Publications by authors named "Bachti Alisjahbana"

128 Publications

High risk of Mycobacterium tuberculosis infection among medical and nursing students in Indonesia: a 1-year prospective study.

Trans R Soc Trop Med Hyg 2021 Mar 15. Epub 2021 Mar 15.

Centre for International Health, Department of Preventive and Social Medicine, University of Otago Medical School, PO Box 56, Dunedin 9054, New Zealand.

Background: Medical and nursing students entering their clinical programmes are at increased risk for tuberculosis (TB) in TB-endemic settings. Relatively little is known about Mycobacterium tuberculosis infection among such students in high-endemic countries.

Methods: We examined M. tuberculosis infection among medical and nursing students starting clinical training in Bandung, Indonesia using interferon-γ release assay (IGRA) QuantiFERON-TB Gold Plus. IGRA-negative students had a repeat test after 1 y and logistic regression was used to identify factors associated with IGRA positivity or conversion.

Results: There were 379 students included in this study: 248 (65.4%) were medical students and 131 (34.6%) were nursing students. Of 379 students, 70 (18.5%) were IGRA positive at baseline. Of 293 IGRA-negative students with 1-y results, 26 (8.9%) underwent IGRA conversion. Being a medical student (adjusted relative risk [ARR] 5.15 [95% confidence interval {CI} 1.82 to 14.59], p=0.002) and participation in sputum collection or bronchoscopy were associated with IGRA conversion (ARR 2.74 [95% CI 1.29 to 5.79], p=0.008).

Conclusions: Medical and nursing students entering clinical training are at high risk of M. tuberculosis infection and need improved infection prevention and control strategies.
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http://dx.doi.org/10.1093/trstmh/trab038DOI Listing
March 2021

BCG-induced protection against Mycobacterium tuberculosis infection: Evidence, mechanisms, and implications for next-generation vaccines.

Immunol Rev 2021 May 12;301(1):122-144. Epub 2021 Mar 12.

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.

The tuberculosis (TB) vaccine Bacillus Calmette-Guérin (BCG) was introduced 100 years ago, but as it provides insufficient protection against TB disease, especially in adults, new vaccines are being developed and evaluated. The discovery that BCG protects humans from becoming infected with Mycobacterium tuberculosis (Mtb) and not just from progressing to TB disease provides justification for considering Mtb infection as an endpoint in vaccine trials. Such trials would require fewer participants than those with disease as an endpoint. In this review, we first define Mtb infection and disease phenotypes that can be used for mechanistic studies and/or endpoints for vaccine trials. Secondly, we review the evidence for BCG-induced protection against Mtb infection from observational and BCG re-vaccination studies, and discuss limitations and variation of this protection. Thirdly, we review possible underlying mechanisms for BCG efficacy against Mtb infection, including alternative T cell responses, antibody-mediated protection, and innate immune mechanisms, with a specific focus on BCG-induced trained immunity, which involves epigenetic and metabolic reprogramming of innate immune cells. Finally, we discuss the implications for further studies of BCG efficacy against Mtb infection, including for mechanistic research, and their relevance to the design and evaluation of new TB vaccines.
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http://dx.doi.org/10.1111/imr.12965DOI Listing
May 2021

The effect of a structured clinical algorithm on glycemic control in patients with combined tuberculosis and diabetes in Indonesia: A randomized trial.

Diabetes Res Clin Pract 2021 Mar 18;173:108701. Epub 2021 Feb 18.

Department of Internal Medicine and Radboud Centre for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.

Aims: Diabetes mellitus (DM) is associated with worse tuberculosis (TB) treatment outcomes, especially among those with poor glycemic control. We examined whether a structured clinical algorithm could improve glycemic control in TB patients with DM.

Methods: In an open label randomized trial, TB-DM patients were randomized to scheduled counselling, glucose monitoring, and adjustment of medication using a structured clinical algorithm (intervention arm) or routine DM management (control arm), with glycated hemoglobin (HbA1c) at month 6 as the primary end point.

Results: We randomized 150 pulmonary TB-DM patients (92% culture positive, 51.3% male, mean age 53 years). Baseline mean HbA1c was 11.0% in the intervention arm (n = 76) and 11.6% in the control arm (n = 74). At 6 months, HbA1c had decreased more in the intervention arm compared with the control arm (a difference of 1.82% HbA1c, 95% CI 0.82-2.83, p < 0.001). Five patients were hospitalized in the intervention arm and seven in the control arm. There was more hypoglycemia (35.0% vs 11.8%; p = 0.002) in the intervention arm. Two deaths occurred in the intervention arm, one due to cardiorespiratory failure and one because of suspected septic shock and multiorgan failure.

Conclusion: Regular monitoring and algorithmic adjustment of DM treatment led to improved glycemic control.
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http://dx.doi.org/10.1016/j.diabres.2021.108701DOI Listing
March 2021

A Bayesian analysis of the association between genotype and survival in tuberculous meningitis.

Elife 2021 Jan 8;10. Epub 2021 Jan 8.

Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.

Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A hydrolase () gene encoding an enzyme that regulates inflammatory eicosanoids. TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it.
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http://dx.doi.org/10.7554/eLife.61722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793626PMC
January 2021

Cerebrospinal fluid IL-1β is elevated in tuberculous meningitis patients but not associated with mortality.

Tuberculosis (Edinb) 2021 01 11;126:102019. Epub 2020 Nov 11.

Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Inflammation contributes to the pathophysiology and high mortality of tuberculous meningitis. The IL-1β pathway has been implicated in immunopathology and could be a target for host-directed therapy. IL-1β was elevated in the cerebrospinal fluid (CSF) of 225 HIV-uninfected tuberculous meningitis patients in Indonesia compared to controls, but did not predict subsequent mortality, nor did IL-6 or IL-1Ra. Furthermore, genetic loci known to regulate IL1B gene expression did not predict mortality in 443 tuberculous meningitis patients, although two of these loci did predict CSF IL-1β concentrations. Collectively, these data argue against a role for IL-1β targeted host-directed therapy in tuberculous meningitis.
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http://dx.doi.org/10.1016/j.tube.2020.102019DOI Listing
January 2021

The detection of Howell-Jolly body-like inclusions in a case of coronavirus disease-2019 (COVID-19).

Blood Res 2020 Dec;55(4):191

Division of Hematology and Medical Oncology, Department of Internal MedicineFaculty of Medicine, Universitas Padjadjaran, Hasan Sadikin General Hospital, Bandung, Indonesia.

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http://dx.doi.org/10.5045/br.2020.2020186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784130PMC
December 2020

Screening diabetes mellitus patients for pulmonary tuberculosis: a multisite study in Indonesia, Peru, Romania and South Africa.

Trans R Soc Trop Med Hyg 2021 Jun;115(6):634-643

Centre for International Health, University of Otago Medical School, University of Otago, Dunedin, New Zealand.

Background: Diabetes mellitus (DM) patients are three times more likely to develop tuberculosis (TB) than the general population. Active TB screening in people with DM is part of a bidirectional approach. The aim of this study was to conduct pragmatic active TB screening among DM patients in four countries to inform policy.

Methods: DM patients were recruited in Indonesia (n=809), Peru (n=600), Romania (n=603) and South Africa (n=51). TB cases were diagnosed using an algorithm including clinical symptoms and chest X-ray. Presumptive TB patients were examined with sputum smear and culture.

Results: A total of 171 (8.3%) individuals reported ever having had TB (South Africa, 26%; Indonesia, 12%; Peru, 7%; Romania, 4%), 15 of whom were already on TB treatment. Overall, 14 (0.73% [95% confidence interval 0.40 to 1.23]) TB cases were identified from screening. Poor glucose control, smoking, lower body mass index, education and socio-economic status were associated with newly diagnosed/current TB. Thirteen of the 14 TB cases diagnosed from this screening would have been found using a symptom-based approach.

Conclusions: These data support the World Health Organization recommendation for routine symptom-based screening for TB in known DM patients in high TB-burden countries. DM patients with any symptoms consistent with TB should be investigated and diagnostic tools should be easily accessible.
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http://dx.doi.org/10.1093/trstmh/traa100DOI Listing
June 2021

Etiologies of severe acute respiratory infection (SARI) and misdiagnosis of influenza in Indonesia, 2013-2016.

Influenza Other Respir Viruses 2021 Jan 14;15(1):34-44. Epub 2020 Jul 14.

Indonesia Research Partnership on Infectious Diseases (INA-RESPOND), Jakarta, Indonesia.

Background: Severe acute respiratory infection (SARI) accounts for a large burden of illness in Indonesia. However, epidemiology of SARI in tertiary hospitals in Indonesia is unknown. This study sought to assess the burden, clinical characteristics, and etiologies of SARI and concordance of clinical diagnosis with confirmed etiology.

Methods: Data and samples were collected from subjects presenting with SARI as part of the acute febrile Illness requiring hospitalization study (AFIRE). In tertiary hospitals, clinical diagnosis was ascertained from chart review. Samples were analyzed to determine the "true" etiology of SARI at hospitals and Indonesia Research Partnership on Infectious Diseases (INA-RESPOND) laboratory. Distribution and characteristics of SARI by true etiology and accuracy of clinical diagnosis were assessed.

Results: Four hundred and twenty of 1464 AFIRE subjects presented with SARI; etiology was identified in 242 (57.6%), including 121 (28.8%) viruses and bacteria associated with systemic infections, 70 (16.7%) respiratory bacteria and viruses other than influenza virus, and 51 (12.1%) influenza virus cases. None of these influenza patients were accurately diagnosed as having influenza during hospitalization.

Conclusions: Influenza was misdiagnosed among all patients presenting with SARI to Indonesian tertiary hospitals in the AFIRE study. Diagnostic approaches and empiric management should be guided by known epidemiology. Public health strategies to address the high burden of influenza should include broad implementation of SARI screening, vaccination programs, clinician education and awareness campaigns, improved diagnostic capacity, and support for effective point-of-care tests.
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http://dx.doi.org/10.1111/irv.12781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405185PMC
January 2021

Out-of-Pocket Costs for Patients Diagnosed with Tuberculosis in Different Healthcare Settings in Bandung, Indonesia.

Am J Trop Med Hyg 2020 09;103(3):1057-1064

Department of Internal Medicine, Faculty of Medicine, Hasan Sadikin General Hospital, Universitas Padjadjaran, Bandung, Indonesia.

Costs related to tuberculosis (TB) can impose a significant burden on patients and their families and create barriers to diagnosis and treatment. Our study aimed to quantify out-of-pocket costs expended by TB patients in Bandung, Indonesia. This cross-sectional study recruited adults with TB from community health centers (CHCs), public and private hospitals, and private practitioners (PPs). An interview was completed at the time of diagnosis or at their return for 2- or 6-month treatment. Costs were converted to U.S. dollars (US$)-presented as median and interquartile range (IQR). Of 469 TB patients recruited, the mean age was 38 years and 57% were male. The median pretreatment direct cost per person was $37.51 (IQR 20.79-71.24). Hospitalization, diagnostic tests, and travel costs were predominant. Higher pretreatment costs were associated with no health insurance ($41.88 versus $27.41, < 0.001), ≥ 6 visits to a healthcare provider ($39.91 versus $24.32, < 0.001), ≥ 60 days pretreatment ($36.35 versus $26.25, = 0.02), and presenting first to a PP ($40.71) or informal provider ($32.72) compared with private hospital ($21.26), public hospital ($19.63), or CHC ($13.52) ( = 0.01). For a subsample of 106 patients with total pre- and posttreatment costs available, the median total cost was $243.66 (IQR 128.46-550.71). For 26.5% of these patients, total costs were ≥ 20% of their annual household income. Despite having a good network of free TB diagnostic and treatment services throughout Bandung, patients experienced significant out-of-pocket costs. Increased uptake of the National Health Insurance, and systems for early recognition and diagnosis of TB, will contribute toward reducing costs.
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http://dx.doi.org/10.4269/ajtmh.19-0848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470549PMC
September 2020

C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis.

Ther Adv Respir Dis 2020 Jan-Dec;14:1753466620937175

Division of Tropical and Infectious Disease, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Hasan Sadikin General Hospital, Bandung, Indonesia.

Background: Patients critically ill with coronavirus disease-2019 (COVID-19) feature hyperinflammation, and the associated biomarkers may be beneficial for risk stratification. We aimed to investigate the association between several biomarkers, including serum C-reactive protein (CRP), procalcitonin (PCT), D-dimer, and serum ferritin, and COVID-19 severity.

Methods: We performed a comprehensive systematic literature search through electronic databases. The outcome of interest for this study was the composite poor outcome, which comprises mortality, acute respiratory distress syndrome, need for care in an intensive care unit, and severe COVID-19.

Results: A total of 5350 patients were pooled from 25 studies. Elevated CRP was associated with an increased composite poor outcome [risk ratio (RR) 1.84 (1.45, 2.33),  < 0.001; I: 96%] and its severe COVID-19 (RR 1.41; I: 93%) subgroup. A CRP ⩾10 mg/L has a 51% sensitivity, 88% specificity, likelihood ratio (LR) + of 4.1, LR- of 0.5, and an area under curve (AUC) of 0.84. An elevated PCT was associated with an increased composite poor outcome [RR 3.92 (2.42, 6.35),  < 0.001; I: 85%] and its mortality (RR 6.26; I: 96%) and severe COVID-19 (RR 3.93; I: 63%) subgroups. A PCT ⩾0.5 ng/ml has an 88% sensitivity, 68% specificity, LR+ of 2.7, LR- of 0.2, and an AUC of 0.88. An elevated D-dimer was associated with an increased composite poor outcome [RR 2.93 (2.14, 4.01),  < 0.001; I: 77%], including its mortality (RR 4.15; I: 83%) and severe COVID-19 (RR 2.42; I: 58%) subgroups. A D-dimer >0.5 mg/L has a 58% sensitivity, 69% specificity, LR+ of 1.8, LR- of 0.6, and an AUC of 0.69. Patients with a composite poor outcome had a higher serum ferritin with a standardized mean difference of 0.90 (0.64, 1.15),  < 0.0001; I: 76%.

Conclusion: This meta-analysis showed that an elevated serum CRP, PCT, D-dimer, and ferritin were associated with a poor outcome in COVID-19.
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http://dx.doi.org/10.1177/1753466620937175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336828PMC
July 2020

Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis.

Clin Infect Dis 2021 01;72(1):69-78

Tuberculosis Centre and Department of Infection and Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity.

Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249).

Results: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients.

Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.
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http://dx.doi.org/10.1093/cid/ciaa751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823074PMC
January 2021

Underdiagnoses of Rickettsia in patients hospitalized with acute fever in Indonesia: observational study results.

BMC Infect Dis 2020 May 24;20(1):364. Epub 2020 May 24.

Hasan Sadikin Hospital - Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia.

Background: Reports of human rickettsial infection in Indonesia are limited. This study sought to characterize the epidemiology of human rickettsioses amongst patients hospitalized with fever at 8 tertiary hospitals in Indonesia.

Methods: Acute and convalescent blood from 975 hospitalized non-dengue patients was tested for Rickettsia IgM and IgG by ELISA. Specimens from cases with seroconversion or increasing IgM and/or IgG titers were tested for Rickettsia IgM and IgG by IFA and Rickettsia genomes using primers for Rickettsia (R.) sp, R. typhi, and Orientia tsutsugamushi. Testing was performed retrospectively on stored specimens; results did not inform patient management.

Results: R. typhi, R. rickettsii, and O. tsutsugamushi IgG antibodies were identified in 269/872 (30.8%), 36/634 (5.7%), and 19/504 (3.8%) of samples, respectively. For the 103/975 (10.6%) non-dengue patients diagnosed with acute rickettsial infection, presenting symptoms included nausea (72%), headache (69%), vomiting (43%), lethargy (33%), anorexia (32%), arthralgia (30%), myalgia (28%), chills (28%), epigastric pain (28%), and rash (17%). No acute rickettsioses cases were suspected during hospitalization. Discharge diagnoses included typhoid fever (44), dengue fever (20), respiratory infections (7), leptospirosis (6), unknown fever (6), sepsis (5), hepatobiliary infections (3), UTI (3), and others (9). Fatalities occurred in 7 (6.8%) patients, mostly with co-morbidities.

Conclusions: Rickettsial infections are consistently misdiagnosed, often as leptospirosis, dengue, or Salmonella typhi infection. Clinicians should include rickettsioses in their differential diagnosis of fever to guide empiric management; laboratories should support evaluation for rickettsial etiologies; and public policy should be implemented to reduce burden of disease.
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http://dx.doi.org/10.1186/s12879-020-05057-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245627PMC
May 2020

Impaired glucose tolerance among adolescents with low birth weight history: The Tanjungsari Cohort Study in Indonesia.

Asia Pac J Clin Nutr 2020 ;29(1):120-126

Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Hasan Sadikin Hospital, Bandung, Indonesia.

Background And Objectives: Diabetes prevalence has been increasing overtime in Indonesia along with its complications and morbidities. Diabetes prevention program is still a challenge. Previous study concluded poor intrauterine nutritional status, low birth weight (LBW), and nutrition status early in life were risk factors for impaired glucose tolerance (IGT) or type 2 diabetes mellitus in adulthood. This study aimed to evaluate the association between both LBW and intrauterine growth restriction (IUGR) with IGT in adolescents.

Methods And Study Design: Total of 536 subjects from Tanjungsari Cohort Study were included in this study. Subjects were in their early adolescence age (12-14 years). Anthropometric data were collected and IGT was determined by using 2- hour postprandial plasma glucose level, then it was assessed based on their birth weight and intrauterine nutritional status.

Results: Subjects with LBW history were shorter, had lower body weight and body mass index (p<0.05, respectively). The proportion of IGT is significantly higher among subject with LBW (RR 1.692 [1.079- 2.653]). There was no difference on proportion of IGT among subjects with IUGR compared with subjects who were not IUGR or born preterm (p=0.286). Multiple regression analysis showed the effect of LBW remain independent after adjusted with sex and socioeconomic variables (RR 1.650 [1.054-2.584]).

Conclusions: Significant association was found between LBW and IGT in comparison to those who were born with normal birth weight. Hence, diabetes should be prevented as early as possible, even since in the pregnancy.
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http://dx.doi.org/10.6133/apjcn.202003_29(1).0016DOI Listing
January 2021

Leptospirosis in Indonesia: diagnostic challenges associated with atypical clinical manifestations and limited laboratory capacity.

BMC Infect Dis 2020 Feb 27;20(1):179. Epub 2020 Feb 27.

National Institute of Health Research and Development (NIHRD), Ministry of Health Republic of Indonesia, Jakarta, Indonesia.

Background: The burden of leptospirosis in Indonesia is poorly understood. Data from an observational study conducted from 2013 to 2016 in seven cities across Indonesia was used to estimate the incidence of leptospirosis and document its clinical manifestations in patients requiring hospitalization.

Methods: Specimens from patients hospitalized with acute fever were collected at enrollment, 14-28 days, and 3 months. Demographic and clinical information were collected during study visits and/or retrieved from medical records and double-entered into clinical report forms. After initially screening for dengue virus and other pathogens, specimens were tested at a central Reference Laboratory for anti-Leptospira IgM using commercial ELISA kits and for Leptospira DNA using an in-house quantitative real-time PCR assay.

Results: Of 1464 patients enrolled, 45 (3.1%) confirmed cases (by PCR and/or sero-coversion or four-fold increase of IgM) and 6 (0.4%) probable cases (by high titer IgM) of leptospirosis were identified by the Reference Laboratory. Disease incidence at sites ranged from 0 (0%) cases in Denpasar to 17 (8.9%) cases in Semarang. The median age of patients was 41.2 years (range of 5.3 to 85.0 years), and 67% of patients were male. Twenty-two patients (43.1%) were accurately diagnosed at sites, and 29 patients (56.9%) were clinically misdiagnosed as having another infection, most commonly dengue fever (11, 37.9%). Clinically, 20 patients (39.2%) did not present with hyperbilirubinemia or increased creatinine levels. Two patients (3.9%) died, both from respiratory failure. Fifteen patients (29.4%) clinically diagnosed with leptospirosis at sites were negative based on IgM ELISA and/or PCR at the Reference Laboratory.

Conclusions: Leptospirosis remains an important cause of hospitalization in Indonesia. It can have diverse clinical presentations, making it difficult to differentiate from other common tropical infections. PCR combined with ELISA is a powerful alternative to the cumbersome gold-standard microscopic agglutination test, particularly in resource-limited settings.
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http://dx.doi.org/10.1186/s12879-020-4903-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045408PMC
February 2020

An observational prospective cohort study of the epidemiology of hospitalized patients with acute febrile illness in Indonesia.

PLoS Negl Trop Dis 2020 01 10;14(1):e0007927. Epub 2020 Jan 10.

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.

Background: The epidemiology of acute febrile illness, a common cause of hospitalization in Indonesia, has not been systematically studied.

Methodology/principal Findings: This prospective observational study enrolled febrile patients (temperature ≥38°C) aged ≥1 year from July 2013 until June 2016 at eight government referral teaching hospitals in seven provincial capitals in Indonesia. Patients were managed according to the hospital standard-of-care (SOC), and blood samples were drawn for molecular and serological assays. Clinical data, laboratory results, and specimens for additional tests were collected at enrollment, days 14-28, and at three months. Regular follow-up visits were then scheduled for every three months either until symptoms resolved or until one year. In total, this study included 1,486 adult and pediatric patients presenting with multi-organ (768, 51.7%), gastrointestinal (497, 33.0%), respiratory (114, 7.7%), constitutional (62, 4.2%), skin and soft-tissue (24, 1.6%), central nervous system (17, 1.1%), or genitourinary (4, 0.3%) manifestations. Microbiological diagnoses were found in 1,003/1,486 (67.5%) participants, of which 351/1,003 (35.0%) were not diagnosed during hospitalization using SOC diagnostic tests. Missed diagnoses included all cases caused by Rickettsia spp., chikungunya, influenza, and Seoul virus. The most common etiologic agents identified were dengue virus (467, 46.6%), Salmonella spp. (103, 10.3%), and Rickettsia spp. (103, 10.3%). The overall mortality was 89 (5.9%).

Conclusions/significance: Febrile illness in Indonesia has various microbiologic etiologies and substantial overall mortality. Diagnostic limitations and lack of epidemiologic data resulted in potentially treatable, and at times fatal, diseases being missed.
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http://dx.doi.org/10.1371/journal.pntd.0007927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977771PMC
January 2020

Diabetes is associated with genotypically drug-resistant tuberculosis.

Eur Respir J 2020 03 20;55(3). Epub 2020 Mar 20.

Radboudumc Center for Infectious Diseases, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, The Netherlands

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http://dx.doi.org/10.1183/13993003.01891-2019DOI Listing
March 2020

Plasma metabolomics in tuberculosis patients with and without concurrent type 2 diabetes at diagnosis and during antibiotic treatment.

Sci Rep 2019 12 10;9(1):18669. Epub 2019 Dec 10.

Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands.

Tuberculosis (TB) and type 2 diabetes mellitus (DM), a major TB risk factor, are both accompanied by marked alterations in metabolic processes. Dissecting the specific metabolic changes induced by disease through metabolomics has shown potential to improve our understanding of relevant pathophysiological mechanisms of disease, which could lead to improved treatment. Targeted tandem liquid chromatography-mass spectrometry (LC-MS/MS) was used to compare amine and acylcarnitine levels in plasma samples of patients with TB or TB-DM from Indonesia at time of diagnosis and during antibiotic treatment. Partial least squares discrimination analysis (PLS-DA) showed good separation of patient groups. Amine levels were strongly altered in both disease groups compared to healthy controls, including low concentrations of citrulline and ornithine. Several amino acid ratios discriminated TB from controls (phenylalanine/histidine; citrulline/arginine; kynurenine/tryptophan), possibly reflecting changes in indoleamine-pyrrole 2,3-dioxygenase (IDO) and nitric oxide synthase (NOS) activity. Choline, glycine, serine, threonine and homoserine levels were lower in TB-DM compared to TB, and, in contrast to other analytes, did not normalize to healthy control levels during antibiotic treatment. Our results not only provide important validation of previous studies but also identify novel biomarkers, and significantly enhance our understanding of metabolic changes in human TB and TB-DM.
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http://dx.doi.org/10.1038/s41598-019-54983-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904442PMC
December 2019

High tuberculosis incidence among people living with diabetes in Indonesia.

Trans R Soc Trop Med Hyg 2020 02;114(2):79-85

Infectious Disease Research Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.

Background: Data regarding the incidence of tuberculosis (TB) among people living with diabetes (PLWD) in TB-endemic settings are scarce. We examined TB incidence among PLWD in Indonesia who had previously been screened for latent TB infection (LTBI) and TB disease.

Methods: PLWD (≥18 y of age) in an urban setting were examined a mean 3.4 y after they had been screened for active TB and LTBI. Data on subsequent TB diagnosis were collected by interview and with chest X-ray, sputum smear and Mycobacterium tuberculosis culture. TB incidence rates were stratified for baseline LTBI status, as determined by the QuantiFERON interferon-gamma release assay (IGRA).

Results: Of 590 PLWD, 101 had died and 163 could not be contacted or refused. Among the 326 who were re-examined, 6 (1.8%; 95% confidence interval [CI] 0.7 to 4.0) reported being diagnosed already and a further 5 were diagnosed with active TB (1.5%; 95% CI 0.50 to 3.5). The TB incidence rate was 9.85 (95% CI 4.03 to 15.68) per 1000 person-years. TB incidence was higher among PLWD with baseline LTBI (17.13; 95% CI 5.25 to 29.00/1000 person-years) compared with those without LTBI (4.79; 95% CI -0.63 to 10.21), with an incidence rate ratio of 3.57 (95% CI 0.86 to 20.92; p=0.054).

Conclusions: PLWD with LTBI in Indonesia and similar settings are likely to benefit from TB preventive therapy.
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http://dx.doi.org/10.1093/trstmh/trz100DOI Listing
February 2020

Dengue viral infection in Indonesia: Epidemiology, diagnostic challenges, and mutations from an observational cohort study.

PLoS Negl Trop Dis 2019 10 21;13(10):e0007785. Epub 2019 Oct 21.

Sanglah Hospital, Bali, Denpasar, Indonesia.

Background: Dengue virus (DENV) infection is a major cause of acute febrile illness in Indonesia. Diagnostic inaccuracy may occur due to its varied and non-specific presentation. Characterization of DENV epidemiology, clinical presentation, and virology will facilitate appropriate clinical management and public health policy.

Methodology/principal Findings: A multicenter observational cohort study was conducted in Indonesia to assess causes of acute fever requiring hospitalization. Clinical information and specimens were collected at enrollment, 14-28 days, and 3 months from 1,486 children and adults. Total of 468 (31.9%) cases of DENV infection were confirmed by reference laboratory assays. Of these, 414 (88.5%) were accurately diagnosed and 54 had been misdiagnosed as another infection by sites. One hundred initially suspected dengue cases were finally classified as 'non-dengue'; other pathogens were identified in 58 of those cases. Mortality of DENV infection was low (0.6%). Prior DENV exposure was found in 92.3% of subjects >12 years. DENV circulated year-round in all cities, with higher incidence from January to March. DENV-3 and DENV-1 were the predominant serotypes. This study identified DENV-1 with TS119(C→T) substitution in the serotyping primer annealing site, leading to failure of serotype determination.

Conclusions/significance: DENV is a common etiology of acute febrile illness requiring hospitalization in Indonesia. Diagnostic accuracy at clinical sites merits optimization since misdiagnosis of DENV infection and over-estimation of dengue can negatively impact management and outcomes. Mutation at the annealing site of the serotyping primer may confound diagnosis. Clinicians should consider following diagnostic algorithms that include DENV confirmatory testing. Policy-makers should prioritize development of laboratory capacity for diagnosis of DENV.
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http://dx.doi.org/10.1371/journal.pntd.0007785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822776PMC
October 2019

The Implementation of Early Detection in Tuberculosis Contact Investigation to Improve Case Finding.

J Epidemiol Glob Health 2019 09;9(3):191-197

Faculty of Public Health, Universitas Airlangga, Kampus C, Surabaya, East Java, Indonesia.

The early detection of Tuberculosis (TB) among TB contacts is a strategy to find TB cases in earlier stage and to stop the transmission. This study aimed to assess the implementation of early detection in TB contact investigation to improve TB case finding. This was an operational research study conducted in Badung District, Bali, Indonesia. The samples were TB contacts, identified in the period July through September (third quarter) 2017. Contacts were household members who were living and sharing a room at least for 3 months with infectious TB patients and were not previously diagnosed with TB. Data were collected through face-to-face interview using structured questionnaires and registration reviews using a checklist. We visited 124 TB patients and successfully identified 498 contacts, thus the ratio of contacts to cases is 4:1. All TB contacts were invited to participate in TB screening and evaluation program. A total of 100 (20.1%) contacts have attended at least one examination session and 41 contacts have completed all sessions. Ten TB cases were found among the contacts, of which four of them were adults (three bacteriologically confirmed and one clinically confirmed) and six were children (aged under 15 years). The positivity rate among children was higher (46.2%) compared with adults (14.3%). The positivity rate of confirmed TB among contacts with any TB symptoms was 43.8% and that without symptoms was 12.0%. The contribution of early detection in TB contact investigation to improve TB case finding was 8.1% through all TB patients. The early detection in TB contact investigation yielded additional notified cases, especially among children. A comprehensive education, covering cognitive and psychological aspect, is needed to encourage TB contacts to completely participate in early detection program until their diagnosis is confirmed.
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http://dx.doi.org/10.2991/jegh.k.190808.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310818PMC
September 2019

IL-32 and its splice variants are associated with protection against Mycobacterium tuberculosis infection and skewing of Th1/Th17 cytokines.

J Leukoc Biol 2020 01 4;107(1):113-118. Epub 2019 Aug 4.

Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS), and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.

Studies in IL-32 transgenic mice and in vitro suggest that IL-32 may have protective effects against Mycobacterium tuberculosis, but so far there are barely any studies in humans. We studied the role of IL-32 and its splice variants in tuberculosis (TB) in vivo and in vitro. Blood transcriptional analysis showed lower total IL-32 mRNA levels in pulmonary TB patients compared to patients with latent TB infection and healthy controls. Also, among Indonesian household contacts who were heavily exposed to an infectious TB patient, IL-32 mRNA levels were higher among those who remained uninfected compared to those who became infected with M. tuberculosis. In peripheral blood mononuclear cells from healthy donors, we found that IL-32γ, the most potent isoform, was down-regulated upon M. tuberculosis stimulation. This decrease in IL-32γ was mirrored by an increase of another splice variant, IL-32β. Also, a higher IL-32γ/IL-32β ratio correlated with IFN-γ production, whereas a lower ratio correlated with production of IL-1Ra, IL-6, and IL-17. These data suggest that IL-32 contributes to protection against M. tuberculosis infection, and that this effect may depend on the relative abundance of different IL-32 isoforms.
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http://dx.doi.org/10.1002/JLB.4AB0219-071RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972663PMC
January 2020

Early Clearance of Mycobacterium tuberculosis: The INFECT Case Contact Cohort Study in Indonesia.

J Infect Dis 2020 03;221(8):1351-1360

Centre for International Health, Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand.

Background: Early clearance of Mycobacterium tuberculosis is the eradication of infection before an adaptive immune response develops. We aimed to identify host factors associated with early clearance.

Methods: Indonesian household contacts patients with smear-positive tuberculosis (TB) had an interferon-γ release assay (IGRA) at baseline and 14 weeks later. Early clearance was defined as a persistently negative IGRA. Contact characteristics, exposure, and disease phenotype were assessed for association with a positive IGRA at each time point.

Results: Of 1347 contacts of 462 TB cases, 780 (57.9%) were IGRA positive and 490 (36.3%) were IGRA negative. After 14 weeks, 116 of 445 (26.1%) initially negative contacts were IGRA converters; 317 (71.2%) remained persistently negative. BCG vaccination reduced the risk of a positive baseline IGRA (relative risk [RR], 0.89 [95% confidence interval {CI} .83-.97]; P = .01), and strongly reduced the risk of IGRA conversion (RR, 0.56 [95% CI, .40-.77]; P < .001). BCG protection decreased with increasing exposure (P = .05) and increasing age (P = .004). Risk of IGRA conversion was positively associated with hemoglobin concentration (P = .04).

Conclusions: A quarter of household TB case contacts were early clearers. Protection against M. tuberculosis infection was strongly associated with BCG vaccination. Lower protection from BCG with increasing M. tuberculosis exposure and age can inform vaccine development.
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http://dx.doi.org/10.1093/infdis/jiz168DOI Listing
March 2020

Are there differences in HIV retention in care between female and male patients in Indonesia? A multi-state analysis of a retrospective cohort study.

PLoS One 2019 25;14(6):e0218781. Epub 2019 Jun 25.

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Little is known about HIV treatment outcomes in Indonesia, which has one of the most rapidly growing HIV epidemics worldwide.

Methods: We examined possible differences in loss to follow-up (LTFU) and survival between HIV-infected females and males over a 7-year period in an HIV clinic in Bandung, West Java. Data imputation was performed on missing covariates and a multi-state Cox regression was used to investigate the effects of sex and other covariates on patient transitions among four states: (1) clinic enrollment with HIV, (2) initiation/continuation/re-initiation of antiretroviral therapy (ART), (3) LTFU, and (4) death.

Results: We followed 3215 patients (33% females), for a total of 8430 person-years. ART was used by 59% of patients at some point. One-year retention was 73% for females and 77% for males (p = 0.06). One-year survival was 98% for both females and males (p = 0.15). Females experienced a higher relative hazard to transition from HIV to LTFU (adjusted hazard ratio 1.21; 95% confidence interval 1.00-1.45), but this decreased after adjustments for clinical variables (aHR 0.94; 95% CI 0.79-1.11). Similarly, a lower relative hazard in females to transition from ART to death (aHR 0.59; 95% CI 0.35-0.99) decreased after adjustments for demographic variables.

Conclusion: This Indonesian cohort has low ART uptake and poor overall pre- and post-ART retention. Female-male differences in survival and retention were gone after adjusting for clinical and sociodemographic factors such as CD4 count and education level. Efforts should be made to improve retention among patients with lower education.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218781PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592601PMC
February 2020

Comparison of Serum Potassium, MagnEsium, and Calcium Levels between Kanamycin and Capreomycin-BASEd Regimen-Treated MultiDrug-Resistant TuBerculosis Patients in Bandung (CEASE MDR-TB): A Retrospective Cohort Study.

Int J Microbiol 2019 14;2019:5065847. Epub 2019 Mar 14.

Clinical Pathology Department, Hasan Sadikin General Hospital/Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.

Treatment of multidrug-resistant tuberculosis (MDR-TB) with second-line injectable drugs may result in an electrolyte imbalance. This retrospective study was performed to compare and evaluate the effect of kanamycin and capreomycin on serum potassium, calcium, and magnesium in the first and second month treatment at a tertiary, top-referral hospital in Bandung, Indonesia. Data from 84 subjects with complete medical records of at least serum potassium during either kanamycin-based or capreomycin-based treatment were retrieved from the institutional database. Among these, 53 subjects had complete serum calcium data and 53 subjects had complete serum magnesium data. After the first month of MDR-TB treatment, there was a significant decrease in mean serum potassium (4.0 ± 0.4 mEq/L to 3.7 ± 0.5 mEq/L, < 0.003) in the kanamycin-based group and (4.1 ± 0.5 mEq/L to 3.2 ± 0.6 mEq/L, < 0.001) in the capreomycin-based group. Serum potassium levels were significantly lower in the capreomycin-based group than in the kanamycin-based group (3.2 ± 0.6 mEq/L vs 3.7 ± 0.5 mEq/L, < 0.001). The incidence of hospitalization and requirement for a change in the treatment regimen due to electrolyte imbalances were higher in the capreomycin-based group. No previous longitudinal study has evaluated serum potassium, magnesium, and calcium from the first month of MDR-TB treatment with either kanamycin-based or capreomycin-based regimens. Our findings emphasize the importance of routine monitoring of serum potassium, magnesium, and calcium during MDR-TB treatment, and that more attention should be paid when treatment is given using the capreomycin-based regimen. Moreover, our study supported the 2018 World Health Organization treatment guideline recommendations for removal of kanamycin and capreomycin from the MDR-TB regimens.
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http://dx.doi.org/10.1155/2019/5065847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437726PMC
March 2019

Early Clearance of Mycobacterium tuberculosis Is Associated With Increased Innate Immune Responses.

J Infect Dis 2020 03;221(8):1342-1350

Department of Internal Medicine and Radboud Center for Infectious Diseases, Nijmegen, The Netherlands.

Background: A proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed "early clearance."

Methods: Indonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post recruitment. Blood cell populations and ex vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive.

Results: Among 1347 case contacts, 317 were early clearers and 116 were converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA-negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA-negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae.

Conclusions: Early clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity.
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http://dx.doi.org/10.1093/infdis/jiz147DOI Listing
March 2020

Diabetes Mellitus Among Pulmonary Tuberculosis Patients From 4 Tuberculosis-endemic Countries: The TANDEM Study.

Clin Infect Dis 2020 02;70(5):780-788

Department of Internal Medicine and Radboud Center of Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Diabetes mellitus (DM) increases active tuberculosis (TB) risk and worsens TB outcomes, jeopardizing TB control especially in TB-endemic countries with rising DM prevalence rates. We assessed DM status and clinical correlates in TB patients across settings in Indonesia, Peru, Romania, and South Africa.

Methods: Age-adjusted DM prevalence was estimated using laboratory glycated hemoglobin (HbA1c) or fasting plasma glucose in TB patients. Detailed and standardized sociodemographic, anthropometric, and clinical measurements were made. Characteristics of TB patients with or without DM were compared using multilevel mixed-effect regression models with robust standard errors.

Results: Of 2185 TB patients (median age 36.6 years, 61.2% male, 3.8% human immunodeficiency virus-infected), 12.5% (267/2128) had DM, one third of whom were newly diagnosed. Age-standardized DM prevalence ranged from 10.9% (South Africa) to 19.7% (Indonesia). Median HbA1c in TB-DM patients ranged from 7.4% (Romania) to 11.3% (Indonesia). Compared to those without DM, TB-DM patients were older and had a higher body mass index (BMI) (P value < .05). Compared to those with newly diagnosed DM, TB patients with diagnosed DM had higher BMI and HbA1c, less severe TB, and more frequent comorbidities, DM complications, and hypertension (P value < .05).

Conclusions: We show that DM prevalence and clinical characteristics of TB-DM vary across settings. Diabetes is primarily known but untreated, hyperglycemia is often severe, and many patients with TB-DM have significant cardiovascular disease risk and severe TB. This underlines the need to improve strategies for better clinical management of combined TB and DM.
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http://dx.doi.org/10.1093/cid/ciz284DOI Listing
February 2020

A novel diagnostic algorithm equipped on an automated hematology analyzer to differentiate between common causes of febrile illness in Southeast Asia.

PLoS Negl Trop Dis 2019 03 14;13(3):e0007183. Epub 2019 Mar 14.

Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands.

Background: Distinguishing arboviral infections from bacterial causes of febrile illness is of great importance for clinical management. The Infection Manager System (IMS) is a novel diagnostic algorithm equipped on a Sysmex hematology analyzer that evaluates the host response using novel techniques that quantify cellular activation and cell membrane composition. The aim of this study was to train and validate the IMS to differentiate between arboviral and common bacterial infections in Southeast Asia and compare its performance against C-reactive protein (CRP) and procalcitonin (PCT).

Methodology/principal Findings: 600 adult Indonesian patients with acute febrile illness were enrolled in a prospective cohort study and analyzed using a structured diagnostic protocol. The IMS was first trained on the first 200 patients and subsequently validated using the complete cohort. A definite infectious etiology could be determined in 190 of 463 evaluable patients (41%), including 89 arboviral infections (81 dengue and 8 chikungunya), 94 bacterial infections (26 murine typhus, 16 salmonellosis, 6 leptospirosis and 46 cosmopolitan bacterial infections), 3 concomitant arboviral-bacterial infections, and 4 malaria infections. The IMS detected inflammation in all but two participants. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the IMS for arboviral infections were 69.7%, 97.9%, 96.9%, and 77.3%, respectively, and for bacterial infections 77.7%, 93.3%, 92.4%, and 79.8%. Inflammation remained unclassified in 19.1% and 22.5% of patients with a proven bacterial or arboviral infection. When cases of unclassified inflammation were grouped in the bacterial etiology group, the NPV for bacterial infection was 95.5%. IMS performed comparable to CRP and outperformed PCT in this cohort.

Conclusions/significance: The IMS is an automated, easy to use, novel diagnostic tool that allows rapid differentiation between common causes of febrile illness in Southeast Asia.
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http://dx.doi.org/10.1371/journal.pntd.0007183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435198PMC
March 2019

Desialylation of platelets induced by Von Willebrand Factor is a novel mechanism of platelet clearance in dengue.

PLoS Pathog 2019 03 8;15(3):e1007500. Epub 2019 Mar 8.

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

Thrombocytopenia and platelet dysfunction are commonly observed in patients with dengue virus (DENV) infection and may contribute to complications such as bleeding and plasma leakage. The etiology of dengue-associated thrombocytopenia is multifactorial and includes increased platelet clearance. The binding of the coagulation protein von Willebrand factor (VWF) to the platelet membrane and removal of sialic acid (desialylation) are two well-known mechanisms of platelet clearance, but whether these conditions also contribute to thrombocytopenia in dengue infection is unknown. In two observational cohort studies in Bandung and Jepara, Indonesia, we show that adult patients with dengue not only had higher plasma concentrations of plasma VWF antigen and active VWF, but that circulating platelets had also bound more VWF to their membrane. The amount of platelet-VWF binding correlated well with platelet count. Furthermore, sialic acid levels in dengue patients were significantly reduced as assessed by the binding of Sambucus nigra lectin (SNA) and Maackia amurensis lectin II (MAL-II) to platelets. Sialic acid on the platelet membrane is neuraminidase-labile, but dengue virus has no known neuraminidase activity. Indeed, no detectable activity of neuraminidase was present in plasma of dengue patients and no desialylation was found of plasma transferrin. Platelet sialylation was also not altered by in vitro exposure of platelets to DENV nonstructural protein 1 or cultured DENV. In contrast, induction of binding of VWF to glycoprotein 1b on platelets using the VWF-activating protein ristocetin resulted in the removal of platelet sialic acid by translocation of platelet neuraminidase to the platelet surface. The neuraminidase inhibitor oseltamivir reduced VWF-induced platelet desialylation. Our data demonstrate that excessive binding of VWF to platelets in dengue results in neuraminidase-mediated platelet desialylation and platelet clearance. Oseltamivir might be a novel treatment option for severe thrombocytopenia in dengue infection.
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http://dx.doi.org/10.1371/journal.ppat.1007500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426266PMC
March 2019

Evaluation of Xpert MTB-RIF guided diagnosis and treatment of rifampicin-resistant tuberculosis in Indonesia: A retrospective cohort study.

PLoS One 2019 28;14(2):e0213017. Epub 2019 Feb 28.

Center for International Health, University of Otago, Dunedin, New Zealand.

Background: Rifampicin-resistant tuberculosis (RR-TB) is largely underdetected in Indonesia. Xpert MTB/RIF (Xpert) has recently been introduced, prioritizing patients at risk of RR-TB, followed by phenotypic drug-susceptibility (DST) if rifampicin resistance is detected.

Objective: This study investigated Xpert-based management of presumptive RR-TB cases under routine practice in West Java, Indonesia.

Methods: We examined all records of patients tested with Xpert in the referral hospital for West Java in 2015-2016. We measured loss across a limited cascade of care, time to Xpert diagnosis and the commencement of initial second-line treatment, and identified factors associated with diagnostic and treatment delay. Additionally, we analyzed the appropriateness of treatment according to DST results.

Results: Of 3415 patients with presumptive RR-TB, 3215 (94%) were tested by Xpert, of whom 339 (10.5%) were diagnosed as RR-TB. 288 (85%) of 339 RR-TB patients started initial second-line TB treatment, with 48 (14%) patients being lost between diagnosis and pre-treatment assessment. Second-line treatment was commenced at a median of 41 days (IQR 29-70) after RR-TB diagnosis. Delays in both diagnosis and treatment initiation were observed in 104 (52%) of 201 RR-TB patients with identifiable referral date. Rural residence was associated with delay to diagnosis (adjusted OR 2.7; 95%CI 1.5-5.2) and treatment initiation (adjusted OR 2.0; 1.2-3.4). Of 162 patients with available DST result, 107 (66%) had multidrug-resistant tuberculosis (MDR-TB) and 32 (20%) had either pre-extensively drug resistant (pre-XDR) or extensively drug resistant tuberculosis (XDR-TB). We estimated that with the current algorithm 41% of pre-XDR or XDR-TB patients are diagnosed, and 33% of them started on an appropriate treatment regimen.

Conclusions: Many patients with Xpert-diagnosed RR-TB either do not start MDR-TB treatment or encountered diagnostic and treatment delays under programmatic conditions in Indonesia, and most pre-XDR and XDR-TB cases remain undiagnosed. Further expansion and ongoing quality improvement of RR-TB services are urgently needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213017PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394995PMC
November 2019