Immunogenicity and safety of Quadrivalent Influenza HA vaccine compared with Trivalent Influenza HA vaccine and evaluation of Quadrivalent Influenza HA vaccine batch-to-batch consistency in Indonesian children and adults.

One of the newest strategies developed by the Global Influenza Strategy has been to broaden the composition of the current influenza vaccine formulations from trivalent products to quadrivalent products. This study aimed to assess the immunogenicity and safety of Quadrivalent Influenza HA vaccine (QIV) compared with Trivalent Influenza HA vaccine (TIV) and to evaluate three consecutive batches of QIV equivalence in Indonesian children and adults. This was an experimental, randomized, double blind, four arm parallel group bridging study involving unprimed healthy children and adults aged 9-40 years. A total of 540 subjects were enrolled in this study and randomized into four arm groups. Each subject received one dose of TIV or QIV with three different batch codes. Serology tests were performed at baseline and 28 days after vaccination. Hemagglutination inhibition (HI) antibody titers were analyzed for Geometric Mean Titer (GMT), seroprotection, and seroconversion rates. Solicited, unsolicited, and serious adverse events were observed up to 28 days after vaccination. A total of 537 subjects completed the study per protocol and were analyzed for immunogenicity criteria. All randomized subjects were analyzed for safety criteria. The percentage of the subjects with anti-HI titer ≥1:40 28 days after QIV vaccination was 99.5% for A/H1N1; 99.5% for A/H3N2; 93.1% for B/Texas, and 99.0% for B/Phuket. The seroprotection, GMT, and seroconversion rates of QIV were not significantly different from those of TIV for the common vaccine strains (p > 0.01) and were significantly different from those of TIV for the added B/Phuket strains (p < 0.01). Most solicited injection-site and systemic reactions with either vaccine were mild to moderate and resolved within a few days. Antibody response to QIV were equivalence among vaccine batches and comparable between age groups for each of the 4 strains. QIV was immunogenic and well-tolerated and had immunogenicity and safety profiles compared with TIV for all common strains. The immunogenicity of the three batches of QIV was equivalent for the four strains. Trial registration. Clinical Trial registration: NCT03336593.

Murine typhus is a common cause of acute febrile illness in Bandung, Indonesia.

Murine typhus (MT), an infection caused by the gram-negative bacteria Rickettsia typhi (R. typhi), is a significant cause of acute febrile illness (AFI) in Southeast Asia but is rarely reported in Indonesia. The current study aimed to describe the clinical characteristics of MT cases in Bandung, West Java. Non-confirmed AFI cases (n = 176) from a prospective cohort study of whom paired serum samples (acute (T1), midterm (T2), or convalescent (T3)) were available were screened using MT serology. IgG against R. typhi was detected in the T2 or T3 samples using an in-house ELISA. Positive IgG samples were further screened for the presence of IgM. If both IgM and IgG were positive, the endpoint titer of T1, T2, or T3 was determined. In cases with a fourfold increase in titer, real-time PCR of T1 samples was performed to detect R. typhi DNA. In total, 71/176 (40.3%) patients tested positive for IgG antibody, and 26 AFI cases were confirmed as MT (23 cases by PCR, 3 cases by fourfold titer increased IgG or IgM titer). The most common clinical symptoms in the confirmed cases were headache (80%), arthralgia (73%), malaise (69%), and myalgia (54%). In these cases, the presumptive clinical diagnoses were typhoid fever (43.2%), dengue (38.5%), and leptospirosis (19.2%). MT was not considered in any of the patients, and no patients received doxycycline. These findings confirmed that MT is an important cause of AFI in Indonesia. MT should be included in the differential diagnosis of AFI, and empirical treatment with doxycycline should be considered.

Antibiotic Resistance in COVID-19 with Bacterial Infection: Laboratory-Based Surveillance Study at Single Tertiary Hospital in Indonesia.

Purpose: Coronavirus disease 2019 (COVID-19) is a new pandemic affecting the respiratory system and caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the increased use of antibiotics, the length of stay of hospitalized patients affects the risk of bacterial infections among the COVID-19 patients. However, this pandemic has interrupted antibiotic surveillance activity and led to an information gap about the prevalence and characteristics of bacterial infection. This study aims to describe the antibiotic resistance in COVID-19 patients with culture-proven bacterial infection using a laboratory-based surveillance approach. Patients and Methods: A retrospective study with a cross-sectional design was conducted on adult patients that confirmed positive for COVID-19 according to the International Classification of Diseases 10th Revision (ICD-10). From March 2020 to October 2021, data were obtained from the hospital information system and merged with the culture and antibiotic susceptibility test from laboratory information system at Hasan Sadikin General Hospital. The outcome is the prevalence percentage of resistance to selected antibiotics in patients with COVID-19. The resistance percentage is considered high when equal to or more than 20%. Results: There was 2786 adult patient confirmed for COVID-19 according to the ICD-10, and 26.3% (n = 733) of them submitted clinical specimen for culture. The prevalence of bacterial infection among COVID-19 patients was 16.4%, predominating Gram-negative bacteria (GNB). The respiratory specimen dominated the positive growth culture. The GNB were predominantly discovered among the respiratory and non-respiratory specimens. High range resistance to ampicillin-sulbactam (24-100%), ceftriaxone (22-81%), cefotaxime (22-73%) and ciprofloxacin (20-86%) are observed among the GNB. Conclusion: There is high resistance to fluoroquinolone and cephalosporins in identified isolate, commonly used as the first-line empirical treatment for respiratory and non-respiratory infection in Indonesia. The continuous antibiotic surveillance is mandatory and crucial to prevent the long-term effects of the COVID-19 pandemic, particularly bacterial infection.

A Comparison of the Accuracy of Handheld Hemoglobinometer and Hematocrit Measurements for Detecting Plasma Leakage in Dengue Hemorrhagic Fever.

Purpose: Practical methods for detecting plasma leakage should be readily available in all areas where dengue is endemic. We compared the accuracy of measurements obtained with a handheld HemoCue® Hb 201 instrument used for hemoglobin point-of-care testing (Hb-POCT) with that of measurements of hematocrit (Ht) levels for detecting plasma leakage in dengue patients. Patients and Methods: We performed both measurements using the HemoCue® Hb201 system and microhematocrit method on EDTA blood taken from dengue patients at three time points during their hospitalization. Ascites, pleural effusion, or gallbladder thickening determined through ultrasound examinations were considered the gold standard for determining dengue hemorrhagic fever (DHF) versus dengue fever (DF). Results: Close agreement between Hb-POCT and Ht measurements was indicated by an r square value of 0.845 in a linear regression. The sensitivity results for distinguishing between DHF and DF at admission were similar for Hb-POCT (63.6%) and Ht (66.7%) (Kappa = 0.75) using the optimal cutoff point determined via ROC analysis. Delta differences (in percentage) for Hb-POCT and Ht between the highest and lowest values showed lower sensitivity (45.5% and 48.5%, respectively; Kappa 0.60) when the optimal cutoff point was applied. Recommended cutoffs of ≥20% to confirm plasma leakage provided a slightly higher sensitivity using Hb-POCT (18.2%) compared with the sensitivity obtained using Ht (15.2%) with Kappa value of 97.9%. Conclusion: Our results showed that the accuracy of Hb POCT measurements was similar and not inferior to Ht measurements for detecting plasma leakage in patients with DHF. We recommend that further evaluations are conducted to determine the optimal cutoff point given the low sensitivity associated with using ≥20% Hb-POCT or Ht increases to determine hemoconcentration.

A phase III, observer-blind, randomized, placebo-controlled study of the efficacy, safety, and immunogenicity of SARS-CoV-2 inactivated vaccine in healthy adults aged 18-59 years: An interim analysis in Indonesia.

BACKGROUND: The WHO declared COVID-19 a pandemic on March 11th, 2020. This serious outbreak and the precipitously increasing numbers of deaths worldwide necessitated the urgent need to develop an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. The development of COVID-19 vaccines has moved quickly. In this study, we assessed the efficacy, safety, and immunogenicity of an inactivated (SARS-CoV-2) vaccine. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy, immunogenicity, and safety of an inactivated SARS-CoV-2 vaccine and its lot-to-lot consistency. A total of 1620 healthy adults aged 18-59 years were randomly assigned to receive 2 injections of the trial vaccine or placebo on a day 0 and 14 schedule. This article was based on an interim report completed within 3 months following the last dose of study vaccine. The interim analysis includes safety and immunogenicity data for 540 participants in the immunogenicity subset and an efficacy analysis of the 1620 subjects. For the safety evaluation, solicited and unsolicited adverse events were collected after the first and second vaccination within 14 and 28 days, respectively. Blood samples were collected for an antibody assay before and 14 days following the second dose. RESULTS: Most of the adverse reactions were in the solicited category and were mild in severity. Pain at the injection site was the most frequently reported symptom. Antibody IgG titer determined by enzyme-linked immunosorbent assay was 97.48% for the seroconversion rate. Using a neutralization assay, the seroconversion rate was 87.15%. The efficacy in preventing symptomatic confirmed cases of COVID-19 occurring at least 14 days after the second dose of vaccine using an incidence rate was 65.30%. CONCLUSIONS: From the 3-month interim analysis, the vaccine exhibited a 65.30% efficacy at preventing COVID-19 illness with favorable safety and immunogenicity profiles.

Development of Nucleic Acid Lateral Flow Immunoassay for Rapid and Accurate Detection of Chikungunya Virus in Indonesia.

Chikungunya fever is an arboviral disease caused by the Chikungunya virus (CHIKV). The disease has similar clinical manifestations with other acute febrile illnesses which complicates differential diagnosis in low-resource settings. We aimed to develop a rapid test for CHIKV detection based on the nucleic acid lateral flow immunoassay technology. The system consists of a primer set that recognizes the E1 region of the CHIKV genome and test strips in an enclosed cassette which are used to detect amplicons labeled with FITC/biotin. Amplification of the viral genome was done using open-source PCR, a low-cost open-source thermal cycler. Assay performance was evaluated using a panel of RNA isolated from patients' blood with confirmed CHIKV (n = 8) and dengue virus (n = 20) infection. The open-source PCR-NALFIA platform had a limit of detection of 10 RNA copies/ml. The assay had a sensitivity and specificity of 100% (95% CI: 67.56% - 100%) and 100% (95% CI: 83.89% - 100%), respectively, compared to reference standards of any positive virus culture on C6/36 cell lines and/or qRT-PCR. Further evaluation of its performance using a larger sample size may provide important data to extend its usefulness, especially its utilization in the peripheral healthcare facilities with scarce resources and outbreak situations.

The performance of point-of-care antibody test for COVID-19 diagnosis in a tertiary hospital in Bandung, Indonesia.

INTRODUCTION: We aim to describe the performance of combined IgM and IgG point-of-care antibody test (POC-Ab) (Wondfo®) compared to real-time reverse transcriptase (rRT-PCR) (Allplex™ 2019-nCoV Assay) in detecting coronavirus disease 2019 (COVID-19). METHODOLOGY: We compared POC-Ab with rRT-PCR results among patients in a tertiary hospital from January to March 2020 in Bandung, Indonesia. We selected presumptive COVID-19 patients with positive rRT-PCR consecutively and 20 patients with negative rRT-PCR results were selected randomly from the same group of patients as controls. We described the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) with corresponding 95% confidence interval using serum and capillary blood samples. We also tested POC-Ab using non-COVID-19 (confirmed dengue and typhoid) patients' sera. RESULTS: Twenty-seven patients with positive rRT-PCR result and 20 negative controls were included (68.1% males, mean age 46 (SD: 15.4)). Using the serum, the sensitivity of the POC-Ab was 63.0% (42.4-80.6), specificity was 95.0% (75.1-99.9), PPV was 94.4% (72.7-99.8), NPV was 65.5% (45.7-82.1). A subset of 20 patients was tested using a capillary blood sample. The accuracy of the capillary blood sample is lower compared to serum (50.0% vs. 78.7%). None of the non-COVID-19 sera tested were reactive. CONCLUSIONS: POC-Ab for COVID-19 has a high specificity with no false-positive result in non-COVID-19 sera. Therefore, it can be used to guide diagnostic among symptomatic patients in resource limited settings. Given its low sensitivity, patients with high suspicion of COVID-19 but non-reactive result should be prioritized for rRT-PCR testing.

Lethal Arrhythmia (Torsade de Pointes) in COVID-19: An Event Synergistically Induced by Viral Associated Cardiac Injury, Hyperinflammatory Response, and Treatment Drug?

Arrhythmias in patients with coronavirus disease 2019 (COVID-19) are prevalent and deserve special attention because they are associated with an increased risk of fatal outcome. The mechanism of arrhythmia in COVID-19 remains unclear. Here, we report our first case of confirmed COVID-19 with documented Torsade de Pointes (TdP). A 64-year-old woman, previously healthy, presented to our emergency department with progressive shortness of breath, dry cough, and 1 week of fever. She was treated with chloroquine phosphate, meropenem, and ciprofloxacin. After 5 days of admission, her condition deteriorated and she was admitted to the intensive care unit. The patient had two episodes of malignant arrhythmias within 24 hours. The former was TdP, and the latter was a fatal pulseless ventricular tachycardia that occured even after chloroquine was discontinued. There was evidence of cardiac injury shown by increased serum level of troponin I. We propose a synergistic concept of lethal arrhythmia due to direct severe acute respiratory syndrome coronavirus (SARS-CoV)-2-associated cardiac injury, hyperinflammatory response, and drug-induced arrhythmia.

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

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.