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Background The optimal antibiotic regimen for the medical management of acute appendicitis remains unknown due to a lack of head-to-head comparisons between different antibiotic regimens. Methods We systematically searched the PubMed, EMBASE, Scopus and Cochrane Central Register of Controlled Trials databases from their inception through to August 2020. We selected randomized controlled trials (RCTs) or observational studies comparing antibiotic therapy and appendectomy as the initial treatment for adult or paediatric patients with acute appendicitis. We performed a Bayesian network meta-analysis (NMA) to obtain the indirect comparison results between different antibiotic regimens by employing the group managed by surgery as a common comparator. Antibiotic regimens were classified into three categories: those including a carbapenem; those including a cephalosporin; and those including a β-lactam/β-lactamase inhibitor combination. Results A total of 9 RCTs (adults, n = 8; paediatrics, n = 1) and 12 observational studies (adults, n = 3; paediatrics, n = 9) were included in the NMA, with a total of 4551 patients. The most commonly administered regimen was a β-lactam/β-lactamase inhibitor combination (9/21; 43%), followed by a cephalosporin (7/21; 33%) or a carbapenem (5/21; 24%). The NMA indicated that surgery significantly increased 1 year treatment success, compared with cephalosporins [OR: 16.79; 95% credible interval: 3.8–127.64] or β-lactam/β-lactamase inhibitor combinations (OR: 19.99; 95% credible interval: 4.87–187.57), but not carbapenems (OR: 3.50, 95% credible interval: 0.55–38.63). In contrast, carbapenems were associated with fewer treatment-related complications compared with surgery (OR: 0.12; 95% credible interval: 0.01–0.85). Conclusions Carbapenems might be recommended as the initial antibiotic regimen for the non-operative management of adult patients with acute appendicitis. Nevertheless, due to the imprecise estimates in our NMA, additional RCTs are needed to corroborate these findings, especially for paediatric patients.

Although transmission of Zika virus (ZIKV) in the Americas has greatly declined since late 2017, recent reports of reduced risks of symptomatic Zika by prior dengue virus (DENV) infection and increased risks of severe dengue disease by previous ZIKV or DENV infection underscore a critical need for serological tests that can discriminate past ZIKV, DENV, and/or other flavivirus infections and improve our understanding of the immune interactions between these viruses and vaccine strategy in endemic regions. As serological tests for ZIKV primarily focus on envelope (E) and nonstructural protein 1 (NS1), antibodies to other ZIKV proteins have not been explored. Here, we employed Western blot analysis using antigens of 6 flaviviruses from 3 serocomplexes to investigate antibody responses following reverse transcription-PCR (RT-PCR)-confirmed ZIKV infection. Panels of 20 primary ZIKV and 20 ZIKV with previous DENV infection recognized E proteins of all 6 flaviviruses and the NS1 protein of ZIKV with some cross-reactivity to DENV. While the primary ZIKV panel recognized only the premembrane (prM) protein of ZIKV, the ZIKV with previous DENV panel recognized both ZIKV and DENV prM proteins. Analysis of antibody responses following 42 DENV and 18 West Nile virus infections revealed similar patterns of recognition by anti-E and anti-NS1 antibodies, whereas both panels recognized the prM protein of the homologous serocomplex but not others. The specificity was further supported by analysis of sequential samples. Together, these findings suggest that anti-prM antibody is a flavivirus serocomplex-specific marker and can be used to delineate current and past flavivirus infections in endemic areas. IMPORTANCE Despite a decline in Zika virus (ZIKV) transmission since late 2017, questions regarding its surveillance, potential reemergence, and interactions with other flaviviruses in regions where it is endemic remain unanswered. Recent studies have reported reduced risks of symptomatic Zika by prior dengue virus (DENV) infection and increased risks of severe dengue disease by previous ZIKV or DENV infection, highlighting a need for better serological tests to discriminate past ZIKV, DENV, and/or other flavivirus infections and improved understanding of the immune interactions and vaccine strategy for these viruses. As most serological tests for ZIKV focused on envelope and nonstructural protein 1, antibodies to other ZIKV proteins, including potentially specific antibodies, remain understudied. We employed Western blot analysis using antigens of 6 flaviviruses to study antibody responses following well-documented ZIKV, DENV, and West Nile virus infections and identified anti-premembrane antibody as a flavivirus serocomplex-specific marker to delineate current and past flavivirus infections in areas where flaviviruses are endemic.

Background/purpose: The clinical manifestations of scrub typhus, murine typhus and acute Q fever in the elderly are not clear. Methods: We conducted a retrospective study to identify the characteristics of the elderly aged ≥65 years with a comparison group aged 18–64 years among patients with scrub typhus, murine typhus, or acute Q fever who were serologically confirmed at three hospitals in Taiwan during 2002–2011. Results: Among 441 cases, including 187 cases of scrub typhus, 166 acute Q fever, and 88 murine typhus, 68 (15.4%) cases were elderly patients. The elderly had a higher severe complication rate (10.3% vs. 3.5%, p = 0.022), but did not have a significantly higher mortality rate (1.47% vs. 0.54%, p = 0.396). Compared with those without severe complications, we found the elderly (p = 0.022), dyspnea (p = 0.006), less relative bradycardia (p = 0.004), less febrile illness (p = 0.004), prolonged prothrombin time (PT) (p = 0.002), higher levels of initial C-reactive protein (p = 0.039), blood leukocyte counts (p = 0.01), and lower platelet counts (p = 0.012) are significantly associated with severe complications. Only prolonged prothrombin time was associated with severe complications in multivariate analysis (p = 0.018, CI 95% 0.01–0.66). Among clinical symptoms and laboratory data, multivariate analysis revealed chills was less frequently occurred in the elderly (p = 0.012, 95% confidence interval [CI]: 1.33–9.99). Conclusion: The elderly cases with scrub typhus, murine typhus, or acute Q fever would be more likely to have severe complications, for which prothrombin time prolongation is an important predictor for severe complications. Keywords: Elderly, Scrub typhus, Acute Q fever, Murine typhus, Complications

Clinical presentations of dengue fever (DF) are diverse and non-specific, causing unpredictable progression and outcomes. Its progression and severity have been associated with cytokine levels alteration. In this study, dengue patients were classified into groups following the 2009 WHO dengue classification scheme to investigate the cytokine signature at different severity of the disease: dengue without warning sign symptoms (A), dengue with warning signs (B), severe dengue (C), other fever (OF) and healthy (Healthy). We analyzed 23 different cytokines simultaneously, namely IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-33, CD14, CD54, CD62E, CD62L, CD62p, CD106, CD121b, CD154, CD178, GM-CSF, IFN-g, MIF, ST2 and TNF from patients admitted to National Cheng Kung University Hospital during the 2015 Taiwan dengue outbreak. Cytokines TNF, CD54, CD62E, CD62L, CD62P, GM-CSF, IL-1b, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, INF-g and MIF were elevated while CD106, CD154, IL-4 and L-33 were decreased when compared to the control. IL-10 demonstrated to be a potential diagnostic marker for DF (H and A group, AUC = 0.944, H and OF group, AUC = 0.969). CD121b demonstrated to be predictive of the SD (A and B group, AUC = 0.744, B and C group, AUC = 0.775). Our results demonstrate the cytokine profile changes during the progression of dengue and highlight possible biomarkers for optimizing effective intervention strategies.

Dengue virus (DENV), the pathogen that causes dengue fever, is mainly transmitted by Aedes aegypti. Surveillance of infected mosquitoes is a major component of integrated mosquito control methods for reducing the risk of vector-born disease outbreaks. However, a specialized rapid test for DENV detection in mosquitoes is not currently available. Utilizing immunoblotting, we found that the secretion of NS1 from both a DENV-infected mosquito cell line and mosquito bodies was below the detection threshold. However, when Triton X-100 was used to lyse infected mosquitoes, intracellular NS1 was released, and could then be effectively detected by the NS1 rapid test. The distribution of DENV NS1 in intrathoracically infected mosquitoes was different from that of orally infected mosquitoes. Next, we performed sensitivity tests by bisecting mosquitoes longitudinally, one half of each mosquito was subjected to the NS1 rapid test while the other half was used for qPCR confirmation. This modified test had a sensitivity of nearly 90% from five days post-infection onwards, while DENV had escaped from the midgut barrier. This adapted test offers a valuable, easy-to-use tool for mosquito surveillance, which is a crucial component of DENV disease control.

Serologic testing remains crucial for Zika virus diagnosis. We found that urea wash in a Zika virus nonstructural protein 1 IgG ELISA distinguishes secondary dengue virus infection from Zika virus infection with previous dengue (sensitivity 87.5%, specificity 93.8%). This test will aid serodiagnosis, serosurveillance, and monitoring of Zika complications in dengue-endemic regions.

Background No study has reported the epidemiology of AIDS-related opportunistic illnesses (AOIs) in patients with newly diagnosed HIV infection in Taiwan in the past decade. Understanding the current trends in AOI-related morbidity/mortality is essential in improving patient care and optimizing current public health strategies to further reduce AOIs in Taiwan in the era of contemporary highly active antiretroviral therapy (HAART). Methods Eligible patients were evaluated at two referral centers between 2010 and 2015. The patients were stratified by date of diagnosis into three periods: 2010–2011, 2012–2013, and 2014–2015. The demographics, HIV stage at presentation according to the United States CDC 2014 case definition, laboratory variables, and the occurrence of AOIs and associated outcomes were compared among the patients. Logistic regression and Cox regression were respectively used to identify variables associated with the occurrence of AOIs within 90 days of HIV enrollment and all-cause mortality. Results Over a mean observation period of 469 days, 1264 patients with newly diagnosed HIV with a mean age of 29 years and mean CD4 count of 275 cells/μL experienced 394 AOI episodes in 290 events. At presentation, 37.7% of the patients had AIDS; the frequency did not significantly differ across groups. The overall proportion of AOIs within the study period was 21.0%, and no decline across groups was observed. The majority of AOIs (91.7%) developed within 90 days of enrollment. All-cause and AOI-related mortality did not significantly differ across groups. Throughout the three study periods, AOIs remained the main cause of death (47/56, 83.9%), especially within 180 days of enrollment (40/42, 95.2%). A CD4 cell count of

Background The explosive spread of Zika virus (ZIKV) and associated microcephaly present an urgent need for sensitive and specific serodiagnostic tests, particularly for pregnant women in dengue virus (DENV)-endemic regions. Recent reports of enhanced ZIKV replication by dengue-immune sera have raised concerns about the role of previous DENV infection on the risk and severity of microcephaly and other ZIKV complications. Methods Enzyme-linked immunosorbent assays (ELISAs) based on ZIKV and DENV nonstructural protein 1 (NS1) were established to test acute, convalescent phase, and post-convalescent phase serum/plasma samples from reverse-transcription polymerase chain reaction-confirmed cases including 20 primary ZIKV, 25 ZIKV with previous DENV, 58 secondary DENV, and 16 primary DENV1 infections. Results ZIKV-NS1 immunoglobulin M (IgM) and immunoglobulin G (IgG) ELISAs combined can detect ZIKV infection with a sensitivity of 95% and specificity of 66.7%. The ZIKV-NS1 IgG cross-reactivity by samples from secondary DENV infection cases ranged from 66.7% to 28.1% (within 1 month to 1-2 years post-illness, respectively). Addition of DENV1-NS1 IgG ELISA can distinguish primary ZIKV infection; the ratio of absorbance of ZIKV-NS1 to DENV1-NS1 IgG ELISA can distinguish ZIKV with previous DENV and secondary DENV infections with a sensitivity of 87.5% and specificity of 81.3%. These findings were supported by analysis of sequential samples. Conclusions An algorithm for ZIKV serodiagnosis based on 3 simple ELISAs is proposed to distinguish primary ZIKV, ZIKV with previous DENV, and secondary DENV infections; this could be applied to serodiagnosis for ZIKV, serosurveillance, and monitoring ZIKV infection during pregnancy to understand the epidemiology, pathogenesis, and complications of ZIKV in dengue-endemic regions.

The explosive spread of Zika virus (ZIKV) and associated complications in flavivirus-endemic regions underscore the need for sensitive and specific serodiagnostic tests to distinguish ZIKV, dengue virus (DENV) and other flavivirus infections. Compared with traditional envelope protein-based assays, several nonstructural protein 1 (NS1)-based assays showed improved specificity, however, none can detect and discriminate three flaviviruses in a single assay. Moreover, secondary DENV infection and ZIKV infection with previous DENV infection, both common in endemic regions, cannot be discriminated. In this study, we developed a high-throughput and multiplex IgG microsphere immunoassay (MIA) using the NS1 proteins of DENV1-DENV4, ZIKV and West Nile virus (WNV) to test samples from reverse-transcription-polymerase-chain reaction-confirmed cases, including primary DENV1, DENV2, DENV3, WNV and ZIKV infections, secondary DENV infection, and ZIKV infection with previous DENV infection. Combination of four DENV NS1 IgG MIAs revealed a sensitivity of 94.3% and specificity of 97.2% to detect DENV infection. The ZIKV and WNV NS1 IgG MIAs had a sensitivity/specificity of 100%/87.9% and 86.1%/78.4%, respectively. A positive correlation was found between the readouts of enzyme-linked immunosorbent assay and MIA for different NS1 tested. Based on the ratio of relative median fluorescence intensity of ZIKV NS1 to DENV1 NS1, the IgG MIA can distinguish ZIKV infection with previous DENV infection and secondary DENV infection with a sensitivity of 88.9–90.0% and specificity of 91.7–100.0%. The multiplex and high-throughput assay could be applied to serodiagnosis and serosurveillance of DENV, ZIKV and WNV infections in endemic regions., Author summary Although there was a decrease of Zika virus (ZIKV) infection since late 2017, the specter of congenital Zika syndrome and its re-emergence in flavivirus-endemic regions emphasize the need for sensitive and specific serological tests to distinguish ZIKV, dengue virus (DENV) and other flaviviruses. Compared with traditional tests based on envelope protein, several nonstructural protein 1 (NS1)-based assays had improved specificity, however, none can discriminate three flaviviruses in a single assay. Moreover, secondary DENV infection and ZIKV infection with previous DENV infection, both common in endemic regions, cannot be distinguished. Herein we developed a high-throughput and multiplex IgG microsphere immunoassay using the NS1 proteins of four DENV serotypes, ZIKV and West Nile virus to test samples from laboratory-confirmed cases with different primary and secondary flavivirus infections. Combination of four DENV NS1 assays revealed a sensitivity of 94.3% and specificity of 97.2%. The ZIKV and WNV NS1 assays had a sensitivity/specificity of 100%/87.9% and 86.1%/78.4%, respectively. Based on the signal ratio of ZIKV NS1 to DENV1 NS1, the assay can distinguish ZIKV infection with previous DENV infection and secondary DENV infection with a sensitivity of 88.9–90.0% and specificity of 91.7–100.0%. This has applications to serodiagnosis and serosurveillance in endemic regions.

The recent outbreaks of Zika virus (ZIKV) and associated birth defects in regions of dengue virus (DENV) endemicity emphasize the need for sensitive and specific serodiagnostic tests. We reported previously that enzyme-linked immunosorbent assays (ELISAs) based on the nonstructural protein 1 (NS1) of DENV serotype 1 (DENV1) and ZIKV can distinguish primary DENV1, secondary DENV, and ZIKV infections. Whether ELISAs based on NS1 proteins of other DENV serotypes can discriminate various DENV and ZIKV infections remains unknown. We herein developed DENV2, DENV3, and DENV4 NS1 IgG ELISAs to test convalescent- and postconvalescent-phase samples from reverse transcription-PCR-confirmed cases, including 25 primary DENV1, 24 primary DENV2, 10 primary DENV3, 67 secondary DENV, 36 primary West Nile virus, 38 primary ZIKV, and 35 ZIKV with previous DENV infections as well as 55 flavivirus-naive samples. Each ELISA detected primary DENV infection with a sensitivity of 100% for the same serotype and 23.8% to 100% for different serotypes. IgG ELISA using a mixture of DENV1-4 NS1 proteins detected different primary and secondary DENV infections with a sensitivity of 95.6% and specificity of 89.5%. The ZIKV NS1 IgG ELISA detected ZIKV infection with a sensitivity of 100% and specificity of 82.9%. On the basis of the relative optical density ratio, the combination of DENV1-4 and ZIKV NS1 IgG ELISAs distinguished ZIKV with previous DENV and secondary DENV infections with a sensitivity of 91.7% to 94.1% and specificity of 87.0% to 95.0%. These findings have important applications to serodiagnosis, serosurveillance, and monitoring of both DENV and ZIKV infections in regions of endemicity.

Background Dengue fever, a mosquito-borne disease, is caused by dengue virus (DENV) which includes four major serotypes (DENV-1, -2, -3, and -4). Some serotypes cause more severe diseases than the other; severe dengue is associated with secondary infections by a different serotype. Timely serotyping can provide early warning of dengue epidemics to improve management of patients and outbreaks. A mobile insulated isothermal PCR (iiPCR) system is available to allow molecular detection of pathogens near points of need. Methodology/principle findings In this study, side-by-side comparison with the CDC DENV-1-4 Real Time RT-PCR (qRT-PCR) was performed to evaluate the performance of four singleplex DENV-1-4 serotyping reverse transcription-iiPCR (RT-iiPCR) reagents for DENV subtyping on the mobile PCR system. The four RT-iiPCRs did not react with Zika virus and chikungunya virus; tests with serial dilutions of the four DENV serotypes made in human serum showed they had detection endpoints comparable to those of the reference method, indicating great analytical sensitivity and specificity. Clinical performance of the RT-iiPCR reagents was evaluated by testing 40 serum samples each (around 20 target serotype-positive and 20 DENV-negative); all four reagents had high agreement (97.5-100%) with the reference qRT-PCR. Moreover, testing of mosquitoes separately infected experimentally with each serotype showed that the four reagents detected specifically their target DENV serotypes in mosquito. Conclusions/significance With analytical and clinical performance comparable to the reference qRT-PCR assay, the four index RT-iiPCR reagents on the field-deployable PCR system can serve as a useful tool for DENV detection near points of needs.

BackgroundInfection is the most common predisposing factor for diabetic ketoacidosis (DKA); however, studies are rare that have investigated the clinical outcomes of septic patients with infection-precipitated DKA.MethodsA retrospective cohort study was conducted at a tertiary hospital from 2004 to 2013. Patients with DKA in whom the presence of a predisposing infection was confirmed were enrolled. Characteristics at initial presentation, primary infection sources, and causative microorganisms were compared between the nonacute kidney injury (non-AKI) group and acute kidney injury (AKI) group at each stage. Risk factors for the development of failure-stage AKI and its outcomes were also analyzed.ResultsOne hundred and sixty DKA episodes were assessed. The most common infection sites were the urinary and respiratory tracts. The leading causative microorganism was Escherichia coli, followed by Klebsiella pneumoniae. A complicated/severe infection state [odds ratio (OR), 15.27; p

In Taiwan, the number of new cases of human immunodeficiency virus (HIV) infection via drug injection has been increasing since 2003. Due to HIV and hepatitis B virus (HBV) having similar transmission routes, HBV and HIV infections among injecting drug users (IDUs) has become an important public health issue. The aim of this study was explore the prevalence of HBV infection among IDUs with and without HIV infection, and examine whether HIV infection is associated with HBV infection among IDUs in Southern Taiwan. We enrolled 566 IDUs, including 87 anti-HBV positive IDUs and 479 anti-HBV negative IDUs, and also analyzed the results of liver function tests, HBV DNA, anti-HIV, HIV RNA, and CD4 cell count. The results showed that the prevalence of HBV infection among IDUs was 15.4%. The prevalence of hepatitis B surface antigen (HBsAg) was higher among individuals born before 1985 (15.9% vs. 4.0%), but this was not significant. Anti-HIV seropositivity was related to HBsAg seropositivity [odds ratio (OR) = 2.47, 95% confidence interval = 1.26–4.82, p = 0.008). Anti-HCV and anti-HIV were risk factors for abnormal alanine aminotransferase (ALT; OR = 2.11, 95% confidence interval = 1.005–4.42, p = 0.048 and OR = 1.47, 95% confidence interval = 1.02–2.10, p = 0.04, respectively), and HBsAg was not a factor related to abnormal ALT. In conclusion, the prevalence of HBV infection was similar in the general population and in IDUs, and due to anti-HIV seropositivity being significantly related to HBsAg seropositivity, HBV infection among IDUs is still important. We suggest that for IDUs, HBsAg should be monitored closely.

Early diagnosis is important for the clinical management of diseases caused by dengue virus (DENV) infections. We investigated the performance of three commercially available DENV nonstructural protein 1 (NS1) rapid diagnostic tests (RDTs) using 173 acute-phase sera collected from dengue fever-suspected patients during the 2012-2013 DENV outbreak in Taiwan. The results of the NS1 RDTs were compared with those of qRT-PCR to calculate the sensitivity and specificity of the NS1 RDTs. The anti-DENV IgM and IgG RDT results were included to increase the probability of detecting acute DENV infection. The anti-DENV IgM/IgG RDT results were also compared with those of IgM/IgG captured ELISA. The sera from DENV qRT-PCR-positive patients were subjected to NS1 RDTs, as well as IgM/IgG captured ELISA. These results suggested that there was no significant difference in the sensitivities of the three commercially available DNEV NS1 RDTs; the SD NS1 RDT results showed the highest agreement with the qRT-PCR reference results, followed in order by the Bio-Rad and CTK NS1 RDT results when the specificity was considered. Inclusion of the IgM or IgG RDT results increased the likelihood of diagnosing either a primary or secondary DENV infection. NS1 RDTs were more sensitive for the detection of primary infections than secondary infections, related to DENV viremia levels determined by qRT-PCR. These results suggested that anti-DENV antibodies reduced the sensitivity of NS1 rapid tests. We also analyzed the sensitivity for the detection of different DENV serotypes, and the results suggested that the NS1 RDTs used in this study were valuable for rapid screening of acute DENV infection with DENV-1, DENV-2 and DENV-3. Our results suggest that the NS1 RDT is a good alternative to qRT-PCR analysis for timely dengue disease management and prevention in dengue-endemic regions where medical resources are lacking or during large dengue outbreaks. However, the relatively low sensitivity for DENV-4 might miss the detection of DENV-4-infected cases.

Dengue virus (DENV) infection causes various clinical presentations, including asymptomatic infection, dengue with or without warning signs and severe dengue. An early and accurate diagnosis of DENV infection during the first few days of illness supports clinical management and significantly reduces dengue-associated mortality and morbidity. However, it is very difficult to confirm DENV infection in endemic regions without qualified dengue diagnostic laboratories. In this study, we evaluated the performance of two commercially available rapid diagnostic tests (RDTs) using serum samples collected in the Solomon Islands during the 2013 DENV-3 outbreak. The sensitivity and specificity of the tests were calculated by comparing the results of DENV nonstructural protein 1 (NS1), IgM and IgG RDTs with those obtained by qRT-PCR. We also compared the results of the DENV IgM/IgG RDT with those obtained using an IgM/IgG capture enzyme-linked immune-sorbent assay (ELISA). The sensitivities of the SD and CTK NS1 RDTs were similar (90.9% and 92.6%), and the specificity of the SD NS1 RDT was significantly higher than that of the CTK NS1 RDT (100% versus 78.8%). The inclusion of IgM and IgG in the RDT did not significantly increase the sensitivity for DENV diagnosis. Compared with the SD IgM RDT, IgM capture ELISA had the same specificity but higher sensitivity. User-friendly RDTs remain the first choice and the most convenient tool in dengue endemic regions, where laboratory facilities and the corresponding infrastructure are lacking. Our study provided important and practical information for comparing the performance and validity of the different RDTs for rapid dengue detection.

Dengue virus (DENV) infection, a mosquito-borne disease, is a major public health problem in tropical countries. Point-of-care DENV detection with good sensitivity and specificity enables timely early diagnosis of DENV infection, facilitating effective disease management and control, particularly in regions of low resources. The Pockit dengue virus reagent set (GeneReach Biotech), a reverse transcription insulated isothermal PCR (RT-iiPCR), is available to detect all four serotypes of DENV on the field-deployable Pockit system, which is ready for on-site applications. In this study, analytical and clinical performances of the assay were evaluated. The index assay did not react with 14 non-DENV human viruses, indicating good specificity. Compared to the U.S. CDC DENV-1–4 real-time quantitative RT-PCR (qRT-PCR) assay, testing with serial dilutions of virus-spiked human sera demonstrated that the index assay had detection endpoints that were separately comparable with the 4 serotypes. Excellent reproducibility was observed among repeat tests done by six operators at three sites. In clinical performance, 195 clinical sera collected around Kaohsiung city in 2012 and 21 DENV-4-spiked sera were tested with the RT-iiPCR and qRT-PCR assays in parallel. The 121 (11 DENV-1, 78 DENV-2, 11 DENV-3, and 21 DENV-4) qRT-PCR-positive and 95 qRT-PCR-negative samples were all positive and negative by the RT-iiPCR reagent results, respectively, demonstrating high (100%) interrater agreement (95% confidence interval [CI 95% ], ∼98.81% to 100%; κ = 1). With analytical and clinical performance equivalent to those of the reference qRT-PCR assay, the index PCR assay on the field-deployable system can serve as a highly sensitive and specific on-site tool for DENV detection.

To determine the prevalence of asymptomatic dengue virus-infected blood donors during the largest dengue outbreak in Taiwan history occurred in 2015, we examined the evidence of dengue virus (DENV) infection by the detection of DENV RNA genome using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR), DENV NS1 antigen using rapid diagnosis test (RDT) and anti-dengue antibody using IgM/IgG capture enzyme-linked immunosorbent assay (capture ELISA) and RDT in eight thousand serum samples from blood donations to the blood centers of the Taiwan Blood Services Foundation (TBSF) in Kaohsiung City and Tainan City during the largest dengue outbreak in Taiwan history occurred in 2015. Only one serum sample was positive for DENV RNA detection by using dengue-specific real-time RT-PCR, the virus was DENV-2 determined by serotype-specific real-time RT-PCR and sequencing, and the DENVs in the serum were confirmed as being infectious by a plaque assay. The recipient of this blood did not develop any dengue fever symptom on follow-up. None of the samples was NS1 RDT-reactive. Seventeen IgM-positive samples were identified. There was a low prevalence of asymptomatic confirmed or probable DENV-infected blood donors in our study (0.013% and 0.21%, respectively), and no symptomatic transfusion-transmitted dengue (TT dengue) was developed during the largest dengue outbreak in Taiwan history in highly endemic areas and periods.

The four serotypes of dengue virus (DENV) cause the most important and rapidly emerging arboviral diseases in humans. The recent phase 2b and 3 studies of a tetravalent dengue vaccine reported a moderate efficacy despite the presence of neutralizing antibodies, highlighting the need for a better understanding of neutralizing antibodies in polyclonal human sera. Certain type-specific (TS) antibodies were recently discovered to account for the monotypic neutralizing activity and protection after primary DENV infection. The nature of neutralizing antibodies after secondary DENV infection remains largely unknown. In this study, we examined sera from 10 vaccinees with well-documented exposure to first and second DENV serotypes through heterotypic immunization with live-attenuated vaccines. Higher serum IgG avidities to both exposed and nonexposed serotypes were found after secondary immunization than after primary immunization. Using a two-step depletion protocol to remove different anti-envelope antibodies, including group-reactive (GR) and complex-reactive (CR) antibodies separately, we found GR and CR antibodies together contributed to more than 50% of neutralizing activities against multiple serotypes after secondary immunization. Similar findings were demonstrated in patients after secondary infection. Anti-envelope antibodies recognizing previously exposed serotypes consisted of a large proportion of GR antibodies, CR antibodies, and a small proportion of TS antibodies, whereas those recognizing nonexposed serotypes consisted of GR and CR antibodies. These findings have implications for sequential heterotypic immunization or primary immunization of DENV-primed individuals as alternative strategies for DENV vaccination. The complexity of neutralizing antibodies after secondary infection provides new insights into the difficulty of their application as surrogates of protection. IMPORTANCE The four serotypes of dengue virus (DENV) are the leading cause of arboviral diseases in humans. Despite the presence of neutralizing antibodies, a moderate efficacy was recently reported in phase 2b and 3 trials of a dengue vaccine; a better understanding of neutralizing antibodies in polyclonal human sera is urgently needed. We studied vaccinees who received heterotypic immunization of live-attenuated vaccines, as they were known to have received the first and second DENV serotype exposures. We found anti-envelope antibodies consist of group-reactive (GR), complex-reactive (CR), and type-specific (TS) antibodies, and that both GR and CR antibodies contribute significantly to multitypic neutralizing activities after secondary DENV immunization. These findings have implications for alternative strategies for DENV vaccination. Certain TS antibodies were recently discovered to contribute to the monotypic neutralizing activity and protection after primary DENV infection; our findings of the complexity of neutralizing activities after secondary immunization/infection provide new insights for neutralizing antibodies as surrogates of protection.

Human respiratory syncytial virus (HRSV) infects all age groups and causes bronchiolitis, pneumonia, and acute respiratory distress syndrome with a significant mortality rate. To date, only ribavirin has been used to manage HRSV infection. However, ribavirin is expensive with an only modest effect. Furthermore, ribavirin has several side effects, which means it has limited clinical benefit. Pueraria lobata Ohwi (P. lobata) is a common ingredient of Ge-Gen-Tang (Kakkon-to) and Sheng-Ma-Ge-Gen-Tang (Shoma-kakkon-to), which are prescriptions of Chinese traditional medicine proven to have antiviral activity against HRSV. Therefore, it was hypothesized that P. lobata might be effective against HRSV. To find a cost-effective therapeutic modality, both human upper (HEp-2) and lower (A549) respiratory tract cell lines were used to test the hypothesis that P. lobata could inhibit HRSV-induced plaque formation. Results showed that the water extract of P. lobata was effective (p

Background: Dengue is one of the most important vector-borne human viral diseases globally. The kinetic changes of hematological parameters of dengue in adult Taiwanese patients have seldomly been systematically investigated and characterized. Methodology/Principal Findings: Serial laboratory data of 1,015 adult patients who were diagnosed with dengue virus serotype 2 (DENV2) and 3 (DENV3) infections in southern Taiwan were retrospectively examined. Prominent parameters were verified with specimens from a 2015 dengue outbreak. Higher absolute monocyte counts on day 5 in severe patients than mild fever subjects after the onset of fever was seen. The absolute number of monocytes was significantly greater in those with DENV2 than DENV3 infections in spite of subtle differences in laboratory tests. Platelet counts were lowest and activated partial thromboplastin time was highest on day 5 in patients with severe conditions. In addition, sudden downward platelet counts corresponding to a transient surge of monocytes on day 4 onward was observed. Fluorescence-activated cell sorting analysis of peripheral blood mononuclear cells obtained from acute dengue patients and experimental investigations revealed that phagocytic effects of innate immune cells contribute to thrombocytopenia in dengue patients. Conclusion: Innate phagocytic cells play an essential role in low platelet counts in adult patients with dengue virus infections.

Dengue virus (DENV) is the leading cause of arboviral diseases in humans worldwide. In this study, we investigated the seroprevalence of DENV infection in two districts of Kaohsiung City, a metropolis in southern Taiwan, where major dengue outbreaks have occurred in the past three decades. We enrolled 1,088 participants from the Sanmin and Nanzih districts after the dengue outbreak of 2015, the largest in Taiwan since World War II, and found an overall DENV seroprevalence of 12.4% (95% confidence interval: 10.5–13.4%) based on the InBios DENV IgG ELISA kit. The ratios of clinically inapparent to symptomatic infections were 2.86 and 4.76 in Sanmin and Nanzih districts, respectively. Consistent with higher case numbers during recent outbreaks, the DENV seroprevalence was higher in Sanmin district (16.4%) than in Nanzih district (6.9%), suggesting district differences in seroprevalence and highlighting the importance of screening the DENV immune status of each individual before using the currently available DENV vaccine, Dengvaxia. In the two districts, the seroprevalence rates increased from 2.1% (in the 30–39-year age group) to 17.1% (60–69) and 50% (70–79). The pattern of a sharp and significant increase in seroprevalence in the 70–79-year age group correlated with a dramatic increase in the proportion of clinically severe DENV infections among total dengue cases in that age group. This differed from observations in the Americas and Southeast Asia and suggested that a large proportion of monotypically immune individuals together with other risk factors may contribute to clinically severe dengue among the elderly in Taiwan., Author summary Dengue virus (DENV) is the most important cause of mosquito-borne viral disease in humans worldwide. Investigating DENV seroprevalence in Kaohsiung City after the largest dengue outbreak in Taiwan since World War II, we found an overall seroprevalence of 12.4% and heterogeneity in seroprevalence within a metropolis; this together with the low efficacy and potential disease enhancement of the currently available dengue vaccine (Dengvaxia) in DENV-naive individuals highlighted the importance of checking the DENV immune status of individuals prior to Dengvaxia vaccination. The pattern of a sharp and significant increase in DENV seroprevalence in the 70–79 year age group in Kaohsiung City was different from that in the Americas and Southeast Asia, and suggested that a large proportion of monotypically immune individuals in that age group together with other risk factors may contribute to clinically severe dengue disease among the elderly in Taiwan.

In regions that are hyperendemic for chronic hepatitis B virus (HBV) infection prevalence of and risk factors associated with isolated anti-hepatitis B core antibody (anti-HBc) in HIV-positive patients are less well described. HIV-positive patients who were tested for hepatitis B surface antigen (HBsAg) anti-hepatitis B surface antibody (anti-HBs) and anti-HBc at designated hospitals for HIV care in Taiwan were included for analysis. HBV DNA was detected by real-time polymerase chain reaction in patients with and without isolated anti-HBc. Of 2351 HIV-positive patients 450 (19.1%) were HBsAg positive 411 (17.5%) were anti-HBc positive alone and 963 (41.0%) for both anti-HBs and anti-HBc. Compared with patients who were positive for both anti-HBs and anti-HBc patients with isolated anti-HBc were older less likely to have anti-hepatitis C virus antibody (anti-HCV) had lower CD4 lymphocyte counts and higher plasma HIV RNA loads. Older age (adjusted odds ratio 1.029; 95% confidence interval 1.015-1.043) and CD4

Enterovirus 71 (EV71) can cause brain encephalitis and mortality. However, effective vaccines or chemotherapeutic agents are not yet available. We tested the hypothesis that Pueraria lobata could inhibit the cytotoxic effect of EV71 in a human foreskin fibroblast cell line by the XTT method. Our results showed that the water extract of P. lobata could inhibit cytopathy induced by EV71 when given before (p < 0.0001), simultaneously with (p < 0.0001), or after viral infection (p < 0.0001). Water extract of P. lobata was effective and its minimal concentration that inhibited 50% of the cytopathic effect (IC50) was 0.028 μg/mL. P. lobata was also safe with a selectivity index greater than 107,000. Water extract of P. lobata appeared to inhibit viral attachment (p < 0.0001) and penetration (p < 0.0001). The anti-EV71 activity of the water extract of P. lobata was not mediated by interferons. In conclusion, the water extract of P. lobata was effective in the management of the disease induced by EV71 infection.

Background and objectives: In the 2002 dengue outbreak in Taiwan, some fatal cases had the underlying disease of renal failure (RF). Physicians faced difficulty in diagnosis and treatment of these patients; however, the impacts of RF on the clinical presentations and outcomes of dengue infection have not been reported previously. Design, setting, participants, & measurements: A retrospective review was conducted of medical records, clinical presentations, laboratory findings, and underlying diseases for all cases of dengue infection in a medical center. Characteristics and outcomes of dengue-infected patients with and without RF were compared. Results: From January 2002 through January 2003, 519 dengue-infected patients were enrolled, including 412 patients with classical dengue fever (DF) and 107 patients with dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). Twelve patients died in this outbreak, and all had DHF/DSS. Twenty-one (4.0%) patients were defined as being in the RF group. The RF group had a higher mortality rate than non-RF group (28.6 versus 1.2%; P < 0.001). The severity of GFR impairment was associated with higher percentages of DHF/DSS (P = 0.029) and mortality (P < 0.001). Differences in symptoms/signs and laboratory abnormalities between DF and DHF/DSS were significant in the non-RF group but not apparent in the RF group. Conclusions: The diagnosis and management of dengue infection among patients with RF must be cautious, because complicated clinical courses with a higher mortality rate were well observed.

In 2002, a dengue outbreak occurred in Taiwan with 5336 confirmed cases, 242 DHF and 21 death, the case fatality rate reached 8.7% (21/242). The demographic data of these age-specific dengue patients showed that dengue virus infection caused symptom primarily occurred in adults. A comparative analysis of clinical and laboratory data for DF, DHF/DSS and fatal DSS found that high fatality from dengue infection was associated with the following patient conditions: (1) age above 55 years, (2) underlying diseases with hypertension, chronic renal insufficiency, or diabetes, (3) abnormal thrombocytopenia, APTT and PT prolongation, low hematocrit (

The levels of neutralizing antibody to a pathogen are an effective indicator to predict efficacy of a vaccine in trial. And yet not all the trial vaccines are in line with the theory. Using dengue virus (DENV) to investigate the viral morphology affecting the predictive value, we evaluated the viral morphology in acute dengue plasma compared to that of Vero cells derived DENV. The virions in plasma were infectious and heterogeneous in shape with a “sunny-side up egg” appearance, viral RNA was enclosed with CD61+ cell-derived membrane interspersed by the viral envelope protein, defined as dengue vesicles. The unique viral features were also observed from ex vivo infected human bone marrow. Dengue vesicles were less efficiently neutralized by convalescent patient serum, compared to virions produced from Vero cells. Our results exhibit a reason why potencies of protective immunity fail in vivo and significantly impact dengue vaccine and drug development.

Purpose: To present the immunologic status and clinical manifestations of patients who had infectious scleritis after pterygium excision. Methods: This prospective noncomparative study of immunologic status and clinical manifestations involved 18 eyes of 18 patients with infectious scleritis (16 bacterial and 2 fungal infections) with a history of pterygium excision from 1999 to 2001. Results: The period between pterygium excision and scleritis ranged from 1 to 36 years. None of the 18 patients had any history of systemic autoimmune disease. Elevated erythrocyte sedimentation rates were found in 9 (50%) of 18 patients. Elevated serum C-reactive protein levels were found in 9 (75%) of 12 patients. Other serologic tests were all negative. The most common pathogen of infectious scleritis, Pseudomonas aeruginosa, was present in 13 patients (72.2%), significantly higher than any others (P < 0.05). All of the eyeballs were salvaged, and 9 (50%) of 18 patients had final vision better than 2/20. Conclusion: There was no underlying autoimmune disease associated with infectious scleritis in this study. Early diagnosis and aggressive medical and surgical treatment might have saved the eyes.

We assessed the seroprevalence of Entamoeba histolytica infection using indirect hemagglutination antibody (IHA) assay among 667 HIV-infected persons (group A), 1,311 asymptomatic HIV-uninfected persons seeking anonymous HIV testing (group B), 616 HIV-uninfected controls with gastrointestinal symptoms (diarrhea and/or liver abscess) seeking medical care (group C), and 2,500 healthy controls undergoing health check-up (group D). An IHA titeror= 128 was detected in 7.1% of group A, 2.5% of group B, 1.8% of group C, and 0.1% of group D (P0.0001). The highest seroprevalence (11.2%) was noted among HIV-infected persons who were men having sex with men (MSM) 30-39 years of age. Compared with persons with gastrointestinal symptoms, the adjusted odds ratio for having high IHA titers among HIV-infected persons was 3.206 (95% confidence interval, 1.433, 7.176; P = 0.005). These findings show that HIV-infected persons, especially MSM 30-39 years of age, are at significantly higher risk of E. histolytica infection.

Hemophagocytic syndrome is a rare complication of acute Q fever. We reported the case of 26-year-old man with fever, chills, severe headache, non-productive cough and progressive thrombocytopenia. Bone marrow aspirate revealed hemophagocytosis. We discussed the differences among the three previous reported cases and the possible mechanisms of hemophagocytic syndrome.

A 33-year-old man had dengue hemorrhagic fever with initial presentation of fever, leukocytosis, and thrombocytopenia. The cause of the subsequent rapid decline in red cell counts without evidence of intravascular hemolysis or massive bleeding was confirmed as hemophagocytosis and dyserythropoiesis by bone marrow study. The patient recovered with supportive care and the bone marrow pattern was normal on repeated bone marrow study. To our knowledge, this is the first reported case of dengue virus-associated hemophagocytosis and dyserythropoiesis in Taiwan. Clinicians should consider that the occurrence of hemophagocytosis and dyserythropoiesis could be due to dengue virus infection. That this dengue virus infection was confirmed by a positive serology result at the convalescent stage but not at the acute symptomatic stage underlines the need for a second dengue serology study, as dengue infection can be missed due to an initial negative serology result.

Long-term care of human HIV and AIDS cases has raised quality of life (QoL) issues. The aim of this study was to identify QoL in HIV/AIDS male outpatients receiving highly active antiretroviral therapy (HAART) and its correlates in Taiwan. In total, 41 HIV/AIDS male outpatients receiving HAART yet presenting few symptoms of infection, were recruited for the study. Their QoL levels were measured with the Taiwan version of the Short Form of the World Health Organization Quality of Life questionnaire (WHOQOL-BREF). The relationships between QoL and demographic characteristics, social support, negative stressors, depression, characteristics of HIV infection, attitude toward HIV infection, and adverse effects of HAART, were examined. The results of the analysis reveal that multiple factors affect QoL for HIV/AIDS male outpatients receiving HAART, including severity of depression, deterioration of work function, inconvenience resulting from medication schedules and medical appointments, lack of social support, negative stressors, and adverse effects of HAART. The results provide screening factors so that clinicians can intervene to improve the QoL for their HIV patients.

Background Dengue fever, rickettsial diseases, and Q fever are acute febrile illnesses with similar manifestations in tropical areas. Early differential diagnosis of scrub typhus, murine typhus, and Q fever from dengue fever may be made by understanding the distinguishing clinical characteristics and the significance of demographic and weather factors. Methods We conducted a retrospective study to identify clinical, demographic, and meteorological characteristics of 454 dengue fever, 178 scrub typhus, 143 Q fever, and 81 murine typhus cases in three Taiwan hospitals. Results Case numbers of murine typhus and Q fever correlated significantly with temperature and rainfall; the scrub typhus case number was only significantly related with temperature. Neither temperature nor rainfall correlated with the case number of dengue fever. The rarity of dengue fever cases from January to June in Taiwan may be a helpful clue for diagnosis in the area. A male predominance was observed, as the male-to-female rate was 2.1 for murine typhus and 7.4 for Q fever. Multivariate analysis revealed the following six important factors for differentiating the rickettsial diseases and Q fever group from the dengue fever group: fever ≥8 days, alanine aminotransferase > aspartate aminotransferase, platelets >63,000/mL, C-reactive protein >31.9 mg/L, absence of bone pain, and absence of a bleeding syndrome. Conclusion Understanding the rarity of dengue in the first half of a year in Taiwan and the six differentiating factors may help facilitate the early differential diagnosis of rickettsial diseases and Q fever from dengue fever, permitting early antibiotic treatment.

The aim of this study is to explore the prevalence of hepatitis C virus (HCV) infection among injection drug users (IDUs) with and without human immunodeficiency virus (HIV) infection in southern Taiwan. For 562 IDUs (265 anti-HIV negative, 297 anti-HIV positive), we analyzed liver function, anti-HIV antibody, anti-HCV antibody, HCV viral loads, and hepatitis B surface antigen (HBsAg). HIV RNA viral loads and CD4 cell count for anti-HIV-seropositive IDUs and the HCV genotype for HCV RNA-seropositive IDUs were measured. The seroprevalence rates of anti-HIV, anti-HCV, and HBsAg were 52.8%, 91.3%, and 15.3%, respectively. All the anti-HIV-seropositive IDUs were positive for HIV RNA. Anti-HCV seropositivity was the most important factor associated with HIV infection (odds ratio [OR], 25.06; 95% confidence intervals [CI], 8.97–74.9), followed by male gender (OR, 6.12; 95% CI, 4.05–9.39) and HBsAg seropositivity (OR, 1.90; 95% CI, 1.11–3.34). Among IDUs positive for anti-HCV, 80.7% had detectable HCV RNA. HCV viremia after HCV exposure was strongly related to HIV infection (OR, 6.262; 95% CI, 1.515–18.28), but negatively correlated to HBsAg seropositivity (OR, 0.161; 95% CI, 0.082–0.317). HCV genotype 6 was the most prevalent genotype among all IDUs (41.0%), followed by genotypes 1 (32.3%), 3 (12.8%), and 2 (5.6%). In conclusion, about half IDUs were infected with HIV and >90% with HCV infection. Male and seropositivity for HBsAg and anti-HCV were factors related to HIV infection among our IDUs. HIV was positively correlated, whereas hepatitis B co-infection was negatively correlated with HCV viremia among IDUs with HCV exposure. Different HCV molecular epidemiology was noted among IDUs.

Eight hundred and seventy-nine HIV-1-infected patients (comprising 46% of reported HIV-1/AIDS cases in Taiwan) were recruited for this study of the molecular epidemiology of HIV-1 in Taiwan from 1988 to 1998. HIV-1 subtypes were determined using a modified peptide-enzyme immunoassay complemented with DNA sequencing and phylogenetic analysis. Of the 807 HIV-1 infected men, 68.2% were infected with HIV-1B, 29.5% with HIV-1 circulating recombinant form (CRF)01_AE and 2.3% with other subtypes. Of the 72 HIV-1-infected women, 72.2% were infected with HIV-1 CRF01_AE, 13.9% with HIV-1B, and 13.9% with other subtypes. All of 8 foreign-born, Southeast Asian women and 6 of 7 (85.7%) Taiwan-native female commercial sex workers were infected with HIV-1 CRF01_AE. Fourteen of the 33 (42.4%) heterosexual married men with CRF01_AE had transmitted HIV-1 to their wives, whereas only 1 of 17 (5.9%) men with HIV-1 B had transmitted HIV-1 to their spouses (p < .01). Of 18 heterosexual male injecting drug users, 1 of 12 (8.5%) with HIV-1B and 5 of 6 (83.3%) with HIV-1 CRF01_AE had had sexual contact with female commercial sex workers (p < .01). Therefore, in this population, CRF01_AE was preferentially associated with heterosexual risk groups, a finding compatible with differences in transmission capability between B and non-B subtypes.

To the Editor: Rickettsia felis, the etiologic agent of flea-borne spotted fever, is carried by fleas worldwide (1). In the past decade, several human cases of R. felis infection have been reported (1–3). Clinical symptoms and biological data for R. felis infections are similar to those for murine typhus and other rickettsial diseases, which makes clinical diagnosis difficult (2). Patients with R. felis infections may have common clinical manifestations, such as fever, headache, myalgia, macular rash, and elevated levels of liver enzymes (4,5). Reportable rickettsioses in Taiwan include scrub typhus, epidemic typhus, and murine typhus. Although there are no known human cases of infections caused by spotted fever group (SFG) rickettsiae in Taiwan, novel strains of SFG rickettsiae have been isolated as recently described (6,7). In addition, evidence for R. felis infections in cat and cat flea populations has been identified by using immunofluorescence assay (IFA), PCR, and organism isolation (K.-H.Tsai et al., unpub. data). We report an indigenous human case of R. felis infection in Taiwan. In January 2005, a 27-year-old woman living in Fongshan City, Kaohsiung County, in southern Taiwan was admitted to Kaohsiung Medical University Hospital with a 4-day history of intermittent fever (37.8°C–38.0°C), chills, headache, and fatigue. Associated symptoms were frequent micturition and a burning sensation upon voiding. The patient was admitted with a possible urinary tract infection; urinalysis showed pyuria (leukocyte count 25–50/high-power field), compatible with the clinical diagnosis. During the 6-day hospital stay, the patient received daily intravenous first-generation cephalosporin (cefazolin); gentamicin was given only on the first 3 days. She was discharged with a prescription for oral antimicrobial drugs (cephradine 500 mg every 6 h) to be taken for 7 days. Micturition-associated symptoms subsided after treatment. The patient also had headaches and glove-and-stocking numbness in both hands because of fever, but denied any associated rash and arthralgia. Although the patient did not recall any arthropod bites, she had noticed some stray dogs and cats nearby and rodents in the neighborhood surrounding her house. Because of acute polyneuropathy-like symptoms and exposure history, we prescribed oral doxycycline (100 mg every 12 hours) for 5 days as empirical therapy on the second day at the hospital, suspecting a zoonosis such as rickettsioses, Q fever, or leptospirosis. Headache and glove-and-stocking numbness subsided. Her blood sugar level and thyroid function were within normal limits. Chest radiograph, liver function, renal function, and levels of electrolytes were all normal. Whole blood counts were normal, although differential counts demonstrated a left shift (polymorphonuclear leukocytes 80.7%, reference range 37%–75%). C-reactive protein level was 66.7 μg/mL, (reference

We report a case of an adult with dengue hemorrhagic fever who developed acute idiopathic scrotal edema and glove-and-stocking polyneuropathy. A 54-year-old man who had fever, chills, bone pain, and skin rash for 4 days was admitted. We diagnosed dengue hemorrhagic fever because of fever, gum bleeding, thrombocytopenia, and hemoconcentration, and confirmed the diagnosis by serology. The patient had scrotal and penile edema and distal limb numbness with a glove-and-stocking distribution. After supportive care, the scrotal edema and other symptoms subsided. Patients with dengue hemorrhagic fever may develop scrotal edema caused by plasma leakage.

Scientific investigations designed to better understand and assess the distinguishing clinical characteristics pave the way to a successful treatment for a disease. Since the peripheral blood is obtained easily, the most frequent type of investigation performed on infectious agents focuses on the hematological components of blood drawn from patients. Bone marrow aspirates, although somewhat more difficult to obtain, should be evaluated more frequently because they provide additional information, giving us a glimpse into the development of the disease. Understanding the distinct and unique changes in hematological components of the bone marrow induced by a particular pathogen or corresponding to a specific illness may be a valuable asset for the diagnosis and prognosis of disease. A good example of a pathogen that could be better evaluated with greater knowledge of the bone marrow is dengue, one of the most important public vector-borne human diseases. Owing to the multitude of clinical manifestations and the dynamic alterations of various blood components over time, this disease is one of the most difficult to prevent and treat in humans. Although large amounts of data have been generated in the literature, there remains a large gap between this information and its relevance for the purpose of patient care. While evaluating the cellular components in the circulated blood from ill patients provides us with valuable information about the pathogenesis of various pathogens, there are other players participating in the progression to disease. The goal of this review is to emphasize the importance of bone marrow hematopoietic progenitor cells in disease and to inspire other researchers to incorporate them into their investigations on dengue pathogenesis. It is anticipated that the knowledge derived from these investigations not only elicit original concepts on the pathogenesis of dengue but also foster a new way of thinking in terms of vaccine or therapeutic development to prevent and treat dengue.

Platelets have been recognized to be an integral part of human immune system. Hematologic disfunction, such as thrombocytopenia, is one of the most salient clinical features in dengue patients. Understanding the parameters released from activated platelets, involving in maintaining the delicate network, can provide a better picture of pathogenic cause of dengue. Ninety four dengue confirmed patients, 24 other febrile patients, and 12 healthy controls were enrolled to study. The parameters including the levels of polyphosphates, bradykinin, thyroxine, nitrite/ nitrate, platelet factor 4 (PF4), and serotonin, from the circulation of dengue patients were quantified by commercial ELISA kits and then compared to that from patients with other febrile illnesses, follow-up samples, and healthy controls. The following results were documented. Results 1. The levels of polyphosphates were on average 30% higher in acute dengue samples than healthy controls. 2. The levels of thyroxine, and nitrite/nitrate were significantly higher in acute dengue samples compared to that of other febrile, follow-up and healthy samples, while bradykinin was significantly lower. 3. The levels of PF4 were not different among samples of acute dengue, other febrile illness and follow-up, but were all significantly higher than the healthy controls. 4. The levels of serotonin were significantly higher in acute febrile stage compared to convalescent stage; while significantly lower than healthy subjects. The dynamic network of biochemical programs that coordinate to maintain hemostasis become unbalanced during and following dengue virus infection. Factors released from activated platelets may influence the vascular permeability

Clinical information regarding murine typhus in Taiwan is limited. In this study, 81 cases of serologically documented murine typhus during 1992-2009 at four referral hospitals in southern Taiwan were analyzed. There was a significant correlation between average environmental temperature and case numbers of murine typhus (r = 0.747, P = 0.005). Acute hepatitis was found in 67% of cases, and hyperbilirubinemia (serum total bilirubin ≥ 23.9 μmol/L) was found in 38%. The intervals between the initiation of appropriate therapy to defervescence were longer in patients with hyperbilirubinemia than those without hyperbilirubinemia (6.1 versus 4.1 days; P = 0.015). Nine (11.1%) showed development of severe illnesses such as acute respiratory distress syndrome (2 patients), aseptic meningitis (3), and acute renal failure (4). Only one died of acute respiratory distress syndrome. Cases of murine typhus were often found during the summer and had acute febrile hepatitis. Those patients with hyperbilirubinemia tended to have a delayed recovery even with appropriate therapy.

Background/Purpose Dengue fever is an important public health problem in Southern Taiwan. The purpose of this study was to develop a dengue scoring system using a three-stage process, which may be used as a guidance tool for the early diagnosis of dengue fever. Methods A retrospective study was conducted to identify factors useful for the early diagnosis of dengue fever. We assessed the clinical and laboratory features of 89 adult patients with dengue from 2002 to 2004 at a community-based hospital. They were compared with 14 patients with scrub typhus, 104 with Q fever, and 35 with murine typhus, which might present similar symptoms and signs as dengue infection. A scoring system was designed after analysis of the retrospective study and with the assistance of 10 expert clinicians. For the second stage, we evaluated efficiency in differentiating dengue fever from Q fever, scrub typhus and murine typhus in three hospitals from 2002 to 2005. For the third stage, we prospectively used the dengue scoring system for 498 cases that clinically were suspected as having dengue infection in the city of Kaohsiung from January 2006 to September 2006. Results The performance of the scoring system was 88.1% sensitivity, 94.9% specificity, 95.7% positive predictive value (PPV), and 86.1% negative predictive value (NPV). Evaluation of the scoring system at the third stage revealed 90.7% sensitivity, 86.9% specificity, 81.4% PPV, and 93.6% NPV. Conclusion The dengue scoring system had a high NPV that might be helpful in the early diagnosis of dengue fever in adults before laboratory data are available.

We aimed to assess the impact of nationwide hepatitis B virus (HBV) vaccination program on the seroprevalence of HBV infection among human immunodeficiency virus (HIV)-positive persons in a country where most HBV exposure occurs during the perinatal period or in early childhood.Data on HBV surface antigen (HBsAg), anti-HBV surface (anti-HBs), anti-HBV core (anti-HBc), and anti-hepatitis C virus (anti-HCV) antibody were retrospectively collected from 3,164 HIV-positive and 2,594 HIV-negative persons between 2004 and 2007. Comparisons of serological markers of HBV and HCV were made between HIV-positive and -negative adults born before and after the implementation of the HBV vaccination program in Taiwan in July 1984.Compared with HIV-negative persons, the adjusted odds ratio for HBsAg seropositivity was 1.100 (95% confidence interval, 0.921-1.315) among HIV-positive persons. Although the seroprevalence of anti-HCV antibody remained similar between HIV-positive persons born before and those born after 1984, the seroprevalence of HBsAg declined from 20.3 to 3.3% in HIV-positive persons (P0.001) and from 15.5 to 8.5% in HIV-negative persons (P0.001). Despite the high seroprevalence of anti-HCV antibody (97.1%) in HIV-positive injecting drug users (IDUs), there was no statistically significant difference in the seroprevalence of HBsAg (5.6% vs. 8.5%, P=0.75) or anti-HBc antibody (40.7% vs. 27.9%, P=0.14) between HIV-positive IDUs and HIV-negative persons who were born after 1984.Our study showed a significant decline of seroprevalence of HBV infection among both HIV-negative and -positive persons who were born in the era of the nationwide HBV vaccination in Taiwan.

To investigate the anti-tuberculosis drug resistance pattern of pulmonary tuberculosis isolates in southern Taiwan, we performed a hospital-based surveillance at a southern Taiwan medical centre from 1996 to 2000. The combined drug resistance rates to at least one of four first-line agents (isoniazid, rifampicin, ethambutol, streptomycin) was 52.4%, and to both isoniazid and rifampicin was 11.4%, indicating high resistance rates compared with those reported in the World Health Organization (WHO)/International Union Against Tuberculosis and Lung Disease (IUATLD) global project and in northern Taiwan. The resistance rates to two second-line drugs, cycloserine, and kanamycin, were 75.7 and 23.7%, respectively. A significant decreasing trend in resistance rates to all tested drugs except streptomycin was observed during the 5-year period. The resistance rates in 1996 and 2000 were 43.1 and 16.4% for isoniazid, 23.4 and 9.5% for rifampicin, 23.4 and 12.1% for ethambutol, 92.7 and 50.9% for pyrazinamide. The combined drug resistance rate may not be the most accurate tool as it includes previously treated cases that may inflate the resistance rate and cases without a history of treatment. However, the observation of trends in the susceptibility of pulmonary tuberculosis with the increasing percentages of tuberculosis patients receiving the complete treatment course and the decreasing percentages of cases lost to follow-up in Kaohsiung after the institution of new governmental regulations for case management in 1997, suggest that such intervention programs are useful.

Background Optimal timing for initiating highly active antiretroviral therapy (HAART) in HIV-TB coinfected patients is challenging for clinicians. We aim to evaluate the impact of different timing of HAART initiation on TB outcome of HIV-infected adults in Taiwan. Methods A population-based retrospective cohort study was conducted through linking the HIV and TB registries of Taiwan Centers for Disease Control (CDC) during 1997 to 2006. Clinical data of HIV-TB co-infected patients, including the presence of immune reconstitution inflammatory syndrome (IRIS), was collected through medical records review. The outcome of interest was all-cause mortality within 1 year following TB diagnosis. The Cox proportional hazard model was used to explore the probability of death and IRIS after TB diagnosis by adjusting for confounding factors and factors of interest. The probability of survival and TB IRIS were calculated by the Kaplan-Meier method and compared between different HAART initiation timing groups by the log-rank test. Results There were 229 HIV-TB co-infected patients included for analysis and 60 cases (26.2%) died within one year. Besides decreasing age and increasing CD4 lymphocyte count, having started HAART during TB treatment was significantly associated with better survival (adjusted Hazard Ratio was 0.11, 95% CI 0.06–0.21). As to the timing of HAART initiation, there was only non-significant benefit on survival among cases initiating HAART within 15 days, at 16–30 days and at 31–60 days of TB treatment than initiating after 60 days. Cases with HAART initiated after 30 days had lower risk in developing IRIS than cases with HAART initiated earlier. Cases with IRIS had significantly higher rate of re-hospitalization (49% vs. 4%, p

The continuing threat of dengue fever necessitates a comprehensive characterisation of its epidemiological trends. Phylogenetic and recombination events were reconstructed based on 100 worldwide dengue virus (DENV) type 1 genome sequences with an outgroup (prototypes of DENV2-4). The phylodynamic characteristics and site-specific variation were then analysed using data without the outgroup. Five genotypes (GI-GV) and a ladder-like structure with short terminal branch topology were observed in this study. Apparently, the transmission of DENV1 was geographically random before gradual localising with human activity as GI-GIII in South Asia, GIV in the South Pacific, and GV in the Americas. Genotypes IV and V have recently shown higher population densities compared to older genotypes. All codon regions and all tree branches were skewed toward a negative selection, which indicated that their variation was restricted by protein function. Notably, multi-epistatic interaction sites were found in both PrM 221 and NS3 1730. Recombination events accumulated in regions E, NS3-NS4A, and particularly in region NS5. The estimated coevolution pattern also highlights the need for further study of the biological role of protein PrM 221 and NS3 1730. The recent transmission of emergent GV sublineages into Central America and Europe mandates closely monitoring of genotype interaction and succession.

Systemic lupus erythematosus (SLE) is an important autoimmune disease with multiple organ system involvement. From preliminary studies, we have found that six Chinese herbs: Atractylodes ovata, Anqelica sinensis, Cordyceps sinensis, Liqustrum lucidum, Codonopsis pilosula and Homo sapiens can improve defective in vitro interleukin-2 (IL-2) production in patients with SLE. In order to investigate the in vivo effects of these herbs, we used NZB/NZW F1 mice, a typical lupus animal model used to test these herbs. It was found that C. pilosula, H. sapiens and C. sinensis could prolong the life span of female NZB/NZW F1 mice and inhibited anti-ds DNA production. Although A. sinensis could prolong the life span of experimental mice, it did not inhibit the production of anti-ds DNA antibody. These herbs may have great potential for the management of human SLE in the future.

Chikungunya virus, a mosquito-borne alphavirus, is endemic in Africa and Southeast Asia but is rarely reported in Taiwan. We report the case of a Taiwanese woman who developed Chikungunya fever, which was first diagnosed by a clinician rather than by fever screening at an airport. The woman presented with fever, maculopapular rash, and arthralgia, the triad for the disease, on the day she returned home after a trip to Malaysia. These symptoms are very similar to those of dengue fever, which is endemic in Southern Taiwan. Chikungunya infection was confirmed by reverse transcriptase-polymerase chain reaction and seroconversion on paired serum specimens. For approximately 40 years until 2006, no cases of Chikungunya fever had been found in Taiwan. Clinicians in Taiwan should consider Chikungunya fever as a possible diagnosis for a febrile patient with arthralgia, rash, and a history of travel to an endemic area, such as Africa or Southeast Asia.

Dengue is becoming recognized as one of the most important vector-borne human diseases. It is predominant in tropical and subtropical zones but its geographical distribution is progressively expanding, making it an escalating global health problem of today. Dengue presents with spectrum of clinical manifestations, ranging from asymptomatic, undifferentiated mild fever, dengue fever (DF), to dengue hemorrhagic fever (DHF) with or without shock (DSS), a life-threatening illness characterized by plasma leakage due to increased vascular permeability. Currently, there are no antiviral modalities or vaccines available to treat and prevent dengue. Supportive care with close monitoring is the standard clinical practice. The mechanisms leading to DHF/DSS remains poorly understood. Multiple factors have been attributed to the pathological mechanism, but only a couple of these hypotheses are popular in scientific circles. The current discussion focuses on underappreciated factors, temperature, natural IgM, and endotoxin, which may be critical components playing roles in dengue pathogenesis.