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Background: Accurate diagnosis of enteric fever is challenging, particularly in low- and middle-income countries, due to the overlap of clinical and laboratory features with other pathogens. To better understand the difficulties in enteric fever diagnosis, we evaluated the characteristics of patients clinically diagnosed with enteric fever and the real-world performance of TUBEX TF, one of the most used tests in Indonesia. Methodology/Principal findings: Patients were recruited through the AFIRE (Etiology of Acute Febrile Illness Requiring Hospitalization) study at eight Indonesian hospitals. Blood culture was performed for all patients, and TUBEX TF was performed for suspected enteric cases. Salmonella PCR and ELISA tests were performed at a reference lab. Sensitivity and specificity of TUBEX TF and IgM and IgG anti-S. Typhi ELISA were determined. Of 301 patients clinically diagnosed with enteric fever, 50 (16.6%) were confirmed by blood culture and/or PCR. Confirmed cases were mostly school-aged children presenting with fever, anorexia, dizziness and/or abdominal pain with normal leukocyte count or leukopenia. TUBEX TF demonstrated a sensitivity of 97.6% to 70.7% and specificity of 38.3% to 67.2% at cutoffs of 4 and 6, respectively. Acute IgG demonstrated the best sensitivity and specificity, at 90.7% and 82.7%, respectively, and the best ROC characteristics. Conclusions/Significance: A substantial proportion of enteric fever was misdiagnosed at all study hospitals, likely due to the overlap of clinical characteristics and lab parameters with those of other common pathogens. The TUBEX TF rapid serological assay demonstrated suboptimal performance in our setting and tended to over-diagnose enteric fever. The role of IgG from acute specimens for identification of enteric fever cases merits additional consideration. Author summary: Enteric fever is a major health problem in Indonesia. Blood culture, the gold standard for enteric fever diagnosis, is expensive and requires several days to produce a result, leading to diagnoses being made through rapid tests such as TUBEX TF in Indonesia and other LMICs. In a real-world setting, we found that TUBEX TF over-diagnosed enteric fever by more than 50% in comparison to blood culture and PCR. Over-diagnosis may result in over-treatment and the subsequent increase of antimicrobial resistance. Given the suboptimal performance of TUBEX TF, the use of readily available clinical and laboratory data to facilitate identification of enteric fever cases has been considered. In our study, the majority of enteric fever patients were school-aged children. Although non-specific, gradually increasing fever, gastrointestinal symptoms, and cough were often present; hematologic parameters did not distinguish enteric fever from other etiologies. Interestingly, diagnostic accuracy was better by S. Typhi IgM and best by S. Typhi IgG in acute specimens. These findings may reflect the inaccuracy or subjectivity of TUBEX TF. The surprisingly excellent performance of S. Typhi IgG ELISA merits further evaluation. [ABSTRACT FROM AUTHOR]

Sponges from the Clathria genus, especially those from Derawan Island, Indonesia, are renowned repositories of microbial symbionts enriched with potent bioactive compounds. Our study delved into these sponges, extracting and examining their bacterial symbionts for their antimicrobial, antioxidant, and enzymatic activities. Using dilution and streak methods, 23 distinct bacterial types were isolated and identified based on cellular morphology. Among these, the SC-06 isolate demonstrated significant antibacterial capabilities against Staphylococcus aureus and Escherichia coli. Further, isolates SC-01, SC-03, SC-11, SC-13, and SC-15 exhibited powerful antioxidant properties, neutralizing over 50% of radicals. Additionally, strains SC-08, SC-02, SC-05, and SC-22 displayed remarkable enzymatic activities, suggesting their potential industrial applications. The Clathria sp. sponges from Derawan offer a promising biotechnological frontier, with their bacterial symbionts poised to redefine marine biotech innovations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis is one of the major causes of death globally. The problems become even more complicated with the rise in prevalence of multidrug resistant tuberculosis (MDR-TB). Many diseases have been reported to occur with tuberculosis making it more difficult to manage. Candida spp., which are yeast-like fungi and a constituent of normal flora in humans, are notoriously reported to be one of the most common opportunistic nosocomial infections. This study aimed to measure the proportion of presumptive MDR-TB patients colonized with Candida spp. and to characterize its susceptibility against azole group antifungal agents. Methods: Sputum from presumptive MDR-TB patients were collected and examined for the presence of Mycobacterium tuberculosis and its rifampicin resistant status using GeneXpert. It was further cultured on Sabouroud's Dextrose Agar (SDA) to isolate the Candida spp. The Candida species were determined using HiCrome™ Candidal Differential Agar. Antifungal susceptibility was tested using microbroth dilution methods. Checkerboard microdilution assays were performed to measure the interaction between rifampicin and fluconazole to C. albicans. Results: There were 355 presumptive MDR-TB patients enrolled. A total of 101 (28.4%) patients were confirmed to have M. tuberculosis. There were 113 (31.8%) sputum positive for Candida spp., which corresponded to 149 Candida spp. isolates. Candida albicans was the most frequent (53.7%) species isolated from all patients. The susceptibility of Candida spp. against fluconazole, itraconazole, and ketoconazole were 38.3%, 1.3%, and 10.7% respectively. There was significant association between rifampicin exposure history and susceptibility of Candida albicans against fluconazole (Odds Ratio: 9.96; 95% CI: 1.83–54.19; p <0.01), but not for ketoconazole and itraconazole. The checkerboard microdilution assays showed that rifampicin decreased the fungicidal activity of fluconazole to C. albicans in a dose-dependent manner. Conclusion: There was high frequency of azole resistant Candida spp. isolates colonizing the respiratory tract of presumptive MDR-TB patients. This presence might indicate the association of chronic exposure to rifampicin, the main drug for tuberculosis therapy, with the induction of azole resistance. [ABSTRACT FROM AUTHOR]

Murine typhus is a tropical disease caused by Rickettsia typhi and is endemic in resource-limited settings such as Southeast Asian countries. Early diagnosis of R. typhi infection facilitates appropriate management and reduces the risk of severe disease. However, molecular detection of R. typhi in blood is insensitive due to low rickettsemia. Furthermore, the gold standard of sero-diagnosis by immunofluorescence assay (IFA) is cumbersome, subjective, impractical, and unavailable in many endemic areas. In an attempt to identify a practical diagnostic approach that can be applied in Indonesia, we evaluated the performance of commercial R. typhi IgM and IgG enzyme-linked immunosorbent assay (ELISA) and IFA using paired plasma from previously studied R. typhi PCR-positive cases and controls with other known infections. Sensitivity and specificity of combined ELISA IgM and IgG anti-R. typhi using paired specimens were excellent (95.0% and 98.3%, respectively), comparable to combined IFA IgM and IgG (97.5% and 100%, respectively); sensitivity of ELISA IgM from acute specimens only was poor (45.0%), but specificity was excellent (98.3%). IFA IgM was more sensitive (77.5%), but less specific (89.7%) for single specimens. [ABSTRACT FROM AUTHOR]

Background: The epidemiology of acute febrile illness, a common cause of hospitalization in Indonesia, has not been systematically studied. Methodology/Principal gindings: 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. Author summary: In tropical countries like Indonesia, fever due to infectious disease is the most common reason for hospitalization. However, diagnoses are mostly unconfirmed, as diagnostic tests are not available or are not performed due to budget constraints. Consequently, many patients are only treated based on clinical syndromes. To gain a better understanding of the epidemiology of acute fever in Indonesia, we conducted a study at eight hospitals in the seven largest cities from 2013–2016. We enrolled 1,486 subjects aged ≥1 year with acute fever ≥38°C. Blood cultures were mandatory for all subjects, while cultures of other biological specimens, microscopic examinations, and rapid tests for specific pathogens were based on clinical judgment and availability. Retrospectively, we performed molecular and serological testing for a panel of bacterial and viral pathogens for systemic, respiratory, and diarrheal diseases. We found six pathogens to be the most prevalent: dengue virus (47%), Salmonella Typhi/Paratyphi (10%), Rickettsia typhi (10%), influenza virus (7%), Leptospira spp. (5%), and chikungunya virus (4%). Rickettsia typhi, influenza, and chikungunya had not been considered in the differential diagnosis of any subject at the hospitals. Thus, multiple pathogens were associated with acute febrile illnesses, and a subset of treatable cases were missed. This may have resulted in increased overall mortality. [ABSTRACT FROM AUTHOR]

Nationally representative observational and translational research is needed to address the public health challenges in Indonesia due to the geographic disparity, recently decentralized health system, and diverse infectious disease priorities. To accomplish this, the Indonesian Ministry of Health in collaboration with the US National Institute of Health has established INA-RESPOND (Indonesia Research Partnership on Infectious Disease) - a clinical research network comprising 9 referral hospitals, 7 medical faculties, and 2 research centres across Indonesia. The network provides a forum to conduct research at a national scale and to address scientific questions that would be difficult to address in smaller research settings. Further, it is currently conducting multi-centre research on the etiologies of fever, sepsis, and tuberculosis. There are opportunities to leverage existing network resources for other public health research needs. INA-RESPOND is an Indonesian-led network in a country with diverse population groups and public health needs which is poised to collaborate with researchers, universities, donors, and industry worldwide. This paper describes the network and its goals and values, as well as the management structure, process for collaboration, and future vision. [ABSTRACT FROM AUTHOR]

The correct Funding statement is as follows: This project has been funded in whole or in part with MOH Indonesia and Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contract Nos. Reference 1 Gasem MH, Kosasih H, Tjitra E, Alisjahbana B, Karyana M, Lokida D, et al. (2020) An observational prospective cohort study of the epidemiology of hospitalized patients with acute febrile illness in Indonesia. [Extracted from the article]

Background: Rotavirus is an important cause of severe diarrhoea in children. The aims of this study were to identify the rotavirus strains that cause diarrhoea in children in Yogyakarta and to determine the association between rotavirus positivity and its clinical manifestations. Methods: Clinical data and stool samples were collected from children hospitalised at Kodya Yogyakarta Hospital, Indonesia. Rotavirus was detected in stool samples using an enzyme immunoassay (EIA), which was followed by genotyping using reverse transcriptase polymerase chain reaction (RT-PCR). Electropherotyping was performed for the rotavirus-positive samples. Results: In total, 104 cases were included in the study, 57 (54.8%) of which were rotavirus-positive. Based on a multiple logistic regression analysis, age group, vomiting and stool mucous were associated with rotavirus positivity. Most of the 56 samples subjected to genotyping were classified as Gi (80.36%) and P[8] (69.64%) genotypes. The genotype combination GiP[8] was identified as the most prevalent strain (66.07%). Of the 19 samples subjected to electropherotyping, 17 G1 isolates and 1 G3 isolate had long patterns, and 1 G1 isolate had a short pattern. Conclusion: G1P[8] was the most dominant strain of rotavirus causing diarrhoea in children in Yogyakarta. Age group, vomiting and stool mucous were associated with rotavirus positivity. [ABSTRACT FROM AUTHOR]

Murine typhus is a tropical disease caused by Rickettsia typhi and is endemic in resource-limited settings such as Southeast Asian countries. Early diagnosis of R. typhi infection facilitates appropriate management and reduces the risk of severe disease. However, molecular detection of R. typhi in blood is insensitive due to low rickettsemia. Furthermore, the gold standard of sero-diagnosis by immunofluorescence assay (IFA) is cumbersome, subjective, impractical, and unavailable in many endemic areas. In an attempt to identify a practical diagnostic approach that can be applied in Indonesia, we evaluated the performance of commercial R. typhi IgM and IgG enzyme-linked immunosorbent assay (ELISA) and IFA using paired plasma from previously studied R. typhi PCR-positive cases and controls with other known infections. Sensitivity and specificity of combined ELISA IgM and IgG anti- R. typhi using paired specimens were excellent (95.0% and 98.3%, respectively), comparable to combined IFA IgM and IgG (97.5% and 100%, respectively); sensitivity of ELISA IgM from acute specimens only was poor (45.0%), but specificity was excellent (98.3%). IFA IgM was more sensitive (77.5%), but less specific (89.7%) for single specimens.