Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome Research Articles

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome in initiating ART among HIV-Infected patients in China-risk factors and management

BackgroundChina is a country burdened with a high incidence of both tuberculosis (TB) and HIV, Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important early complication in TB and HIV co-infected patients, but data from China are limited. Additionally, as an integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) regimen becomes the first-line treatment, concerns have arisen regarding the potential increase in the incidence of paradoxical TB-IRIS. Nevertheless, the existing data are inconclusive and contradictory.MethodsWe conducted a retrospective study at Chongqing Public Health Clinical Center from January 2018 to December 2021. We collected demographic and clinical data of HIV/TB co-infected patients who initiated ART. We described the patient characteristics, identified predictors for TB-IRIS, and determined clinical outcomes. The Statistical Package for Social Science (SPSS 25) was used to analyse the data. Continuous variables were compared using Student’s t-test or rank sum test. Counting data were compared using the chi-square test or Fisher’s exact test. The variables with statistical significance in the univariate analysis were added to the binary logistic regression. A p-value less than 0.05 was considered statistically significant.ResultsA total of 384 patients co-infected with naive HIV and pulmonary TB (PTB) who were given ATT and ART combination were included. 72 patients (18.8%) developed paradoxical TB-IRIS with a median of 15 (12, 21) days after initiating ART. Baseline age ≤ 40years, CD4 + T-cell counts ≤ 50cells/µL, HIV viral load ≥ 500,000 copies/mL were found to be significantly associated with development of paradoxical TB-IRIS. Mortality rates were similar in the TB-IRIS (n = 5, 6.9%) group and non-TB-IRIS (n = 13, 4.2%) group. Interestingly, CD4+ T-cell counts recovery post-ART was significant higher in the TB-IRIS group when compared to the non-TB-IRIS group at the end of 24 weeks (P = 0.004), as well as at 48 weeks (P = 0.015). In addition, we consider that INSTI- based ART regimen do not increased the risk of Paradoxical TB-IRIS.ConclusionParadoxical TB-IRIS, while often leading to clinical deterioration and hospitalization, is generally manageable. It appears to have a positive impact on the recovery of CD4 + T-cell counts over time. Importantly, our data suggest that INSTI-based ART regimens do not elevate the risk of TB-IRIS. Thus, paradoxical TB-IRIS should not be considered an impediment to initiating ART in adults with advanced immunodeficiency, except in the case of tuberculous meningitis (TBM).

Predicting the Risk of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients with Central Nervous System Tuberculosis

Objective — to identify risk factors associated with the development of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) in HIV-infected patients with central nervous system tuberculosis. The analysis assessed the relationship between the risk of develo­ping TB-IRIS with neurological manifestations and the following factors: 1) viral load before antiretroviral therapy (ART) initiation; 2) CD4+ lymphocyte of blood before ART initiation; 3) duration of antituberculosis therapy before starting ART; 4) presence of active tuberculosis at the time of ART initiation. Materials and methods. 112 cases of neurological TB-IRIS were analyzed. These patients were treated and observed during the 1 year in anti-tuberculosis facilities in Kyiv and Kyiv region in 2017—2021. All patients received ART in accordance with the HIV treatment protocols adopted in Ukraine. Treatment according to the standard of tuberculosis treatment adopted in Ukraine. The logistic regression model construction method was used to analyze. Statistical processing of the obtained data was carried out using free software — the EZR package (version 1.61; https://www.jichi.ac.jp/).The study was carried out as part of the applied research work 0121U107800 «Predicting the development of the incidence of tuberculosis in Ukraine in connection with the COVID-19 pandemic», funded by the Ministry of Health of Ukraine. Results and discussion. After calculations, two factor signs were identified, associated with the of deve­loping TB-IRIS with neurological manifestations: the baseline level of CD4+ lymphocytes in 1 μl of blood at the beginning of treatment and the presence of active tuberculosis at the time of ART initiation. Conclusions. It was found that the risk of developing TB-IRIS with neurological manifestations is significantly associated (p < 0.05) with the following factors: 1) the level of CD4+ lymphocytes in 1 μl at the beginning of treatment; 2) presence of active tuberculosis at the time of ART initiation.

Relationship Between LTA4H Promotor Polymorphism and Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome and Its Prevention With Prednisone.

The development of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) and its prevention using prednisone may potentially be mediated by the LTA4H genotype. We assessed this hypothesis in a clinical trial evaluating prednisone to prevent TB-IRIS. We did not find an association between LTA4H genotype and TB-IRIS incidence or prednisone efficacy.

Changes in the balance of Th17/Treg cells and oxidative stress markers in patients with HIV‑associated pulmonary tuberculosis who develop IRIS.

Tuberculosis (TB) is the most common opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) infection and is one of the primary causes of death from AIDS. The increased accessibility to highly active antiretroviral therapy (HAART) has significantly improved the clinical outcome of patients with HIV infection. However, following ART, rapid restoration of the immune system leads to immune reconstitution inflammatory syndrome (IRIS). Oxidative stress and innate immunity play a role in TB-associated IRIS (TB-IRIS). The present study investigated the changes that occur in oxidative stress markers and T helper (Th)17/regulatory T (Treg) cell balance and their significance in IRIS patients with HIV-associated pulmonary TB. A total of 316 patients with HIV-associated pulmonary TB were treated with HAART and followed up regularly for 12 weeks. Those who developed IRIS were included in the IRIS group (n=60), while the remaining patients were included in the non-IRIS group (n=256). The changes in plasma oxidative stress markers superoxide dismutase (SOD) and malondialdehyde (MDA) were detected with the ELISA, and the ratio of Th17 to Treg cells in whole blood were analyzed before and after treatment through the flow cytometric assay. Following treatment, MDA and Th17 cells levels were significantly increased while SOD and Treg cells levels were decreased in the IRIS group (P<0.05) compared with before treatment. In the non-IRIS group, a non-significant decrease was observed in SOD levels (P>0.05), while the MDA levels significantly decreased compared with before treatment (P<0.05) and the Th17 and Treg cells levels were both significantly increased (P<0.05). After treatment, compared with the non-IRIS group, the IRIS group showed a significant increase in MDA and Th17 cells and decrease in SOD and Treg cells levels (P<0.05). In addition, Th17 cells levels were positively correlated with MDA but negatively correlated with SOD levels. Treg levels were negatively correlated with MDA and positively correlated with SOD levels (P<0.05). The area under the curve values of serum MDA and SOD, Th17 and Treg levels predicting the occurrence of IRIS were 0.738, 0.883, 0.722 and 0.719, respectively (P<0.05). These results indicated that the above parameters have certain diagnostic value for the occurrence of IRIS. The occurrence of IRIS in patients with HIV-associated pulmonary TB may be associated with oxidative stress and Th17/Treg cell imbalance.

Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome-An Extempore Game of Misfiring with Defense Arsenals.

The lethal combination involving TB and HIV, known as "syndemic" diseases, synergistically act upon one another to magnify the disease burden. Individuals on anti-retroviral therapy (ART) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). The underlying inflammatory complication includes the rapid restoration of immune responses following ART, eventually leading to exaggerated inflammatory responses to MTB antigens. TB-IRIS continues to be a cause of morbidity and mortality among HIV/TB coinfected patients initiating ART, and although a significant quantum of knowledge has been acquired on the pathogenesis of IRIS, the underlying pathomechanisms and identification of a sensitive and specific diagnostic marker still remain a grey area of investigation. Here, we reviewed the latest research developments into IRIS immunopathogenesis, and outlined the modalities to prevent and manage strategies for better clinical and diagnostic outcomes for IRIS.

Phenotypic Profile of Mycobacterium tuberculosis-Specific CD4 T-Cell Responses in People With Advanced Human Immunodeficiency Virus Who Develop Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of cotreatment for TB and human immunodeficiency virus (HIV)-1. We characterized Mycobacterium tuberculosis (Mtb)-specific CD4 T-cell phenotype and transcription factor profile associated with the development of TB-IRIS. We examined the role of CD4 T-cell transcription factors in a murine model of mycobacterial IRIS. In humans, we used a longitudinal study design to compare the magnitude of antiretroviral therapy, activation, transcription factor profile, and cytotoxic potential of Mtb-specific CD4 T cells between TB-IRIS (n = 25) and appropriate non-IRIS control patients (n = 18) using flow cytometry. In the murine model, CD4 T-cell expression of Eomesodermin (Eomes), but not Tbet, was associated with experimentally induced IRIS. In patients, TB-IRIS onset was associated with the expansion of Mtb-specific IFNγ+CD4 T cells (P = .039). Patients with TB-IRIS had higher HLA-DR expression (P = .016), but no differences in the expression of T-bet or Eomes were observed. At TB-IRIS onset, Eomes+Tbet+Mtb-specific IFNγ+CD4+ T cells showed higher expression of granzyme B in patients with TB-IRIS (P = .026). Although the murine model of Mycobacterium avium complex-IRIS suggests that Eomes+CD4 T cells underly IRIS, TB-IRIS was not associated with Eomes expression in patients. Mycobacterium tuberculosis-specific IFNγ+CD4 T-cell responses in TB-IRIS patients are differentiated, highly activated, and potentially cytotoxic.

2 Tuberculosis-associated immune reconstitution inflammatory syndrome management

2 Tuberculosis-associated immune reconstitution inflammatory syndrome management

Risk of Immune Reconstitution Inflammatory Syndrome With Integrase Inhibitors Versus Other Classes of Antiretrovirals: A Systematic Review and Meta-analysis of Randomized Trials.

BackgroundIntegrase strand transfer inhibitors (InSTIs) decrease HIV plasma viral load faster than other antiretroviral classes. More rapid viral load decline has been associated with higher risk of immune reconstitution inflammatory syndrome (IRIS). There are conflicting reports on the association between InSTI and IRIS. We performed a systematic review and meta-analysis to compare the risk of IRIS among treatment-naïve HIV-positive patients starting InSTI versus non-InSTI regimens.MethodsWe searched PubMed, Scopus, Web of Science, Africa-Wide, and Cochrane databases from earliest available date to 26 November 2021, for randomised controlled trials (RCTs) having intervention arms with InSTI versus control arms without InSTI in patients initiating first-line antiretroviral therapy. The primary outcome was relative risk (RR) of IRIS, while the secondary outcome was RR of paradoxical tuberculosis-associated IRIS (TB-IRIS). Data were combined by random-effects meta-analysis according to the Mantel-Haenszel method. The protocol for this study is registered with PROSPERO, CRD42020213976.ResultsWe included 14 RCTs comprising 8696 participants from six continents for the primary outcome of IRIS, and a subset of 674 participants (from three RCTs) for the secondary outcome of paradoxical TB-IRIS. Risk of IRIS was similar between InSTI and non-InSTI regimens (RR, 0.93, 95% confidence interval [CI], 0.75 – 1.14). There was a trend towards a lower risk of paradoxical TB-IRIS with InSTI versus efavirenz regimens that was not statistically significant (RR, 0.64, 95% CI, 0.34 – 1.19).ConclusionsIn this meta-analysis among treatment-naïve patients commencing first-line antiretroviral therapy, InSTI regimens were not associated with higher risk of IRIS.

CD4 Tcells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection.

HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals have an increased risk of tuberculosis prior to loss of peripheral CD4 Tcells, raising the possibility that HIV co-infection leads to CD4 Tcell depletion in lung tissue before it is evident in blood. Here, we use rhesus macaques to study the early effects of simian immunodeficiency virus (SIV) co-infection on pulmonary granulomas. Two weeks after SIV inoculation of Mtb-infected macaques, Mtb-specific CD4 Tcells are dramatically depleted from granulomas, before CD4 Tcell loss in blood, airways, and lymph nodes, or increases in bacterial loads or radiographic evidence of disease. Spatially, CD4 Tcells are preferentially depleted from the granuloma core and cuff relative to B cell-rich regions. Moreover, live imaging of granuloma explants show that intralesional CD4 Tcell motility is reduced after SIV co-infection. Thus, granuloma CD4 Tcells may be decimated before many co-infected individuals experience the first symptoms of acute HIV infection.

Frequency of CXCR3+ CD8+ T-Lymphocyte Subsets in Peripheral Blood Is Associated With the Risk of Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome Development in Advanced HIV Disease.

BackgroundTuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a clinical aggravation of TB symptoms observed among a fraction of HIV coinfected patients shortly after the start of antiretroviral therapy (ART). Of note, TB-IRIS is characterized by exacerbated inflammation and tissue damage that occurs in response to the elevated production of CD4+ T cell-derived IFN-γ. Nevertheless, the possible participation of CD8+ T cells in TB-IRIS development remains unclear.MethodsWe performed a comprehensive assessment of the composition of CD8+ T cell memory subsets and their association with circulating inflammation-related molecules in TB-HIV coinfected patients initiating ART.ResultsWe found that TB-IRIS individuals display higher frequencies of Antigen-experienced CD8+ T cells during the onset of IRIS and that the levels of these cells positively correlate with baseline mycobacterial smear grade. TB-IRIS individuals exhibited higher frequencies of effector memory and lower percentages of naïve CD8+ T cells than their Non-IRIS counterparts. In both TB-IRIS and Non-IRIS patients, ART commencement was associated with fewer significant correlations among memory CD8+ T cells and cells from other immune compartments. Networks analysis revealed distinct patterns of correlation between each memory subset with inflammatory cytokines suggesting different dynamics of CD8+ T cell memory subsets reconstitution. TB-IRIS patients displayed lower levels of memory cells positive for CXCR3 (a chemokine receptor that plays a role in trafficking activated CD8+ T cells to the tissues) than Non-IRIS individuals before and after ART. Furthermore, we found that CXCR3+ naïve CD8+ T cells were inversely associated with the risk of TB-IRIS development. On the other hand, we noticed that the frequencies of CXCR3+ effector CD8+ T cells were positively associated with the probability of TB-IRIS development.ConclusionOur data suggest that TB-IRIS individuals display a distinct profile of memory CD8+ T cell subsets reconstitution after ART initiation. Moreover, our data point to a differential association between the frequencies of CXCR3+ CD8+ T cells and the risk of TB-IRIS development. Collectively, our findings lend insights into the potential role of memory CD8+ T cells in TB-IRIS pathophysiology.

Risk factors for lethal outcome in tuberculosis­associated immune reconstitution inflammatory syndrome with tuberculous lesions of the central nervous system

Objective — to study the relation of death in tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) and central nervous system (CNS) tuberculosis with the following factors: 1) baseline CD4+ T-lymphocyte count, cells/µL, at the beginning of treatment; 2) the level of viral load at the beginning of treatment; 3) resistance to antimycobacterial drugs (R, HR, HR + others) or its absence at the beginning of treatment; 4) age of patients; 5) gender of patients.&#x0D; Materials and methods. 55 cases of neurological TB-IRIS were analyzed. These patients were treated and observed during the 1 year in anti-tuberculosis facilities in Kyiv and Kyiv region in 2017—2019. All patients received ART in accordance with the HIV treatment protocols adopted in Ukraine. Treatment of tuberculosis was carried out taking into account the susceptibility of the pathogen to antimycobacterial therapy according to the standard of tuberculosis treatment adopted in Ukraine. The logistic regression model construction method was used to analyze. A multifactor model for predicting the risk of death in neurological TB-IRIS was built.&#x0D; Results and discussion. After calculations, two factor signs were identified, associated with the risk of death: the baseline level of CD4+ lymphocytes in 1 μl of blood at the beginning of treatment and the level of viral load (copies of HIV RNA in 1 μl) at the beginning of treatment.&#x0D; Conclusions. It was found that the risk of death in TB-IRIS with tuberculous lesions of the CNS is significantly associated (p &lt; 0.05) with the following factors: 1) the level of CD4+ lymphocytes in 1 μl at the beginning of treatment; 2) the level of viral load at the beginning of treatment (copies of HIV RNA in 1 μl).

Tuberculosis associated immune reconstitution inflammatory syndrome in patients infected with HIV: the current state of the problem

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an enhanced inflammatory immune response to Mycobacterium tuberculosis antigens due to immune system recovery in HIV-infected patients within 6 months of antiretroviral therapy (ART).&#x0D; Objective — to assess the incidence of TB-IRIS in patients with tuberculous meningitis. Evaluation of mortality caused by TB-IRIS.&#x0D; Materials and methods. A retrospective analysis of 60 cases of confirmed tuberculous meningitis in patients who were treated in anti-tuberculosis institutions in Kiev and Kiev region in 2017—2019 was carried out. The medical records of the patients were studied.Results and discussion. Co-infection with HIV-TB among patients was confirmed in 57 (95 %) cases. In 21 patients (36.8 %; CI 24.7—50.0 %) with HIV-TB co-infection, a link was established between the appointment of ART and the development of tuberculous meningitis. 19 (90.5 %) of them had risk factors at the time of ART. Fifteen (71.4 %) patients had other localizations of tuberculosis besides tuberculosis of the central nervous system (pulmonary tuberculosis, tuberculosis of intrathoracic lymph nodes, tuberculosis of peripheral lymph nodes, tuberculosis of the genitourinary system). The mean CD4+-lymphocyte count before ART was (61.6 ± 16.9) cells/µL (p ≤ 0.05). All patients were prescribed standard antimycobacterial therapy and ART. 9 (42.8 %) patients were cured. One (4.7 %) developed severe disability: peripheral tetraparesis and severe cerebrosthenia. 11 patients died, mortality was 52.4 % (CI 30.2—74.1 %).&#x0D; Conclusions. TB-IRIS is the cause of tuberculous meningitis in HIV-infected patients in 36.8 % of cases; (CI 24.7—50.0 %). Tuberculous meningitis always complicates the prognosis with TB-IRIS, while the mortality rate is 52.4 % (CI 30.2—74.1 %).

Increased risk of IRIS-associated tuberculosis in HIV-infected patients receiving Integrase Inhibitors

BackgroundTuberculosis is associated with a risk of immune reconstitution inflammatory syndrome (IRIS) after ART initiation. MethodsData from all patients with newly diagnosed tuberculosis disease and uncontrolled HIV infection from 1997 to 2017 in a French center were retrospectively collected. We evaluated the incidence of tuberculosis-IRIS in patients initiating ART with or without integrase inhibitors (INSTI) ResultsFifty-five patients were included: 21 receiving an INSTI regimen and 34 a non-INSTI regimen. Except with regard to ART regimen, the two groups were comparable (median CD4 of 85/mm3). The overall percentage of IRIS was 34% (19/55), with 52% IRIS in INSTI regimen and 23% in non-INSTI regimen respectively (P=0.04). In a multivariate logistic model, we observed an increased risk of IRIS in the INSTI regimen compared to the non-INSTI, with an OR at 3.33 [95% CI, 1.01–11.1] (P=0.05) ConclusionsART containing integrase inhibitors could be associated with increased incidence of TB-associated IRIS.

Clinical and laboratory profile of tuberculosis in HIV-positive patients and occurrence of tuberculosis-associated immune reconstitution inflammatory syndrome

Background: Tuberculosis (TB) is the most common opportunistic disease in human immunodeficiency virus (HIV)-positive persons.Methods: We prospectively studied the clinical, radiological, cytological, histopathological and microbiological presentation of TB in HIV-positive patients and occurrence of immune reconstitution inflammatory syndrome (IRIS) in HIV TB co-infected patients.Results: Out of 70 patients studied, 47 were male. Fever was the most common symptom (n = 61, 87.1%). The most common laboratory finding was anaemia (n = 67, 95.7%). In 32 (45.7%) patients presenting with TB, HIV infection was diagnosed. A CD4+ count <200/mm3 was seen in 57 (81.4%) patients. Extra-pulmonary TB (44.3%) was more common than pulmonary TB. All patients were started on anti-TB treatment; 6 had developed IRIS.Conclusions: Our observations suggest that screening all HIV-seropositive patients for TB and careful monitoring for the occurrence of IRIS while on anti-TB treatment are helpful in managing HIV HIV-TB co-infected patients.

Diagnostic Accuracy of the INSHI Consensus Case Definition for the Diagnosis of Paradoxical Tuberculosis-IRIS.

The diagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) relies on characteristic clinical features synthesized as the International Network for the Study of HIV-associated IRIS (INSHI) case definition. There is no confirmatory laboratory test. Site B HIV-TB clinic in Khayelitsha, Cape Town, South Africa. Using data of participants with HIV-associated tuberculosis starting antiretroviral treatment from a prospective trial evaluating prednisone for TB-IRIS prevention, we applied latent class analysis to model a gold standard for TB-IRIS. The model-predicted probability of TB-IRIS for each participant was used to assess the performance of the INSHI case definition and compare its diagnostic accuracy with several adapted case definitions. Data for this analysis were complete for 217 participants; 41% developed TB-IRIS. Our latent class model included the following parameters: respiratory symptoms; night sweats; INSHI major criteria 1, 2, and 4; maximum C-reactive protein >90 mg/L; maximum heart rate >120/min; maximum temperature >37.7°C; and preantiretroviral therapy CD4 count <50 cells/µL. The model estimated a TB-IRIS incidence of 43% and had optimal goodness of fit (χ2 = 337, P = 1.0). The INSHI case definition displayed a sensitivity of 0.77 and a specificity of 0.86. Replacing all the minor INSHI criteria with objectives measures (C-reactive protein elevation, fever, and/or tachycardia) resulted in a definition with better diagnostic accuracy, with a sensitivity of 0.89 and a specificity of 0.88. The INSHI case definition identifies TB-IRIS with reasonable accuracy. Amending the case definition by replacing INSHI minor criteria with objective variables improved sensitivity without loss of specificity.

Tuberculosis IRIS: Pathogenesis, Presentation, and Management across the Spectrum of Disease.

Antiretroviral therapy (ART), while essential in combatting tuberculosis (TB) and HIV coinfection, is often complicated by the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Depending on the TB disease site and treatment status at ART initiation, this immune-mediated worsening of TB pathology can take the form of paradoxical TB-IRIS, unmasking TB-IRIS, or CNS TB-IRIS. Each form of TB-IRIS has unique implications for diagnosis and treatment. Recently published studies have emphasized the importance of neutrophils and T cell subtypes in TB-IRIS pathogenesis, alongside the recognized role of CD4 T cells and macrophages. Research has also refined our prognostic understanding, revealing how the disease can impact lung function. While corticosteroids remain the only trial-supported therapy for prevention and management of TB-IRIS, increasing interest has been given to biologic therapies directly targeting the immune pathology. TB-IRIS, especially its unmasking form, remains incompletely described and more data is needed to validate biomarkers for diagnosis. Management strategies remain suboptimal, especially in the highly morbid central nervous system (CNS) form of the disease, and further trials are necessary to refine treatment. In this review we will summarize the current understanding of the immunopathogenesis, the presentation of TB-IRIS and the evidence for management recommendations.

Indole Propionic Acid, an Unusual Antibiotic Produced by the Gut Microbiota, With Anti-inflammatory and Antioxidant Properties.

Most antibiotics are produced by soil microbes and typically interfere with macromolecular synthesis processes as their antibacterial mechanism of action. These natural products are often large and suffer from poor chemical tractability. Here, we discuss discovery, mechanism of action, and the therapeutic potentials of an unusual antibiotic, indole propionic acid (IPA). IPA is produced by the human gut microbiota. The molecule is small, chemically tractable, and targets amino acid biosynthesis. IPA is active against a broad spectrum of mycobacteria, including drug resistant Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM). Interestingly, the microbiota-produced metabolite is detectable in the serum of healthy individuals, tuberculosis (TB) patients, and several animal models. Thus, the microbiota in our gut may influence susceptibility to mycobacterial diseases. If a gut-lung microbiome axis can be demonstrated, IPA may have potential as a biomarker of disease progression, and development of microbiota-based therapies could be explored. In addition to its antimycobacterial activity, the molecule displays anti-inflammatory and antioxidant properties. This raises the possibility that IPA has therapeutic potential as both antibiotic and add-on host-directed drug for the treatment of TB in patient populations where disease morbidity and mortality is driven by excessive inflammation and tissue damage, such as TB-associated immune reconstitution inflammatory syndrome, TB-meningitis, and TB-diabetes.

The Role of Cytokines and Cellular Receptors in the TuberculosisAssociated Immune Reconstitution Inflammatory Syndrome

Tuberculosis (TB) is the most prevalent opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) and the major reason for morbidity and mortality. In this review, we focus on pathological immune restoration in AIDS patients after antiretroviral therapies (ART) initiation. This manuscript discusses the importance of T cell immunity for antigen-specific immune reconstitution and the production of cytokines, which are divided into 2 subgroups: interferons (IFN), and interleukins (IL). We overview the role they play in connection between innate and adaptive immunity during immune restoration. We describe how hypercytokinemia produced by innate and adaptive immune cells, leads to the manifestations of tuberculosisassociated immune reconstitution inflammatory syndrome (TB-IRIS) in AIDS patients during the recovery of CD4+ T cells on ART. We conclude with a brief synopsis of treatment approaches

Prevalence and risk factors of paradoxical tuberculosis associated immune reconstitution inflammatory syndrome among HIV-infected patients in Beijing, China

BackgroundIn this study, we aimed to describe the prevalence, clinical presentation and risk factors of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) cases in China.MethodsWe performed a descriptive analysis of demographic and clinical data of HIV/TB coinfected patients receiving ART at Beijing Ditan Hospital between January 2014 and October 2018.ResultsOf 199 patients included, 45 (22.6%) developed paradoxical TB-IRIS, and 19 (9.5%) TB-IRIS cases presented miliary TB. The pre-ART CD4 count lower than 50 cells/mm3 was found to be significantly associated with development of TB-IRIS. Similarly, patients with higher than 4-fold increase in CD4 cell count after antiretroviral therapy (ART) had significantly higher odds of having TB-IRIS. When patients aged 25–44 years were utilized as the control group, youths (< 25 years old) were more likely to have miliary TB. No significant difference was observed in the intervals from initiation of ART to IRIS presentation between miliary and non-miliary group.ConclusionsIn conclusion, our data demonstrate that approximate one quarter of patients coinfected with TB and HIV develop paradoxical TB-IRIS after initial of ART therapy in China. Lower baseline CD4 count and rapid increase in CD4 count are the major risk factors associated with the occurrence of paradoxical TB-IRIS.

Characteristics of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome and its influence on tuberculosis treatment outcomes in persons living with HIV

ObjectiveThe influence of tuberculosis (TB)-immune reconstitution inflammatory syndrome (IRIS) on TB treatment outcomes and its risk factors were investigated among people with human immunodeficiency virus (HIV) and co-infected with TB. MethodsNewly diagnosed, culture-confirmed, pulmonary TB patients with HIV and enrolled in a clinical trial (NCT00933790) were retrospectively analysed for IRIS occurrence. Risk factors and TB outcomes (up to 18 months after initiation of anti-TB treatment [ATT]) were compared between people who experienced IRIS (IRIS group) and those who did not (non-IRIS group). ResultsTB-IRIS occurred in 82 of 292 (28%) participants. Significant baseline risk factors predisposing to TB-IRIS occurrence in univariate analysis were: lower CD4+ T-cell count, CD4/CD8 ratio, haemoglobin levels, presence of extra-pulmonary TB focus, and higher HIV viral load; the last two retained significance in the multivariate analysis. After 2 months of ATT commencement, sputum smear conversion was documented in 45 of 80 (56.2%) vs. 124 of 194 (63.9%) (p=0.23), culture conversion was in 75 of 80 (93.7%) vs. 178 of 194 (91.7%) (p=0.57) and the median decline in viral load (log10copies/mm3) was 2.7 in the IRIS vs. 1.1 in the non-IRIS groups (p<0.0001), respectively. An unfavourable response to TB therapy was detected in 17 of 82 (20.7%) and 28 of 210 (13.3%) in the IRIS and non-IRIS groups, respectively (p=0.14). ConclusionsTB-IRIS frequently occurred in people with advanced HIV infection and in those who presented with extra-pulmonary TB lesions, without influencing subsequent TB treatment outcomes.