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Background The pandemic threat of influenza has attracted great attention worldwide. To assist public health decision-makers, new suites of tools are needed to rapidly process and combine viral information retrieved from public-domain databases for a better risk assessment. Results Using our recently developed FluConvert and IniFlu software, we automatically processed and rearranged sequence data by standard viral nomenclature, determined the group-related consensus sequences, and identified group-specific polygenic signatures. The software possesses powerful ability to integrate viral, clinical, and epidemiological data. We demonstrated that both multiple basic amino acids at the cleavage site of the HA gene and also at least 11 more evidence-based viral amino acid substitutions present in global highly pathogenic avian influenza H5N2 viruses during the years 2009–2016 that are associated with viral virulence and human infection. Conclusions FluConvert and IniFlu are useful to monitor and assess all subtypes of influenza viruses with pandemic potential. These programs are implemented through command-line and user-friendly graphical interfaces, and identify molecular signatures with virological, epidemiological and clinical significance. FluConvert and IniFlu are available at https://apps.flutures.com or https://github.com/chinrur/FluConvert_IniFlu

The COVID-19 outbreak has drawn heightened attention from public health scholars researching ways to limit its spread. Much of the research has been focused on minimizing transmission in hospitals and in the general community. However, a particularly vulnerable community that has received relatively little attention is elders residing in long-term care facilities (LTCFs). In this article we address this relative lack of attention, arguing that enhanced traffic control bundling (eTCB) can and should be adopted and implemented as a means of protecting LTCF residents and staff. Enhanced TCB has been widely applied in hospital settings and has proven effective at limiting droplet and fomite transmissions both within hospitals and between hospitals and the general community. By effectively adapting eTCB to LTCF conditions, particularly by incorporating compartmentalization within zones plus active surveillance, COVID-19 transmission into and throughout LTCFs can be minimized, thereby saving numerous lives among an especially vulnerable population.

Dengue virus (DENV) infections may cause life-threatening dengue hemorrhagic fever (DHF). Suppressed protective immunity was shown in these patients. Although several hypotheses have been formulated, the mechanism of DENV-induced immunosuppression remains unclear. Previously, we found that cross-reactive antibodies against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4 [DR4]) were elicited in DHF patients, and that anti-DR4 autoantibody fractions were elicited by nonstructural protein 1 (NS1) immunizations in experimental mice. In this study, we found that anti-DR4 antibodies could suppress B lymphocyte function in vitro and in vivo. Treatment with the anti-DR4 immunoglobulin (Ig) induced caspase-dependent cell death in immortalized B lymphocyte Raji cells in vitro. Anti-DR4 Igs elicited by NS1 and DR4 immunizations markedly suppressed mouse spleen transitional T2 B (IgM+IgD+), bone marrow pre-pro-B (B220+CD43+), pre-B (B220+CD43−), and mature B cell (B220+IgD+) subsets in mice. Furthermore, functional analysis revealed that the pre-elicitation of anti-NS1 and anti-DR4 Ig titers suppressed subsequently neutralizing antibody production by immunization with DENV envelop protein. Our data suggest that the elicitation of anti-DR4 titers through DENV NS1 immunization plays a suppressive role in humoral immunity in mice.

SARS-CoV-2 breakthrough infection occurs due to waning immunity time-to-vaccine, to which the globally-dominant, highly-contagious Delta variant is behind the scene. In the primary 2-dose and booster series of clinical Phase-1 trial, UB-612 vaccine, which contains S1-RBD and synthetic Th/CTL peptide pool for activation of humoral and T-cell immunity, induces substantial, prolonged viral-neutralizing antibodies that goes parallel with a long-lasting T-cell immunity; and a booster (3rd ) dose can prompt recall of memory immunity to induce profound, striking antibodies with the highest level of 50% viral-neutralizing GMT titers against live Delta variant reported for any vaccine. The unique design of S1-RBD only plus multitope T-cell peptides may have underpinned UB-612’s potent anti-Delta effect, while the other full S protein-based vaccines are affected additionally by mutations in the N-terminal domain sequence which contains additional neutralizing epitopes. UB-612, safe and well-tolerated, could be effective for boosting other vaccine platforms that have shown modest homologous boosting. [Funded by United Biomedical Inc., Asia; ClinicalTrials.gov ID: NCT04967742 and NCT04545749]

Emerging infectious diseases (EIDs), including the latest COVID-19 pandemic, have emerged and raised global public health crises in recent decades. Without existing protective immunity, an EID may spread rapidly and cause mass casualties in a very short time. Therefore, it is imperative to identify cases with risk of disease progression for the best allocation of medical resources in case medical facilities are overwhelmed with a flood of patients. This study aimed to exploit machine learning technologies to cope with this challenge. The study was based on 83,227 hospital admissions with influenza-like illness and we analysed the risk effects of 19 comorbidities along with age and gender for severe illness or mortality risk. The experimental results revealed that the conventional decision tree (DT) models built with only 6 features, including age, gender, and four comorbidities, delivered the same level of prediction accuracy as the state-of-the-art deep neural network models built with 18 features. Accordingly, we further studied how to exploit the DT models with different sensitivity levels to determine patient triage and optimize medical resource allocation in different stages of an EID disaster to aid the frontline clinicians and policy-makers. In conclusion, our study demonstrated an approach to exploit machine learning technologies to cope with the challenges during the outbreak of an EID.

Objectives This study evaluated the effectiveness of two major citizens’ mobilized intervention strategies - facemasks and alcohol-based hand hygiene and their changes from the 2003 SARS outbreak to the 2020 COVID-19 pandemic (pdmCOVID-19). Methods We surveyed 2,328 Taiwanese from July 29 to August 6, 2020, assessing demographics, information sources, and practice of preventive behaviors from the 2003 SARS or 2009 pandemic influenza H1N1 (2009pdmH1N1) era to the current pdmCOVID-19 as well as post-survey intention to continue preventive practices. Logistic regression was employed to identify characteristics associated with close adherence to preventive behavior practices in 2020. Results About 70.2% of participants adhered closely to recommended preventive behavior practices. Compared with 2003SARS/2009pdmH1N1, there was a significant increase in the use of facemasks during pdmCOVID-19 (66.6% vs. 99.2% [indoors], p

A shift in dengue cases toward the adult population, accompanied by an increased risk of severe cases of dengue in the elderly, has created an important emerging issue in the past decade. To understand the level of past DENV infection among older adults after a large dengue outbreak occurred in southern Taiwan in 2015, we screened 1498 and 2603 serum samples from healthy residents aged ≥ 40 years in Kaohsiung City and Tainan City, respectively, to assess the seroprevalence of anti-DENV IgG in 2016. Seropositive samples were verified to exclude cross-reaction from Japanese encephalitis virus (JEV), using DENV/JEV-NS1 indirect IgG ELISA. We further identified viral serotypes and secondary DENV infections among positive samples in the two cities. The overall age-standardized seroprevalence of DENV-IgG among participants was 25.77% in Kaohsiung and 11.40% in Tainan, and the seroprevalence was significantly higher in older age groups of both cities. Although the percentages of secondary DENV infection in Kaohsiung and Tainan were very similar (43.09% and 44.76%, respectively), DENV-1 and DENV-2 spanned a wider age range in Kaohsiung, whereas DENV-2 was dominant in Tainan. As very few studies have obtained the serostatus of DENV infection in older adults and the elderly, this study highlights the need for further investigation into antibody status, as well as the safety and efficacy of dengue vaccination in these older populations., Author summary The dengue virus (DENV) has rapidly spread out in tropical and sub-tropical regions. To measure the level of past DENV infections in the older population, we conducted a post-outbreak serosurvey in 2016 among a total of 4,101 older and elderly adults in Kaohsiung and Tainan cities in southern Taiwan. Our results showed district- and city-level differences in the overall seroprevalence of anti-DENV IgG antibody, increased seroprevalence with age, heterogeneous distributions of DENV serotypes, and similar percentages of secondary DENV infection in both metropolises, closely matching past histories of dengue outbreaks. This study demonstrates the importance of monitoring individual’s antibody status among the older and elderly population and highlights the need to investigate the safety and efficacy of dengue vaccination in these populations in the future.

We argue that enhanced Traffic Control Bundling (eTCB) can interrupt the community-hospital-community transmission cycle, thereby limiting COVID-19's impact. Enhanced TCB is an expansion of the traditional TCB that proved highly effective during Taiwan's 2003 SARS outbreak. TCB's success derived from ensuring that Health Care Workers (HCWs) and patients were protected from fomite, contact and droplet transmission within hospitals. Although TCB proved successful during SARS, achieving a similar level of success with the COVID-19 outbreak requires adapting TCB to the unique manifestations of this new disease. These manifestations include asymptomatic infection, a hyper-affinity to ACE2 receptors resulting in high transmissibility, false negatives, and an incubation period of up to 22 days. Enhanced TCB incorporates the necessary adaptations. In particular, eTCB includes expanding the TCB transition zone to incorporate a new sector - the quarantine ward. This ward houses patients exhibiting atypical manifestations or awaiting definitive diagnosis. A second adaptation involves enhancing the checkpoint hand disinfection and gowning up with Personal Protective Equipment deployed in traditional TCB. Under eTCB, checkpoint hand disinfection and donning of face masks are now required of all visitors who seek to enter hospitals. These enhancements ensure that transmissions by droplets, fomites and contact are disrupted both within hospitals and between hospitals and the broader community. Evidencing eTCB effectiveness is Taiwan's success to date in containing and controlling the community-hospital-community transmission cycle.

During major epidemic outbreaks, demand for healthcare workers (HCWs) grows even as the extreme pressures they face cause declining availability. We draw on Taiwan’s severe acute respiratory syndrome (SARS) experience to argue that a modified form of traffic control bundling (TCB) protects HCW safety and by extension strengthens overall coronavirus disease 2019 (COVID-19) epidemic control.

Dengue virus (DENV) circulates in tropical and subtropical areas around the world, where it causes high morbidity and mortality. There is no effective treatment of infection, with supportive care being the only option. Furthermore, early detection and diagnosis are important to facilitate clinical decisions. In this study, seven monoclonal antibodies (mAbs) recognizing nonstructural protein 1 (NS1) of DENV were generated by hybridoma techniques. These antibodies can be divided into two groups: serotype-specific (DB6-1, DB12-3, and DB38-1) and nonspecific (consisting of antibodies DB16-1, DB20-6, DB29-1, and DB41-2). The B-cell epitopes of DB20-6 and DB29-1 were identified by phage display and site-directed mutagenesis, and its binding motif, WXXWGK, was revealed to correspond to amino acid residues 115-120 of the DENV-2 NS1 protein. A diagnostic platform, consisting of a serotype-specific capture antibody and a complex detection antibody, exhibited a detection limit of about 1 ng/mL, which is sufficient to detect NS1 in clinical serum samples from dengue patients. This diagnostic platform displayed better specificity and sensitivity than two examined commercial NS1 diagnostic platforms. In summary, our results indicate that these newly generated mAbs are suitable for detection of NS1 protein of DENV-2 in clinical samples.

ObjectivesThis study aimed to examine comprehensively the prognostic impact of underlying comorbidities among hospitalised patients with influenza-like illness (ILI) in different age groups and provide recommendations targeting the vulnerable patients.Setting and participantsA retrospective cohort of 83 227 hospitalised cases with ILI were identified from Taiwan’s National Health Insurance Research Database from January 2005 to December 2010. Cases were stratified into three different age groups: paediatric (0–17 years), adult (18–64 years) and elderly (≧65 years), and their age, sex, comorbidity and past healthcare utilisation were analysed for ILI-associated fatality.Main outcome measuresORs for ILI-related fatality in different age groups were performed using multivariable analyses with generalised estimating equation models and adjusted by age, sex and underlying comorbidities.ResultsHospitalised ILI-related fatality significantly increased with comorbidities of cancer with metastasis (adjusted OR (aOR)=3.49, 95% CI: 3.16 to 3.86), haematological malignancy (aOR=3.02, 95% CI: 2.43 to 3.74), cancer without metastasis (aOR=1.72, 95% CI: 1.54 to 1.91), cerebrovascular (aOR=1.24, 95% CI: 1.15 to 1.33) and heart diseases (aOR=1.19, 95% CI: 1.11 to 1.27) for all age groups. Adult patients with AIDS; adult and elderly patients with chronic kidney disease, tuberculosis and diabetes were significantly associated with elevated risk of death. Severe liver diseases and hypothyroidism among elderly, and dementia/epilepsy among elderly and paediatrics were distinctively associated with likelihood of ILI-related fatality.ConclusionsDifferent age-specific comorbidities were associated with increasing risk of death among hospitalised ILI patients. These findings may help update guidelines for influenza vaccination and other prevention strategies in high-risk groups for minimising worldwide ILI-related deaths.

In recent decades, the global incidence of dengue has increased. Affected countries have responded with more effective surveillance strategies to detect outbreaks early, monitor the trends, and implement prevention and control measures. We have applied newly developed machine learning approaches to identify laboratory-confirmed dengue cases from 4,894 emergency department patients with dengue-like illness (DLI) who received laboratory tests. Among them, 60.11% (2942 cases) were confirmed to have dengue. Using just four input variables [age, body temperature, white blood cells counts (WBCs) and platelets], not only the state-of-the-art deep neural network (DNN) prediction models but also the conventional decision tree (DT) and logistic regression (LR) models delivered performances with receiver operating characteristic (ROC) curves areas under curves (AUCs) of the ranging from 83.75% to 85.87% [for DT, DNN and LR: 84.60% ± 0.03%, 85.87% ± 0.54%, 83.75% ± 0.17%, respectively]. Subgroup analyses found all the models were very sensitive particularly in the pre-epidemic period. Pre-peak sensitivities (, Author summary Identifying dengue cases early is crucial but challenging for healthcare professionals. This challenge is increased during large epidemics and is a particular problem in non-endemic areas with limited experienced staff. To improve dengue diagnosis, we investigated how to exploit machine learning (ML)-based prediction models and identified four key variables [age, fever, white blood cell counts (WBCs), and platelet counts], which are compatible with clinical and epidemiological knowledge. With these variables, the ML prediction models [decision tree (DT), deep neural network (DNN)] and the logistic regression model developed for identifying laboratory-confirmed dengue cases produced areas under curve (AUCs) of the receiver operating characteristic (ROC) curves ranging from 83.75% to 85.87%. This implies that the prediction models may serve as a pivotal component of an integrated dengue surveillance system and they required only a single complete blood count (CBC) examination. The sensitivities, positive prediction values, and accuracies for major risk factors in the two machine learning models were close to those of the regression models. For future applications, the DNN models with superior performance can be employed at epidemic sites with adequate computer facilities, while the DT and regression models with interpretable prediction logic can be employed at sites with limited or no computer facilities. Artificial intelligence and clinical parameters identified from this study may aid when laboratories are overwhelmed, but should never replace laboratory confirmation.

The largest epidemic of avian influenza (AI) in history attacked poultry and wild birds throughout Taiwan starting January 6, 2015. This study analyzed surveillance results, epidemiologic characteristics, and viral sequences by using government-released information, with the intention to provide recommendations to minimize future pandemic influenza. The H5 clade 2.3.4.4 highly pathogenic AI viruses (HPAIVs) had not been detected in Taiwan before 2015. During this epidemic, four types of etiologic agents were identified: the three novel subtypes H5N2, H5N8, and H5N3 clade 2.3.4.4 HPAIVs and one endemic chicken H5N2 subtype (Mexican-like lineage) of low pathogenic AI viruses. Cocirculation of mixed subtypes also occurred, with H5N2 clade 2.3.4.4 HPAIVs accompanied by the H5N8 and H5N3 subtypes or old H5N2 viruses in the same farm. More than 90% of domestic geese died from this AI epidemic; geese were affected the most at the early outbreaks. The epidemic peaked in mid-January for all three novel H5 subtypes. Spatial epidemiology found that most affected areas were located in southwestern coastal areas. In terrestrial poultry (mostly chickens), different geographic distributions of AI virus subtypes were detected, with hot spots of H5N2 clade 2.3.4.4 vs. past-endemic old H5N2 viruses in Changhwa (P = 0.03) and Yunlin (P = 0.007) counties, respectively, of central Taiwan. Phylogenetic and sequence analyses of all the early 10 Taiwan H5 clade 2.3.4.4 isolates covering the three subtypes showed that they were very different from the HA of the past local H5 viruses from domestic ducks (75%-80%) and chickens (70%-75%). However, they had the highest sequence identity percentages (99.53%-100%), with the HA of A/crane/Kagoshima/KU13/2014(H5N8) isolated on December 7, 2014, in Japan being higher than those of recent American and Korean H5 HPAIVs [A/Northern pintail/Washington/40964/2014 (H5N2) and A/gyrfalcon/Washington/41088-6/2014 (H5N8): 99.02%-99.54% and A/Baikal teal/Korea/Donglim3/2014 (H5N8): 98.61%-99.08%], implying a likely common ancestor of these H5 clade 2.3.4.4 viruses. The multiple subtypes of H5 clade 2.3.4.4 HPAIVs imply high viral reassortment. We recommend establishing an integrated surveillance system, involving clinical, virologic, and serologic surveillance in poultry and wild birds, swine and other mammals prevalent on multiple-animal mixed-type traditional farms, and high-risk human populations, as a crucially important step to minimize future pandemic influenza.

Purifying selection during dengue viral infection has been suggested as the driving force of viral evolution and the higher complexity of the intra-host quasi-species is thought to offer an adaptive advantage for arboviruses as they cycle between arthropod and vertebrate hosts. However, very few studies have been performed to investigate the viral genetic changes within (intra-host) and between (inter-host) humans in a spatio-temporal scale. Viruses of different serotypes from various countries imported to Taiwan cause annual outbreaks. During 2001–2003, two consecutive outbreaks were caused by dengue virus serotype 2 (DENV-2) and resulted in a larger-scale epidemic with more severe dengue cases in the following year. Phylogenetic analyses showed that the viruses from both events were similar and related to the 2001 DENV-2 isolate from the Philippines. We comprehensively analyzed viral sequences from representative dengue patients and identified three consensus genetic variants, group Ia, Ib and II, with different spatio-temporal population dynamics. The phylodynamic analysis suggested group Ib variants, characterized by lower genetic diversity, transmission rate, and intra-host variant numbers, might play the role of maintenance variants. The residential locations among the patients infected by group Ib variants were in the outer rim of case clusters throughout the 2001–2003 period whereas group Ia and II variants were located in the centers of case clusters, suggesting that group Ib viruses might serve as “sheltered overwintering” variants in an undefined ecological niche. Further deep sequencing of the viral envelope (E) gene directly from individual patient serum samples confirmed the emergence of variants belonging to three quasi-species (group Ia, Ib, and II) and the ancestral role of the viral variants in the latter phase of the 2001 outbreak contributed to the later, larger-scale epidemic beginning in 2002. These findings enhanced our understanding of increasing epidemic severity over time in the same epidemic area. It also highlights the importance of combining phylodynamic and deep sequencing analysis as surveillance tools for detecting dynamic changes in viral variants, particularly searching for and monitoring any specific viral subpopulation. Such subpopulations might have selection advantages in both fitness and transmissibility leading to increased epidemic severity., Author summary Virus genomes can show changes due to transmission between hosts. In evolutionary scale, replacements with new viral lineages are usually associated with alternating clinical burdens or epidemic potentials, but few studies have integrated viral dynamics from intra-host viral variations to macro-level clade (a monophyletic group) replacements. In this study, we combined both levels of research to study the changes in viral genomes during two consecutive dengue outbreaks (2001–2003) in southern Taiwan. We identified a potential overwintering candidate virus group characterized by lower genetic diversity, transmission rate, number of intra-host variants and a more pervasive geographical distribution pattern. Deep sequencing data revealed the temporal dynamics of minor variants in different nucleotide positions, correlated with the phylogenetic analyses of consensus sequences derived from different patients. We thus propose that investigating the quasi-species complexity of viruses from intra-host and inter-host infections can provide a novel understanding of virus evolution. Such investigations could also be a useful method to monitor the dynamics of viral changes and be included in the virological surveillance.

The mechanisms leading to the life-threatening dengue hemorrhagic fever (DHF) remain elusive. DHF preferentially occurs during secondary dengue infections, suggesting that aberrant immune responses are involved in its development. We previously demonstrated that the autoantibodies elicited by dengue virus (DENV) nonstructural protein 1 (NS1; anti–NS1 Igs) induce plasma leakage and mortality in mice with warfarinized anticoagulant suppression. However, the involved pathogenic Ig fractions of anti–NS1 Igs remain unclear. In this study, the autoreactive Igs in patients with DHF and in NS1-immunized rabbits crossreacted with TNF-related apoptosis-inducing ligand receptor 1 (death receptor [DR]4). Challenges with the DENV in a subcytotoxic dose sensitized endothelial cells to apoptosis. Treatments with the autoantibodies induced proapoptotic activities and suppressed the surface expression of endothelial anticoagulant thrombomodulin. Combined treatments comprising the DENV and DR4 affinity-purified fractions of anti–NS1 IgGs (anti–NS1-DR4 Ig), but not preimmune control IgGs, in subcytotoxic doses led to apoptosis in endothelial cells. Treatments with the anti–NS1-DR4 Ig led to plasma leakage, coagulopathy, and morality in mice with warfarinized anticoagulant suppression. These results suggest that DR4-induced endothelial cell sensitization through NS1-elicited autoantibodies exacerbates anticoagulant suppression, vascular injury, and plasma leakage. Detecting and blocking anti–DR Igs in patients may be novel strategies for managing severe DENV infection.

The virulence of genotype I (GI) Japanese encephalitis virus (JEV) is under debate. We investigated differences in the virulence of GI and GIII JEV by calculating asymptomatic ratios based on serologic studies during GI- and GIII-JEV endemic periods. The results suggested equal virulence of GI and GIII JEV among humans.

Summary In anticipation of a future pandemic potentially arising from H5N1, H7N9 avian influenza or Middle East Respiratory Syndrome, and in large part in response to severe acute respiratory syndrome (SARS) in 2003, the city of Taipei, Taiwan, has developed extensive new strategies to manage pandemics. These strategies were tested during the 2009 H1N1 outbreak. This article assesses pandemic preparedness in Taipei in the wake of recent pandemic experiences in order to draw lessons relevant to the broader international public health community. Drawing on Taiwan and Taipei Centers for Disease Control data on pandemic response and control, we evaluated the effectiveness of the changes in pandemic response policies developed by these governments over time, emphasizing hospital and medical interventions with particular attention paid to Traffic Control Bundling. SARS and H1N1 2009 catalysed the Taiwan and Taipei CDCs to continuously improve and adjust their strategies for a future pandemic. These new strategies for pandemic response and control have been largely effective at providing interim pandemic containment and control, while development and implementation of an effective vaccination programme is underway. As Taipei's experiences with these cases illustrate, in mitigating moderate or severe pandemic influenza, a graduated process including Traffic Control Bundles accompanied by hospital and medical interventions, as well as school- and community-focused interventions, provides an effective interim response while awaiting vaccine development. Once a vaccine is developed, to maximize pandemic control effectiveness, it should be allocated with priority given to vulnerable groups, healthcare workers and school children.

Identification of high-risk severe cases from influenza-like illness (ILI) is crucial for disease surveilance and clinical management. Comorbidity and demography profile may be a good risk estimation. The study utilized Taiwanese National Health Insurance Database, ICD-9, and Marsden-Haug’s ILI Codes to measure the effect of systemic classes of comorbidity on four outcomes: ospitalization cost, length of stay (LOS), death, and intensive care unit (ICU) entry. From 2008 to 2010, there were 319,775 ILI inpatient cases, of which 8.82% entered ICU and 3.83% died at hospital discharge. The significant comorbidity attributes varied in each age stratum: heart failure in any age, non-dialyzed renal insufficiency in any age, cancer in school-age children up to mid-age adults, tuberculosis in the elderly, stroke in adults, congenital anomaly in children and adolescents, transplant in school-age up to adolescents, or HIV in young adults. Comorbidity vector was (heart failure, non-dialyzed renal insufficiency, cancer, tuberculosis, stroke, congenital anomaly, transplant, HIV). Age vector was (1, 1, 6 The risk estimation model could facilitate us to address population measures for upcoming severe influenza epidemics, and further allocate resources optimally.

The largest nosocomial outbreak of Middle East respiratory syndrome (MERS) occurred in South Korea in 2015. Health Care Personnel (HCP) are at high risk of acquiring MERS-Coronavirus (MERS-CoV) infections, similar to the severe acute respiratory syndrome (SARS)-Coronavirus (SARS-CoV) infections first identified in 2003. This study described the similarities and differences in epidemiological and clinical characteristics of 183 confirmed global MERS cases and 98 SARS cases in Taiwan associated with HCP. The epidemiological findings showed that the mean age of MERS-HCP and total MERS cases were 40 (24~74) and 49 (2~90) years, respectively, much older than those in SARS [SARS-HCP: 35 (21~68) years, p = 0.006; total SARS: 42 (0~94) years, p = 0.0002]. The case fatality rates (CFR) was much lower in MERS-HCP [7.03% (9/128)] or SARS-HCP [12.24% (12/98)] than the MERS-non-HCP [36.96% (34/92), p

Increasing global connectivity makes emerging infectious diseases (EID) more threatening than ever before. Various information systems (IS) projects have been undertaken to enhance public health capacity for detecting EID in a timely manner and disseminating important public health information to concerned parties. While those initiatives seemed to offer promising solutions, public health researchers and practitioners raised concerns about their overall effectiveness. In this paper, we argue that the concerns about current public health IS projects are partially rooted in the lack of a comprehensive framework that captures the complexity of EID management to inform and evaluate the development of public health IS. We leverage loose coupling to analyze news coverage and contact tracing data from 479 patients associated with the severe acute respiratory syndrome (SARS) outbreak in Taiwan. From this analysis, we develop a framework for outbreak management. Our proposed framework identifies two types of causal circles—coupling and decoupling circles—between the central public health administration and the local capacity for detecting unusual patient cases. These two circles are triggered by important information-centric activities in public health practices and can have significant influence on the effectiveness of EID management. We derive seven design guidelines from the framework and our analysis of the SARS outbreak in Taiwan to inform the development of public health IS. We leverage the guidelines to evaluate current public health initiatives. By doing so, we identify limitations of existing public health IS, highlight the direction future development should consider, and discuss implications for research and public health policy.

Summary Objective This study aimed to examine whether spatial–temporal patterns of dengue can be used to identify areas at risk of dengue hemorrhagic fever (DHF). Methods Three indices – probability of case-occurrence, mean duration per wave, and transmission intensity – were used to differentiate eight local spatial–temporal patterns of dengue during the 2002 epidemic in Kaohsiung, Taiwan. DHF densities (DHF cases/km 2 per 100 dengue cases) in each spatial–temporal typed area were compared. Results Areas with three high indices correlated with the highest DHF density: (1) high transmission intensity only; (2) long duration of wave only, and (3) high transmission intensity plus long duration of wave. However, cumulative incidences of dengue cases were not correlated with DHF densities. Conclusion Three spatial–temporal indices of dengue could provide useful information to identify areas at high risk of DHF.

Influenza viruses cause pandemics in humans. The aim of this study was therefore to evaluate filter/real-time qPCR to quickly and accurately determine and quantify the airborne influenza and avian influenza virus. In this study, the sampling stress of filtration to influenza virus and the storage effects for both the virus and extracted RNA were evaluated in the laboratory. Then, the collection efficiencies of open-face and closed-face filter cassettes were compared in a wet poultry market. From July 8 to August 19, 2006, a total of 36 air samples were quantified by filter/real-time qPCR. The recovery rate of the virus on a filter stored at 4°C reached 0.94 after 3-day storage, whereas the RNA stored at –80°C was 100% after 3-month storage. In terms of collection efficiency, the closed-face filter cassette was superior to the open-face filter cassette in the field study. In the wet poultry market, it was revealed that both the positive rate and concentration of influenza A virus in the chicken pen were hi...

To investigate viral determinants and evolution linked to outbreak with increased severity, we examined dengue virus type 2 (DENV-2) sequences from plasma of 31 patients (14 dengue fever, 17 dengue hemorrhagic fever, DHF) continuously during the 2001 and 2002 outbreaks in southern Taiwan, in which both the total cases and proportion of DHF cases increased. Analysis of envelope (E) and full-genome sequences between viruses of the two outbreaks revealed 5 nucleotide changes in E, NS1, NS4A, and NS5 genes. None was identical to those reported in the DENV-2 outbreak in Cuba in 1997, suggesting viral determinants linked to severe outbreak are genotype dependent. Compared with previous reports of lineage turnover years apart, our findings that the 2002 viruses descended from a minor variant of the 2001 viruses in less than 6 months was novel, and may represent a mechanism of evolution of DENV from one outbreak to another.

This study analyzed the spatio-temporal patterns of 4,587 (94% of the total) confirmed dengue cases in Kaohsiung and Fengshan Cities (a two-city area) that occurred in Taiwan from 2001 to 2003. The epidemic had two simultaneous distinct diffusion patterns. One was a contiguous pattern, mostly limited to 1 km from an initial cluster, reflecting that there was a rapid dispersal of infected Aedes aegypti and viremic persons. The second followed a relocation pattern, involving clusters of cases that diffused over 10 weeks starting from the southern and moving to the northern parts of the two-city area. The virus from one clustering site jumped to several distant areas where it rapidly dispersed through a series of human-mosquito transmission cycles to several localities. In both patterns, transmission of disease quickly enlarged the epidemic areas. Future dengue control efforts would benefit from a timely syndromic surveillance system plus extensive public education on how to avoid further transmission.

OBJECTIVE To investigate the effect of gender on mortality of HIV-infected adults receiving antiretroviral therapy (ART) and its possible reasons. METHODS A retrospective study to review the records for outcomes of adult cases receiving ART at Mzuzu Central Hospital, Malawi, between July 2004 and December 2006. RESULTS Over the study period, 2838 adult AIDS patients received ART. Of these, 2029 (71.5%) were alive and still on ART, 376 (13.2%) were dead and 433 (15.3%) were lost to follow-up. Survival analysis with Kaplan-Meier estimator showed significantly higher survival rates among females than males in WHO stage 1, 2 and 3 (both P < 0.0001) and borderline in stage 4 (P = 0.076). The Cox model revealed a death hazard ratio (males vs. females) of 1.70 (95% confidence interval 1.35-2.15) after controlling for WHO clinical stages, body mass index and age. More men than women were lost to follow-up in all occupations except health workers. CONCLUSIONS The most important reasons for a higher mortality in male patients starting ART may relate to their seeking medical care at a more advanced stage of immunodeficiency and poorer compliance with therapy. The issue needs to be addressed in scaling up ART programmes in Africa.

Summary. Background: The mechanisms responsible for thrombocytopenia associated with dengue fever (DF) and dengue hemorrhage fever (DHF) remain unclear. Objective: In this study, we investigated the pathogenic effects of dengue virus (DENV) non-structural protein 1 (NS1) on the elicitation of platelet cross-reactive antibodies. Results: The results showed that anti-DENV NS1 immunoglobulins (Igs) derived from both patients with DF/DHF and recombinant NS1-immunized rabbits could opsonize normal human platelets and enhance platelet–macrophage engagements in vitro. In addition, treatments with anti-NS1 Igs abnormally activated human platelets and induced thrombocytopenia in mice. These prothrombotic characteristics of anti-NS1 Ig might increase the disease burden of coagulant-aberrant DHF patients. To test this hypothesis, we injected anti-NS1 Igs into C57BL/6J mice that were preconditioned into a hypercoagulable state by warfarin treatments. When given before but not after platelet-lysate pre-adsorption, the anti-NS1 Igs injection treatments significantly increased mortality, fibrin deposition in lung, and plasma D-dimer levels, but significantly decreased anticoagulant proteins C, protein S and antithrombin III. Conclusions: These results suggest that the platelet-bound antibody fractions of anti-NS1 Ig are prothrombotic, which might exacerbate the severity of disease in hosts with an imbalanced coagulant system.

Dengue virus (DEN), the pathogen behind dengue hemorrhagic fever, remains a public health problem in Asia and South America. In this study, monoclonal antibodies (MAbs) against DEN serotype 1 (DEN-1) were generated by fusing NSI/1-Ag4-1 mouse myeloma cells with lymphocytes from BALB/c mice immunized with DEN-1. Twelve MAbs were found to react specifically to the DENs by enzyme-linked immunosorbent assay, immunofluorescence analysis, and immunoblotting analysis. Five MAbs, namely, DA4-7, DA6-7, DA9-5, DA10-2, and DA11-13, were found to react with envelope proteins of DEN-1. Two serotype-specific MAbs of DEN-1, DA6-7 and DA11-13, were further shown to neutralize DEN-1 infection by a plaque reduction neutralization test. The neutralizing epitopes of these MAbs were further identified from a random peptide library displayed on phage. Immunopositive phage clones reacted specifically with these MAbs and did not react with normal mouse serum. Epitope-based peptide antigens were proved able to detect antibodies in serum samples collected from DEN-1-infected patients but not in those taken from DEN-2-infected patients or healthy controls. We believe that these MAbs and neutralizing epitopes will provide information that will lead to the development of DEN-1 serotype-specific diagnostic reagents and vaccines.

Because the severe acute respiratory syndrome (SARS) outbreak in Taiwan in 2003 was worsened by hospital infections, we analyzed 229 questionnaires (84.8% of 270 sent) completed by surveyed healthcare workers who cared for patients with SARS in 3 types of hospitals, to identify surveillance problems. Atypical clinical presentation was the most often reported problem, regardless of hospital type, which strongly indicates that more timely syndromic surveillance was needed.

Background The novel avian influenza H7N9 virus has caused severe diseases in humans in eastern China since the spring of 2013. On January 18th 2014, a doctor working in the emergency department of a hospital in Shanghai died of H7N9 virus infection. To understand possible reasons to explain this world’s first fatal H7N9 case of a health care worker (HCW), we summarize the clinical presentation, epidemiological investigations, laboratory results, and prevention and control policies and make important recommendations to hospital-related workers. Case presentation The patient was a 31-year-old male Chinese surgeon who was obese and had a five-year history of hypertension and suspected diabetes. On January 11th 2014, he showed symptoms of an influenza-like illness. Four days later, his illness rapidly progressed with bilateral pulmonary infiltration, hypoxia and lymphopenia. On January 17th, the case had a high fever, productive cough, chest tightness and shortness of breath, so that he was administered with oseltamivir, glucocorticoid, immunoglobulin, and broad-spectrum antibiotic therapy. The case died in the early morning of next day after invasive ventilation. He had no contact with poultry nor had he visited live-poultry markets (LPMs), where positive rates of H7N9 were 14.6 % and 18.5 %. Before his illness, he cared for three febrile patients and had indirect contact with one severe pneumonia patient. Follow-up with 35 close contacts identified two HCWs who had worked also in emergency department but had not worn masks were anti-H7N9-positive. Viral sequence identity percentages between the patient and two LPM-H7N9 isolates were fewer than between the patient and another human case in shanghai in January of 2014. Conclusions Important reasons for the patient’s death might include late treatment with oseltamivir, and the infected H7N9 virus carrying both mammalian-adapted signature (HA-Q226L) and aerosol transmissibility (PB2-D701N). The LPM he passed every day was an unlikely source of his infection, but a contaminated environment, or an unidentified mild/asymptomatic H7N9 carrier were more probable. We advocate rigorous standard operating procedures for infection control practices in hospital settings and evaluations thereafter.

School children may transmit pathogens with cluster cases occurring on campuses and in families. In response to the 2009 influenza A (H1N1) pandemic, Taipei City Government officials developed a School-based Infectious Disease Syndromic Surveillance System (SID-SSS). Teachers and nurses from preschools to universities in all 12 districts within Taipei are required to daily report cases of symptomatic children or sick leave requests through the SID-SSS. The pre-diagnosis at schools is submitted firstly as common pediatric disease syndrome-groups and re-submitted after confirmation by physicians. We retrieved these data from January 2010 to August 2011 for spatio-temporal analysis and evaluated the temporal trends with cases obtained from both the Emergency Department-based Syndromic Surveillance System (ED-SSS) and the Longitudinal Health Insurance Database 2005 (LHID2005). Through the SID-SSS, enterovirus-like illness (EVI) and influenza-like illness (ILI) were the two most reported syndrome groups (77.6% and 15.8% among a total of 19,334 cases, respectively). The pre-diagnosis judgments made by school teachers and nurses showed high consistency with physicians' clinical diagnoses for EVI (97.8%) and ILI (98.9%). Most importantly, the SID-SSS had better timeliness with earlier peaks of EVI and ILI than those in the ED-SSS. Furthermore, both of the syndrome groups in these two surveillance systems had the best correlation reaching 0.98 and 0.95, respectively (p

BackgroundHuman infections with avian influenza viruses (AIVs) have frequently raised global concerns of emerging, interspecies-transmissible viruses with pandemic potential. Waterfowl, the predominant reservoir of influenza viruses in nature, harbor precursors of different genetic lineages that have contributed to novel pandemic influenza viruses in the past.MethodsTwo duck influenza H5N2 viruses, DV518 and DV413, isolated through virological surveillance at a live-poultry market in Taiwan, showed phylogenetic relatedness but exhibited different replication capabilities in mammalian Madin-Darby Canine Kidney (MDCK) cells. This study characterizes the replication properties of the two duck H5N2 viruses and the determinants involved.ResultsThe DV518 virus replicated more efficiently than DV413 in both MDCK and chicken DF1 cells. Interestingly, the infection of MDCK cells by DV518 formed heterogeneous plaques with great differences in size [large (L) and small (S)], and the two viral strains (p518-L and p518-S) obtained from plaque purification exhibited distinguishable replication kinetics in MDCK cells. Nonetheless, both plaque-purified DV518 strains still maintained their growth advantages over the plaque-purified p413 strain. Moreover, three amino acid substitutions in PA (P224S), PB2 (E72D), and M1 (A128T) were identified in intra-duck variations (p518-L vs p518-S), whereas other changes in HA (N170D), NA (I56T), and NP (Y289H) were present in inter-duck variations (DV518 vs DV413). Both p518-L and p518-S strains had the N170D substitution in HA, which might be related to their greater binding to MDCK cells. Additionally, polymerase activity assays on 293T cells demonstrated the role of vRNP in modulating the replication capability of the duck p518-L viruses in mammalian cells.ConclusionThese results demonstrate that intra-host phenotypic variation occurs even within an individual duck. In view of recent human infections by low pathogenic AIVs, this study suggests possible determinants involved in the stepwise selection of virus variants from the duck influenza virus population which may facilitate inter-species transmission.