occurs as a rare complication with SARS. [8] abnormalities would be more apparent within a few days after Laboratory abnormalities most often associated with SARS hospitalization. [2] Tests for evaluation of specific organisms assoinclude absolute lymphopenia, mild neutropenia, and thrombociated with pneumonia should be performed, and include: blood cytopenia. Mild to moderately elevated plasma levels of creatine cultures, sputum Gram stain and culture, and testing for viral phosphokinase, lactate dehydrogenase, and transaminases were respiratory pathogens -especially influenza and respiratory synseen in 30-80% of cases (table II) . cytial virus. Urinary antigen for both Pneumococcus spp. and Lee et al. [23] found that advanced age, male sex, and high levels Legionella spp. should also be considered. Acute and convalescent of serum creatine phosphokinase, serum lactate dehydrogenase, a serum (preferably 28 days after onset of symptoms) should be relatively high initial neutrophil count (i.e. mean 4.6 vs 3.7 × collected from each patient who meets the SARS clinical case 10 -9 L), and a low levels of serum sodium were significant predic-definition. However, if acute and convalescent phase sera are tive factors for intensive care unit admission, and death. On collected at least 8-10 days apart, a 4-fold or greater rise in different RT-PCR assays performed on different specimen aliquots identify the coronavirus RNA. [33] Because of the possibility of false-negative cultures and RT-PCR assays, only the absence of antibody in a serum specimen obtained >21 days after symptom onset is considered by the CDC to be a negative laboratory test for SARS coronavirus. The likelihood of detecting SARS-CoV is increased if multiple specimens (e.g. stool, serum, respiratory tract specimens) are collected during the course of illness. Clinicians should consult with their local laboratory personnel and health department about obtaining such tests. The priority of specimens for SARS-CoV testing and optimal timing for collection are presented in table III. Of the 50 patients with clinical SARS described by Peiris et al., [8] 45 had serological or PCR evidence of SARS-associated coronavirus infection; and of the 5 who were unconfirmed, 4 had serological testing prior to 14 days of onset of illness (possibly prior to the time of seroconversion). Another series of 72 cases in Hong Kong showed that despite significantly high dosages of corticosteroid therapy, a seroconversion of 95.8% occurred on day 21 after onset of illness. [35] This differs from the US experience where of the 74 probable cases of SARS reported by 15 July 2003, only 8 had been confirmed by laboratory diagnosis (all by serology); 38 were negative and 28 had no result. b Antibody testing should also be carried out on a serum sample collected >28 days after symptom onset. antibody titer when tested in parallel should be considered indicative of a confirmed case. A variety of methods for detection of coronavirus infection are now available. These include culture methods, PCR-based methods, and serological tests. [31] Culture of the SARS coronavirus is considered solid evidence of infection, but there have been problems with the various generations of RT-PCR assays, both with false-positive results and with inconsistent detection of viral genome in the first days of illness as well as later in the convalescent phase. It is therefore recommended that detection of SARS-CoV RNA by RT-PCR be validated by a second reference laboratory. [32] Because antibodies to SARS coronavirus have not been found in the general population, background SARS coronavirus antibodies do not appear to be a substantial concern. However, the current serologic assays (both ELISA and IFA [indirect fluorescent antibody] formats) do not reliably detect antibodies until the titers rise substantially after the second week of illness. According to the USCDC, suspect or probable cases are considered laboratory-confirmed if SARS coronavirus is isolated, if antibody to SARS coronavirus is detected and confirmed by a second reference laboratory, or if two Table IV . A summary of infection control precautions for patients hospitalized with suspected/probable severe acute respiratory syndrome (SARS) [reproduced from Sampathkumar et al., [39] with permission] Place patient in a negative pressure, specially vented, room A number of other agents have been suggested for therapy of SARS-CoV, including interferon-α, glycyrrhizin, and protease inhibitors. [1] In one preliminary, uncontrolled study by Loutfy et al. [38] from Toronto, use of interferon 9 μg/day for a minimum of 2 days and increased to 15 μg/day for a total of 10 days, plus corticosteroids (oral prednisone 50mg twice a day, or intravenous methylprednisolone 40mg every 12 hours) was associated with reduced disease-associated impaired oxygen saturation and more rapid resolution of radiographic lung abnormalities. The authors acknowledge, however, that these findings need to be interpreted cautiously in view of lack of randomization, the retrospective dosing, and the limited sample size (a total of 21 patients). Table V . A summary of protective measures taken by severe acute respiratory syndrome (SARS)-infected and non-infected staff in Hong Kong hospitals (reproduced from Seto et al., [40] c Comparing proportion of infected (n = 11) over non-infected staff (n = 72), with those without mask. Since the causative agent of SARS is contagious, in the absence of effective drugs or vaccines the only currently effective strategy 6. Treatment for limiting the impact of SARS is implementation of preventive At the time of writing (24 May 2004), no specific therapy is recommended. A variety of treatments have been attempted, but there are no controlled data. Most patients have been treated throughout the illness with broad-spectrum antimicrobials, supplemental oxygen, intravenous fluids, and other supportive measures. Some clinicians have advocated a combination of ribavirin and corticosteroids, but the efficacy of these drugs has not been established. The use of systemic corticosteroids in SARS is controversial, and the efficacy based on controlled studies is unavailable. [36] One study found initial use of pulse-dosed methyl prednisolone (≥500 mg/day) to be more efficacious and equally well tolerated as a lower dose of methyl prednisolone, but this was based on retrospective observational evaluation. [35] The use of corticosteroids in patients with viral infections can be hazardous when not accompanied by an effective anti-viral agent. [36] Early testing of ribavirin and other antiviral compounds against the novel coronavirus have not produced evidence of in vitro activity. [31] An evaluation of the use of ribavirin was published by Knowles et al., [37] who reported adverse events in 110 patients with suspected or probable SARS treated with ribavirin. Of those 110 patients 61% had evidence of hemolytic anemia; hypocalcemia and hypomagnesemia were detected in 58% and 46% of patients, respectively. [33] The authors felt the benefits of ribavirin may not outweigh the risk of adverse events. There was a potential for ribavirin to have negative clinical and economic consequences because of the adverse events. It is now considered among the Table VI . Recommendations for the evaluation of patients with communityacquired respiratory illness in the presence or absence of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) transmission in the world [34] In the absence of SARS-CoV transmission anywhere in the world, the diagnosis of SARS-CoV disease should be considered only in patients who require hospitalization for radiographically confirmed pneumonia and who have an epidemiologic history that raises the suspicion of SARS-CoV disease. In the absence of SARS-CoV transmission anywhere in the world, suspicion of SARS infection is raised if, within 10 days of symptom onset: the patient had a history of recent travel to mainland China, Hong Kong, or Taiwan; was in close contact with ill people with a history of recent travel to such areas; is employed in an occupation at particular risk for SARS-CoV exposure, including a healthcare worker with direct contact or a worker in a laboratory that contains live SARS-CoV; or is part of a cluster of cases of atypical pneumonia without an alternative diagnosis Once SARS-CoV transmission has been documented in the world, a diagnosis of SARS should still be considered in patients who require hospitalization for pneumonia and who have an epidemiologic history described above. In addition, all patients with fever or respiratory symptoms should be questioned about whether within 10 days of symptom onset they have had: close contact with someone suspected of having SARS-CoV disease; a history of foreign travel (or close contact with an ill person with a history of travel) to a location with documented or suspected SARS-CoV infection; exposure to a domestic location with documented suspected SARS-CoV (including a laboratory that contains live SARS-CoV); or close contact with an ill person with such an exposure history Fig. 4 . Algorithm for evaluating and managing patients requiring hospitalization for radiographically confirmed pneumonia, in the absence of person-toperson transmission of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) anywhere in the world. [34] measures centered on avoidance of exposure and infection. Such Hospitalized patients with suspected SARS should be isolated measures include global and regional surveillance, early detection in negative pressure rooms; healthcare workers should wear masks of new cases, identification of patient contacts, and strict adher-(a high efficiency mask such as the N-95 respirator used for ence to infection control policies. Guidelines for infection control tuberculosis) to prevent air-droplet and airborne acquisition. Behave been published and should be consulted for updated recom-cause coronaviruses can survive on environmental surfaces, good mendations. [34, 39] Healthcare workers encountering a possible case hand-washing with soap and water or use of an alcohol-based hand of SARS (suspected or probable) should take meticulous safety rub is highly recommended as well. Environmental surfaces that precautions and seek advice from an expert in SARS infection are frequently touched by the patient or are soiled with body fluids control. should be cleaned and disinfected with a household disinfectant. The early symptoms of SARS-CoV disease usually include fever, chills, rigors, myalgia, and headache. Respiratory symptoms often do not appear until 2-7 days after the onset of illness. 2 In settings with more extensive transmission, all patients with fever or respiratory symptoms should be evaluated for possible SARS-CoV disease. 3 Depending on symptoms and exposure history, initial diagnostic testing for patients may include complete blood count, chest x-ray (CXR), pulse oximetry, blood cultures, sputum Gram stain and culture, testing for viral respiratory pathogens (notably influenza and respiratory syncytial virus), Legionella sp. and pneumococcal urinary antigen. 4 An alternative diagnosis should be based on laboratory tests with high-predictive value (e.g. blood culture, urinary antigen). 5 Chest computed tomography (CT) may show evidence of an inflitrate before a CXR. Therefore, a chest CT should be considered in patients with a strong epidemiologic link to a known case of SARS and a negative CXR 6 days after onset of symptoms. 6 SARS isolation precautions should be discontinued after consultation with local public health authorities and the evaluating physician. An important characteristic of the recent SARS outbreaks has been infection transmission. Table IV lists precautions for patients hospitalized with SARS. the predilection for transmission to healthcare providers after patient care. For the most part this has occurred after close, Patients with SARS-CoV disease who do not otherwise need to unprotected contact with symptomatic individuals. Healthcare be hospitalized can be managed appropriately as outpatients. workers who have had unprotected exposure and who develop These patients should limit interactions outside the home. They fever or respiratory symptoms should not come to work, and should be instructed to wear surgical masks in the presence of should report their symptoms to the infection control/employee household contacts, contain respiratory secretions in facial tissues, health service and their physician immediately. Healthcare workand wash hands frequently. They should stay away from work, ers who have had unprotected exposure during procedures with school, or other public places for 10 days after resolution of fever. high risk of aerosolization (e.g. intubations, bronchoscopy) should Household members or other close contacts of these patients should wear gloves and practice good hand hygiene. In the abbe quarantined for a 10-day period, since there is a high risk of sence of fever or respiratory symptoms, they need not limit their SARS. [20] This policy has been running since the middle of March 2003 at Queen Mary Hospital of the University of Hong Kong, activities. despite the disappearance of SARS in Hong Kong since June The importance of SARS precautions was demonstrated in a 2003. Only authorized and minimum number of staff working in case-control study in five Hong Kong hospitals, with 241 nonthese wards may enter the premises. All staff entering these infected and 13 infected healthcare providers who had documentrestricted areas follow strict and stepwise 'gowning' and 'degowned contacts with SARS patients (table V) . [40] All of the healthcare ing' procedures, and use standard personal protection equipment providers were surveyed concerning the use of masks, gloves, (disposable surgical paper cap, N-95 mask, and reusable eye gowns, and hand-washing, as recommended under droplet precaugoggles and cotton surgical gown). Patients are treated with potent tions. No staff member who reported use of all four measures was antibiotics, usually in the form of a combination of cephalosporin infected. In contrast, all 13 infected staff members had omitted at and macrolide, or in the event of allergy to these antibiotics with least one of the measures (p = 0.0224). The authors observed that levofloxacin. Patients who improve clinically and radiologically both surgical and high efficiency masks (N-95 masks) were proare unlikely to have SARS, and are moved to wards that don't tective against infection, whereas paper masks did not significantrequire the level of intensive care and/or isolation as would be ly reduce the transmission (such masks are easily wet with saliva required for those patients who have SARS, for observation for and are not recommended for precautions against droplets). 5-7 days before discharge. In the event of confirmed or suspected In order to be prepared for the recurrence of SARS and the need SARS, a patient will be diverted to the appropriate wards to for early implementation of control measures, the US CDC reminimize exposure of fellow patients, if no single-room accomleased clinical guidelines for the identification and evaluation of modation could be provided. possible SARS-CoV disease among patients presenting with community-acquired illness. [34] The key principles upon which control 8. Conclusion measures are based have taken into consideration the fact that in the year 2003 a vast majority of patients with SARS-CoV disease Because a new virus causes SARS, it is very difficult to predict had a clear history of exposure either to a SARS patient or to a the eventual significance of this infection. However, the resetting in which SRS-CoV transmission occurred (i.e. hospital); emergence of sporadic cases in China, has caused great concern as and developed pneumonia. Recommendations for the evaluation to its future impact. It has had enormous economic and political of patients with community-acquired respiratory illness were deimpact on the affected areas of the world. Although important veloped for two primary circumstances: firstly in the absence of progress has been made concerning the etiology, epidemiology, SARS-CoV transmission anywhere in the world, and secondly and prevention of this virus, many important questions remain. once transmission had been documented (these were released prior Without answers to some of these questions, the eventual Province in China (or close contact with an ill person with a outcome of SARS remains unclear. history of recent travel to the area) in the 10 days before onset of symptoms. [19] When such patients are identified, appropriate isola- A major outbreak of severe acute respiratory syndrome References in Hong Kong outcomes of 144 patients with SARS in the greater Toronto Area Management of severe acute respiratory syndrome: the Center for Disease Control and Prevention. Outbreak of severe acute respiratory 417-24 syndrome: worldwide Case definitions for surveillance of Severe Acute Respiratory Syndrome SARS Clinical description of a completed outbreak Sever Acute Respiratory Syndrome (SARS) [online]. Available from URL: of SARS in Vietnam Severe acute respiratory syndrome: radiographic High-resolution CT findings of severe acute cases: United States and Worldwide A novel coronavirus associated with severe acute respiratory syndrome Evaluation of WHO criteria for identifying patients with severe respiratory syndrome out of hospital: prospective observa Identification of a novel coronavirus in patients with severe acute respiratory syndrome Coronavirus as a possible cause of severe (SARS) and coronavirus testing: United States Center for Disease Control and Prevention. Interpreting SARS-CoV test results the SARS coronavirus from animals in southern China Koch's postulates fulfilled for SARS 20] virus Detection of SARS coronavirus in plasma by Mosaic evolution of the severe acute respiratory real-time RT-PCR Available level preparedness and response to severe acute respiratory syndrome (SARS) from URL High-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome The use of corticosteroids in SARS Severe acute respiratory syndrome Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome Clinical progression and viral load in a roids in severe acute respiratory syndrome: a preliminary study SARS: epidemiology, clinical 18. Center for Disease Control and Prevention / presentation, management, and infection control measures Center for Disease Control and Prevention. Recent SARS cases in China Accessed 2004 and contact in prevention of nosocomial transmission of severe acute respirato-May 20] ry syndrome (SARS) Center for Disease Control and Prevention. China reports ninth recent possible SARS case Correspondence and offprints: Professor Thomas M. File, Jr, Infectious A cluster of cases of severe acute respiratory Disease Service Identification of severe acute respiratory syndrome in Canada