Cognitive Impairment in Tuberculous Meningitis.

BACKGROUND: Cognitive impairment is reported as a common complication in adult tuberculous meningitis (TBM), yet few studies have systematically assessed the frequency and nature of impairment. Moreover, the impact of impairment on functioning and medication adherence has not been described. METHODS: A cognitive test battery (10 measures assessing 7 cognitive domains) was administered to 34 participants with human immunodeficiency virus (HIV)-associated TBM 6 months after diagnosis. Cognitive performance was compared with that a comparator group of 66 people with HIV without a history of tuberculosis. A secondary comparison was made between participants with TBM and 26 participants with HIV 6 months after diagnosis of tuberculosis outside the central nervous system (CNS). Impact on functioning was evaluated, including through assessment of medication adherence. RESULTS: Of 34 participants with TBM, 16 (47%) had low performance on cognitive testing. Cognition was impaired across all domains. Global cognitive performance was significantly lower in participants with TBM than in people with HIV (mean T score, 41 vs 48, respectively; P < .001). These participants also had lower global cognition scores than those with non-CNS tuberculosis (mean global T score, 41 vs 46; P = .02). Functional outcomes were not significantly correlated with cognitive performance in the subgroup of participants in whom this was assessed (n = 19). CONCLUSIONS: Low cognitive performance following HIV-associated TBM is common. This effect is independent of, and additional to, effects of HIV and non-CNS tuberculosis disease. Further studies are needed to understand longer-term outcomes, clarify the association with treatment adherence, a key predictor of outcome in TBM, and develop context-specific tools to identify individuals with cognitive difficulties in order to improve outcomes in TBM.

Host transcriptomic signatures of tuberculosis can predict immune reconstitution inflammatory syndrome in HIV patients.

Immune reconstitution inflammatory syndrome (IRIS) can be a complication of antiretroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille-Calmette-Guerin (BCG) vaccination in children. With no predictive or confirmatory tests at present, IRIS remains a diagnosis of exclusion. We tested whether RISK6 and Sweeney3, validated immune-based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults. Transcripts were measured by RT-qPCR in BCG-vaccinated children and by microarray in HIV+ adults with TB including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS. In children, RISK6 and Sweeney3 discriminated IRIS cases from non-IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half-week on ART and at TB-IRIS onset. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB-IRIS onset. Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults.

Transcriptomic Characterization of Tuberculous Sputum Reveals a Host Warburg Effect and Microbial Cholesterol Catabolism.

The crucial transmission phase of tuberculosis (TB) relies on infectious sputum and yet cannot easily be modeled. We applied one-step RNA sequencing (RNA-Seq) to sputum from infectious TB patients to investigate the host and microbial environments underlying transmission of Mycobacterium tuberculosis. In such TB sputa, compared to non-TB controls, transcriptional upregulation of inflammatory responses, including an interferon-driven proinflammatory response and a metabolic shift toward glycolysis, was observed in the host. Among all bacterial sequences in the sputum, approximately 1.5% originated from M. tuberculosis, and its transcript abundance was lower in HIV-1-coinfected patients. Commensal bacterial abundance was reduced in the presence of M. tuberculosis infection. Direct alignment to the genomes of the predominant microbiota species also reveals differential adaptation, whereby firmicutes (e.g., streptococci) displayed a nonreplicating phenotype with reduced transcription of ribosomal proteins and reduced activities of ATP synthases, while Neisseria and Prevotella spp. were less affected. The transcriptome of sputum M. tuberculosis more closely resembled aerobic replication and shared similarity in carbon metabolism to in vitro and in vivo models with significant upregulation of genes associated with cholesterol metabolism and downstream propionate detoxification pathways. In addition, and counter to previous reports on intracellular M. tuberculosis infection in vitro, M. tuberculosis in sputum was zinc, but not iron, deprived, and the phoP loci were also significantly downregulated, suggesting that the pathogen is likely extracellular in location. IMPORTANCE Although a few studies have described the microbiome composition of TB sputa based on 16S ribosomal DNA, these studies did not compare to non-TB samples and the nature of the method does not allow any functional inference. This is the first study to apply such technology using clinical specimens and obtained functional transcriptional data on all three aspects simultaneously. We anticipate that an improved understanding on the biological interactions in the respiratory tract may also allow novel interventions, such as those involving microbiome manipulation or inhibitor targeting disease-specific metabolic pathways.

T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy.

HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations.

Tuberculosis in Myasthenia Gravis patients on immunosuppressive therapy in a high-risk area: Implications for preventative therapy.

Data regarding the risk of tuberculosis (TB) in myasthenia gravis (MG) patients receiving immunosuppressive therapy is limited, and the benefit of TB preventative therapy in these patients is uncertain. We audited observational data collected at an MG clinic in South Africa over a ~ 10-year period, of cases who received immunosuppressive therapy. The total time that the cohort was at risk (patient-years) was used as the denominator to calculate TB incidence after immunosuppressive therapy initiation. Multivariate logistic regression analysis was performed to identify differences between patients who did, and those who did not, develop TB. Of 480 cases, only two received TB preventative therapy when starting immunotherapy. Seventeen of 282 (6%) patients tested, were HIV-infected. With a median follow-up of 3.6 years (interquartile range 1;7.5), 13 (3%) patients (all HIV-uninfected) developed TB (38% within 12 months of starting immunosuppressive therapy). The incidence rate of TB in the study population (≤401/100000 person-years) was not higher than that for the hospital's catchment area during the same period (>500/100000 population). The maximum dose of prescribed prednisone was higher in patients who developed TB compared to those who did not (median: 0.6 mg/kg/day vs 0.4; 0.002); Odds ratio for TB increased 1.26-fold for every 0.1 mg/kg/day increase in maximum dose (p = 0.001). In our TB endemic setting, receiving immunosuppressive therapy was not associated with excess TB in MG patients. Preventative therapy may be considered in those who are at greatest risk of developing TB and receiving high-dose prednisone.

International Survey Reveals Opportunities to Improve Tuberculous Meningitis Management and the Need for Standardized Guidelines.

BACKGROUND: Tuberculous meningitis (TBM) is a medical emergency, yet there are no standardized treatment guidelines for the medical or neurosurgical management of these patients and little data on neurocritical care. We conducted an international survey to understand current medical and neurosurgical TBM management and resource availability to provide baseline data needed for future multicenter trials addressing unanswered clinical research questions and the establishment of standardized guidelines. METHODS: An online survey of 77 questions covering medical and neurosurgical TBM management aimed at clinicians/nurses treating TBM was distributed as an anonymous link through email invitation, international organizations' membership distribution, and direct links on organizational webpages or social media. The survey remained open for 5 months. Data were summarized with frequencies and percentages. RESULTS: The survey had 222 responses from 43 countries representing 6 continents. Most respondents were from tertiary care facilities, with broad access to medical and neurosurgical resources. There was significant heterogeneity in general supportive care, and TBM-specific management demonstrated considerable divergence from current standard-of-care practices. The lack of standardized guidelines was identified as a major challenge in TBM management. General and neurocritical care were largely absent. Resources for bedside supportive care and noninvasive monitoring were broadly accessible. CONCLUSIONS: These findings suggest that current TBM management could be improved by the establishment of internationally accepted treatment guidelines based on available evidence, and that numerous centers have resources available to participate in future multicenter trials, even for basic interventions, that may further improve patient outcomes globally.

Management Issues in Myasthenia Gravis Patients Living With HIV: A Case Series and Literature Review.

South Africa is home to more than seven million people living with human immunodeficiency virus (HIV) and a high prevalence of tuberculosis. Human immunodeficiency virus-infected individuals may develop myasthenia gravis (MG), which raises questions regarding their management. An MG database, with 24 years of observational data, was audited for HIV-infected persons. Case reports of MG in HIV-infected persons were reviewed. We identified 17 persons with MG and HIV infection. All had generalized MG with a mean age at onset of 37.8 years. Eleven had acetylcholine receptor antibody-positive MG; one had antibodies against muscle-specific kinase. Six developed MG prior to HIV infection (mean CD4+ 361 cells/mm3); four worsened <6 months of starting antiretrovirals. Eleven developed MG while HIV-infected (mean CD4+ 423 cells/mm3); five presented with mild MG; three in MG crisis requiring rescue therapies (intravenous immune globulin or plasma exchange and/or intravenous cyclophosphamide). Two were diagnosed with HIV infection and MG at the same time. Fifteen required maintenance steroid-sparing immune therapies, predominantly azathioprine, or methotrexate. Plasma HIV viral loads remained below detectable levels on antiretrovirals during immunosuppressant treatment. Over the average follow-up of 6 years, 10 achieved minimal manifestation status, and the remainder improved to mild symptoms. Three cases had tuberculosis before MG, but none developed tuberculosis reactivation on immunosuppressive therapy; one used isoniazid prophylaxis. Herpes zoster reactivation during treatment occurred in one. Conclusions include the following: MG in HIV-infected patients should be managed similarly to individuals without HIV infection; half develop moderate-severe MG; MG symptoms may worsen within 6 months of antiretroviral initiation; safety monitoring must include plasma HIV viral load estimation. Isoniazid prophylaxis may not be indicated in all cases.

Management of intracranial tuberculous mass lesions: how long should we treat for?

Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis of such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting Mycobacterium tuberculosis ( M.tb) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3 rd International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with M.tb strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-based guidelines regarding the treatment duration of patients with intracranial tuberculous mass lesions.

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study).

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019).

Posttubercular syringomyelia in HIV-infected patients: A report of 10 cases and literature review.

OBJECTIVES: To describe the clinical presentation, spinal magnetic resonance imaging (MRI) findings and outcome of HIV-infected patients with tuberculosis (TB)-associated syringomyelia and to compare these findings between all HIV-infected and -uninfected cases published in the literature. METHODS: A retrospective observational study conducted over a 12.5-year period at a public-sector referral hospital in South Africa. HIV-infected adults with neurological TB in whom MRI confirmed a syrinx were included. We searched PubMed to identify all published syringomyelia cases. RESULTS: Ten patients were enrolled. Syringomyelia complicated neurological TB within four years of initial diagnosis in all patients (median: 21 months, range: 0-39) after initial diagnosis. Six patients were treated conservatively (TB treatment = 5, no treatment = 1); four improved, but only one was ambulant during follow-up. Four patients underwent syringoperitoneal shunting; three improved and one died three months later. Our literature review identified 50 additional cases (HIV-infected = 2, HIV-uninfected = 9, HIV status not documented = 39 [presumed HIV-uninfected]). Clinical and imaging findings and outcomes were similar between HIV-infected and -uninfected cases, except for time of presentation following neurological TB diagnosis, which was delayed (>4 years) in 46% of HIV-uninfected cases, compared to 8% of HIV-infected cases. Conclusions Syringomyelia is a disabling complication of neurological TB that usually presents early after neurological TB diagnosis in HIV coinfected patients.

Improving the microbiological diagnosis of tuberculous meningitis: A prospective, international, multicentre comparison of conventional and modified Ziehl-Neelsen stain, GeneXpert, and culture of cerebrospinal fluid.

OBJECTIVES: Tuberculous meningitis (TBM) is the severest form of tuberculosis, but current diagnostic tests are insensitive. Recent reports suggest simple modifications to conventional cerebrospinal fluid (CSF) Ziehl-Neelsen (ZN) staining may greatly improve sensitivity. We sought to define the performance of modified and conventional ZN stain for TBM diagnosis. METHODS: In hospitals in Vietnam, South Africa and Indonesia we conducted a prospective study of modified ZN with or without cytospin, conventional ZN smear, GeneXpert, and culture on CSF in adults with suspected TBM. RESULTS: A total of 618 individuals were enrolled across 3 sites. Compared with the TBM clinical diagnostic gold standard for research (definite probable or possible TBM), sensitivity of conventional ZN and modified ZN with cytospin were 33.9% and 34.5% respectively (p = 1.0 for the difference between tests), compared with culture 31.8% and Xpert 25.1%. Using culture as a reference, sensitivities of conventional ZN, modified ZN with cytospin, and Xpert were 66.4%, 67.5%, and 72.3%, respectively. Higher CSF volume and lactate, and lower CSF:blood glucose ratio were independently associated with microbiologically confirmed TBM. CONCLUSIONS: Modified ZN stain does not improve diagnosis of TBM. Currently available tests are insensitive, but testing large CSF volumes improves performance. New diagnostic tests for TBM are urgently required.

Spinal Tuberculosis: Clinicoradiological Findings in 274 Patients.

Background: Mycobacterium tuberculosis is a major cause of myelopathy and radiculopathy in settings with a high prevalence of tuberculosis/human immunodeficiency virus (HIV) coinfection. However, a paucity of publications exists on the spectrum of neurological and magnetic resonance (MR) imaging findings of spinal tuberculosis in these populations. Methods: We conducted a retrospective study of adults with spinal tuberculosis at a referral center in South Africa for patients with spinal disease without bony involvement seen at plain film radiography. We report the clinical, laboratory and spinal MR imaging findings, compare HIV-infected and HIV-uninfected patients, and correlate clinical and cerebrospinal fluid findings with those of MR imaging. Results: Of 274 patients, 209 (76%) were HIV infected and 49 (18%) were HIV uninfected. Radiculomyelitis occurred in 77% (n = 210), and spondylitis in 39% (n = 106). Subdural abscess (n = 42) and intramedullary tuberculoma (n = 33) were common. In 24% of HIV-infected and 14% of HIV-uninfected patients, spinal disease manifested as a paradoxical tuberculosis reaction, frequently following tuberculous meningitis. The triad of neurological deficit, fever, and back pain was similar in patients with spondylitis (24%), epi/subdural abscess without bony disease (14%), meningoradiculitis (17%), and isolated myelitis (17%) . Conclusions: Radiculomyelitis is a common manifestation of spinal tuberculosis in settings with high tuberculosis/HIV prevalence, often presenting as a paradoxical reaction. We describe a high frequency of rarely reported spinal tuberculosis manifestations, suggesting that these are more common than implied by the literature.

Standardized Methods for Enhanced Quality and Comparability of Tuberculous Meningitis Studies.

Tuberculous meningitis (TBM) remains a major cause of death and disability in tuberculosis-endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of TBM clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrollment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention TBM studies should improve the quality of future research outputs, can facilitate multicenter studies and meta-analyses of pooled data, and could provide the foundation for a global TBM data repository.

Inflammasome Activation Underlying Central Nervous System Deterioration in HIV-Associated Tuberculosis.

Tuberculous meningitis (TBM) is a frequent cause of meningitis in individuals with human immunodeficiency virus (HIV) infection, resulting in death in approximately 40% of affected patients. A severe complication of antiretroviral therapy (ART) in these patients is neurological tuberculosis-immune reconstitution inflammatory syndrome (IRIS), but its underlying cause remains poorly understood. To investigate the pathogenesis of TBM-IRIS, we performed longitudinal whole-blood microarray analysis of HIV-infected patients with TBM and reflected the findings at the protein level. Patients in whom TBM-IRIS eventually developed had significantly more abundant neutrophil-associated transcripts, from before development of TBM-IRIS through IRIS symptom onset. After ART initiation, a significantly higher abundance of transcripts associated with canonical and noncanonical inflammasomes was detected in patients with TBM-IRIS than in non-IRIS controls. Whole-blood transcriptome findings complement protein measurement from the site of disease, which together suggest a dominant role for the innate immune system in the pathogenesis of TBM-IRIS.

GeneXpert MTB/Rif to Diagnose Tuberculous Meningitis: Perhaps the First Test but not the Last.

Tuberculous meningitis (TBM) is the most severe form of tuberculous with substantial mortality. In May 2015, 54 researchers from 10 countries met in Da Lat, Vietnam, to discuss advances in TBM. Among the attendees were researchers involved in pivotal studies on the use of Xpert MTB/Rif for TBM diagnosis. Attendees discussed the 2014 World Health Organization strong recommendation favoring the use of Xpert "in preference to conventional microscopy and culture as the initial diagnostic test for cerebrospinal fluid (CSF) if the sample volume is low or if additional specimens cannot be obtained to make a quick diagnosis." Attendees were concerned that the limitations of Xpert testing for TBM are not emphasized. Clear guidance is needed for the investigational pathway for TBM, including recommendations on the diagnostic package of investigations, which does not stop with Xpert testing. Second, emphasis on the large CSF volumes (ideally 8-10 mL) needed for Xpert testing is required. Guidelines should also emphasize that TBM is a medical emergency and early treatment reduces mortality.

Interleukin-17 mediated differences in the pathogenesis of HIV-1-associated tuberculous and cryptococcal meningitis.

OBJECTIVE: Mycobacterium tuberculosis and Cryptococcus neoformans are major causes of meningitis in HIV-1-infected patients. Identifying differences in the inflammatory profiles of HIV-1-associated tuberculous meningitis (TBM) and cryptococcal meningitis may inform differences in immunopathogenic mechanisms in these diseases. In this study we compared the clinical and inflammatory features of HIV-1-associated TBM, and cryptococcal meningitis. METHODS: A prospective study of HIV-1-infected adults who presented with either TBM [antiretroviral therapy (ART)-naive] or cryptococcal meningitis (regardless of ART prescription). Clinical and laboratory findings and concentrations of 40 inflammatory mediators measured in cerebrospinal fluid (CSF, 33 paired with blood) were compared between TBM and cryptococcal meningitis patients regardless of ART prescription and between TBM and cryptococcal meningitis patients not receiving ART. RESULTS: Clinical and laboratory findings were similar in TBM (n=34) and cryptococcal meningitis (n = 19; ART prescribed: n = 10, no ART prescribed: n = 9). Exceptions included a higher median CD4 cell count [interquartile: 113 (69-199) vs. 25 (8-49) cells/µl, P = 0.0001] and higher HIV-1 median viral load [plasma: 5.46 (4.82-5.89) vs. 4.87 (4.36-5.17) log10copies/ml, P = 0.037; CSF: 6.05 (5.43-6.56) vs. 5.56 (4.52-5.80) log10copies/ml, P = 0.03] in TBM vs. cryptococcal meningitis patients not receiving ART. CSF interleukin (IL)-17A was lower in TBM compared with cryptococcal meningitis [1.00 (0.25-2.35) vs. 9.31 (1.24-23.36) pg/ml, P-adjusted = 0.03]. CONCLUSION: Despite presenting with higher peripheral CD4 cell counts, TBM patients also presented with higher HIV-1 viral loads compared with cryptococcal meningitis patients, suggesting a greater propensity of M. tuberculosis compared with C. neoformans to increase HIV-1 replication in vivo. CSF IL-17A was lower in TBM; its role in the immunopathogenesis of TBM and cryptococcal meningitis deserves further research.

HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.

Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.