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1.  Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS) in Toronto, Canada 
Severe acute respiratory syndrome (SARS) was introduced into Canada by a visitor to Hong Kong who returned to Toronto on Feb. 23, 2003. Transmission to a family member who was later admitted to a community hospital in Toronto led to a large nosocomial outbreak. In this report we summarize the preliminary results of the epidemiological investigation into the transmission of SARS between 128 cases associated with this hospital outbreak.
We collected epidemiologic data on 128 probable and suspect cases of SARS associated with the hospital outbreak, including those who became infected in hospital and the next generation of illness arising among their contacts. Incubation periods were calculated based on cases with a single known exposure. Transmission chains from the index family to hospital contacts and within the hospital were mapped. Attack rates were calculated for nurses in 3 hospital wards where transmission occurred.
The cases ranged in age from 21 months to 86 years; 60.2% were female. Seventeen deaths were reported (case-fatality rate 13.3%). Of the identified cases, 36.7% were hospital staff. Other cases were household or social contacts of SARS cases (29.6%), hospital patients (14.1%), visitors (14.1%) or other health care workers (5.5%). Of the 128 cases, 120 (93.8%) had documented contact with a SARS case or with a ward where there was a known SARS case. The remaining 8 cases without documented exposure are believed to have had exposure to an unidentified case and remain under investigation. The attack rates among nurses who worked in the emergency department, intensive care unit and coronary care unit ranged from 10.3% to 60.0%. Based on 42 of the 128 cases with a single known contact with a SARS case, the mean incubation period was 5 days (range 2 to 10 days).
Evidence to date suggests that SARS is a severe respiratory illness spread mainly by respiratory droplets. There has been no evidence of further transmission within the hospital after the elapse of 2 full incubation periods (20 days).
PMCID: PMC180651  PMID: 12925421
2.  From SARS coronavirus to novel animal and human coronaviruses 
Journal of Thoracic Disease  2013;5(Suppl 2):S103-S108.
In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) caused one of the most devastating epidemics known to the developed world. There were two important lessons from this epidemic. Firstly, coronaviruses, in addition to influenza viruses, can cause severe and rapidly spreading human infections. Secondly, bats can serve as the origin and natural animal reservoir of deadly human viruses. Since then, researchers around the world, especially those in Asia where SARS-CoV was first identified, have turned their focus to find novel coronaviruses infecting humans, bats, and other animals. Two human coronaviruses, HCoV-HKU1 and HCoV-NL63, were identified shortly after the SARS-CoV epidemic as common causes of human respiratory tract infections. In 2012, a novel human coronavirus, now called Middle East respiratory syndrome coronavirus (MERS-CoV), has emerged in the Middle East to cause fatal human infections in three continents. MERS-CoV human infection is similar to SARS-CoV in having a high fatality rate and the ability to spread from person to person which resulted in secondary cases among close contacts including healthcare workers without travel history to the Middle East. Both viruses also have close relationships with bat coronaviruses. New cases of MERS-CoV infection in humans continue to occur with the origins of the virus still unknown in many cases. A multifaceted approach is necessary to control this evolving MERS-CoV outbreak. Source identification requires detailed epidemiological studies of the infected patients and enhanced surveillance of MERS-CoV or similar coronaviruses in humans and animals. Early diagnosis of infected patients and appropriate infection control measures will limit the spread in hospitals, while social distancing strategies may be necessary to control the outbreak in communities if it remained uncontrolled as in the SARS epidemic.
PMCID: PMC3747523  PMID: 23977429
Severe acute respiratory syndrome coronavirus (SARS-CoV); novel coronaviruses; Middle East respiratory syndrome coronavirus (MERS-CoV)
3.  Epidemiological and Genetic Correlates of Severe Acute Respiratory Syndrome Coronavirus Infection in the Hospital with the Highest Nosocomial Infection Rate in Taiwan in 2003†  
Journal of Clinical Microbiology  2006;44(2):359-365.
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).
PMCID: PMC1392693  PMID: 16455884
4.  Factors associated with nosocomial SARS-CoV transmission among healthcare workers in Hanoi, Vietnam, 2003 
BMC Public Health  2006;6:207.
In March of 2003, an outbreak of Severe Acute Respiratory Syndrome (SARS) occurred in Northern Vietnam. This outbreak began when a traveler arriving from Hong Kong sought medical care at a small hospital (Hospital A) in Hanoi, initiating a serious and substantial transmission event within the hospital, and subsequent limited spread within the community.
We surveyed Hospital A personnel for exposure to the index patient and for symptoms of disease during the outbreak. Additionally, serum specimens were collected and assayed for antibody to SARS-associated coronavirus (SARS-CoV) antibody and job-specific attack rates were calculated. A nested case-control analysis was performed to assess risk factors for acquiring SARS-CoV infection.
One hundred and fifty-three of 193 (79.3%) clinical and non-clinical staff consented to participate. Excluding job categories with <3 workers, the highest SARS attack rates occurred among nurses who worked in the outpatient and inpatient general wards (57.1, 47.4%, respectively). Nurses assigned to the operating room/intensive care unit, experienced the lowest attack rates (7.1%) among all clinical staff. Serologic evidence of SARS-CoV infection was detected in 4 individuals, including 2 non-clinical workers, who had not previously been identified as SARS cases; none reported having had fever or cough. Entering the index patient's room and having seen (viewed) the patient were the behaviors associated with highest risk for infection by univariate analysis (odds ratios 20.0, 14.0; 95% confidence intervals 4.1–97.1, 3.6–55.3, respectively).
This study highlights job categories and activities associated with increased risk for SARS-CoV infection and demonstrates that a broad diversity of hospital workers may be vulnerable during an outbreak. These findings may help guide recommendations for the protection of vulnerable occupational groups and may have implications for other respiratory infections such as influenza.
PMCID: PMC1562405  PMID: 16907978
5.  Human Monoclonal Antibody Combination against SARS Coronavirus: Synergy and Coverage of Escape Mutants 
PLoS Medicine  2006;3(7):e237.
Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties.
Methods and Findings
Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318–510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one.
The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection.
Editors' Summary
Late in 2002, severe acute respiratory syndrome (SARS) emerged in the Guangdong province of China. In February 2003, an infected doctor from the province carried this new viral threat to human health to Hong Kong. Here, people staying in the same hotel caught the disease and took it to other countries. SARS was on the move, hitching lifts with international travellers. Because the virus responsible for SARS—SARS-CoV—spread by close person-to-person contact and killed 10% of the people it infected, health experts feared a world-wide epidemic. This was avoided by the World Health Organization issuing a global alert and warning against unnecessary travel to affected areas and by public-health officials isolating patients and their close contacts. By July 2003, the first SARS epidemic was over. 8,098 people had been infected; 774 people had died. Since then, sporadic cases of SARS have been contained locally.
Why Was This Study Done?
The first epidemic of SARS was caused by an animal virus that became adapted to spread between people. There is no reason this process won't be repeated. If it is, stringent quarantine measures could again prevent a global epidemic, but at considerable economic cost. What is needed is a way to prevent SARS developing in healthy people who have been exposed to SARS-CoV and to treat sick people so that they are less infectious and can fight the virus. In this study, researchers have been investigating “passive immunization” as a way to limit SARS epidemics. In passive immunization, short-term protection against illness is achieved by injecting antibodies—proteins that recognize specific molecules (called antigens) on foreign organisms such as bacteria and viruses and prevent those organisms from causing disease. Antibodies for passive immunization can be isolated from blood taken from people who have had SARS, or they can be manufactured as so-called “human monoclonal antibodies” in a laboratory. One of these human monoclonal antibodies—CR3014—had been previously made and shown to prevent lung damage in ferrets infected with SARS-CoV and to stop the infected animals from infecting others. But for effective disease prevention in people, a single monoclonal antibody might not be enough. There are strains of SARS-CoV that CR3014 does not recognize and therefore cannot act against. Also, the virus can alter the antigen recognized by CR3014 when it is grown at a low antibody concentration, producing so-called escape variants; if this happens CR3014 can no longer prevent these escape variants from killing human cells.
What Did the Researchers Do and Find?
The researchers tested how well a combination of two monoclonal antibodies controlled SARS-CoV killing of human cells. First, they showed that CR3014 escape variants all had the same small change in a part of the virus surface that interacts with human cells. CR3014 blocked this interaction in the parent SARS-CoV strain but not in the escape variants. They then made a new monoclonal antibody—CR3022—that prevented both the parent SARS-CoV stain and the CR3014 escape viruses from killing human cells. The two antibodies bound to neighboring parts of the virus surface, and both of them could bind at the same time. CR3022 also bound to surfaces of SARS-CoV strains to which CR3014 does not bind. And when they tried, the researchers could not generate any viral escape variants to which CR3022 was unable to bind. Finally, the effect of the two antibodies together on inhibition of SARS-CoV killing of human cells was more than the sum of their individual effects.
What Do These Findings Mean?
A combination of two (or more) human monoclonal antibodies that recognize different parts of the SARS-CoV surface that interacts with human cells might be a good way to immunize people passively against SARS-CoV. It might minimize the possibility of escape variants arising, broaden the range of virus strains against which protection is provided, and reduce the amount of antibody needed for effective protection. Before the approach is tried in people, it will have to be tested in animals—results from experiments done on human cells in dishes are not always replicated in whole animals or people. If the approach passes further tests, the hope is that passive immunization of people with SARS and their close contacts might reduce disease severity in infected people and reduce viral spread as effectively as dramatic quarantine measures
Additional Information.
Please access these websites via the online version of this summary at
• Medline Plus pages on SARS
• US Centers for Disease Control and Prevention information on SARS
• US National Institute of Allergy and Infectious Diseases factsheet about research on SARS
• Wikipedia page on SARS and monoclonal antibodies (note: Wikipedia is a free online encyclopedia that anyone can edit)
Two human monoclonal antibodies that bind to different parts of the viral glycoprotein spike show synergistic effects in virus neutralization and suppress the emergence of resistant virus in vitro.
PMCID: PMC1483912  PMID: 16796401
6.  Vaccine Efficacy in Senescent Mice Challenged with Recombinant SARS-CoV Bearing Epidemic and Zoonotic Spike Variants  
PLoS Medicine  2006;3(12):e525.
In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) was identified as the etiological agent of severe acute respiratory syndrome, a disease characterized by severe pneumonia that sometimes results in death. SARS-CoV is a zoonotic virus that crossed the species barrier, most likely originating from bats or from other species including civets, raccoon dogs, domestic cats, swine, and rodents. A SARS-CoV vaccine should confer long-term protection, especially in vulnerable senescent populations, against both the 2003 epidemic strains and zoonotic strains that may yet emerge from animal reservoirs. We report the comprehensive investigation of SARS vaccine efficacy in young and senescent mice following homologous and heterologous challenge.
Methods and Findings
Using Venezuelan equine encephalitis virus replicon particles (VRP) expressing the 2003 epidemic Urbani SARS-CoV strain spike (S) glycoprotein (VRP-S) or the nucleocapsid (N) protein from the same strain (VRP-N), we demonstrate that VRP-S, but not VRP-N vaccines provide complete short- and long-term protection against homologous strain challenge in young and senescent mice. To test VRP vaccine efficacy against a heterologous SARS-CoV, we used phylogenetic analyses, synthetic biology, and reverse genetics to construct a chimeric virus (icGDO3-S) encoding a synthetic S glycoprotein gene of the most genetically divergent human strain, GDO3, which clusters among the zoonotic SARS-CoV. icGD03-S replicated efficiently in human airway epithelial cells and in the lungs of young and senescent mice, and was highly resistant to neutralization with antisera directed against the Urbani strain. Although VRP-S vaccines provided complete short-term protection against heterologous icGD03-S challenge in young mice, only limited protection was seen in vaccinated senescent animals. VRP-N vaccines not only failed to protect from homologous or heterologous challenge, but resulted in enhanced immunopathology with eosinophilic infiltrates within the lungs of SARS-CoV–challenged mice. VRP-N–induced pathology presented at day 4, peaked around day 7, and persisted through day 14, and was likely mediated by cellular immune responses.
This study identifies gaps and challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations. The availability of a SARS-CoV virus bearing heterologous S glycoproteins provides a robust challenge inoculum for evaluating vaccine efficacy against zoonotic strains, the most likely source of future outbreaks.
Experiments in mice suggest challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations.
Editors' Summary
Severe acute respiratory syndrome (SARS) is a flu-like illness and was first recognized in China in 2002, after which the disease rapidly spread around the world. SARS was associated with high death rates, much higher than those for flu. Around 10% of people recognized as being infected with SARS died, and the death rate approached 50% among elderly people. The virus causing SARS was identified as a member of the coronavirus family; it is generally thought that this virus “jumped” to humans from bats, which harbor related viruses. Although SARS was declared eradicated by the World Health Organization in May 2005, there is still the possibility that similar viruses will again cross the species barrier and infect humans, with potentially serious consequences. As a result, many groups are working to develop vaccines that will protect against SARS infection.
Why Was This Study Done?
A SARS vaccine should be effective in people of all ages, including the elderly who are more likely to get seriously ill or die if they become infected. In addition, potential vaccines should protect against different variants of the virus, because there are different types of the virus that could potentially cross the species barrier from animals to humans. Of the different proteins that make up the SARS coronavirus, the spike glycoprotein is thought to elicit an immune response in humans that can protect against future infection. The researchers therefore examined vaccine candidates based on this particular protein (termed SARS-CoV S), as well as a second one called SARS-CoV N, in mice. Specifically, they tested whether the vaccines would protect against SARS infection in both young and older mice, and whether they would protect against infection by different strains of the SARS virus.
What Did the Researchers Do and Find?
The researchers created vaccines based on SARS-CoV S and SARS-CoV N by taking the genes coding for those proteins and inserting them into another type of virus particle that acted as a delivery vehicle. They injected mice with these vaccines and then tested whether the mice generated an immune response against the specific SARS proteins, which they did. The next step was to work out whether mice injected with the vaccines would be protected against later infection with SARS-CoV. The researchers found that mice injected with vaccine based on SARS-CoV S were protected against later infection with a standard SARS-CoV strain, both in the short term (eight weeks after vaccination) and the long term (54 weeks after vaccination). However, the vaccine based on SARS-CoV N did not seem to result in protection, and, worryingly, caused pathological changes in the lungs of mice following virus challenge. To find out if their candidate vaccines would protect against different strains of SARS, the researchers made a synthetic test virus that contained a mixture of genetic material from different natural variants of the virus. This test virus was used to “challenge” mice that had been immunized with the two different vaccines. The researchers found that the vaccine based on SARS-CoV S protected against infection by the test virus when mice were vaccinated young, but it failed to efficiently protect when administered to older mice.
What Do These Findings Mean?
The findings confirm others suggesting that vaccines based on the SARS-CoV S protein are more effective than those based on SARS-CoV N. They also suggest that the former can provide long-term protection in animals vaccinated young against closely related viruses. However, protection against more distantly related viruses remains a challenge, especially when vaccinating older animals. The differences seen between young and older mice suggest that older mice might provide a useful model for animal testing of candidate vaccines for diseases like SARS, flu, and West Nile virus that pose a particular threat to elderly people. Overall, these results provide useful lessons toward future SARS vaccine development in animals. The synthetic virus strain generated here, and others like it, are likely to be useful tools for such future studies.
Additional Information.
Please access these Web sites via the online version of this summary at
• The World Health Organization provides guidance, archives, and other information resources on SARS
• Information from the US Centers for Disease Control on SARS
• Wikipedia (an internet encyclopedia anyone can edit) has an entry on SARS
• Collected resources from MedLinePlus about SARS
PMCID: PMC1716185  PMID: 17194199
7.  SARS Surveillance during Emergency Public Health Response, United States, March–July 2003 
Emerging Infectious Diseases  2004;10(2):185-194.
In response to the emergence of severe acute respiratory syndrome (SARS), the United States established national surveillance using a sensitive case definition incorporating clinical, epidemiologic, and laboratory criteria. Of 1,460 unexplained respiratory illnesses reported by state and local health departments to the Centers for Disease Control and Prevention from March 17 to July 30, 2003, a total of 398 (27%) met clinical and epidemiologic SARS case criteria. Of these, 72 (18%) were probable cases with radiographic evidence of pneumonia. Eight (2%) were laboratory-confirmed SARS-coronavirus (SARS-CoV) infections, 206 (52%) were SARS-CoV negative, and 184 (46%) had undetermined SARS-CoV status because of missing convalescent-phase serum specimens. Thirty-one percent (124/398) of case-patients were hospitalized; none died. Travel was the most common epidemiologic link (329/398, 83%), and mainland China was the affected area most commonly visited. One case of possible household transmission was reported, and no laboratory-confirmed infections occurred among healthcare workers. Successes and limitations of this emergency surveillance can guide preparations for future outbreaks of SARS or respiratory diseases of unknown etiology.
PMCID: PMC3322912  PMID: 15030681
severe acute respiratory syndrome; United States; surveillance; incidence; SARS virus; Coronaviridae; pneumonia; travel; respiratory tract infections
8.  Association of HLA class I with severe acute respiratory syndrome coronavirus infection 
The human leukocyte antigen (HLA) system is widely used as a strategy in the search for the etiology of infectious diseases and autoimmune disorders. During the Taiwan epidemic of severe acute respiratory syndrome (SARS), many health care workers were infected. In an effort to establish a screening program for high risk personal, the distribution of HLA class I and II alleles in case and control groups was examined for the presence of an association to a genetic susceptibly or resistance to SARS coronavirus infection.
HLA-class I and II allele typing by PCR-SSOP was performed on 37 cases of probable SARS, 28 fever patients excluded later as probable SARS, and 101 non-infected health care workers who were exposed or possibly exposed to SARS coronavirus. An additional control set of 190 normal healthy unrelated Taiwanese was also used in the analysis.
Woolf and Haldane Odds ratio (OR) and corrected P-value (Pc) obtained from two tails Fisher exact test were used to show susceptibility of HLA class I or class II alleles with coronavirus infection. At first, when analyzing infected SARS patients and high risk health care workers groups, HLA-B*4601 (OR = 2.08, P = 0.04, Pc = n.s.) and HLA-B*5401 (OR = 5.44, P = 0.02, Pc = n.s.) appeared as the most probable elements that may be favoring SARS coronavirus infection. After selecting only a "severe cases" patient group from the infected "probable SARS" patient group and comparing them with the high risk health care workers group, the severity of SARS was shown to be significantly associated with HLA-B*4601 (P = 0.0008 or Pc = 0.0279).
Densely populated regions with genetically related southern Asian populations appear to be more affected by the spreading of SARS infection. Up until recently, no probable SARS patients were reported among Taiwan indigenous peoples who are genetically distinct from the Taiwanese general population, have no HLA-B* 4601 and have high frequency of HLA-B* 1301. While increase of HLA-B* 4601 allele frequency was observed in the "Probable SARS infected" patient group, a further significant increase of the allele was seen in the "Severe cases" patient group. These results appeared to indicate association of HLA-B* 4601 with the severity of SARS infection in Asian populations. Independent studies are needed to test these results.
PMCID: PMC212558  PMID: 12969506
9.  Temporal Variability and Social Heterogeneity in Disease Transmission: The Case of SARS in Hong Kong 
PLoS Computational Biology  2009;5(8):e1000471.
The extent to which self-adopted or intervention-related changes in behaviors affect the course of epidemics remains a key issue for outbreak control. This study attempted to quantify the effect of such changes on the risk of infection in different settings, i.e., the community and hospitals. The 2002–2003 severe acute respiratory syndrome (SARS) outbreak in Hong Kong, where 27% of cases were healthcare workers, was used as an example. A stochastic compartmental SEIR (susceptible-exposed-infectious-removed) model was used: the population was split into healthcare workers, hospitalized people and general population. Super spreading events (SSEs) were taken into account in the model. The temporal evolutions of the daily effective contact rates in the community and hospitals were modeled with smooth functions. Data augmentation techniques and Markov chain Monte Carlo (MCMC) methods were applied to estimate SARS epidemiological parameters. In particular, estimates of daily reproduction numbers were provided for each subpopulation. The average duration of the SARS infectious period was estimated to be 9.3 days (±0.3 days). The model was able to disentangle the impact of the two SSEs from background transmission rates. The effective contact rates, which were estimated on a daily basis, decreased with time, reaching zero inside hospitals. This observation suggests that public health measures and possible changes in individual behaviors effectively reduced transmission, especially in hospitals. The temporal patterns of reproduction numbers were similar for healthcare workers and the general population, indicating that on average, an infectious healthcare worker did not infect more people than any other infectious person. We provide a general method to estimate time dependence of parameters in structured epidemic models, which enables investigation of the impact of control measures and behavioral changes in different settings.
Author Summary
Recent epidemics have shown that healthcare workers may be overrepresented among cases and how critical it is to protect them. For example, during the 2002–2003 severe acute respiratory syndrome (SARS) epidemics in Hong Kong, 27%of cases were healthcare workers when they were <1% of the population. Better means of protection require understanding how healthcare workers were infected and assessing their role in disease transmission. Here, we describe a method for estimating the temporal profile of the risk of infection and probability of transmission in the community and hospitals. The 2002–2003 SARS outbreak in Hong Kong is used as an example. For the SARS epidemic, we show that the risk of infection in the community and hospitals decreased with time down to zero in hospitals but remained larger in the community. This observation suggests that public health measures and behavioural changes most effectively reduced transmission in hospitals. Besides, we find that the large number of cases observed among healthcare workers is more likely a result of large and sustained exposure to hospitalized cases than to transmission among healthcare workers. These results are of interest to design control measures in the event of an influenza pandemic.
PMCID: PMC2717369  PMID: 19696879
10.  Possible SARS Coronavirus Transmission during Cardiopulmonary Resuscitation 
Emerging Infectious Diseases  2004;10(2):287-293.
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.
PMCID: PMC3322904  PMID: 15030699
SARS virus; resuscitation; occupational health; infection control; transmission; healthcare worker
11.  Appropriate use of personal protective equipment among healthcare workers in public sector hospitals and primary healthcare polyclinics during the SARS outbreak in Singapore 
Chia, S | Koh, D | Fones, C | Qian, F | Ng, V | Tan, B | Wong, K | Chew, W | Tang, H | Ng, W | Muttakin, Z | Emmanuel, S | Fong, N | Koh, G | Lim, M
Background: Singapore was affected by an outbreak of severe acute respiratory syndrome (SARS) from 25 February to 31 May 2003, with 238 probable cases and 33 deaths.
Aims: To study usage of personal protective equipment (PPE) among three groups of healthcare workers (HCWs: doctors, nurses, and administrative staff), to determine if the appropriate PPE were used by the different groups and to examine the factors that may determine inappropriate use.
Methods: A self-administered questionnaire survey of 14 554 HCWs in nine healthcare settings, which included tertiary care hospitals, community hospitals, and polyclinics, was carried out in May–July 2003. Only doctors, nurses, and clerical staff were selected for subsequent analysis.
Results: A total of 10 236 valid questionnaires were returned (70.3% response); 873 doctors, 4404 nurses, and 921 clerical staff were studied. A total of 32.5% of doctors, 48.7% of nurses, and 77.1% of the administrative staff agreed that paper and/or surgical masks were "useful in protecting from contracting SARS". Among this group, 23.6% of doctors and 42.3% of nurses reported working with SARS patients. The view that a paper and/or surgical mask was adequate protection against SARS was held by 33.3% of doctors and 55.9% of nurses working at the A&E unit, 30.5% of doctors and 49.4% of nurses from medical wards, and 27.5% of doctors and 37.1% of nurses from intensive care units. Factors which predicted for agreement that paper and/or surgical masks were protective against SARS, included HCW's job title, reported contact with SARS patients, area of work, and Impact Events Scale scores.
Conclusion: A variety of factors determine appropriate use of personal protective equipment by HCWs in the face of a major SARS outbreak.
PMCID: PMC1741057  PMID: 15961624
12.  Impact of an outbreak of severe acute respiratory syndrome on a hospital in Taiwan, ROC 
Emergency Medicine Journal : EMJ  2004;21(3):311-316.
Study objective: To estimate the impact of the severe acute respiratory syndrome (SARS) outbreak in early 2003 on a tertiary care hospital in Taiwan, ROC.
Methods: The study estimated the utilisation of resources related to infection control, SARS related medical services, and routine medical services, and SARS related medical outcomes at National Cheng Kung University Hospital (NCKUH) from 25 March to 16 June 2003 through a cross sectional survey of hospital records.
Results: A mean of 5100 persons per day (95%CI 4580 to 5610) underwent fever screening at the outpatient and emergency department (ED) entrances to the hospital, of which 35 per day (95% CI 30 to 40) were referred for further evaluation for suspected or probable SARS. ED isolation surge capacity was created via 12 new beds outside the ED: eight for SARS assessment, three for patients awaiting inhospital bed assignment, and one for resuscitation. A total of 382 patients were fully evaluated for suspected or probable SARS outside the ED, of which 27 were admitted. The mean numbers of outpatient clinic patient visits, ED visits, ED trauma patient visits, ED admissions, hospital admissions, and operative procedures decreased during the outbreak. Thirty eight patients were hospitalised with suspected SARS, of which three received the final diagnosis of probable SARS. Two patients with probable SARS died. No cases of nosocomial SARS transmission occurred.
Conclusions: This SARS outbreak was associated with substantial use of hospital and ED resources aimed at infection control, comparatively less use of resources related to the medical care of patients with suspected or probable SARS, and decreased use of routine medical services.
PMCID: PMC1726342  PMID: 15107369
13.  Identification and containment of an outbreak of SARS in a community hospital 
Severe acute respiratory syndrome (SARS) is continuing to spread around the world. All hospitals must be prepared to care for patients with SARS. Thus, it is important to understand the transmission of this disease in hospitals and to evaluate methods for its containment in health care institutions. We describe how we cared for the first 2 patients with SARS admitted to our 419-bed community hospital in Richmond Hill, Ont., and the response to a SARS outbreak within our institution.
We collected clinical and epidemiological data about patients and health care workers at our institution who during a 13-day period had a potential unprotected exposure to 2 patients whose signs and symptoms were subsequently identified as meeting the case definition for probable SARS. The index case at our hospital was a patient who was transferred to our intensive care unit (ICU) from a referral hospital on Mar. 16, 2003, where he had been in close proximity to the son of the individual with the first reported case of SARS in Toronto. After 13 days in the ICU, a diagnosis of probable SARS was reached for our index case. Immediately upon diagnosis of our index case, respiratory isolation and barrier precautions were instituted throughout our hospital and maintained for a period of 10 days, which is the estimated maximum incubation period reported for this disease. Aggressive surveillance measures among hospital staff, patients and visitors were also maintained during this time.
During the surveillance period, 15 individuals (10 hospital staff, 3 patients and 2 visitors) were identified as meeting the case definition for probable or suspected SARS, in addition to our index case. All but 1 individual had had direct contact with a symptomatic patient with SARS during the period of unprotected exposure. No additional cases were identified after infection control precautions had been implemented for 8 days. No cases of secondary transmission were identified in the 21 days following the implementation of these precautions at our institution.
SARS can easily be spread by direct personal contact in the hospital setting. We found that the implementation of aggressive infection control measures is effective in preventing further transmission of this disease.
PMCID: PMC155957  PMID: 12771070
14.  Clinical course and management of SARS in health care workers in Toronto: a case series 
Severe acute respiratory syndrome (SARS) has only recently been described. We provide individual patient data on the clinical course, treatment and complications experienced by 14 front-line health care workers and hospital support staff in Toronto who were diagnosed with SARS, and we provide follow-up information for up to 3 weeks after their discharge from hospital.
As part of the initial response to the SARS outbreak in Toronto, our health care centre was asked to establish a SARS unit for health care workers who were infected. Patients were admitted to this unit and were closely monitored and treated until they were well enough to be discharged. We prospectively compiled information on their clinical course, management and complications and followed them for 3 weeks after discharge.
The 11 women and 3 men described here (mean age 42 [standard deviation {SD} 9] years) were all involved in providing medical or ancillary hospital services to patients who were later found to have SARS. Onset of symptoms in 4 of our patients who could clearly identify only a single contact with a patient with SARS occurred on average 4 (SD 3) days after exposure. For the remaining 10 patients with multiple patient contacts, symptom onset followed exposure by a mean of 3.5 (SD 3) days after their exposure. All patients were treated with ribavirin, and all patients received levofloxacin. Many experienced major complications. Dyspnea was present in 12 patients during their stay in hospital, and all developed abnormalities on chest radiograph; 3 patients developed severe hypoxemia (PaO2 < 50 mm Hg). All patients experienced a drop in hemoglobin. Nine patients had hemolytic anemia. Three patients experienced numbness and tingling in their hands and feet, and 2 developed frank tetany. All 3 had magnesium levels that were less than 0.1 mmol/L. All patients recovered and were discharged home. At a follow-up examination 3 weeks after discharge (5 weeks after onset of illness), all patients were no longer weak but continued to become fatigued easily and had dyspnea on minimal exertion. For 5 patients, chest radiographs still showed residual disease.
SARS is a very serious illness even in healthy, relatively young people. The clinical course in our patients, all of whom met the case definition for SARS (which requires pulmonary involvement), resulted in dyspnea and, in some individuals, severe hypoxemia. Severe hemolytic anemia may be a feature of SARS or may be a complication of therapy, possibly with ribavirin.
PMCID: PMC161610  PMID: 12821618
15.  Air Cleaning Technologies 
Executive Summary
This health technology policy assessment will answer the following questions:
When should in-room air cleaners be used?
How effective are in-room air cleaners?
Are in-room air cleaners that use combined HEPA and UVGI air cleaning technology more effective than those that use HEPA filtration alone?
What is the Plasmacluster ion air purifier in the pandemic influenza preparation plan?
The experience of severe acute respiratory syndrome (SARS) locally, nationally, and internationally underscored the importance of administrative, environmental, and personal protective infection control measures in health care facilities. In the aftermath of the SARS crisis, there was a need for a clearer understanding of Ontario’s capacity to manage suspected or confirmed cases of airborne infectious diseases. In so doing, the Walker Commission thought that more attention should be paid to the potential use of new technologies such as in-room air cleaning units. It recommended that the Medical Advisory Secretariat of the Ontario Ministry of Health and Long-Term Care evaluate the appropriate use and effectiveness of such new technologies.
Accordingly, the Ontario Health Technology Advisory Committee asked the Medical Advisory Secretariat to review the literature on the effectiveness and utility of in-room air cleaners that use high-efficiency particle air (HEPA) filters and ultraviolet germicidal irradiation (UVGI) air cleaning technology.
Additionally, the Ontario Health Technology Advisory Committee prioritized a request from the ministry’s Emergency Management Unit to investigate the possible role of the Plasmacluster ion air purifier manufactured by Sharp Electronics Corporation, in the pandemic influenza preparation plan.
Clinical Need
Airborne transmission of infectious diseases depends in part on the concentration of breathable infectious pathogens (germs) in room air. Infection control is achieved by a combination of administrative, engineering, and personal protection methods. Engineering methods that are usually carried out by the building’s heating, ventilation, and air conditioning (HVAC) system function to prevent the spread of airborne infectious pathogens by diluting (dilution ventilation) and removing (exhaust ventilation) contaminated air from a room, controlling the direction of airflow and the air flow patterns in a building. However, general wear and tear over time may compromise the HVAC system’s effectiveness to maintain adequate indoor air quality. Likewise, economic issues may curtail the completion of necessary renovations to increase its effectiveness. Therefore, when exposure to airborne infectious pathogens is a risk, the use of an in-room air cleaner to reduce the concentration of airborne pathogens and prevent the spread of airborne infectious diseases has been proposed as an alternative to renovating a HVAC system.
Airborne transmission is the spread of infectious pathogens over large distances through the air. Infectious pathogens, which may include fungi, bacteria, and viruses, vary in size and can be dispersed into the air in drops of moisture after coughing or sneezing. Small drops of moisture carrying infectious pathogens are called droplet nuclei. Droplet nuclei are about 1 to 5μm in diameter. This small size in part allows them to remain suspended in the air for several hours and be carried by air currents over considerable distances. Large drops of moisture carrying infectious pathogens are called droplets. Droplets being larger than droplet nuclei, travel shorter distances (about 1 metre) before rapidly falling out of the air to the ground. Because droplet nuclei remain airborne for longer periods than do droplets, they are more amenable to engineering infection control methods than are droplets.
Droplet nuclei are responsible for the airborne transmission of infectious diseases such as tuberculosis, chicken pox (varicella), measles (rubeola), and dessiminated herpes zoster, whereas close contact is required for the direct transmission of infectious diseases transmitted by droplets, such as influenza (the flu) and SARS.
The Technology
In-room air cleaners are supplied as portable or fixed devices. Fixed devices can be attached to either a wall or ceiling and are preferred over portable units because they have a greater degree of reliability (if installed properly) for achieving adequate room air mixing and airflow patterns, which are important for optimal effectiveness.
Through a method of air recirculation, an in-room air cleaner can be used to increase room ventilation rates and if used to exhaust air out of the room it can create a negative-pressure room for airborne infection isolation (AII) when the building’s HVAC system cannot do so. A negative-pressure room is one where clean air flows into the room but contaminated air does not flow out of it. Contaminated room air is pulled into the in-room air cleaner and cleaned by passing through a series of filters, which remove the airborne infectious pathogens. The cleaned air is either recirculated into the room or exhausted outside the building. By filtering contaminated room air and then recirculating the cleaned air into the room, an in-room air cleaner can improve the room’s ventilation. By exhausting the filtered air to the outside the unit can create a negative-pressure room. There are many types of in-room air cleaners. They vary widely in the airflow rates through the unit, the type of air cleaning technology used, and the technical design.
Crucial to maximizing the efficiency of any in-room air cleaner is its strategic placement and set-up within a room, which should be done in consultation with ventilation engineers, infection control experts, and/or industrial hygienists. A poorly positioned air cleaner may disrupt airflow patterns within the room and through the air cleaner, thereby compromising its air cleaning efficiency.
The effectiveness of an in-room air cleaner to remove airborne pathogens from room air depends on several factors, including the airflow rate through the unit’s filter and the airflow patterns in the room. Tested under a variety of conditions, in-room air cleaners, including portable or ceiling mounted units with either a HEPA or a non-HEPA filter, portable units with UVGI lights only, or ceiling mounted units with combined HEPA filtration and UVGI lights, have been estimated to be between 30% and 90%, 99% and 12% and 80% effective, respectively. However, and although their effectiveness is variable, the United States Centers for Disease Control and Prevention has acknowledged in-room air cleaners as alternative technology for increasing room ventilation when this cannot be achieved by the building’s HVAC system with preference given to fixed recirculating systems over portable ones.
Importantly, the use of an in-room air cleaner does not preclude either the need for health care workers and visitors to use personal protective equipment (N95 mask or equivalent) when entering AII rooms or health care facilities from meeting current regulatory requirements for airflow rates (ventilation rates) in buildings and airflow differentials for effective negative-pressure rooms.
The Plasmacluster ion technology, developed in 2000, is an air purification technology. Its manufacturer, Sharp Electronics Corporation, says that it can disable airborne microorganisms through the generation of both positive and negative ions. (1) The functional unit is the hydroxyl, which is a molecule comprised of one oxygen molecule and one hydrogen atom.
Plasmacluster ion air purifier uses a multilayer filter system composed of a prefilter, a carbon filter, an antibacterial filter, and a HEPA filter, combined with an ion generator to purify the air. The ion generator uses an alternating plasma discharge to split water molecules into positively and negatively charged ions. When these ions are emitted into the air, they are surrounded by water molecules and form cluster ions which are attracted to airborne particles. The cluster ion surrounds the airborne particle, and the positive and negative ions react to form hydroxyls. These hydroxyls steal the airborne particle’s hydrogen atom, which creates a hole in the particle’s outer protein membrane, thereby rendering it inactive.
Because influenza is primarily acquired by large droplets and direct and indirect contact with an infectious person, any in-room air cleaner will have little benefit in controlling and preventing its spread. Therefore, there is no role for the Plasmacluster ion air purifier or any other in-room air cleaner in the control of the spread of influenza. Accordingly, for purposes of this review, the Medical Advisory Secretariat presents no further analysis of the Plasmacluster.
Review Strategy
The objective of the systematic review was to determine the effectiveness of in-room air cleaners with built in UVGI lights and HEPA filtration compared with those using HEPA filtration only.
The Medical Advisory Secretariat searched the databases of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, INAHATA (International Network of Agencies for Health Technology Assessment), Biosis Previews, Bacteriology Abstracts, Web of Science, Dissertation Abstracts, and NIOSHTIC 2.
A meta-analysis was conducted if adequate data was available from 2 or more studies and where statistical and clinical heterogeneity among studies was not an issue. Otherwise, a qualitative review was completed. The GRADE system was used to summarize the quality of the body of evidence comprised of 1 or more studies.
Summary of Findings
There were no existing health technology assessments on air cleaning technology located during the literature review. The literature search yielded 59 citations of which none were retained. One study was retrieved from a reference list of a guidance document from the United States Centers for Disease Control and Prevention, which evaluated an in-room air cleaner with combined UVGI lights and HEPA filtration under 2 conditions: UVGI lights on and UVGI lights off. Experiments were performed using different ventilation rates and using an aerosolized pathogen comprised of Mycobaterium parafortuitum, a surrogate for the bacterium that causes tuberculosis. Effectiveness was measured as equivalent air changes per hour (eACH). This single study formed the body of evidence for our systematic review research question.
Experimental Results
The eACH rate for the HEPA-UVGI in-room air cleaner was statistically significantly greater when the UV lights were on compared with when the UV lights were off. (P < .05). However, subsequent experiments could not attribute this to the UVGI. Consequently, the results are inconclusive and an estimate of effect (benefit) is uncertain.
The study was reviewed by a scientific expert and rated moderate for quality. Further analysis determined that there was some uncertainty in the directness of the outcome measure (eACH); thus, the GRADE level for the quality of the evidence was low indicating that an estimate of effect is very uncertain.
There is uncertainty in the benefits of using in-room air cleaners with combined UVGI lights and HEPA filtration over systems that use HEPA filtration alone. However, there are no known risks to using systems with combined UVGI and HEPA technology compared with those with HEPA alone. There is an increase in the burden of cost including capital costs (cost of the device), operating costs (electricity usage), and maintenance costs (cleaning and replacement of UVGI lights) to using an in-room air cleaner with combined UVGI and HEPA technology compared with those with HEPA alone. Given the uncertainty of the estimate of benefits, an in-room air cleaner with HEPA technology only may be an equally reasonable alternative to using one with combined UVGI and HEPA technology
In-room air cleaners may be used to protect health care staff from air borne infectious pathogens such as tuberculosis, chicken pox, measles, and dessiminated herpes zoster. In addition, and although in-room air cleaners are not effective at protecting staff and preventing the spread of droplet-transmitted diseases such as influenza and SARS, they may be deployed in situations with a novel/emerging infectious agent whose epidemiology is not yet defined and where airborne transmission is suspected.
It is preferable that in-room air cleaners be used with a fixed and permanent room placement when ventilation requirements must be improved and the HVAC system cannot be used. However, for acute (temporary) situations where a novel/emerging infectious agent presents whose epidemiology is not yet defined and where airborne transmission is suspected it may be prudent to use the in room air cleaner as a portable device until mode of transmission is confirmed. To maximize effectiveness, consultation with an environmental engineer and infection control expert should be undertaken before using an in-room air cleaner and protocols for maintenance and monitoring of these devices should be in place.
If properly installed and maintained, in room air cleaners with HEPA or combined HEPA and UVGI air cleaning technology are effective in removing airborne pathogens. However, there is only weak evidence available at this time regarding the benefit of using an in-room air cleaner with combined HEPA and UVGI air cleaner technology instead of those with HEPA filter technology only.
PMCID: PMC3382390  PMID: 23074468
16.  Persistent Replication of Severe Acute Respiratory Syndrome Coronavirus in Human Tubular Kidney Cells Selects for Adaptive Mutations in the Membrane Protein▿  
Journal of Virology  2008;82(11):5137-5144.
Severe acute respiratory syndrome (SARS) is a systemic disease characterized by both lung pathology and widespread extrapulmonary virus dissemination causing multiple organ injuries. In this regard, renal dysfunction is an ominous sign in patients with SARS. Indeed, clusters of SARS coronavirus (SARS-CoV) particles have been detected in the cytoplasm of renal tubular epithelial cells in postmortem studies, explaining the presence of infectious virus in the urine of SARS patients. In order to investigate the potential SARS-CoV kidney tropism, we have evaluated the susceptibility of human renal cells of tubular and glomerular origin to in vitro SARS-CoV infection. Immortalized cultures of differentiated proximal tubular epithelial cells (PTEC), glomerular mesangial cells (MC), and glomerular epithelial cells (podocytes) were found to express the SARS-CoV receptor angiotensin-converting enzyme 2 on their surface. Productive infection, however, occurred only in PTEC but not in glomerular cells. A transient infection with poor virus production was observed in MC, whereas podocytes were not permissive to SARS-CoV infection. In contrast to the cytopathic infection of the Vero E6 cell line, SARS-CoV did not cause overt cytopathic effects in PTEC or MC. Of interest, PTEC, but not MC, maintained stable levels of SARS-CoV production in serial subcultures, suggesting a persistent state of infection. In this regard, a SARS-CoV variant with increased replication capacity in PTEC was selected after four serial subculture passages. This SARS-CoV variant acquired a single nonconservative amino acid change from glutamic acid (E) to alanine (A) at position 11 in the viral membrane (M) protein. The E11A point mutation was sufficient for enhanced SARS-CoV replication and persistence in PTEC when introduced in a SARS-CoV recombinant infectious clone. These findings indicate that human PTEC may represent a site of SARS-CoV productive and persistent replication favoring the emergence of viral variants with increased replication capacity, at least in these kidney cells.
PMCID: PMC2395189  PMID: 18367528
17.  Anti–SARS-CoV Immunoglobulin G in Healthcare Workers, Guangzhou, China 
Emerging Infectious Diseases  2005;11(1):89-94.
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.
PMCID: PMC3294349  PMID: 15705328
SARS; Seroprevalence; Healthcare workers; China; research
18.  Two-Way Antigenic Cross-Reactivity between Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Group 1 Animal CoVs Is Mediated through an Antigenic Site in the N-Terminal Region of the SARS-CoV Nucleoprotein▿  
Journal of Virology  2007;81(24):13365-13377.
In 2002, severe acute respiratory syndrome-associated coronavirus (SARS-CoV) emerged in humans, causing a global epidemic. By phylogenetic analysis, SARS-CoV is distinct from known CoVs and most closely related to group 2 CoVs. However, no antigenic cross-reactivity between SARS-CoV and known CoVs was conclusively and consistently demonstrated except for group 1 animal CoVs. We analyzed this cross-reactivity by an enzyme-linked immunosorbent assay (ELISA) and Western blot analysis using specific antisera to animal CoVs and SARS-CoV and SARS patient convalescent-phase or negative sera. Moderate two-way cross-reactivity between SARS-CoV and porcine CoVs (transmissible gastroenteritis CoV [TGEV] and porcine respiratory CoV [PRCV]) was mediated through the N but not the spike protein, whereas weaker cross-reactivity occurred with feline (feline infectious peritonitis virus) and canine CoVs. Using Escherichia coli-expressed recombinant SARS-CoV N protein and fragments, the cross-reactive region was localized between amino acids (aa) 120 to 208. The N-protein fragments comprising aa 360 to 412 and aa 1 to 213 reacted specifically with SARS convalescent-phase sera but not with negative human sera in ELISA; the fragment comprising aa 1 to 213 cross-reacted with antisera to animal CoVs, whereas the fragment comprising aa 360 to 412 did not cross-react and could be a potential candidate for SARS diagnosis. Particularly noteworthy, a single substitution at aa 120 of PRCV N protein diminished the cross-reactivity. We also demonstrated that the cross-reactivity is not universal for all group 1 CoVs, because HCoV-NL63 did not cross-react with SARS-CoV. One-way cross-reactivity of HCoV-NL63 with group 1 CoVs was localized to aa 1 to 39 and at least one other antigenic site in the N-protein C terminus, differing from the cross-reactive region identified in SARS-CoV N protein. The observed cross-reactivity is not a consequence of a higher level of amino acid identity between SARS-CoV and porcine CoV nucleoproteins, because sequence comparisons indicated that SARS-CoV N protein has amino acid identity similar to that of infectious bronchitis virus N protein and shares a higher level of identity with bovine CoV N protein within the cross-reactive region. The TGEV and SARS-CoV N proteins are RNA chaperons with long disordered regions. We speculate that during natural infection, antibodies target similar short antigenic sites within the N proteins of SARS-CoV and porcine group 1 CoVs that are exposed to an immune response. Identification of the cross-reactive and non-cross-reactive N-protein regions allows development of SARS-CoV-specific antibody assays for screening animal and human sera.
PMCID: PMC2168854  PMID: 17913799
19.  Control of Severe Acute Respiratory Syndrome in Singapore 
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.
PMCID: PMC2723408  PMID: 21432128
outbreak control; SARS; patient isolation; quarantine; contact tracing
20.  The severe acute respiratory syndrome coronavirus in tears 
Background: Severe acute respiratory syndrome (SARS) is a new infectious disease that caused a global outbreak in 2003. Research has shown that it is caused by a novel coronavirus. A series of cases is reported where polymerase chain reaction (PCR) testing on tears had demonstrated the presence of the virus. Detection of ocular infection from tears using the PCR technique has been widely used by ophthalmologists to diagnose infections for other viruses.
Methods: This is a case series report from cases classified as probable or suspect SARS cases. Tear samples were collected from 36 consecutive patients who were suspected of having SARS in Singapore over a period of 12 days (7–18 April 2003), and analysed by PCR using protocols developed by the WHO network of laboratories.
Results: Three patients with probable SARS (one female and two male patients) had positive results from their tear samples. Tear samples were used to confirm SARS in the female patient, who was positive only from her tears. The positive specimens were found in cases sampled early in their course of infection.
Conclusions: This is the first case series reported with the detection of the SARS coronavirus from tears, and has important implications for the practice of ophthalmology and medicine. The ability to detect and isolate the virus in the early phase of the disease may be an important diagnostic tool for future patients and tear sampling is both simple and easily repeatable. Many healthcare workers are in close proximity to the eyes of patients and this may be a source of spread among healthcare workers and inoculating patients. Ophthalmic practices may need to change as more stringent barrier methods, appropriate quarantine, and isolation measures are vital when managing patients with SARS.
PMCID: PMC1772213  PMID: 15205225
severe acute respiratory syndrome; SARS; virus; tears; polymerase chain reaction
21.  The rationale of fever surveillance to identify patients with severe acute respiratory syndrome in Taiwan 
Emergency Medicine Journal : EMJ  2006;23(3):202-205.
Study objective
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.
PMCID: PMC2464446  PMID: 16498157
SARS; RT‐PCR; scoring system; fever; triage
22.  Interpretation of diagnostic laboratory tests for severe acute respiratory syndrome: the Toronto experience 
An outbreak of severe acute respiratory syndrome (SARS) began in Canada in February 2003. The initial diagnosis of SARS was based on clinical and epidemiological criteria. During the outbreak, molecular and serologic tests for the SARS-associated coronavirus (SARS-CoV) became available. However, without a “gold standard,” it was impossible to determine the usefulness of these tests. We describe how these tests were used during the first phase of the SARS outbreak in Toronto and offer some recommendations that may be useful if SARS returns.
We examined the results of all diagnostic laboratory tests used in 117 patients admitted to hospitals in Toronto who met the Health Canada criteria for suspect or probable SARS. Focusing on tests for SARS-CoV, we attempted to determine the optimal specimen types and timing of specimen collection.
Diagnostic test results for SARS-CoV were available for 110 of the 117 patients. SARS-CoV was detected by means of reverse-transcriptase polymerase chain reaction (RT-PCR) in at least one specimen in 59 (54.1%) of 109 patients. Serologic test results of convalescent samples were positive in 50 (96.2%) of 52 patients for whom paired serum samples were collected during the acute and convalescent phases of the illness. Of the 110 patients, 78 (70.9%) had specimens that tested positive by means of RT-PCR, serologic testing or both methods. The proportion of RT-PCR test results that were positive was similar between patients who met the criteria for suspect SARS (50.8%, 95% confidence interval [CI] 38.4%–63.2%) and those who met the criteria for probable SARS (58.0%, 95% CI 44.2%–70.7%). SARS-CoV was detected in nasopharyngeal swabs in 33 (32.4%) of 102 patients, in stool specimens in 19 (63.3%) of 30 patients, and in specimens from the lower respiratory tract in 10 (58.8%) of 17 patients.
These findings suggest that the rapid diagnostic tests in use at the time of the initial outbreak lack sufficient sensitivity to be used clinically to rule out SARS. As tests for SARS-CoV continue to be optimized, evaluation of the clinical presentation and elucidation of a contact history must remain the cornerstone of SARS diagnosis. In patients with SARS, specimens taken from the lower respiratory tract and stool samples test positive by means of RT-PCR more often than do samples taken from other areas.
PMCID: PMC305313  PMID: 14707219
23.  Outbreak of severe acute respiratory syndrome in a tertiary hospital in Singapore, linked to an index patient with atypical presentation: epidemiological study 
BMJ : British Medical Journal  2004;328(7433):195.
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.
PMCID: PMC318482  PMID: 14726369
24.  The experience of the 2003 SARS outbreak as a traumatic stress among frontline healthcare workers in Toronto: lessons learned. 
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.
PMCID: PMC1693388  PMID: 15306398
25.  Which preventive measures might protect health care workers from SARS? 
BMC Public Health  2009;9:81.
Despite the use of a series of preventive measures, a high incidence of severe acute respiratory syndrome (SARS) was observed among health care workers (HCWs) during the SARS epidemic. This study aimed to determine which preventive measures may have been effective in protecting HCWs from infection, and which were not effective.
A retrospective study was performed among 758 'frontline' health care workers who cared for SARS patients at the Second Affiliated Hospital and the Third Affiliated Hospital of Sun Yat-sen University. The HCWs with IgG against SARS and those without IgG against SARS were respectively defined as the "case group" and the "control group", and logistic regression was conducted to explore the risk factors for SARS infection in HCWs.
After adjusting for age, gender, marital status, educational level, professional title, and the department in which an individual worked, the results of a multivariate logistic regression analysis indicated that incidence of SARS among HCWs was significantly and positively associated with: performing tracheal intubations for SARS patients, methods used for air ventilation in wards, avoiding face-to-face interaction with SARS patients, the number of pairs of gloves worn by HCWs, and caring for serious SARS cases.
Some measures, particularly good air ventilation in SARS wards, may be effective in minimizing or preventing SARS transmission among HCWs in hospitals.
PMCID: PMC2666722  PMID: 19284644

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