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.

Isoniazid exposures and acetylator status in Indonesian tuberculous meningitis patients.

The effect of acetylator status on the exposure to isoniazid in plasma and CSF in tuberculous meningitis (TBM) patients remains largely unexplored. Here, we describe isoniazid exposures and acetylator status of 48 subjects in the ReDEFINe study (NCT02169882). Fifty percentwere fast (half-life <130 min) or slow (half-life >130 min) acetylators. Slow acetylators had higher AUC0-24, Cmax and CSF concentrations than fast acetylators (GM AUC0-24 25.5 vs 10.6 mg/L*h, p < 0.001); plasma Cmax 5.5 vs 3.6 mg/L, p = 0.023; CSF concentration 1.9 vs 1.1 mg/L, p = 0.008). Higher isoniazid doses may benefit fast acetylators in TBM.

Current Insights into Diagnosing and Treating Neurotuberculosis in Adults.

Neurotuberculosis has the highest morbidity and mortality risk of all forms of extrapulmonary tuberculosis (TB). Early treatment is paramount, but establishing diagnosis are challenging in all three forms of neurotuberculosis: tuberculous meningitis (TBM), spinal TB and tuberculomas. Despite advancements in diagnostic tools and ongoing research aimed at improving TB treatment regimens, the mortality rate for neurotuberculosis remains high. While antituberculosis drugs were discovered in the 1940s, TB treatment regimens were designed for and studied in pulmonary TB and remained largely unchanged for decades. However, new antibiotic regimens and host-directed therapies are now being studied to combat drug resistance and contribute to ending the TB epidemic. Clinical trials are necessary to assess the effectiveness and safety of these treatments, addressing paradoxical responses in neurotuberculosis cases and ultimately improving patient outcomes. Pharmacokinetic-pharmacodynamic analyses can inform evidence-based dose selection and exposure optimization. This review provides an update on the diagnosis and treatment of neurotuberculosis, encompassing both sensitive and resistant antituberculosis drug approaches, drawing on evidence from the literature published over the past decade.

Severe mononeuritis multiplex as a rare case of neuro leptospirosis: A case report.

Leptospirosis is a zoonotic bacterial disease caused by infection of spirochetes of the genus Leptospira. While typically self-limiting and non-fatal, severe manifestations can arise, including various neurological complications that are often overlooked. This case study presents a 59-year-old man with serologically positive Leptospirosis, who subsequently developed asymmetrical progressive leg weakness, severe back pain, and overflow incontinence suggestive of mononeuritis multiplex. Doxycycline treatment was started and intended to last for seven days. The patient had ongoing paraparesis, but all other problems were disappeared. The present case emphasizes the significance of identifying and treating neurological problems brought on by leptospirosis. To improve suitable treatment plans and patient outcomes, more research on these problems is necessary.

Platelet Selectin Levels in Patients with Cerebral Venous Sinus Thrombosis: Preliminary Findings.

Background: Cerebral Venous Sinus Thrombosis (CVST) is a cerebrovascular disease with an estimated annual incidence of 3-4 cases per 1 million population with an 8% mortality rate caused by hypercoagulable conditions and hyper aggregation and also Platelet Selectin (P-Selectin) as one of coagulation biomarker for both of them. This study aimed to describe the levels of P-selectin in CVST patients at RSHS Bandung. Objective: This study aimed to describe the levels of P-selectin in CVST patients at RSHS Bandung. Methods: This is a descriptive observational study on patients ≥18 years old diagnosed with CVST at the Neurology outpatient polyclinic of RSUP Dr. Hasan Sadikin Bandung for March-May 2022. All samples that meet the inclusion criteria will be included as research subjects. Results: There were 55 research subjects with a median age of 48 (range 22-69 years), the majority were women (80%), the most complaints were headaches (92.7%), the majority onset was chronic (96.4%) with a length of treatment ≥12 months (61.8%). P-selectin levels were found to increase in the group of subjects with subacute onset (mean 5.20 ± 2.977), infectious etiology (mean 5.26 ± 3.561), duration of treatment <3 Months (mean 3.79 ± 3.065), history of hyper aggregation (mean 3.89±2.805), hypercoagulation (mean 3.50±2.719), increased D-dimer (mean 3.93±2.710), normal fibrinogen (mean 3.38±2.693), and in the group with multiple affected sinuses (mean 6.08±2.681). Conclusion: P-selectin could be a diagnostic marker for hyper aggregation and hypercoagulable state in patients with CVST, but it still needs further research to prove it.

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).

MUC5AC Genetic Variation Is Associated With Tuberculous Meningitis Cerebral Spinal Fluid Cytokine Responses and Mortality.

BACKGROUND: The purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes. METHODS: Independent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with tumor necrosis factor (TNF) concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality. RESULTS: MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF (P = 1.8 × 10-8) and IFN-γ (P = 2.3 × 10-6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.03-1.49; P = .02), but not pulmonary tuberculosis (OR, 1.11, 95% CI, .98-1.25; P = .10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank P = .005) in a Vietnam discovery cohort (n = 210), an independent Vietnam validation cohort (n = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank P = .02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P = .06). CONCLUSIONS: MUC5AC variants may contribute to immune changes that influence TBM 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 tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-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. Conclusion: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of mortality. 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).

Cerebral toxoplasmosis in HIV-infected patients: a review.

Toxoplasma gondii infection in the central nervous system commonly occurs among immunodeficient patients. Its prevalence is high in countries with a high burden of HIV and low coverage of antiretroviral drugs. The brain is one of the predilections for T. gondii infection due to its low inflammatory reaction, and cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection. Several immune elements have recently been recognized to have an essential role in the immunopathogenesis of cerebral toxoplasmosis. Although real-time isothermal amplification, next-generation sequencing, and enzyme-linked aptamer assays from blood samples have been the recommended diagnostic tools in some in-vivo studies, a combination of clinical symptoms, serology examination, and neuroimaging are still the daily standard for the presumptive diagnosis of cerebral toxoplasmosis and early anti-toxoplasma administration. Clinical trials are needed to find a new therapy that is less likely to affect folate synthesis, have neuroprotective properties, or cure the latent phase of infection. The development of a vaccine is being extensively tested in animals, but its efficacy and safety for humans are still not proven.

A Rarely Occurring Spinal Fracture Precipitated by Generalized Spasms of Tetanus Patient with Spondylitis Tuberculosis.

Background: The occurrence of spinal fracture due to tetanus nowadays is extremely rare, as compared to the 1950s, since the widely available anti-tetanus and antispasmodic therapy. The spinal fracture in tetanus patients is usually reported in higher thoracic vertebrae, previously with a rate as high as 57.5%. Spondylitis is the most common form of skeletal tuberculosis (TB) and can cause a spinal fracture. In Indonesia, tetanus is still reported, while tuberculosis is still endemic; however, co-infection of both diseases is rarely reported. Case Presentation: A 36-year-old male was brought to our hospital with jaw stiffness, accompanied by fever. A history of dental cavities was present, and 5 days prior, he experienced a fishing hook wound on his right index finger. There was no history of TB. Physical examination showed meningismus, 2 cm trismus, abdominal spasm, opisthotonus, and spontaneous muscle spasms, without dysautonomia. In the third week of hospitalization, while his tetanus condition improved, he complained of weakness in both legs. A thorough history taking revealed a history of backache for 3 years. A wedge-shaped fracture on his 11th and 12th thoracic vertebrae was observed on radiographic examination. A spinal TB diagnosis was made, and treatment was started. He refused to get spinal surgery, then went home with 4 out of 5 motor strength scale. After three months, he returned to his routine activity as a food hawker with no motor deficits. Conclusion: Tetanus spinal fracture is extremely rare nowadays; a thorough history of spinal problems/medication is compulsory for anticipation. This patient's spinal fracture was deemed due to a preexisting TB spinal infection that was precipitated by prolonged continuous tetanic spasm due to general tetanus.

Brain MRI Volumetry Analysis in an Indonesian Family of SCA 3 Patients: A Case-Based Study.

Introduction: Spinocerebellar ataxia type-3 (SCA3) is an adult-onset autosomal dominant neurodegenerative disease. It is caused by expanding of CAG repeat in ATXN3 gene that later on would affect brain structures. This brain changes could be evaluated using brain MRI volumetric. However, findings across published brain volumetric studies have been inconsistent. Here, we report MRI brain volumetric analysis in a family of SCA 3 patients, which included pre-symptomatic and symptomatic patients. Methodology: The study included affected and unaffected members from a large six-generation family of SCA 3, genetically confirmed using PolyQ/CAG repeat expansion analysis, Sanger sequencing, and PCR. Clinical evaluation was performed using Scale for the Assessment and Rating of Ataxia (SARA). Subjects' brains were scanned using 3.0-T MRI with a 3D T1 BRAVO sequence. Evaluations were performed by 2 independent neuroradiologists. An automated volumetric analysis was performed using FreeSurfer and CERES (for the cerebellum). Result: We evaluated 7 subjects from this SCA3 family, including 3 subjects with SCA3 and 4 unaffected subjects. The volumetric evaluation revealed smaller brain volumes (p < 0.05) in the corpus callosum, cerebellar volume of lobules I-II, lobule IV, lobule VIIB and lobule IX; and in cerebellar gray matter volume of lobule IV, and VIIIA; in the pathologic/expanded CAG repeat group (SCA3). Conclusion: Brain MRI volumetry of SCA3 subjects showed smaller brain volumes in multiple brain regions including the corpus callosum and gray matter volumes of several cerebellar lobules.

Neurological Disease Associated with Chikungunya in Indonesia.

Chikungunya virus (CHIKV) is recognized but rarely considered as a cause of central nervous system infection in endemic areas. A total of 244 patients with acute meningoencephalitis in Indonesia were retrospectively tested to identify whether any CHIKV infection was associated with neurological manifestations, especially in provinces known for CHIKV endemicity. Cerebrospinal fluid (CSF) and blood specimens were tested using CHIKV-specific real-time reverse transcription polymerase chain reaction and IgM ELISA, alongside a panel of neurotropic viruses. We report four cases of suspected or confirmed CHIKV-associated neurological disease, including CHIKV RNA detection in CSF of one patient and in acute serum of another, and CHIKV IgM in CSF of three patients and in serum of a fourth. In conclusion, CHIKV should be considered as a cause of neurologic disease in endemic areas and especially during outbreaks, in addition to the more common arboviral diseases such as dengue and Japanese encephalitis viruses.

Central nervous system tuberculosis.

PURPOSE OF REVIEW: Central nervous system (CNS) tuberculosis is the most devastating form of tuberculosis (TB), with mortality and or neurological sequelae in over half of individuals. We reviewed original research and systematic reviews published since 1 January 2019 for new developments in CNS TB pathophysiology, diagnosis, management and prognosis. RECENT FINDINGS: Insight in the pathophysiology is increasing steadily since the landmark studies in 1933, focussing on granuloma type classification, the relevance of the M. tuberculosis bacterial burden and the wide range of immunological responses. Although Xpert/RIF has been recommended by the WHO for extrapulmonary TB diagnosis, culture is still needed to increase the sensitivity of TB meningitis diagnosis. Sequential MRIs can improve understanding of neurological deficits at baseline and during treatment. Pharmacokinetic/pharmacodynamic modelling suggests that higher doses of rifampicin and isoniazid in TB meningitis could improve survival. SUMMARY: Recent studies in the field of CNS-TB have largely focussed on TB meningitis. The outcome may improve by optimizing treatment dosing. This needs to be confirmed in clinical trials. Due to the important role of inflammation, these trials should be used as the platform to study the inflammatory and metabolomic responses. This could improve understanding of the biology of this disease and improve patient outlook by enabling individualised host-directed therapy.

A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis.

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 A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory eicosanoids. LTA4H 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 LTA4H TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that LTA4H 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. LTA4H genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it.

Tuberculous meningitis is a serious infection of the lining of the brain, which affects over 100,000 people a year. Without treatment, it is always fatal: even with proper antibiotics, about a quarter of patients do not survive and many will have permanent brain damage. Overactive inflammation is thought to contribute to this process. Corticosteroid drugs, which dampen the inflammatory process, are therefore often used during treatment. However, they merely reduce mortality by 30%, suggesting that only some people benefit from them. Two recent studies have linked the genetic makeup of individuals who have tuberculous meningitis to how they respond to corticosteroids. There were, in particular, differences in the LTA4H gene that codes for an inflammation-causing protein. According to these results, only individuals carrying high-inflammation versions of the LTA4H gene would benefit from the treatment. Yet a third study did not find any effect of the genetic background of patients. All three papers used frequentist statistics to draw their conclusions, only examining the percentage of people who survived in each group. Yet, this type of analysis can miss important details. It also does not work well when the number of patients is small, or when the effectiveness of a drug varies during the course of an illness. Another method, called Bayesian statistics, can perform better under these limitations. In particular, it takes into account the probability of an event based on prior knowledge ­ for instance, that the risk of dying varies smoothly with time. Here, Whitworth et al. used Bayesian statistics to reanalyse the data from these studies, demonstrating that death rates were correlated with the type of LTA4H gene carried by patients. In particular, corticosteroid treatment worked best for people with the high inflammation versions of the gene. However, regardless of genetic background, corticosteroids were not effective if patients were extremely sick before being treated. The work by Whitworth et al. demonstrates the importance of using Bayesian statistics to examine the effectiveness of medical treatments. It could help to design better protocols for tuberculous meningitis treatment, tailored to the genetic makeup of patients.

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

Inflammation contributes to the pathophysiology and high mortality of tuberculous meningitis. The IL-1ß pathway has been implicated in immunopathology and could be a target for host-directed therapy. IL-1ß 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-1ß concentrations. Collectively, these data argue against a role for IL-1ß targeted host-directed therapy in tuberculous meningitis.

Brain MRI findings in relation to clinical characteristics and outcome of tuberculous meningitis.

Neuroradiological abnormalities in tuberculous meningitis (TBM) are common, but the exact relationship with clinical and inflammatory markers has not been well established. We performed magnetic resonance imaging (MRI) at baseline and after two months treatment to characterise neuroradiological patterns in a prospective cohort of adult TBM patients in Indonesia. We included 48 TBM patients (median age 30, 52% female, 8% HIV-infected), most of whom had grade II (90%), bacteriologically confirmed (71%) disease, without antituberculotic resistance. Most patients had more than one brain lesion (83%); baseline MRIs showed meningeal enhancement (89%), tuberculomas (77%), brain infarction (60%) and hydrocephalus (56%). We also performed an exploratory analysis associating MRI findings to clinical parameters, response to treatment, paradoxical reactions and survival. The presence of multiple brain lesion was associated with a lower Glasgow Coma Scale and more pronounced motor, lung, and CSF abnormalities (p-value <0.05). After two months, 33/37 patients (89%) showed worsening of MRI findings, mostly consisting of new or enlarged tuberculomas. Baseline and follow-up MRI findings and paradoxical responses showed no association with six-month mortality. Severe TBM is characterized by extensive MRI abnormalities at baseline, and frequent radiological worsening during treatment.

Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials.

BACKGROUND: Intensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis. METHODS: An individual patient meta-analysis was performed on data from 3 Indonesian randomized controlled phase 2 trials comparing oral rifampicin 450 mg (~10 mg/kg) to intensified regimens including 750-1350 mg orally, or a 600-mg intravenous infusion. Pharmacokinetic data from plasma and cerebrospinal fluid (CSF) were analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models. RESULTS: Pharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured 2 disposition compartments, saturable clearance, and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5%; 95% confidence interval [CI], 4.5%-6.4%) and half-life for distribution plasma to CSF (2.1 hours; 95% CI, 1.3-2.9 hours). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 dropouts) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score, and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from approximately 50% to approximately 70% upon increasing the oral rifampicin dose from 10 to 30 mg/kg, and predicted that even higher doses would further improve survival. CONCLUSIONS: Higher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30 mg/kg to be investigated in phase 3 clinical trials.

The neurological significance of COVID-19: Lesson learn from the pandemic.

Coronavirus Infectious Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously known as 2019 novel coronavirus) is an emerging and rapidly evolving health issue that has been widespread globally and become a pandemic. The typical symptoms of COVID-19 are: a cough, shortness of breath and a fever; from the initial estimates, about 15% of COVID-19 patients present with severe respiratory symptoms and requires hospitalization and intensive care. Recent accumulated evidences showed that the neurological insults also occurred in patients with COVID-19, ranging from mild headache to severe neurological symptoms. In this review, we summarize the COVID-19 and neurological significance of COVID-19.

Immune cell characteristics and cytokine responses in adult HIV-negative tuberculous meningitis: an observational cohort study.

Immunopathology contributes to high mortality in tuberculous meningitis (TBM) but little is known about the blood and cerebrospinal fluid (CSF) immune response. We prospectively characterised the immune response of 160 TBM suspects in an Indonesian cohort, including 67 HIV-negative probable or definite TBM cases. TBM patients presented with severe disease and 38% died in 6 months. Blood from TBM patients analysed by flow cytometry showed lower αßT and γδT cells, NK cells and MAIT cells compared to 26 pulmonary tuberculosis patients (2.4-4-fold, all p < 0.05) and 27 healthy controls (2.7-7.6-fold, p < 0.001), but higher neutrophils and classical monocytes (2.3-3.0-fold, p < 0.001). CSF leukocyte activation was higher than in blood (1.8-9-fold). CSF of TBM patients showed a predominance of αßT and NK cells, associated with better survival. Cytokine production after ex-vivo stimulation of whole blood showed a much broader range in TBM compared to both control groups (p < 0.001). Among TBM patients, high ex-vivo production of TNF-α, IL-6 and IL-10 correlated with fever, lymphocyte count and monocyte HLA-DR expression (all p < 0.05). TBM patients show a strong myeloid blood response, with a broad variation in immune function. This may influence the response to adjuvant treatment and should be considered in future trials of host-directed therapy.