Significant Inverse Correlation of Serum Levels of Osteoprotegerin (OPG) and Transferrin Saturation in Thalassemia Dependent Transfusion (TDT) Patients.

BACKGROUND: Osteoporosis is a major problem in transfusion-dependent thalassemia patients (TDT) patients. Osteoprotegerin (OPG) is one of several bone markers that are closely associated with osteoporosis in TDT patients. OPG is a glycoprotein that functions as a feedback receptor for the Receptor Activator of Nuclear Factor kappa B Ligand (RANKL), which is an alpha tumor necrosis factor receptor. One of the causes of decreased bone mass density is iron toxicity, which can be identified by showing elevated transferrin saturation. Bone mass dual X-ray absorptiometry (DEXA) is a gold standard for the diagnosis of osteoporosis, these procedures are not commonly available in Indonesia. This study was conducted to analyze the correlation between serum levels of OPG and transferrin saturation in TDT patients. METHODS: A correlational study with a cross-sectional approach analyzed data from TDT patients at Hemato-Oncology Medic Outpatient Clinic, Hasan Sadikin General Hospital, Bandung, Indonesia. Primary data were obtained through blood sampling and anthropometry measurement while secondary data were obtained from the patient's medical records. OPG and transferrin saturation levels were assessed using the ELISA method. Research data were analyzed using the rank Spearman correlation test. RESULTS: Data were collected from 51 research subjects (30 women dan 21 men). The median OPG level was 380 (170-1230) pg/mL and the median transferrin saturation level was 89.4 (66.7 - 96.2)%. Analysis of correlation showed a significant correlation between and transferrin saturation level with a coefficient value of r -0.539 and p-value <0.001. CONCLUSION: There was a significant inverse correlation between OPG with transferrin saturation in TDT patients.

Global tuberculosis disease and infection in systemic lupus erythematosus patients: A systematic review and meta-analysis.

BACKGROUND: Tuberculosis (TB) is one of the most common infections among systemic lupus erythematosus (SLE) patients. We aimed to evaluate the global prevalence of TB infection and disease, its type, and medication risk factors in SLE patients. METHODS: We searched PubMed, Science Direct, EBSCO, and Web of Science databases from inception to April 30, 2023, and included studies assessing TB among SLE patients. We estimated the prevalence of TB disease (including type of TB disease), TB infection, and SLE medication as TB risk factors. Meta-analysis was performed using Stata 14.2 and Review Manager 5.3. RESULTS: Twenty-seven studies met the eligibility criteria. The global prevalence of TB disease was 4% (95% confidence interval (CI): 3-4%, n = 25) and TB infection was 18% (95% CI: 10-26%, n = 3). The pooled prevalence of pulmonary TB, extrapulmonary TB, and disseminated TB were 2% (95% CI: 2-3%, n = 20), 1% (95% CI: 1-2%, n = 17), and 1% (95% CI: 0-1%, n = 6), respectively. The 1-year cumulative glucocorticoid (GC) dose in SLE patients contracting TB was higher than in those without TB, having a mean difference of 2.56 (95% CI: 0.22-4.91, p < .00001, n = 3). The odd ratio of TB was 2.11 (95% CI: 1.01-4.41, p = .05, n = 3) in SLE patients receiving methylprednisolone (MP) pulse therapy as compared to those without MP pulse therapy. Other immunosuppressive agents were not significantly associated with TB. CONCLUSION: TB prevalence in SLE was relatively high and associated with GC. Awareness of TB and lowering GC dose are warranted to alleviate the TB burden in SLE.

Tuberculin skin test and Interferon-gamma release assay agreement, and associated factors with latent tuberculosis infection, in medical and nursing students in Bandung, Indonesia.

BACKGROUND: No gold standard diagnostic test exists for latent tuberculosis infection (LTBI). The intra-dermal tuberculin skin test (TST) has known limitations and Interferon-gamma release assays (IGRA) have been developed as an alternative. We aimed to assess agreement between IGRA and TST, and risk factors for test positivity, in Indonesian healthcare students. METHODS: Medical and nursing students starting their clinical training were screened using IGRA and TST. Agreement between the two tests was measured using Cohen's Kappa coefficient. Logistic regression was used to identify factors associated with test positivity. RESULTS: Of 266 students, 43 (16.2%) were IGRA positive and 85 (31.9%) TST positive. Agreement between the two tests was 74.7% (kappa 0.33, 95% CI 0.21-0.45, P<0.0001). Students who had direct contact with family or friends with TB were less likely to be test positive using IGRA (AOR 0.18, 95% CI 0.05-0.64) and using TST (AOR 0.51, 95% CI 0.26-0.99). CONCLUSION: Test positivity for LTBI was lower when measured by IGRA than by TST, with poor agreement between the two tests. Known close TB contact was unexpectedly negatively associated with positivity by either test. Longitudinal studies may be required to help determine the best test for LTBI in healthcare students in Indonesia.

Management of drug-resistant tuberculosis in Indonesia: a four-year cascade of care analysis.

Background: In Indonesia, drug resistance testing for TB largely relies on Xpert MTB/RIF, and it is unknown what proportion of drug-resistant (DR) TB is adequately diagnosed and treated. Methods: We conducted a cascade of care analysis on a cohort of presumptive rifampicin-resistant (RR) TB patients registered in 2015-2018 in a tertiary hospital in Indonesia. Estimated incidences of (presumptive) DR-TB cases were assumption-based using global reports. Data on diagnosis and consecutive cascades steps, including their timing were collected from national electronic registers, and medical records. We described a secondary cascade for patients receiving treatment not supported by phenotypic drug susceptibility testing (pDST). Factors associated with delay and loss between diagnosis and treatment were identified using logistic regression. Findings: Less than a third of estimated incident TB cases at risk of DR-TB were identified as presumptive DR-TB case and tested, and 9.8% (982/10,065) of estimated true DR-TB cases was diagnosed. Of those diagnosed, only 45.1% (443/982) had treatment regimens supported by pDST results, but this did not significantly influence treatment outcomes. Only 25.5% (250/982) of diagnosed patients completed all steps of the cascade including successful treatment. Delays between diagnosis and treatment were substantial, and more common among those referred from a primary healthcare facility, and among those who were employed, living outside of Bandung, and reporting engagement with the private sector. Interpretation: The DR-TB care cascade in this urban setting in Indonesia is characterized by substantial attrition and delays. Strategies to increase access to DR-TB diagnosis accompanied by optimisation of clinical care could substantially improve outcomes and reduce onward transmission. Funding: Radboud university medical center and University of Otago.

Clinical presentation, management, and outcome of suspected central nervous system infections in Indonesia: a prospective cohort study.

BACKGROUND: Little is known about the etiology, clinical presentation, management, and outcome of central nervous system (CNS) infections in Indonesia, a country with a high burden of infectious diseases and a rising prevalence of HIV. METHODS: We included adult patients with suspected CNS infections at two referral hospitals in a prospective cohort between April 2019 and December 2021. Clinical, laboratory, and radiological assessments were standardized. We recorded initial and final diagnoses, treatments, and outcomes during 6 months of follow-up. RESULTS: Of 1051 patients screened, 793 were diagnosed with a CNS infection. Patients (median age 33 years, 62% male, 38% HIV-infected) presented a median of 14 days (IQR 7-30) after symptom onset, often with altered consciousness (63%), motor deficits (73%), and seizures (21%). Among HIV-uninfected patients, CNS tuberculosis (TB) was most common (60%), while viral (8%) and bacterial (4%) disease were uncommon. Among HIV-infected patients, cerebral toxoplasmosis (41%) was most common, followed by CNS TB (19%), neurosyphilis (15%), and cryptococcal meningitis (10%). A microbiologically confirmed diagnosis was achieved in 25% of cases, and initial diagnoses were revised in 46% of cases. In-hospital mortality was 30%, and at six months, 45% of patients had died, and 12% suffered from severe disability. Six-month mortality was associated with older age, HIV, and severe clinical, radiological and CSF markers at presentation. CONCLUSION: CNS infections in Indonesia are characterized by late presentation, severe disease, frequent HIV coinfection, low microbiological confirmation and high mortality. These findings highlight the need for earlier disease recognition, faster and more accurate diagnosis, and optimized treatment, coupled with wider efforts to improve the uptake of HIV services.

Care pathways of individuals with tuberculosis before and during the COVID-19 pandemic in Bandung, Indonesia.

The COVID-19 pandemic is thought to have undone years' worth of progress in the fight against tuberculosis (TB). For instance, in Indonesia, a high TB burden country, TB case notifications decreased by 14% and treatment coverage decreased by 47% during COVID-19. We sought to better understand the impact of COVID-19 on TB case detection using two cross-sectional surveys conducted before (2018) and after the onset of the pandemic (2021). These surveys allowed us to quantify the delays that individuals with TB who eventually received treatment at private providers faced while trying to access care for their illness, their journey to obtain a diagnosis, the encounters individuals had with healthcare providers before a TB diagnosis, and the factors associated with patient delay and the total number of provider encounters. We found some worsening of care seeking pathways on multiple dimensions. Median patient delay increased from 28 days (IQR: 10, 31) to 32 days (IQR: 14, 90) and the median number of encounters increased from 5 (IQR: 4, 8) to 7 (IQR: 5, 10), but doctor and treatment delays remained relatively unchanged. Employed individuals experienced shorter delays compared to unemployed individuals (adjusted medians: -20.13, CI -39.14, -1.12) while individuals whose initial consult was in the private hospitals experienced less encounters compared to those visiting public providers, private primary care providers, and informal providers (-4.29 encounters, CI -6.76, -1.81). Patients who visited the healthcare providers >6 times experienced longer total delay compared to those with less than 6 visits (adjusted medians: 59.40, 95% CI: 35.04, 83.77). Our findings suggest the need to ramp up awareness programs to reduce patient delay and strengthen private provide engagement in the country, particularly in the primary care sector.

Impact of the COVID-19 pandemic on quality of tuberculosis care in private facilities in Bandung, Indonesia: a repeated cross-sectional standardized patients study.

BACKGROUND: Indonesia has the second highest incidence of tuberculosis in the world. While 74% of people with tuberculosis in Indonesia first accessed the private health sector when seeking care for their symptoms, only 18% of tuberculosis notifications originate in the private sector. Little is known about the impact of the COVID-19 pandemic on the private sector. Using unannounced standardized patient visits to private providers, we aimed to measure quality of tuberculosis care during the COVID-19 pandemic. METHODS: A cross-sectional study was conducted using standardized patients in Bandung City, West Java, Indonesia. Ten standardized patients completed 292 visits with private providers between 9 July 2021 and 21 January 2022, wherein standardized patients presented a presumptive tuberculosis case. Results were compared to standardized patients surveys conducted in the same geographical area before the onset of COVID-19. RESULTS: Overall, 35% (95% confidence interval (CI): 29.2-40.4%) of visits were managed correctly according to national tuberculosis guidelines. There were no significant differences in the clinical management of presumptive tuberculosis patients before and during the COVID-19 pandemic, apart from an increase in temperature checks (adjusted odds ratio (aOR): 8.05, 95% CI: 2.96-21.9, p < 0.001) and a decrease in throat examinations (aOR 0.16, 95% CI: 0.06-0.41, p = 0.002) conducted during the pandemic. CONCLUSIONS: Results indicate that providers successfully identify tuberculosis in their patients yet do not manage them according to national guidelines. There were no major changes found in quality of tuberculosis care due to the COVID-19 pandemic. As tuberculosis notifications have declined in Indonesia due to the COVID-19 pandemic, there remains an urgent need to increase private provider engagement in Indonesia and improve quality of care.

Performance of a Point-of-Care Fluorescence Immunoassay Test to Measure the Anti-Severe Acute Respiratory Syndrome Corona Virus 2 Spike, Receptor Binding Domain Antibody Level.

Quantitative determination of anti-SARS-CoV2-S-RBD is necessary for the evaluation of vaccination effectiveness. The surrogate viral neutralization test (SVNT) is approved for measuring anti-SARS-CoV2-S-RBD, but a point-of-care platform is needed to simplify anti-SARS-CoV-2-S-RBD measurement. We aimed to evaluate the performance of a rapid fluorescent immunoassay-based kit, FastBio-RBDTM, compared to the SVNT. During April-September 2021, we enrolled two groups of subjects, convalescent subjects and subjects without a COVID-19 history. The subjects were tested for the anti-SARS-CoV2-S-RBD antibody using FastBio-RBDTM and the GenScript-cPASSTM SVNT. We measured the correlation coefficient and conducted an ROC analysis to determine the best cut-off value of anti-SARS-CoV2-S-RBD against the SVNT percent inhibition levels of 30% and 60%. We included 109 subjects. Anti-SARS-CoV-2-S-RBD strongly correlated to SVNT % inhibition with an R value of 0.866 (p < 0.0001). The ROC analysis showed that the anti-SARS-CoV-2-S-RBD of 6.71 AU/mL had 95.7% sensitivity and 87.5% specificity to detect a percentage inhibition of 30%. The anti-SARS-CoV-2-S-RBD of 59.76 AU/mL had a sensitivity of 88.1% and specificity of 97.0% to detect a percentage inhibition of 60%. FastBio-RBDTM could determine the presence and level of anti-SARS-CoV-2-S-RBD with good sensitivity and specificity. It has the potential to be deployed in health facilities with limited resources.

Antibody Response to SARS-CoV-2 Vaccination in Patients with End-Stage Kidney Disease on Hemodialysis.

Patients with end-stage kidney disease on hemodialysis (ESKD-HD) have a high risk of contracting severe COVID-19. Vaccination can help reduce disease severity, but the immune dysregulation observed in these patients may result in an inadequate antibody response. Therefore, we aimed to evaluate the immune response postvaccination in ESKD-HD patients. This prospective cohort study was conducted in two hemodialysis centers in Indonesia. We enrolled ESKD-HD patients (n = 143) pre- and postvaccination and compared them to healthy subjects (n = 67). SARS-CoV-2 antibody response was assessed using anti-S-RBD antibodies and SVNT % inhibition tests. We performed bivariate and multivariate analysis to determine factors associated with SARS-CoV-2 antibody levels. Seropositive conversion was observed in 97% ESKD-HD subjects postvaccination. Compared with healthy subjects, ESKD-HD patients showed a comparable anti-S-RBD antibody titer postvaccination. mRNA vaccines remained a significant factor for the high immune response, while hypoalbuminemia correlated with lower immune response. In conclusion, ESKD-HD patients showed a robust immune response postvaccination. mRNA vaccines induced a stronger antibody response than other vaccines. Lower levels of serum albumin correlate with lower immune responses in ESKD-HD patients after vaccination.

Central nervous system infection in a pediatric population in West Java.

Central nervous system (CNS) viral infections are critical causes of morbidity and mortality in children; however, comprehensive data on etiology is lacking in developing countries such as Indonesia. To study the etiology of CNS infections in a pediatric population, 50 children admitted to two hospitals in Bandung, West Java, during 2017-2018 were enrolled in a CNS infection study. Cerebrospinal fluid and serum specimens were tested using molecular, serological, and virus isolation platforms for a number of viral and bacteriological agents. Causal pathogens were identified in 10 out of 50 (20%) and included cytomegalovirus (n = 4), Streptococcus pneumoniae (n = 2), tuberculosis (n = 2), Salmonella serotype Typhi (n = 1) and dengue virus (n = 1). Our study highlights the importance of using a wide range of molecular and serological detection methods to identify CNS pathogens, as well as the challenges of establishing the etiology of CNS infections in pediatric populations of countries with limited laboratory capacity.

Anti-SARS-CoV-2 Antibody Level Is Associated with a History of COVID-19 Infection and mRNA Vaccination in Patients with Diabetes.

Type 2 diabetes mellitus (T2DM) is associated with higher severity and mortality in SARS-CoV-2 infections. Vaccination has been encouraged to boost immunity and prevent these unfortunate outcomes. Few studies have evaluated antibody levels after COVID-19 vaccination in patients with T2DM. Therefore, we examined the vaccination status and anti-SARS-CoV-2 antibody levels to identify the factors that affect the antibody levels in patients with T2DM. This cross-sectional study was conducted at the Dr. Hasan Sadikin Hospital and Bandung Kiwari Hospital, Bandung, West Java, Indonesia, between October and November 2022. Adult participants with and without T2DM were tested for SARS-CoV-2 antibodies using a point-of-care quantitative immunochromatographic assay. We enrolled 289 participants: 201 participants with T2DM and 88 participants without T2DM. The T2DM participants had a lower vaccination rate compared with the non-T2DM participants. However, no significant differences in antibody levels were observed between the two groups. Higher antibody levels among the T2DM participants were associated with mRNA vaccination and a history of COVID-19 illness. The lower antibody response observed among the T2DM participants with chronic obstructive pulmonary disease suggests that such patients may need antibody level measurement and an additional booster vaccine.

High Levels of Anti-SARS-CoV-2 Receptor-Binding Domain (RBD) Antibodies One Year Post Booster Vaccinations among Hospital Workers in Indonesia: Was the Second Booster Needed?

In August 2022, Indonesia prioritized healthcare workers to receive the second booster dose. We conducted a sequential serosurvey to understand the dynamics of the antibody titers. The first serosurvey, which was conducted in June 2021, 1-6 months after Sinovac vaccination, showed a median antibody level of 41.4 BAU/mL (interquartile range (IQR): 10-629.4 BAU/mL). The second serosurvey was conducted one month (August 2021) after the first Moderna booster vaccine and showed a median level of 4000 BAU/mL (IQR: 3081-4000 BAU/mL). The last serosurvey was conducted a year (August 2022) after the booster and showed a median level of 4000 BAU/mL (IQR: 4000-4000 BAU/mL). In this last survey, only 39 (11.9%) of healthcare workers had antibody levels below the maximum level of 4000 BAU/mL. Thus, one year after the first booster dose, we did not observe the waning of antibody levels. The average increase was perhaps because of natural infection. Based on these considerations, we believe that a second booster dose was not necessary for this category of subjects at that time. Because vaccine supply is often limited, priority could be given to the general population or other high-risk patient groups with low antibody titers based on serological tests.

Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity.

BACKGROUND: People with diabetes are more likely to develop tuberculosis (TB) and to have poor TB-treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB-diabetes (TB-DM) co-morbidity have excessive inflammatory and reduced interferon responses at diagnosis. It is unknown whether this persists through treatment and contributes to the adverse outcomes. METHODS: Pulmonary TB patients recruited in South Africa, Indonesia and Romania were classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or TB-only, based on glycated haemoglobin concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood at diagnosis and intervals throughout treatment was measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification. Transcriptomic data were analysed by longitudinal mixed-model regression to identify whether genes were differentially expressed between clinical groups through time. Predictive models of TB-treatment response across groups were developed and cross-tested. RESULTS: Gene expression differed between TB and TB-DM patients at diagnosis and was modulated by TB treatment in all clinical groups but to different extents, such that differences remained in TB-DM relative to TB-only throughout. Expression of some genes increased through TB treatment, whereas others decreased: some were persistently more highly expressed in TB-DM and others in TB-only patients. Genes involved in innate immune responses, anti-microbial immunity and inflammation were significantly upregulated in people with TB-DM throughout treatment. The overall pattern of change was similar across clinical groups irrespective of diabetes status, permitting models predictive of TB treatment to be developed. CONCLUSIONS: Exacerbated transcriptome changes in TB-DM take longer to resolve during TB treatment, meaning they remain different from those in uncomplicated TB after treatment completion. This may indicate a prolonged inflammatory response in TB-DM, requiring prolonged treatment or host-directed therapy for complete cure. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes for use across populations.

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.

The inclusion of diagnostics in national health insurance schemes in Cambodia, India, Indonesia, Nepal, Pakistan, Philippines and Viet Nam.

The Lancet Commission on Diagnostics highlighted a huge gap in access to diagnostic testing even for basic tests, particularly at the primary care level, and emphasised the need for countries to include diagnostics as part of their universal health coverage benefits packages. Despite the poor state of diagnostic-related services in low-income and middle-income countries (LMICs), little is known about the extent to which diagnostics are included in the health benefit packages. We conducted an analysis of seven Asian LMICs-Cambodia, India, Indonesia, Nepal, Pakistan, Philippines, Viet Nam-to understand this issue. We conducted a targeted review of relevant literature and applied a health financing framework to analyse the benefit packages available in each government-sponsored scheme. We found considerable heterogeneity in country approaches to diagnostics. Of the seven countries, only India has developed a national essential diagnostics list. No country presented a clear policy rationale on the inclusion of diagnostics in their scheme and the level of detail on the specific diagnostics which are covered under the schemes was also generally lacking. Government-sponsored insurance expansion in the eligible populations has reduced the out-of-pocket health payment burden in many of the countries but overall, there is a lack of access, availability and affordability for diagnostic-related services.

The effect of diabetes mellitus on COVID-19 mortality among patients in a tertiary-level hospital in Bandung, Indonesia.

Immune system dysregulation in people with diabetes mellitus (DM) increases the risk of acquiring severe infection. We compared the clinical characteristics and laboratory parameters of coronavirus disease 2019 (COVID-19) patients with and without DM and estimated the effect of DM on mortality among COVID-19 patients. A retrospective cohort study collecting patients' demographic, clinical characteristics, laboratory parameters and treatment outcomes from medical records was conducted in a hospital in Bandung City from March to December 2020. Univariable and multivariable logistic regression was performed to determine the association between DM and death. A total of 664 COVID-19 patients with positive real-time reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 were included in this study, of whom 147 were with DM. Half of DM patients presented HbA1c ≥10%. DM patients were more likely to present with comorbidities and severe to critical conditions at admission (P <0.001). Laboratory parameters such as neutrophil-lymphocyte count ratio, C-reactive protein, D-dimer, ferritin, and lactate dehydrogenase were higher in the DM group. In the univariate analysis, variables associated with death were COVID-19 severity at baseline, neurologic disease, DM, age ≥60 years, hypertension, cardiovascular disease, and chronic kidney disease. DM remained associated with death (aOR 1.82; 95% CI 1.13-2.93) after adjustment with sex, age, hypertension, cardiovascular disease, and chronic kidney disease. In conclusion, COVID-19 patients with DM are more likely to present with a very high HbA1c, comorbidities, and severe-critical illness. Chronic inflammation in DM patients may be aggravated by the disruption of immune response caused by COVID-19, leading to worse laboratory results and poor outcomes.

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusions: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Comparison of interferon-gamma production between TB1 and TB2 tubes of QuantiFERON-TB Gold Plus: a meta-analysis.

OBJECTIVES: CD8 T-cells play an important role in interferon-gamma (IFN-γ) production as a host defense against tuberculosis (TB) infection. Therefore, QuantiFERON-TB Gold Plus (QFT-Plus) was developed by adding a TB2 tube beside the TB1 tube. This study aimed to compare and analyze the difference in IFN-γ production between the two tubes in general and specific populations. CONTENT: PubMed, Web of Science, and EBSCO were searched for studies reporting IFN-γ production levels in the TB1 and TB2 tubes. Statistical analysis was performed using RevMan 5.3. SUMMARY: A total of 17 studies met the inclusion criteria. The IFN-γ production in the TB2 tube was statistically higher than that in the TB1 tube (mean difference (MD)=0.02, 95 % confidence interval (95 % CI): 0.01-0.03). Further subgroup analysis in specific populations revealed that the MD of IFN-γ production between the TB2 and TB1 tubes was significantly higher in active TB subjects than in latent TB infection (LTBI) subjects (MD=1.13, 95 % CI: 0.49-1.77, and MD=0.30, 95 % CI: 0.00-0.60, respectively). A similar finding was found in immune-mediated inflammatory disease subjects, but not statistically significant. Interestingly, IFN-γ production capacity was lower in active TB subjects than in LTBI subjects in each of the TB1 and TB2 tubes. OUTLOOK: This study is the first to systematically compare IFN-γ production between the TB1 and TB2 tubes. The IFN-γ production was higher in the TB2 tube than in the TB1 tube, representing the host's CD8 T-cell response magnitude to TB infection.

Howell-Jolly Body-Like Inclusions in Coronavirus Disease 2019 (COVID-19): Possible Novel Findings.

Background: During COVID-19 pandemic, it is difficult to distinguish febrile patient infected by SARS-CoV-2 or bacterial causes. Howell-Jolly bodies are a well-known entity found in red blood cells. They are nuclear fragments, composed of deoxyribonucleic acid, commonly observed in the peripheral blood smears of hyposplenic or asplenic patients. Recently, similar inclusions often referred to as Howell-Jolly body-like inclusions (HJBLIs) have been reported in the neutrophils of patients with acquired immune deficiency syndrome (AIDS) and COVID-19 patient. Aim: To explore whether HJBLIs in peripheral blood smear could differentiate between patients with confirmed SARS-CoV-2 and bacterial pneumonia. Methods: We performed cross-sectional study using secondary data from COVID-19 database and re-evaluated peripheral blood smears to identify HJBLIs. We included confirmed COVID-19 adults age >18 years who were hospitalized in Dr. Hasan Sadikin General Hospital, Bandung, Indonesia from March 1st 2020-May 31st 2020. We also examined peripheral blood smears in patients with confirmed bacterial pneumonia as a control group. Clinical characteristics including disease severity, CURB-65 score, comorbidity, and the present of HJBLIs in peripheral blood smears were evaluated. Results: Overall, 33 patients were included: 22 were confirmed COVID-19 and 11 were confirmed bacterial pneumonia. The median (interquartile range) age in COVID-19 and patients with bacterial pneumonia were 53 years (40-64) vs 57 years (53-71), respectively. Compared with patients with bacterial pneumonia, HJBLIs were significantly higher in COVID-19 patients [21/22 (80.8%) vs 5/11 (45.5%), p 0.001]. Conclusion: Howell-Jolly body-like inclusions could be a potential feature to help differentiate between COVID-19 and bacterial pneumonia.

Antibodies against Histoplasma capsulatum and Aspergillus fumigatus among chronic TB patients in Indonesia: a cross-sectional study.

Chronic pulmonary fungal infections may occur in patients with previous history of pulmonary tuberculosis (TB), and are often clinically misclassified as TB, especially when bacteriological confirmation for Mycobacterium tuberculosis is absent. In this study, we investigated the prevalence of antibody against Histoplasma capsulatum and Aspergillus fumigatus in patients with confirmed and clinically chronic TB. Antibodies against H. capsulatum and A. fumigatus were measured from serum samples using enzyme-linked immunosorbent assay (ELISA). The presence M. tuberculosis in sputum was confirmed using smear microscopy, GeneXpert MTB/RIF assay, or culture. Antibodies against H. capsulatum and A. fumigatus were elevated in 16.9% and 26.9% of bacteriologically confirmed chronic TB patients, and 12.1% and 18.2% in those without bacteriological confirmation, respectively. Approximately one-third of patients who had positive anti-Histoplasma antibody also had elevated levels of antibody against Aspergillus fumigatus (P < .001). Our study highlights the importance of chronic pulmonary fungal infection in post-TB patients with recurrent respiratory symptoms.

This study describes the presence of antibodies against Aspergillus fumigatus and Histoplasma capsulatum in patient with pulmonary TB patients. Our study highlights the importance of chronic pulmonary fungal infections in post-TB patients with recurrent respiratory symptoms.