The largest outbreak of severe acute respiratory syndrome (SARS) struck Beijing in spring 2003. Multiple importations of SARS to Beijing initiated transmission in several healthcare facilities. Beijing’s outbreak began March 5; by late April, daily hospital admissions for SARS exceeded 100 for several days; 2,521 cases of probable SARS occurred. Attack rates were highest in those 20–39 years of age; 1% of cases occurred in children <10 years. The case-fatality rate was highest among patients >65 years (27.7% vs. 4.8% for those 20–64 years, p < 0.001). Healthcare workers accounted for 16% of probable cases. The proportion of case-patients without known contact to a SARS patient increased significantly in May. Implementation of early detection, isolation, contact tracing, quarantine, triage of case-patients to designated SARS hospitals, and community mobilization ended the outbreak.
severe acute respiratory syndrome; disease outbreaks; epidemiology; China; nosocomial infection; SARS virus; disease transmission
Infection of healthcare workers with the severe acute respiratory syndrome–associated coronavirus (SARS-CoV) is thought to occur primarily by either contact or large respiratory droplet transmission. However, infrequent healthcare worker infections occurred despite the use of contact and droplet precautions, particularly during certain aerosol-generating medical procedures. We investigated a possible cluster of SARS-CoV infections in healthcare workers who used contact and droplet precautions during attempted cardiopulmonary resuscitation of a SARS patient. Unlike previously reported instances of transmission during aerosol-generating procedures, the index case-patient was unresponsive, and the intubation procedure was performed quickly and without difficulty. However, before intubation, the patient was ventilated with a bag-valve-mask that may have contributed to aerosolization of SARS-CoV. On the basis of the results of this investigation and previous reports of SARS transmission during aerosol-generating procedures, a systematic approach to the problem is outlined, including the use of the following: 1) administrative controls, 2) environmental engineering controls, 3) personal protective equipment, and 4) quality control.
SARS virus; resuscitation; occupational health; infection control; transmission; healthcare worker
Low level of immunity for SARS-CoV among well healthcare workers reinforces the need for infection control measures in hospitals to prevent epidemics.
To determine the prevalence of inapparent infection with severe acute respiratory syndrome (SARS) among healthcare workers, we performed a serosurvey to test for immunoglobulin (Ig) G antibodies to the SARS coronavirus (SARS-CoV) among 1,147 healthcare workers in 3 hospitals that admitted SARS patients in mid-May 2003. Among them were 90 healthcare workers with SARS. As a reference group, 709 healthcare workers who worked in 2 hospitals that never admitted any SARS patients were similarly tested. The seroprevalence rate was 88.9% (80/90) for healthcare workers with SARS and 1.4% (15/1,057) for healthcare workers who were apparently healthy. The seroprevalence in the reference group was 0.4% (3/709). These findings suggest that inapparent infection is uncommon. Low level of immunity among unaffected healthcare workers reinforces the need for adequate personal protection and other infection control measures in hospitals to prevent future epidemics.
SARS; Seroprevalence; Healthcare workers; China; research
Whether severe acute respiratory syndrome–associated coronavirus (SARS-CoV) infection can be asymptomatic is unclear. We examined the seroprevalence of SARS-CoV among 674 healthcare workers from a hospital in which a SARS outbreak had occurred. A total of 353 (52%) experienced mild self-limiting illnesses, and 321 (48%) were asymptomatic throughout the course of these observations. None of these healthcare workers had antibody to SARS CoV, indicating that subclinical or mild infection attributable to SARS CoV in adults is rare.
Coronavirus; health care worker; hospital; prevalence; severe acute respiratory syndrome; SARS
As of April 14, 2003, Taiwan had had 23 probable cases of severe acute respiratory syndrome (SARS), all imported. Taiwan isolated these first 23 patients with probable SARS in negative-pressure rooms; extensive personal protective equipment was used for healthcare workers and visitors. For the first 6 weeks of the SARS outbreak, recognized spread was limited to one healthcare worker and three household contacts.
SARS; pneumonia; prevention; Taiwan; dispatch
Taiwan experienced a series of outbreaks of nosocomial severe acute respiratory syndrome (SARS) infections in 2003. Two months after the final outbreak, we recruited 658 employees from the hospital that suffered the first and most severe SARS infections to help us investigate epidemiological and genetic factors associated with the SARS coronavirus (SARS-CoV). SARS-CoV infections were detected by using enzyme immunoassays and confirmed by a combination of Western blot assays, neutralizing antibody tests, and commercial SARS tests. Risk factors were analyzed via questionnaire responses and sequence-specific oligonucleotide probes of human leukocyte antigen (HLA) alleles. Our results indicate that 3% (20/658) of the study participants were seropositive, with one female nurse identified as a subclinical case. Identified SARS-CoV infection risk factors include working in the same building as the hospital's emergency room and infection ward, providing direct care to SARS patients, and carrying a Cw*0801 HLA allele. The odds ratio for contracting a SARS-CoV infection among persons with either a homozygous or a heterozygous Cw*0801 genotype was 4.4 (95% confidence interval, 1.5 to 12.9; P = 0.007).
A Severe Acute Respiratory Syndrome (SARS) outbreak occurred in Singapore from February to May 2003. A high vigilance for the disease, frequent and regular temperature monitoring, early case identification and isolation of patients, as well as tracing and home quarantine of contacts, played major roles in controlling the outbreak. Hospitals were dedicated to the screening and treatment of SARS patients. Within and between hospitals, movement by healthcare workers, patients and visitors were restricted, as was the number of hospital visitors. Staff education and audits of infection control practices also featured prominently.
To prevent cross-border transmission, incoming travellers from SARS affected areas had to complete health declaration cards. They, as well as all outgoing travellers from Singapore, were monitored for fever. In the meantime, the public was urged to refrain from travelling to SARS affected regions.
Containment elements targeting the community included school closure, public education on good hygiene and readily accessible public information.
In response to a laboratory acquired SARS infection, laboratories were audited, and directives issued on the mandatory use of biosafety level 3 laboratories for SARS virus culture, and compliance of laboratory workers to biosafety guidelines.
outbreak control; SARS; patient isolation; quarantine; contact tracing
The outbreak of severe acute respiratory syndrome (SARS) in the first half of 2003 in Canada was unprecedented in several respects. Understanding the psychological impact of the outbreak on healthcare workers, especially those in hospitals, is important in planning for future outbreaks of emerging infectious diseases. This review draws upon qualitative and quantitative studies of the SARS outbreak in Toronto to outline the factors that contributed to healthcare workers' experiencing the outbreak as a psychological trauma. Overall, it is estimated that a high degree of distress was experienced by 29-35% of hospital workers. Three categories of contributory factors were identified. Relevant contextual factors were being a nurse, having contact with SARS patients and having children. Contributing attitudinal factors and processes were experiencing job stress, perceiving stigmatization, coping by avoiding crowds and colleagues, and feeling scrutinized. Pre-existing trait factors also contributed to vulnerability. Lessons learned from the outbreak include: (i) that effort is required to mitigate the psychological impact of infection control procedures, especially the interpersonal isolation that these procedures promote; (ii) that effective risk communication is a priority early in an outbreak; (iii) that healthcare workers may have a role in influencing patterns of media coverage that increase or decrease morale; (iv) that healthcare workers benefit from resources that facilitate reflection on the effects of extraordinary stressors; and (v) that healthcare workers benefit from practical interventions that demonstrate tangible support from institutions.
To establish a predictive scoring system and to determine its effectiveness for severe acute respiratory syndrome (SARS) cases confirmed by RT‐PCR in patients with fever.
A study was conducted of 484 consecutive patients seen in the emergency department (ED) of our tertiary care center during the SARS outbreak in Taiwan. The scoring system was divided into triage and screening station stages. Data were analysed with multivariable and logistic regression analysis.
Of 737 patients who presented to our ED for possible SARS from March to June 2003, we enrolled 484 patients with a temperature >38.0°C (>100.3°F) (age >18 years). Dyspnoea, diarrhoea, travel, close contact, hospital exposure, and household history were identified as predictive indicators in the triage stage. The triage score was the total of six items. With a one‐point cutoff value, the sensitivity and specificity were 81.8% (18/22) and 73.6% (340/462). Leukocytosis, thrombocytopenia, lymphopenia, and CXR were identified as predictive indicators in the fever screening stage. Screening station scores (the sum of 10 items) consisted of triage scores, white blood cell count, and CXR. With a three‐point cutoff value, the sensitivity and specificity were 95.5% (21/22) and 87.2% (403/462).
Syndromic and traditional surveillance play a role in early identification of SARS in an endemic area. The SARS scoring system described is easily applicable and highly effective in screening patients during outbreaks.
SARS; RT‐PCR; scoring system; fever; triage
Healthcare workers accounted for a large proportion of persons with severe acute respiratory syndrome (SARS) during the worldwide epidemic of early 2003. We conducted an investigation of healthcare workers exposed to laboratory-confirmed SARS patients in the United States to evaluate infection-control practices and possible SARS-associated coronavirus (SARS-CoV) transmission. We identified 110 healthcare workers with exposure within droplet range (i.e., 3 feet) to six SARS-CoV–positive patients. Forty-five healthcare workers had exposure without any mask use, 72 had exposure without eye protection, and 40 reported direct skin-to-skin contact. Potential droplet- and aerosol-generating procedures were infrequent: 5% of healthcare workers manipulated a patient’s airway, and 4% administered aerosolized medication. Despite numerous unprotected exposures, there was no serologic evidence of healthcare-related SARS-CoV transmission. Lack of transmission in the United States may be related to the relative absence of high-risk procedures or patients, factors that may place healthcare workers at higher risk for infection.
severe acute respiratory distress syndrome; healthcare workers; nosocomial; transmission
Severe acute respiratory syndrome (SARS) has been transmitted extensively within hospitals, and healthcare workers (HCWs) have comprised a large proportion of SARS cases worldwide. We present a stochastic model of a SARS outbreak in a community and its hospital. For a range of basic reproductive numbers (R(0)) corresponding to conditions in different cities (but with emphasis on R(0) approximately 3 as reported for Hong Kong and Singapore), we evaluate contact precautions and case management (quarantine and isolation) as containment measures. Hospital-based contact precautions emerge as the most potent measures, with hospital-wide measures being particularly important if screening of HCWs is inadequate. For R(0) = 3, case isolation alone can control a SARS outbreak only if isolation reduces transmission by at least a factor of four and the mean symptom-onset-to-isolation time is less than 3 days. Delays of a few days in contact tracing and case identification severely degrade the utility of quarantine and isolation, particularly in high-transmission settings. Still more detrimental are delays between the onset of an outbreak and the implementation of control measures; for given control scenarios, our model identifies windows of opportunity beyond which the efficacy of containment efforts is reduced greatly. By considering pathways of transmission in our system, we show that if hospital-based transmission is not halted, measures that reduce community-HCW contact are vital to preventing a widespread epidemic. The implications of our results for future emerging pathogens are discussed.
The healthcare setting was important in the early spread of severe acute respiratory syndrome (SARS) in both Toronto and Taiwan. Healthcare workers, patients, and visitors were at increased risk for infection. Nonetheless, the ability of individual SARS patients to transmit disease was quite variable. Unrecognized SARS case-patients were a primary source of transmission and early detection and intervention were important to limit spread. Strict adherence to infection control precautions was essential in containing outbreaks. In addition, grouping patients into cohorts and limiting access to SARS patients minimized exposure opportunities. Given the difficulty in implementing several of these measures, controls were frequently adapted to the acuity of SARS care and level of transmission within facilities. Although these conclusions are based only on a retrospective analysis of events, applying the experiences of Toronto and Taiwan to SARS preparedness planning efforts will likely minimize future transmission within healthcare facilities.
severe acute respiratory syndrome; infection control; delivery of healthcare
TOC Summary Line: Healthcare workers in hospitals affected by SARS experience increased psychological stress 1–2 years after the outbreak.
Healthcare workers (HCWs) found the 2003 outbreak of severe acute respiratory syndrome (SARS) to be stressful, but the long-term impact is not known. From 13 to 26 months after the SARS outbreak, 769 HCWs at 9 Toronto hospitals that treated SARS patients and 4 Hamilton hospitals that did not treat SARS patients completed a survey of several adverse outcomes. Toronto HCWs reported significantly higher levels of burnout (p = 0.019), psychological distress (p<0.001), and posttraumatic stress (p<0.001). Toronto workers were more likely to have reduced patient contact and work hours and to report behavioral consequences of stress. Variance in adverse outcomes was explained by a protective effect of the perceived adequacy of training and support and by a provocative effect of maladaptive coping style and other individual factors. The results reinforce the value of effective staff support and training in preparation for future outbreaks.
Severe Acute Respiratory Syndrome; Stress, Psychological; Health Personnel; Stress, Traumatic; Burnout, Professional, research
Quarantine for SARS during the 2003 Taiwan outbreak expedited case detection, thereby indirectly preventing infections.
During the 2003 outbreak of severe acute respiratory syndrome (SARS) in Taiwan, >150,000 persons were quarantined, 24 of whom were later found to have laboratory-confirmed SARS-coronavirus (SARS-CoV) infection. Since no evidence exists that SARS-CoV is infective before the onset of symptoms and the quarantined persons were exposed but not symptomatic, we thought the quarantine's effectiveness should be investigated. Using the Taiwan quarantine data, we found that the onset-to-diagnosis time of previously quarantined confirmed case-patients was significantly shortened compared to that for those who had not been quarantined. Thus, quarantine for SARS in Taiwan screened potentially infective persons for swift diagnosis and hospitalization after onset, thereby indirectly reducing infections. Full-scale quarantine measures implemented on April 28 led to a significant improvement in onset-to-diagnosis time of all SARS patients, regardless of previous quarantine status. We discuss the temporal effects of quarantine measures and other interventions on detection and isolation as well as the potential usefulness of quarantine in faster identification of persons with SARS and in improving isolation measures.
SARS; emerging infectious disease; quarantine; intervention; Taiwan; research
Objective To describe an outbreak of severe acute respiratory syndrome (SARS) in a tertiary hospital in Singapore, linked to an index patient with atypical presentation, and the lessons learnt from it.
Design Descriptive study.
Setting A tertiary hospital in Singapore.
Participants Patients, healthcare workers, and visitors who contracted SARS in Singapore General Hospital.
Main outcome measures Probable SARS as defined by the World Health Organization.
Results The index patient presented with gastrointestinal bleeding, initially without changes to his chest radiograph. Altogether 24 healthcare workers, 15 patients, and 12 family members and visitors were infected. The incubation period ranged from three to eight days. Only 13 patients were isolated on their dates of onset.
Conclusions Atypical presentation of SARS infection must be taken into consideration when managing patients with a history of contact with SARS patients. The main gap in the containment strategy in this outbreak was the failure to identify the index patient as someone who had been discharged from a ward in another hospital that managed probable SARS cases. Strict infection control measures, a good surveillance system, early introduction of isolation procedures, and vigilant healthcare professionals are essential for controlling outbreaks.
Most cases of severe acute respiratory syndrome (SARS) have occurred in close contacts of SARS patients. However, in Beijing, a large proportion of SARS cases occurred in persons without such contact. We conducted a case-control study in Beijing that compared exposures of 94 unlinked, probable SARS patients with those of 281 community-based controls matched for age group and sex. Case-patients were more likely than controls to have chronic medical conditions or to have visited fever clinics (clinics at which possible SARS patients were separated from other patients), eaten outside the home, or taken taxis frequently. The use of masks was strongly protective. Among 31 case-patients for whom convalescent-phase (>21 days) sera were available, 26% had immunoglobulin G to SARS-associated coronavirus. Our finding that clinical SARS was associated with visits to fever clinics supports Beijing’s strategy of closing clinics with poor infection-control measures. Our finding that mask use lowered the risk for disease supports the community’s use of this strategy.
SARS virus; case-control studies; risk factor; China; mask; disease transmission; disease outbreaks
To determine factors that predispose or protect healthcare workers from severe acute respiratory syndrome (SARS), we conducted a retrospective cohort study among 43 nurses who worked in two Toronto critical care units with SARS patients. Eight of 32 nurses who entered a SARS patient’s room were infected. The probability of SARS infection was 6% per shift worked. Assisting during intubation, suctioning before intubation, and manipulating the oxygen mask were high-risk activities. Consistently wearing a mask (either surgical or particulate respirator type N95) while caring for a SARS patient was protective for the nurses, and consistent use of the N95 mask was more protective than not wearing a mask. Risk was reduced by consistent use of a surgical mask, but not significantly. Risk was lower with consistent use of a N95 mask than with consistent use of a surgical mask. We conclude that activities related to intubation increase SARS risk and use of a mask (particularly a N95 mask) is protective.
SARS; severe acute respiratory syndrome; critical care; risk factors; respiratory protective devices; masks; intubation; nursing; infection control
We describe a patient with severe acute respiratory syndrome (SARS) whose clinical symptoms were masked by Escherichia coli bacteremia. SARS developed in a cluster of healthcare workers who had contact with this patient. SARS was diagnosed when a chest infiltrate developed and when the patient’s brother was hospitalized with acute respiratory failure. We highlight problems in atypical cases and offer infection control suggestions.
atypical severe acute respiratory syndrome; SARS; dispatch
Superspreading events were pivotal in the global spread of severe acute respiratory syndrome (SARS). We investigated superspreading in one transmission chain early in Beijing’s epidemic. Superspreading was defined as transmission of SARS to at least eight contacts. An index patient with onset of SARS 2 months after hospital admission was the source of four generations of transmission to 76 case-patients, including 12 healthcare workers and several hospital visitors. Four (5%) case circumstances met the superspreading definition. Superspreading appeared to be associated with older age (mean 56 vs. 44 years), case fatality (75% vs. 16%, p = 0.02, Fisher exact test), number of close contacts (36 vs. 0.37) and attack rate among close contacts (43% vs. 18.5%, p < 0.025). Delayed recognition of SARS in a hospitalized patient permitted transmission to patients, visitors, and healthcare workers. Older age and number of contacts merit investigation in future studies of superspreading.
SARS virus; disease outbreaks; nosocomial infection; disease transmission; risk factors; epidemiology; contact tracing
Objectives To determine the clinical and radiological features of
severe acute respiratory syndrome (SARS) and to evaluate the accuracy of the
World Health Organization's guidelines on defining cases of SARS.
Design Prospective observational study.
Setting A newly set up SARS screening clinic in the emergency
department of a university hospital in Hong Kong's New Territories.
Participants 556 hospital staff, patients, and relatives who
attended the screening clinic and who had had contact with someone with
Main outcome measure Number of confirmed cases of SARS.
Results Of the 556 people, 141 were admitted to hospital, and 97 had
confirmed SARS. Fever, chills, malaise, myalgia, rigor, loss of appetite,
vomiting, diarrhoea, and neck pain but not respiratory tract symptoms were
significantly more common among the 97 patients than among the other patients.
The overall accuracy of the WHO guidelines for identifying suspected SARS was
83% and their negative predictive value was 86% (95% confidence interval 83%
to 89%). They had a sensitivity of 26% (17% to 36%) and a specificity of 96%
(93% to 97%).
Conclusions Current WHO guidelines for diagnosing suspected SARS may
not be sufficiently sensitive in assessing patients before admission to
hospital. Daily follow up, evaluation of non-respiratory, systemic symptoms,
and chest radiography would be better screening tools.
Severe acute respiratory syndrome (SARS) caused the first epidemic of the 21st century and continues to threaten the global community.
To assess the incidence of coinfection in patients confirmed to have SARS-associated coronavirus (SARS-CoV) infection, and thus, to determine the risk of ruling out SARS by ruling in another diagnosis.
The present report is a retrospective study evaluating the incidence and impact of laboratory-confirmed SARS-CoV and other pulmonary pathogens in 117 patients. These patients were evaluated in a Toronto, Ontario, community hospital identified as the epicentre for the second SARS outbreak.
Coinfection with other pulmonary pathogens occured in patients with SARS. Seventy-three per cent of the patient population evaluated had laboratory-confirmed SARS-CoV infection. Serology showing acute or recent Chlamydophila pneumoniae or Mycoplasma pneumoniae infection revealed an incidence of 30% and 9%, respectively, in those with SARS. These rates are similar to previously published studies on coinfection in pneumonia. All nucleic acid diagnostic assays were negative for C pneumoniae and M pneumoniae in respiratory samples from patients with SARS having serological evidence for these atypical pathogens.
Diagnostic assays for well-recognized pulmonary pathogens have limitations, and ruling out SARS-CoV by ruling in another pulmonary pathogen carries significant risk. Despite positive serology for atypical pathogens, in a setting where clinical suspicion for SARS is high, specific tests for SARS should be performed to confirm or exclude a diagnosis.
Coinfection; Coronavirus; Epidemic; Pneumonia; SARS
In the 2003 Toronto SARS outbreak, SARS-CoV was transmitted in hospitals despite adherence to infection control procedures. Considerable controversy resulted regarding which procedures and behaviours were associated with the greatest risk of SARS-CoV transmission.
A retrospective cohort study was conducted to identify risk factors for transmission of SARS-CoV during intubation from laboratory confirmed SARS patients to HCWs involved in their care. All SARS patients requiring intubation during the Toronto outbreak were identified. All HCWs who provided care to intubated SARS patients during treatment or transportation and who entered a patient room or had direct patient contact from 24 hours before to 4 hours after intubation were eligible for this study. Data was collected on patients by chart review and on HCWs by interviewer-administered questionnaire. Generalized estimating equation (GEE) logistic regression models and classification and regression trees (CART) were used to identify risk factors for SARS transmission.
45 laboratory-confirmed intubated SARS patients were identified. Of the 697 HCWs involved in their care, 624 (90%) participated in the study. SARS-CoV was transmitted to 26 HCWs from 7 patients; 21 HCWs were infected by 3 patients. In multivariate GEE logistic regression models, presence in the room during fiberoptic intubation (OR = 2.79, p = .004) or ECG (OR = 3.52, p = .002), unprotected eye contact with secretions (OR = 7.34, p = .001), patient APACHE II score ≥20 (OR = 17.05, p = .009) and patient Pa02/Fi02 ratio ≤59 (OR = 8.65, p = .001) were associated with increased risk of transmission of SARS-CoV. In CART analyses, the four covariates which explained the greatest amount of variation in SARS-CoV transmission were covariates representing individual patients.
Close contact with the airway of severely ill patients and failure of infection control practices to prevent exposure to respiratory secretions were associated with transmission of SARS-CoV. Rates of transmission of SARS-CoV varied widely among patients.
Severe acute respiratory syndrome (SARS) emerged as a new disease in Guangdong Province, People's Republic of China in late 2002. Within weeks it had spread to Hong Kong and thence globally to affect over 25 countries across five continents. The disease had the propensity to cause clusters of pneumonia, particularly in healthcare workers or close family contacts. A global effort coordinated by the World Health Organization successfully defined the aetiology, epidemiology and clinical characteristics of the disease, and the implementation of case identification, isolation and infection control measures led to the interruption of the global outbreak by July 2003. The pattern of disease emergence and strategies for control of SARS provides lessons for coping with future emerging infectious disease threats.
An outbreak of severe acute respiratory syndrome (SARS) was detected in Singapore at the beginning of March 2003. The outbreak, initiated by a traveler to Hong Kong in late February 2003, led to sequential spread of SARS to three major acute care hospitals in Singapore. The critical factor in containing this outbreak was early detection and complete assessment of movements and follow-up of patients, healthcare workers, and visitors who were contacts. Visitor records were important in helping identify exposed persons who could carry the infection into the community. In the three hospital outbreaks, three different containment strategies were used to contain spread of infection: closing an entire hospital, removing all potentially infected persons to a dedicated SARS hospital, and managing exposed persons in place. On the basis of this experience, if a nosocomial outbreak is detected late, a hospital may need to be closed in order to contain spread of the disease. Outbreaks detected early can be managed by either removing all exposed persons to a designated location or isolating and managing them in place.
coronavirus; cross infections; hospital; infection control; nosocomial infections; severe acute respiratory syndrome; Singapore
The outbreak of severe acute respiratory syndrome (SARS) caused a severe global epidemic in 2003 which led to hundreds of deaths and many thousands of hospitalizations. The virus causing SARS was identified as a novel coronavirus (SARS-CoV) and multiple genomic sequences have been revealed since mid-April, 2003. After a quiet summer and fall in 2003, the newly emerged SARS cases in Asia, particularly the latest cases in China, are reinforcing a wide-spread belief that the SARS epidemic would strike back. With the understanding that SARS-CoV might be with humans for years to come, knowledge of the evolutionary mechanism of the SARS-CoV, including its mutation rate and emergence time, is fundamental to battle this deadly pathogen. To date, the speed at which the deadly virus evolved in nature and the elapsed time before it was transmitted to humans remains poorly understood.
Sixteen complete genomic sequences with available clinical histories during the SARS outbreak were analyzed. After careful examination of multiple-sequence alignment, 114 single nucleotide variations were identified. To minimize the effects of sequencing errors and additional mutations during the cell culture, three strategies were applied to estimate the mutation rate by 1) using the closely related sequences as background controls; 2) adjusting the divergence time for cell culture; or 3) using the common variants only. The mutation rate in the SARS-CoV genome was estimated to be 0.80 – 2.38 × 10-3 nucleotide substitution per site per year which is in the same order of magnitude as other RNA viruses. The non-synonymous and synonymous substitution rates were estimated to be 1.16 – 3.30 × 10-3 and 1.67 – 4.67 × 10-3 per site per year, respectively. The most recent common ancestor of the 16 sequences was inferred to be present as early as the spring of 2002.
The estimated mutation rates in the SARS-CoV using multiple strategies were not unusual among coronaviruses and moderate compared to those in other RNA viruses. All estimates of mutation rates led to the inference that the SARS-CoV could have been with humans in the spring of 2002 without causing a severe epidemic.