Curtailing transmission of severe acute respiratory syndrome within a community and its hospital

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.     

Mathematical modeling of severe acute respiratory syndrome nosocomial transmission in Japan: the dynamics of incident cases and prevalent cases

An outbreak of Severe Acute Respiratory Syndrome (SARS) occurred in Hong Kong in late February 2003, resulting in 8,096 cumulative cases with 774 deaths. The outbreak was amplified by nosocomial transmission in many hospitals. Using mathematical modeling, we simulated the number of new incident and prevalent cases of SARS after one infected person was admitted to a hospital (index case). The simulation was tested stochastically using the SEIR model based on previously reported Gamma distributions. We estimated the duration time until 10 beds in negative pressure rooms in Chiyoda-ku, one of the 23 wards in Tokyo, were fully occupied with SARS-infected patients. We determined the impact of an increasing number of days on the number of prevalent cases until the index case was isolated. The prevalent cases increase exponentially along with the increase of the non-isolation period of the index case, and all the beds were fully occupied if the index case was not isolated until more than 6 days. However even 2 days non-isolation period of the index case could fill up all the beds when 16% of secondary infections are transmitted outside the hospital. There is a possibility that an epidemic will occur with the isolation of the index case even at early days if the infection is transmitted outside the hospital. The simulation results revealed that it was important to recognize and isolate SARS patients as early as possible and also to prevent the transmission spreading outside the hospital to control an epidemic.     

Modelling strategies for controlling SARS outbreaks

Severe acute respiratory syndrome (SARS), a new, highly contagious, viral disease, emerged in China late in 2002 and quickly spread to 32 countries and regions causing in excess of 774 deaths and 8098 infections worldwide. In the absence of a rapid diagnostic test, therapy or vaccine, isolation of individuals diagnosed with SARS and quarantine of individuals feared exposed to SARS virus were used to control the spread of infection. We examine mathematically the impact of isolation and quarantine on the control of SARS during the outbreaks in Toronto, Hong Kong, Singapore and Beijing using a deterministic model that closely mimics the data for cumulative infected cases and SARS-related deaths in the first three regions but not in Beijing until mid-April, when China started to report data more accurately. The results reveal that achieving a reduction in the contact rate between susceptible and diseased individuals by isolating the latter is a critically important strategy that can control SARS outbreaks with or without quarantine. An optimal isolation programme entails timely implementation under stringent hygienic precautions defined by a critical threshold value. Values below this threshold lead to control, but those above are associated with the incidence of new community outbreaks or nosocomial infections, a known cause for the spread of SARS in each region. Allocation of resources to implement optimal isolation is more effective than to implement sub-optimal isolation and quarantine together. A community-wide eradication of SARS is feasible if optimal isolation is combined with a highly effective screening programme at the points of entry.     

Revaccination of children during school-based measles outbreaks: potential impact of a new policy recommendation.

OBJECTIVE: To evaluate the potential impact of revaccination on measles outbreak control during school-based epidemics. DESIGN: Retrospective cohort study. SETTING: Thirty-two public elementary and high schools in 14 communities on the west island of Montreal. PARTICIPANTS: All 19,439 children attending these schools during the 1989 measles epidemic in Quebec. INTERVENTION: After notification of a case children with provider-verified records of vaccination on or after their first birthday were identified; the remaining children were vaccinated or excluded from school. OUTCOME MEASURE: Clinical or confirmed measles cases not prevented by this intervention that could have been prevented had revaccination been included during the outbreak. RESULTS: Of the 88 measles cases (74 confirmed) proof of one adequate vaccination was present in 48 (55%). Intervention generally occurred within 5 school days after case notification. The nonpreventable cases involved 75 children who had measles onset before the intervention and 11 (7 vaccinated) who had onset within 8 days after the intervention. The two remaining cases occurred 20 and 25 days after the intervention among nonvaccinated students who refused to be vaccinated. Except for these two cases measles was eliminated at every school. Application of the new Canadian guidelines for measles outbreak control would have required the administration of at least 10,000 additional doses during the outbreak to students vaccinated before 1980; implementation of the new US guidelines would have required the administration of 16,629 additional doses to children previously vaccinated only once. Well-enforced provincial regulations ensuring vaccination of every student upon school entry might have prevented 38 (43%) of the cases. The US recommendation of two routine doses of vaccine before school entry might have prevented 86 (98%) of the cases. However, revaccination during the outbreak would not have prevented a single additional case. CONCLUSION: Revaccination of previously vaccinated students during a measles outbreak would have been costly and of little benefit.     

Using models to identify routes of nosocomial infection: a large hospital outbreak of SARS in Hong Kong

Two factors dominated the epidemiology of severe acute respiratory syndrome (SARS) during the 2002-2003 global outbreak, namely super-spreading events (SSE) and hospital infections. Although both factors were important during the first and the largest hospital outbreak in Hong Kong, the relative importance of different routes of infection has not yet been quantified. We estimated the parameters of a novel mathematical model of hospital infection using SARS episode data. These estimates described levels of transmission between the index super-spreader, staff and patients, and were used to compare three plausible hypotheses. The broadest of the supported hypotheses ascribes the initial surge in cases to a single super-spreading individual and suggests that the per capita risk of infection to patients increased approximately one month after the start of the outbreak. Our estimate for the number of cases caused by the SSE is substantially lower than the previously reported values, which were mostly based on self-reported exposure information. This discrepancy suggests that the early identification of the index case as a super-spreader might have led to biased contact tracing, resulting in too few cases being attributed to staff-to-staff transmission. We propose that in future outbreaks of SARS or other directly transmissible respiratory pathogens, simple mathematical models could be used to validate preliminary conclusions concerning the relative importance of different routes of transmission with important implications for infection control.     

Management and prevention of SARS in China

The case fatality was the lowest (3.8%) among 1512 cases with severe acute respiratory syndrome (SARS) in Guangdong Province, China. Rational use of corticosteroid, non-invasive ventilation and the integration of traditional Chinese medicine and modern medicine may partly have contributed to the lowest fatality figure. There was a close linkage between civet cats and humans in terms of transmission of SARS. Strict control of the wild-animal market may be significant in preventing a new outbreak of SARS this year.     

Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2

Human angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS coronavirus (SARS-CoV). Here we identify the SARS-CoV spike (S)-protein-binding site on ACE2. We also compare S proteins of SARS-CoV isolated during the 2002-2003 SARS outbreak and during the much less severe 2003-2004 outbreak, and from palm civets, a possible source of SARS-CoV found in humans. All three S proteins bound to and utilized palm-civet ACE2 efficiently, but the latter two S proteins utilized human ACE2 markedly less efficiently than did the S protein obtained during the earlier human outbreak. The lower affinity of these S proteins could be complemented by altering specific residues within the S-protein-binding site of human ACE2 to those of civet ACE2, or by altering S-protein residues 479 and 487 to residues conserved during the 2002-2003 outbreak. Collectively, these data describe molecular interactions important to the adaptation of SARS-CoV to human cells, and provide insight into the severity of the 2002-2003 SARS epidemic.     

Candidate Genes Associated with Susceptibility for SARS-Coronavirus

Assuming that no human had any previously acquired immunoprotection against severe acute respiratory syndrome coronavirus (SARS-CoV) during the 2003 SARS outbreak, the biological bases for possible difference in individual susceptibility are intriguing. However, this issue has never been fully elucidated. Based on the premise that SARS patients belonging to a given genotype group having a significantly higher SARS infection rate than others would imply that genotype group being more susceptible, we make use of a compartmental model describing disease transmission dynamics and clinical and gene data of 100 laboratory confirmed SARS patients from Chinese Han population in Taiwan to estimate the infection rates of distinct candidate genotype groups among these SARS-infected individuals. The results show that CXCL10(−938AA) is always protective whenever it appears, but appears rarely and only jointly with either Fgl2(+158T/*) or HO-1(−497A/*), while (Fgl2)(+158T/*) is associated with higher susceptibility unless combined with CXCL10/IP-10(−938AA), when jointly is associated with lower susceptibility. The novel modeling approach proposed, which does not require sizable case and control gene datasets, could have important future public health implications in swiftly identifying potential high-risk groups associated with being highly susceptible to a particular infectious disease.     

Moderate mutation rate in the SARS coronavirus genome and its implications

Background

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.

Results

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.

Conclusions

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.

     

Molecular pathogenesis of severe acute respiratory syndrome

The global outbreak in 2002-2003 of severe acute respiratory syndrome (SARS) posed a serious threat to public health and had a significant impact on socioeconomic stability. Although the global outbreak of SARS has been contained, there are serious concerns over its re-emergence and bioterrorism potential, and up to date, no specific treatment exists for this disease. Here we review the progress of studies on the pathogenesis of the disease, in particular, studies on the molecular level.     

Operational experience with liquidation of avian flu foci in Zdvinsk of Novosibirsk region

The operational experience on liquidation of the centers of the avian flu in separate region of Novosibirsk is considered. From 32 settlements in 7 (22%) have been registered the centers of a case of a bird. Despite of undertaken measures under the prevention of distribution of an infection and occurrence of the new centers, during first time the case of a bird proceeded because of proceeding free ride out of poultry on lakes. Carrying out quarantine and actions on mass depopulation of birds appeared effectual measures on liquidation of the foci. Taking into account features of this area (a plenty of lakes) with nesting a wild waterfowl and accepted free ride out for poultry, the conclusion about an opportunity of occurrence and development new epizootia of bird's flu is made during spring-autumn of 2006.     

SARS: understanding the virus and development of rational therapy

In late 2002 a new disease, severe atypical respiratory syndrome (SARS), emerged in China. A hitherto unknown animal coronavirus (CoV) that had crossed the species barrier through close contact of humans with infected animals was identified as the etiological agent. It rapidly adapted to the new host and not only became readily transmissible between humans but also more pathogenic. Air travel spread it rapidly around the world and ultimately the virus infected 8096 people and caused 774 deaths in 26 countries on 5 continents. Aggressive quarantine measures successfully terminated the disease. Currently, there are no SARS cases recorded and most likely the virus no longer circulates in the human population. In this review we present an overview over SARS-Co virus biology, the disease and discuss strategies to develop antiviral drugs and vaccines.     

Harnessing Case Isolation and Ring Vaccination to Control Ebola

As a devastating Ebola outbreak in West Africa continues, non-pharmaceutical control measures including contact tracing, quarantine, and case isolation are being implemented. In addition, public health agencies are scaling up efforts to test and deploy candidate vaccines. Given the experimental nature and limited initial supplies of vaccines, a mass vaccination campaign might not be feasible. However, ring vaccination of likely case contacts could provide an effective alternative in distributing the vaccine. To evaluate ring vaccination as a strategy for eliminating Ebola, we developed a pair approximation model of Ebola transmission, parameterized by confirmed incidence data from June 2014 to January 2015 in Liberia and Sierra Leone. Our results suggest that if a combined intervention of case isolation and ring vaccination had been initiated in the early fall of 2014, up to an additional 126 cases in Liberia and 560 cases in Sierra Leone could have been averted beyond case isolation alone. The marginal benefit of ring vaccination is predicted to be greatest in settings where there are more contacts per individual, greater clustering among individuals, when contact tracing has low efficacy or vaccination confers post-exposure protection. In such settings, ring vaccination can avert up to an additional 8% of Ebola cases. Accordingly, ring vaccination is predicted to offer a moderately beneficial supplement to ongoing non-pharmaceutical Ebola control efforts.     

Temporal Variability and Social Heterogeneity in Disease Transmission: The Case of SARS in Hong Kong

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.     

The Kermack-McKendrick epidemic model revisited

The Kermack-McKendrick epidemic model of 1927 is an age of infection model, that is, a model in which the infectivity of an individual depends on the time since the individual became infective. A special case, which is formulated as a two-dimensional system of ordinary differential ordinary differential equations, has often been called the Kermack-McKendrick model. One of the products of the SARS epidemic of 2002-2003 was a variety of epidemic models including general contact rates, quarantine, and isolation. These models can be viewed as age of infection epidemic models and analyzed using the approach of the full Kermack-McKendrick model. All these models share the basic properties that there is a threshold between disappearance of the disease and an epidemic outbreak, and that an epidemic will die out without infecting the entire population.     

Confronting SARS: a view from Hong Kong

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.     

Quantification of Bird-to-Bird and Bird-to-Human Infections during 2013 Novel H7N9 Avian Influenza Outbreak in China

From February to May, 2013, 132 human avian influenza H7N9 cases were identified in China resulting in 37 deaths. We developed a novel, simple and effective compartmental modeling framework for transmissions among (wild and domestic) birds as well as from birds to human, to infer important epidemiological quantifiers, such as basic reproduction number for bird epidemic, bird-to-human infection rate and turning points of the epidemics, for the epidemic via human H7N9 case onset data and to acquire useful information regarding the bird-to-human transmission dynamics. Estimated basic reproduction number for infections among birds is 4.10 and the mean daily number of human infections per infected bird is 3.16*10⁻⁵ [3.08*10⁻⁵, 3.23*10⁻⁵]. The turning point of 2013 H7N9 epidemic is pinpointed at April 16 for bird infections and at April 9 for bird-to-human transmissions. Our result reveals very low level of bird-to-human infections, thus indicating minimal risk of widespread bird-to-human infections of H7N9 virus during the outbreak. Moreover, the turning point of the human epidemic, pinpointed at shortly after the implementation of full-scale control and intervention measures initiated in early April, further highlights the impact of timely actions on ending the outbreak. This is the first study where both the bird and human components of an avian influenza epidemic can be quantified using only the human case data.     

橘小实蝇快速检疫鉴定方法

采用形态学观察与PCR技术相结合的方法,针对台湾水果中截获的可疑橘小实蝇Bactroceradorsalis(Hendel)幼虫和蛹进行快速鉴定。采用异硫氰酸胍方法快速提取昆虫基因组DNA,并根据特异性引物,采用PCR技术从截获的可疑橘小实蝇幼虫和蛹样本中均扩增得到224 bp的特异性条带,经测序比较发现,扩增产物序列与橘小实蝇目的基因序列完全相同,由此证明可疑样本为橘小实蝇的幼虫和蛹。该方法解决了橘小实蝇幼虫和蛹等未成熟虫态的快速检疫难题,大大缩短了检测周期,值得口岸检验检疫借鉴应用。     

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.     

Is there an ideal animal model for SARS?

The outbreak of severe acute respiratory syndrome (SARS) in 2003 was controlled by public health measures at a time when specific interventions such as antiviral drugs, vaccines and immunotherapy were not available. Since then, several animal models have been developed for the study of SARS and, although no model replicates the human disease in all aspects, the use of animal models for SARS has led to the establishment of several important principles for vaccine and immunotherapy. Consistency and reproducibility of findings in a given model must be demonstrated to establish the superiority of one model over others. Here, we suggest aspects of an ideal animal model for studies of SARS pathogenesis and vaccine development and present our assessment of the strengths and limitations of the current animal models for SARS.