Severe Acute Respiratory Syndrome: The Evolution of a New Epidemic

Abstract

Review ArticleSevere Acute Respiratory Syndrome: The Evolution of a New Epidemic Fahad A. A. Al-AteegMHA, M.Ed., Dr.P.H. Fahad A. A. Al-Ateeg Correspondence to: Dr. F. Al-Ateeg, P.O. Box 58026, Riyadh 11594, Saudi Arabia From the Health Programs Sector, Insitute of Public Administration, Riyadh, Saudi Arabia Search for more papers by this author Published Online::1 May 2003https://doi.org/10.5144/0256-4947.2003.118SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionAt this moment the world health community is struggling to cope with a severe and rapidly spreading new disease in humans – severe acute respiratory syndrome (SARS). So far, the new disease has been diagnosed in more than 30 countries worldwide. It appears to be the first severe and easily transmissible new disease to emerge in the 21st century. What distinguishes the international health community response to this epidemic is the almost instantaneous communication and information exchange that has supported every aspect of the response. The World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), and national and local health agencies across the globe have disseminated up-to-the-minute information tailored for clinicians, public health officials, health care workers, travelers, household contacts, and many other affected parties. Immediate communication of interim guidance, updated as soon as new information becomes available, has become the norm. Use of the Internet has expedited information exchange and helped overcome the problems presented by asynchrony in the activities of investigators in many time zones. Scientists at the international collaborating laboratories are exchanging laboratory results and images on secure Web sites. Coordination of the international response strategies has been fostered by regular videoconferences with senior leaders in the operations centers at the WHO and the CDC. Satellite broadcasrs, webcasts and videoconferencing are supporting the dissemination of emerging information to the entire global health community.It is impossible for traditional print medial journals to stay on top of the SARS story.1 The reader is invited to visit the internet sources referred to in this article, particularly the web sites of the WHO and CDC, to find the latest information on SARS. This review documents the first few months in the evolution of the new epidemic. It presents the state of clinical and virologic knowledge at the outset of this epidemic, diagnostic procedures, and treatment and preventive measures based on information collected from the world wide web.THE EMERGENCE OF A NEW PATHOGENThe WHO was first officially informed of the outbreak on 11 February 2003, when the Chinese Ministry of Health reported 305cases of acute respiratory syndrome of unknown cause had occurred in six municipalities in Guangdong Province in southern China.2,3 Five deaths were reported and transmission was largely confined to health care workers (105 doctors, nurses, and other medical workers) and household contacts. On February 14, 2003, WHO was informed by the Chinese Ministry of Health that the outbreak was clinically consistent with atypical pneumonia with reported that cases had been detected as far back as November 16, 2002, in Foshan city in Guangdong Province in China, and the outbreak was coming under control. However, cases during that time were not openly reported for fear of social and economic consequences, thus allowing a severe disease to become silently established in ways that made further international spread almost inevitable.In mid-February, some Chinese experts concluded that the outbreak was caused by chlamydial organisms. Others speculated that a virus might be the cause.2 In late February, the CDC termed this condition the Severe Acute Respiratory Syndrome (SARS). However, SARS was first identified in Vietnam on February 28, 2003 by Dr. Carlo Urbani, the 46-year-old WHO physician and infectious disease specialist who died on 29 March 2003, of the disease.4On March 12, 2003, as the condition began to spread from China, the WHO issued a rare global health alert after an assessment of the situation in Asia by WHO teams in Hanoi. The alert instructed health authorities worldwide to be aware of a new atypical pneumonia of unknown etiology that appeared to place health workers at high risk. The global alert called for increased attention to patients with atypical pneumonia who fit specific case definitions. The case definitions for surveillance of SARS were revised on May 1,2003 (see Box).6Following the WHO global health alert, the CDC formed an emergency operations unit to track and investigate the development of the outbreak. On March 15,2003, the WHO decided to increase the level of the global alert issued on March 12,2003, by issuing emergency guidance for travelers and airlines. The decision was based on five different but related factors. First, the causative agent, and therefore, the potential for continued spread, of this new disease were not yet known. Second, the outbreaks appeared to pose a great risk to health workers who managed patients, and to family members and other close contacts of patients. Third, many different antibiotics and antivirals had been tried empirically and did not seem to have an effect. Fourth, though thenumbers were initially small, a significant percentage of patients had rapidly progressed to respiratory failure, which required intensive care and caused some deaths in previously healthy persons. Finally, the disease had moved out of its initial focus in Asia and had spread to several countries in North America and Europe in a short period of time.World Health Organization case definitions for surveillance of Severe Acute Respiratory Syndrome (SARS) revised on May 1, 2003Suspect CaseA person presenting after 1 November 2002 with history of high fever (> 38 °C ), cough or breathing difficulty and one or more of the following exposures during the 10 days prior to onset of symptoms: close contact2 with a person who is a suspect or probable case of SARS; history of travel to an area with recent local transmission of SARS; and residing in an area with recent local transmission of SARS.A person with an unexplained acute respiratory illness resulting in death after 1 November 2002,1 but on whom no autopsy has been performed and one or more of the following exposures during the 10 days prior to onset of symptoms: close contact2 with a person who is a suspect or probable case of SARS; history of travel to an area with recent local transmission of SARS; and residing in an area with recent local transmission of SARS.Probable CaseA suspect case with radiographic evidence of infiltrates consistent with pneumonia or respiratory distress syndrome (RDS) on chest x-ray;A suspect case of SARS that is positive for SARS coronavirus by one or more assays;A suspect case with autopsy findings consistent with the pathology of RDS without identifiable cause.Exclusion criteriaA case should be excluded if an alternative diagnosis can fully explain their illness.Reclassification of casesAs SARS is currently a diagnosis of exclusion, the status of a reported case may change over time. A patient should always be managed as clinically appropriate, regardless of their case status.A case initially classified as suspect or probable, for whom an alternative diagnosis can fully explain the illness, should be discarded after carefully considering the possibility of co-infection.A suspect case who, after investigation, fulfils the probable case definition should be reclassified as “probable”.A suspect case with a normal chest x-ray should be treated, as deemedappropriate, and monitored for 7 days. Those cases in whom recovery is inadequate should be re-evaluated by chest x-ray.Those suspect cases in whom recovery is adequate but whose illness cannot be fully explained by an alternative diagnosis should remain as “suspect”.A suspect case who dies, on whom no autopsy is conducted, should remain classified as “suspect”. However, if this case is identified as being part of a chain transmission of SARS, the case should be reclassified as “probable”.If an autopsy is conducted and no pathological evidence of RDS is found, the case should be “discarded”.The surveillance period begins on 1 November 2002 to capture cases of atypical pneumonia in China now recognized as SARS. International transmission of SARS was first reported in March 2003 for cases with onset in February 2003.Close contact: having cared for, lived with, or had direct contact with respiratory secretions or body fluids of a suspect or probable case of SARS. www.who.int/csr/sars/casedefinition/en/On March 22, 2003, a team of scientists in the department of microbiology at the University of Hongkong announced their success in culturing the viral agent that causes SARS.7 Using a special cellline, the Hongkong scientists isolated the virus from the lung tissue of a patient who developed pneumonia following contact with a professor and the contact died. Two days later, scientists at the CDC and in Hongkong announced that a new coronavirus had been isolated from patients with SARS. On April 16, 2003, WHO officially announced that a new pathogen, a member of the coronavirus family never before seen in humans, was the cause of SARS.8The speed at which this virus was identified has been astounding. It was the direct result of the close and unprecedented international collaboration of 13 laboratories from 10 countries. Close collaboration, with findings shared daily in teleconferences and by email, has allowed advanced to take place in a matter of days that normally take months. The successful identification of the causative agent meant that scientists could now confidently turn to other challenges related SARS (e.g, the development of diagnostic tests, effective treatment and hopefully a vaccine).ETIOLOGYCoronaviruses have a halo or crown-like (corona) appearance when viewed under a microscope. The three known groups of coronaviruses are associated with a variety of diseases in human and domestic animals, including mild to moderate upper-respiratory illness in humans (the common cold) and respiratory, gastrointestinal, liver, and neurologicdisease in animals. Although coronaviruses cause up to 30% of colds, they rarely cause lower respiratory tract diseases. In contrast, coronaviruses cause devastating epizootics of respiratory or enteric diseases in livestock and poultry. They can survive in the environment for as long as 3 hours.9A novel virus with the distinctive shape and appearance of coronaviruses was isolated from clinical specimens taken from patients with SARS in six countries. Its etiologic role in the disease has been confirmed.10,11 The available sequence data on this new coronavirus suggest that it is sufficiently distinct from those previously reported in animals and humans that its source is yet to be discovered. The name Urbani SARS-associated coronavirus has been proposed for the new virus.10The rapid isolation, characterization, and recognition of the etiologic agent in the SARS outbreak has allowed for the rapid formulation of diagnostic tests, which should aid in understanding the epidemiology of the disease and its prevention. Early recognition of the etiologic agent also has made the virus available for rapid investigation of antiviral compounds and vaccines.Recently, there have been several media reports speculating about the origin of this novel coronavirus. One report suggests that the SARS virus originated in farm animals (cattle, pigs, chicken) and that intensive livestock production might be the breeding ground for the virus.12 The argument is that a human population density in close contact with several species of intensively farmed livestock provides a potential substrate for cross-species transmission, evolution and amplification of many pathogenic agents. However, there is currently no evidence to support this hypothesis since genetic fingerprinting of the SARS virus shows it to be clearly different from any other animal or human coronavirus.In another report, a team of scientists led by Professor Chandra Wickramasinghe of Britain’s Cardiff University, found the SARS coronavirus to be so differenct from viruses previously known that it might have come from outer space on a comet.13 These scientists say that their extraterrestial origin theory follows the panspermia theory, which holds that life evolved in space and has been carried from planet to planet on comets. However, virologists and other medical scientists have ridiculed this hypothesis as bizarre. The insist that the SARS virus evolved from other viruses already found on earth.EPIDEMIOLOGYDuring the period November 1,2002 to May 31,2003, a total of 8360 cases with 764 deaths were officially reported by the WHO from 32 countries on five continents. Of this total, approximately 64% of all cases and 43% of all deaths were reported from mainland China (Table 1). Estimates of the case fatality ration range from 100% in South Africa to 40% in Malaysia, 25% in Thailand and 6.2% in mainland China. However, Calculation of the case fatality ration as the number of deaths reported divided by the number of cases reported irrespective of the time elapsed since becoming ill, underestimates the true case fatality ratio.Table 1. Cumulative number of reported cases, number of deaths, and fatality ratio of SARS from the 10 countries with reported deaths as of 31 May 2003.Table 1. Cumulative number of reported cases, number of deaths, and fatality ratio of SARS from the 10 countries with reported deaths as of 31 May 2003.The countries with the largest number of probable SARS cases as of May 31, 2003, were China (5328), the Hongkong Specialist Administrative Region (1739), Taiwan (676), Singapore (206), Canada (188), the United States (66) and Vietnam (63). Aside from the one case that was reported in Kuwait on April 20, 2003, no cases have been reported in the Gulf region. This is an amazing development given the large number of expatriates from Southeast Asia working in the Gulf region and the continuous and heavy air traffic between the two regions.As of May 31, 2003, the majority of patients identified as having SARS have been adults aged 24 to 78 years whowere previously healthy. Few suspected cases have been reported among children aged 15 years or younger.14However, cases among affected children appear to be very mild. The majority of cases in the US were patients between the ages of 18 and older and of white or Asian origins (Table 2). Most cases are associated with travel to mainland China, Hongkong, Hanoi, Singapore or Toronto; a small number of cases have resulted from secondary spread to household members or health care workers and did not require mechanical ventilation. In most cases, SARS associated coronavirus laboratory findings were either negative or undetermined because of lack of collection and/or laboratory testing of specimens.Table 2. Number and percentage of reported severe acute respiratory syndrome (SARS) cases* by selected characteristics -United States 2003 (N=289).Table 2. Number and percentage of reported severe acute respiratory syndrome (SARS) cases* by selected characteristics -United States 2003 (N=289).TRANSMISSIONEpidemiologic evidence indicates that transmission of SARS is facilitated by close person-to-person contact. Some evidence suggests that a few persons may be especially infectious and that most others are less likely to serve as sources of infection, but this concept is still speculative. There is no evidence of transmission following casual contact. Most reported cases with SARS have involved people who lived with or cared for someone with SARS, or had direct contact with infectious material (for example, respiratory secretions or body fluids) from a person who had SARS.15,16,17 SARS might spread by touching the skin of an infected person or touching objects that are contaminated with infectious droplets and then touching the eyes, nose, or mouth. This could happen when someone sick with SARS coughs or sneezes droplets onto themselves, other people, or nearby surfaces. Airborne transmission may have a role in some settings and could account for the extensive spread within buildings and other confined areas that has been observed in some places in Asia.18It is possible that SARS can be spread more broadly through the air or by means that are currently unknown. Fomites or other modes of transmission could also be relevant, since coronaviruses can survive on contaminated objects in the environment for at least few hours and have been isolated from the stool of some animals. Hence, in an era of global interconnectedness through rapid air travel, an outbreak anywhere in the world is a potential threat to health anywhere.PATHOGENESISBecause of its novelty, much about the behavior of the SARS virus is poorly understood. Intense study is currently underway to identify when viral shedding is highest and to determine concentrations of virus in different body fluids. Scientists are also trying to determine the amount of time the virus can survive in the environment on both dry surfaces and in suspension, including suspension in fecal matter.19 Shedding of the SARS virus in feces, respiratory secretions, and urine is now well-established.On 05 May 2003, scientists in the WHO network of collaborating laboratories reported results of the first scientific studies designed to determine the survival time of the SARS virus in different environmental media and in feces. Results from studies of the effectiveness of different disinfectants commonly used in hospitals were also reported, confirming the validity of currently recommended measures for infection control.20 The new studies confirm that the SARS virus can survive after drying on plastic surfaces for up to48 hours. The virus can survive in feces for at least 2 days, and in urine for 24 hours. Studies conducted at a second collaborating laboratory in Hongkong found that virus in feces taken from patients suffering from diarrhea, which has a lower acidity than normal stools, could survive for 4 days.20However, the dose of virus needed to cause infection remains unknown.CLINICAL MANIFESTATIONSAs suggested by several reports, the incubation period for SARS (the time from exposure to a causative agent to onset of disease) is as short as 1 day and as long as 11 days, with a median of about 5 days.4,17 The WHO, however, has reviewed many individual cases with well defined single point exposure and has adopted a maximum incubation period of 10 days as the best estimate. The incubation period is the most important consideration in the decision to remove a country from the list of areas with recent local transmission. Knowledge of the incubation period can help physicians make diagnostic decisions about whether the presenting symptoms and clinical history of a patient point to SARS or to some other disease. In a study of 10 patients in Hongkong (5 men and 5 women, 38 to 72 years old),17 all patients presented with fever (>38.00°C for over 24 hours) and most presented with rigor, dry cough, dyspnea, malaise, headache and hypoxemia. The most common presenting symptoms in 10 cases studied in Canada16 were fever (in 100 percent of cases, and malaise (in 70 percent), followed by nonproductive cough (in 100 percent) and dyspnea (in 80 percent), elevated aspartate aminotransferase levels (in 78 percent), and elevated creatinine kinase levels (in 56 percent) were also common. Less common symptoms include sputum production, sore throat, coryza, nausea, vomiting and diarrhea.The illness generally begins with a prodrome of fever (>38.0°C of >100.4 F). Fever often is high, sometimes associated with chills and rigors, and might be accompanied by other symptoms including headache, malaise, and myalgia. At the onset of illness, some persons have mild respiratory symptoms. Typically, rash and neurologic or gastrointestinal findings are absent; however, some patients have reported diarrhea during the febrile prodrome. After 3 to 7 days, a lower respiratory phase begins with the onset of a dry, nonproductive cough or dyspnea, which might beaccompanied by or progress to hypoxemia. In 10% to 20% of cases, the respiratory illness is severe enough to require intubation and mechanical ventilation.EVALUATIONThe CDC recommends that initial diagnostic testing for suspected SARS patients include a chest radiograph, pulse oximetry, blood cultures, sputum Grams stain and culture, and testing for viral respiratory pathogens, notably influenza A and B, and respiratory syncytial virus. A specimen collected for Legionella and pneumococcal urinary antigen testing should also be considered.21 To enhance the future understanding of SARS, WHO recommends that clinicians collect and store sequential samples from patients with SARS for testing when diagnostic tests become readily available.22 This is particularly important for the first case(s) recognized in countries that have not previously reported SARS.The current imaging protocol indicates that if SARS is clinically suspected, a chest radiograph should be performed. If the chest radiograph is abnormal (i.e. varying degrees of pneumonia and ARDS), then no further imaging investigation is required other than serial radiographs for follow-up.15,22However, if the chest radiograph is normal, high resolution computed tomography (HRCT) is recommended. This may slow changes one to two days before they become radiographically apparent.Based on the initial experience with over 2400 radiographs and 160 CTs in the past several weeks at the Department of Diagnostic Radiology and Organ Imaging at Chinese University of Hongkong and Prince of Wales Hospital in Hongkong,23 imaging findings in SARS include radiographs and HRCT. In the early stage of the disease, a peripheral/pleural based opacity may be the only abnormality. The radiograph may range from ground-glass to consolidation in appearance. A particular area to review is the paraspinal region behind the heart. Based on the department’s experience, this is frequently where lung lesions are detected on HRCT in suspected SARS patients with normal radiographs. In the more advanced cases, there is widespread opacification, which may be ground-glass or consolidative, affecting large areas. This tends to affect the lower zones first and is not uncommonly bilateral. Calcification, cavitation, pleural effusion or lymphadenopathy are not features of SARS. On HRCT, solitary of multiple patchy area(s) of ground-glass opacification (with or without thickening of the intra-lobular interstitium or interlobular interstitium, consolidation, or a combination of the two, tend to occupy a sub-pleural rather than axial position. Again, calcification, cavitation, pleural effusion or lymphadenopathy are not features of this disease.Histologic features of SARS have also been documented. In one study, histopathological evaluation of lung tissues obtained from the autopsy of three patients andby open-lung biopsy in one patient showed diffuse alveolar damage at various levels of progression and severity. 10 Changes included hyaline membrane formation, interstitial mononuclear inflammatory infiltrates, and desquamation of pneumocytes in alveolar spaces. Other findings identified in some patients included focal intra-alveolar hemorrhage, necrotic inflammatory debris in small airways, and organizing pneumonia. Multinucleated syncutial cells were identified in the intra-alveolar spaces in two patients. These cells contained abundant vacuolated cytoplasm with cleaved and convoluted nuclei. No obvious intranuclear or intracytoplasmic viral inclusions were identified, and electron-microscopical examination of a limited number of these syncytial cells revealed no coronavirus particles. Postmortem findings in two cases from another study showed similar results and no evidence of the involvement of other organs.13The present role of tests in diagnosis has proved more problematic than hoped. At this time, tests for the new human coronavirus are still being refined, and no sensitivity or specificity data are available, Currently, there are three tests available that are helping to improve understanding of how the virus causes disease in human.9,24,25 However, all three tests have limitations as tools for bringing the SARS outbreak quickly under control.The enzyme linked immunosorbant assay (ELISA) detects antibodies reliably, but only from about day 20 after the onset of clinical symptoms. Therefore, it can not be used to detect cases at an early stage before they have chance to spread the infection to others. Serum antibody tests, which include both the indirect immunofluorescence antibody (IFA) and enzyme immunoassay (EIA), detect antibodies reliably as of day 10 of the infection, but are comparatively slow tests that require the growth of virus in cell culture. The most currently available tests, which is useful in the early stages of infection, is the reverse transcription polymerase chain reaction (RT-PCR) molecular test for detection of SARS virus genetic material. The test can detect coronavirus RNA in clinical specimens including blood, serum, stool, and nasal secretions or body tissue. However, it produces many false-negatives, which means that many persons who actually carry the virus may not be detected. This can create a dangerous sense of false security for a virus that is known to spread easily in close person-to-person contacts. In the absence of a proven diagnostic test(s), SARS will continue to be diagnosed on the basis of symptoms and exposures, as described in the current SARS case definition, and not on laboratory test results.TREATMENT/MANAGEMENTSeveral antibiotics have been used in an attempt to presumptively treat known bacterial agents of atypical pneumonia. Treatment regimens have included cefotaximeand clarithromycin (or levofloxacin) to target common pathogens causing community-acquired pneumonia.15 Antiviral agents such as oseltamivir (Tamiflu), have been used to treat possible influenza infection. If fever has persisted for more than 48 hours and the blood count has shown leukopenia, thrombocytopenia, or both oral ribavirin (1.2 g three times a day) and corticosteroid therapy (prednisolone at a dose of 1 mg per kilogram of body weight intravenous ribavirin (400 mg every eight hours) and corticosteroid therapy (an additional two to three pulses of 0.5 mg of methylprednisolone daily). Patients in whom hypoxemia developed were given oxygen through a nasal cannula. Patients were admitted to the ICU if respiratory failure developed, as evidenced by an arterial oxygen saturation of less than 90% while the patient was receiving 50% supplemental oxygen, a respiratory rate that exceeded 35 breaths per minute, or both. Corticosteroids have also been administered orally or intravenously to patients in combinations with ribavirin and other antimicrobials.14However, some authorities have warned against the use of corticosteroids.26 A successful response to therapy can be demonstrated by serial chest radiographs showing the resolution of lung opacities.PROGNOSISThe severity of illness can be highly variable, ranging from mild illness to death. Although a few close contacts of patients with SARS have developed a similar illness, the majority have remained well. Some close contacts have reported a mild, febrile illness without respiratory signs or symptoms, suggesting that illness might not always progress to the respiratory phase.14 On the basis of more detailed and complete data and reliable methods, the WHO estimates that the case fatality ratio of SARS ranges from 0% to 50% depending on the age group affected, with an overall estimate of case fatality of 14% to 15% (a case fatality ratio measures the proportion of all people with a disease who will die from the disease).The likelihood of dying from SARS in a given area has been shown to depend on the profile of the cases, including the age group most affected and the presence of underlying disease. Based on data received by the WHO to date, the case fatality ratio is estimated to be less than 1% in persons aged 24 years or younger, 6% in persons aged 25 to 44 years, 15% in persons aged 45 to 64 years, and greater than 50 %in persons aged 65 years or older.27PREVENTIONDespite our long experience with other viral respiratory infections, we have no proven successful population-based strategy for their prevention. In the early stages of a global outbreak, public health authorities rely on may measures to contain the spread of a contagious illness. Isolation andquarantine are two common practices in public health and both aim to control the spread of infectious diseases. The two measures may be undertaken voluntarily or compelled by public health authorities. Isolation applies to people who are known to have an illness and restricts their movement to stop the spread of that illness. It allows for the focused delivery of specialized health care to people who are ill, and protects healthy people from getting sick. Isolated people may be cared for in their homes, in hospitals, or at designated health care facilities. Quarantine, in Contrast, applies to people who have been exposed and may be infected but are not yet ill. It is medically very effective measure in protecting the public from a contagious disease and intended to stop the spread of that disease.SARS patients in many affected countries are being isolated until they are no longer infectious. To date, the WHO and CDC have recommended isolation of individuals with SARS, but has not compelled quarantine or isolation for these individuals. However, several countries are introducing maximum measur