Dengue virus (DENV) infection in the presence of reactive, non-neutralizing immunoglobulin G (IgG) (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, because only a fraction of infections occurring in the presence of RNNIg advance to DHF/DSS, the presence of RNNIg alone cannot account for disease severity. We discovered that DHF/DSS patients respond to infection by producing IgGs with enhanced affinity for the activating Fc receptor FcγRIIIA due to afucosylated Fc glycans and IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Thus, therapeutics and vaccines restricting production of afucosylated, IgG1 RNNIg during infection may prevent ADE of DENV disease.

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IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity

Antimicrobial resistance (AMR) is an increasing threat to global health. There are > 14 million cases of enteric fever every year and > 135,000 deaths. The disease is primarily controlled by antimicrobial treatment, but this is becoming increasingly difficult due to AMR. Our objectives were to assess the prevalence and geographic distribution of AMR in Salmonella enterica serovars Typhi and Paratyphi A infections globally, to evaluate the extent of the problem, and to facilitate the creation of geospatial maps of AMR prevalence to help targeted public health intervention. We performed a systematic review of the literature by searching seven databases for studies published between 1990 and 2018. We recategorised isolates to allow the analysis of fluoroquinolone resistance trends over the study period. The prevalence of multidrug resistance (MDR) and fluoroquinolone non-susceptibility (FQNS) in individual studies was illustrated by forest plots, and a random effects meta-analysis was performed, stratified by Global Burden of Disease (GBD) region and 5-year time period. Heterogeneity was assessed using the I2 statistics. We present a descriptive analysis of ceftriaxone and azithromycin resistance. We identified 4557 articles, of which 384, comprising 124,347 isolates (94,616 S. Typhi and 29,731 S. Paratyphi A) met the pre-specified inclusion criteria. The majority (276/384; 72%) of studies were from South Asia; 40 (10%) articles were identified from Sub-Saharan Africa. With the exception of MDR S. Typhi in South Asia, which declined between 1990 and 2018, and MDR S. Paratyphi A, which remained at low levels, resistance trends worsened for all antimicrobials in all regions. We identified several data gaps in Africa and the Middle East. Incomplete reporting of antimicrobial susceptibility testing (AST) and lack of quality assurance were identified. Drug-resistant enteric fever is widespread in low- and middle-income countries, and the situation is worsening. It is essential that public health and clinical measures, which include improvements in water quality and sanitation, the deployment of S. Typhi vaccination, and an informed choice of treatment are implemented. However, there is no licenced vaccine for S. Paratyphi A. The standardised reporting of AST data and rollout of external quality control assessment are urgently needed to facilitate evidence-based policy and practice. PROSPERO CRD42018029432.

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Drug-resistant enteric fever worldwide, 1990 to 2018: a systematic review and meta-analysis

Trends in Infectious Disease Mortality in the United States During the 20th Century

Background Dengue is an arboviral disease caused by dengue virus. Symptomatic dengue infection causes a wide range of clinical manifestations, from mild dengue fever (DF) to potentially fatal disease, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). We conducted a literature review to analyze the risks of DHF and current perspectives for DHF prevention and control. Methods According to the PRISMA guidelines, the references were selected from PubMed, Web of Science and Google Scholar database using search strings containing a combination of terms that included dengue hemorrhagic fever, pathogenesis, prevention and control. Quality of references were evaluated by independent reviewers. Results DHF was first reported in the Philippines in 1953 and further transmitted to the countries in the region of South-East Asia and Western Pacific. Plasma leakages is the main pathophysiological hallmark that distinguishes DHF from DF. Severe plasma leakage can result in hypovolemic shock. Various factors are thought to impact disease presentation and severity. Virus virulence, preexisting dengue antibodies, immune dysregulation, lipid change and host genetic susceptibility are factors reported to be correlated with the development of DHF. However, the exact reasons and mechanisms that triggers DHF remains controversial. Currently, no specific drugs and licensed vaccines are available to treat dengue disease in any of its clinical presentations. Conclusion This study concludes that antibody-dependent enhancement, cytokine dysregulation and variation of lipid profiles are correlated with DHF occurrence. Prompt diagnosis, appropriate treatment, active and continuous surveillance of cases and vectors are the essential determinants for dengue prevention and control.

Dengue Hemorrhagic Fever- A Systemic Literature Review of Current Perspectives on Pathogenesis, Prevention and Control

Background: Dengue is a major public health problem worldwide. Assessment of adaptive immunity is important to understanding immunopathology and to define correlates of protection against dengue virus (DENV). To enable global assessment of CD4+T cell responses, we mapped HLA-DRB1 restricted DENV-specific CD4+ T cell epitopes in individuals previously exposed to DENV in the general population of the dengue-endemic region of Managua, Nicaragua. Methods: HLA class II epitopes in the population of Managua were identified by an in vitro IFNγ ELISPOT assay. CD4+ T cells purified by magnetic bead negative selection were stimulated with HLA-matched epitope pools in the presence of autologous antigen presenting cells (APCs), followed by pool deconvolution to identify specific epitopes. The epitopes identified in this study were combined with those previously identified in the DENV endemic region of Sri Lanka, to generate a “megapool” (MP) consisting of 180 peptides specifically designed to achieve balanced HLA and DENV serotype coverage. The DENV CD4MP180 was validated by Intracellular Cytokine Staining (ICS) assays. Results: We detected responses directed against a total of 431 epitopes, representing all four DENV serotypes, restricted by 15 different HLA-DRB1 alleles. The responses were associated with a similar pattern of protein immunodominance, overall higher magnitude of responses, as compared to what was observed previously in the Sri Lanka region. Based on these epitope mapping studies, we designed a DENV CD4 MP180 with higher and more consistent coverage, which allowed the detection of CD4+ T cell DENV responses ex vivo in various cohorts of DENV exposed donors worldwide, including donors from Nicaragua, Brazil, Singapore, Sri Lanka and and U.S. domestic flavivirus-naive subjects immunized with Tetravalent Dengue Live Attenuated Vaccine (TV005). This broad reactivity reflects that the 21 HLA-DRB1 alleles analyzed in this and previous studies account for more than 80% of alleles present with a phenotypic frequency ≥ 5% worldwide, corresponding to 92% phenotypic coverage of the general population (i.e., 92% of individuals express at least one of these alleles). Conclusion: The DENV CD4 MP180 can be utilized to measure ex vivo responses to DENV irrespective of geographical location.

Global Assessment of Dengue Virus-Specific CD4+ T Cell Responses in Dengue-Endemic Areas

Dengue disease is an emerging mosquito-borne viral infection transmitted between humans by Aedes spp. that are distributed mainly in the tropical and subtropical region along with chikungunya and zika diseases. The distribution of dengue disease is influenced by local variation, such as geography, rainfall, temperature, and rapid urbanization or migration. The epidemy of mosquito-borne infection significantly led to increased number of cases and hyperendemicity which induce a more severe form of dengue accompanied by cocirculation of chikungunya and zika. The rapid global spreading of dengue disease created public health burdens that are presently unfulfilled by the absence of specific therapy, simple diagnosis tool for the early phase, and effective and efficient vector control system. This review highlights the current situation of dengue distribution, epidemiology, and new strategies for early dengue diagnosis and risk prediction of severity that can be used to improve oversight and alleviate the heavy burden of the disease.

https://journals.sagepub.com/doi/pdf/10.1177/1178122X17695836

Trends of Dengue Disease Epidemiology.

Dengue virus (DENV) infection is an emerging arboviral infection in tropical and sub-tropical countries in South-East Asia, the Western Pacific and South and Central America. Secondary DENV infection is the most widely accepted risk factor for the development of severe forms. Methods to discriminate primary and secondary DENV infection may be of great prognostic value. ELISA based detection of specific antibodies (IgG and IgM) to the four DENV serotypes is valuable for detemination of primary or secondary infection. Several studies had been performed to discriminate primary and secondary DENV infection using the ratio of IgG and IgM at the various days of symptoms onset. The aim of this study is to determine the best cut-off point of IgG to IgM ratio is able to discriminating secondary from primary DENV infection in adult using samples from early days of symptoms onset. This prospective cohort study on 48 adult patients with DENV infected patients on the period of August 2011–January 2012 in 5 out-patient settings health facilities in Tangerang district, Banten province, Indonesia with chief complaint of fever less than 3 days. Datas were collected on the day the patients attended health facilities, consisted of demographic, clinical, laboratory, and serological data. Serological data from 48 serum sample from adult patients were evaluated using Focus Diagnostics Dengue Virus IgM and IgG Capture DxSelect™ ELISA Kits to determine IgG, IgM index values and SD Bioline Dengue Duo™ Rapid Tests to determine NS1, IgG, and IgM result. According to NS1, IgG and IgM results, 36 patients were classified as secondary infection, 12 were primary Infection. The mean (SD) of IgG/IgM ratios for secondary and primary infection were 3.28 (0.54) and 0.18 (0.11) consecutively. The IgG/IgM ratio of ≥ 1.14 confirmed secondary infection with sensitivity of 80.56 %, specificity 91.67 %, accuracy level 83.33 %, and likely hood ratio of (LR) 9.67. The IgG/IgM ratio of ≥ 1.14 as the best cut off point to determine secondary DENV infection in early days of symptoms onset.

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Immunoglobulin G (IgG) to IgM ratio in secondary adult dengue infection using samples from early days of symptoms onset

Sphingomonas paucimobilis is a yellow-pigmented, glucose nonfermenting, aerobic, Gram negative bacillus of low pathogenicity. This organism was found in the implantation of indwelling catheters, sterile intravenous fluid, or contaminated hospital environment such as tap and distilled water, nebulizer, ventilator, and hemodialysis device. A 55-year-old female was hospitalized for diabetic foot ulcer in the presence of multiple comorbidities: diabetes mellitus, colonic tuberculosis, end-stage renal disease, and indwelling catheters for central venous catheter and hemodialysis. The patient passed away on the 44th day of admission due to septic shock. The organism found on blood culture on the 29th day of admission was multidrug resistant S. paucimobilis. Severe infection and septic shock due to S. paucimobilis have been reported particularly in immunocompromised patients, but there has been only one reported case of death in a premature neonate with septic shock. This is the first reported lethal case of S. paucimobilis bacteremia in an adult patient.

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A Lethal Case of Sphingomonas paucimobilis Bacteremia in an Immunocompromised Patient

Typhoid and paratyphoid fever known as enteric fever pose important global public health problem, with 21.6 million cases and approximately 250,000 deaths annually. It is a prevalent disease in Indonesia, but data on the antimicrobial resistance pattern is limited. This study aim was to provide data on the antimicrobial resistance pattern of S. Typhi and S. Paratyphi bloodstream isolates in a general hospital in Karawaci, Tangerang, Banten, Indonesia, during the period of January 2011 to December 2015. Susceptibility against antimicrobials was detected according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI). Out of a total of 168 isolates 55.4% were S. Typhi and 44.6% S. Paratyphi A. Most of the isolates, 92.9%, were from children aged 6–18 years and adult population. There was low resistance of S. Typhi against ampicillin, trimethoprim-sulfamethoxazole, ceftriaxone, ciprofloxacin, and levofloxacin, similar to previous studies in Indonesia. In the 2011–2015 period, resistance rates against most antimicrobials and MDR rate of S. Typhi and S. Paratyphi were low, emphasizing that there is a distinct epidemiological dynamic of the enteric fever in Indonesia.

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Antimicrobial Resistance of Salmonella enterica Serovars Typhi and Paratyphi Isolates from a General Hospital in Karawaci, Tangerang, Indonesia: A Five-Year Review.

Background: Tuberculosis (TB) is the fourth leading cause of death in Indonesia. In 2017, the World Health Organization (WHO) estimated that only 2% of the TB patients in Indonesia had only been tested with rapid diagnostics at the time of diagnosis, resulting in largely underdetected rifampicin-resistant TB (RR-TB). Utilization of GeneXpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) assay as a point-of-care molecular assay to detect TB and RR-TB and serving its purpose in accordance with the first pillar of the WHO End-TB Strategy. Objective: This study investigated the use of GeneXpert MTB/RIF assay to determine the molecular epidemiology of RR-TB in an urban setting of Indonesia. Methods: All molecular epidemiological and microbiological databases were retrospectively examined from GeneXpert MTB/RIF assay results in Siloam Hospital Lippo Village. The sociodemographic characteristics and results of microbiological examinations consisting of Ziehl–Neelsen staining and GeneXpert MTB/RIF assay were analyzed. Results: During the study period, 600 cases were registered, and GeneXpert MTB/RIF tests were done in which the tests yielded 597 (99.5%) valid results; 62.0% were male and adult of age category; of whom 29 samples (4.9%) were found to be RR-TB, 186 samples (31.2%) were RIF sensitive, and remainders were negative. Conclusions: The results of GeneXpert MTB/RIF to be a fundamental diagnosis of RR-TB and subsequently to notify MDR-TB were satisfying and valuable in this study. This further increased and reinforced TB surveillance and national TB program to finally bring about WHO end-TB strategy one step closer in Indonesia.

GeneXpert Mycobacterium tuberculosis/rifampicin assay for molecular epidemiology of rifampicin-Resistant Mycobacterium tuberculosis in an Urban Setting of Banten province, Indonesia.

Cucunawangsih

Papers

Trends of Dengue Disease Epidemiology.

Immunoglobulin G (IgG) to IgM ratio in secondary adult dengue infection using samples from early days of symptoms onset

A Lethal Case of Sphingomonas paucimobilis Bacteremia in an Immunocompromised Patient

Antimicrobial Resistance of Salmonella enterica Serovars Typhi and Paratyphi Isolates from a General Hospital in Karawaci, Tangerang, Indonesia: A Five-Year Review.

GeneXpert Mycobacterium tuberculosis/rifampicin assay for molecular epidemiology of rifampicin-Resistant Mycobacterium tuberculosis in an Urban Setting of Banten province, Indonesia.