Immune Reconstitution Inflammatory Syndrome In HIV Research Articles

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.

Anti‐GM2 antibodies‐associated meningoradiculitis in the context of HIV immune reconstitution inflammatory syndrome

AbstractBackgroundAutoimmune manifestations can occur in the context of HIV immune reconstitution inflammatory syndrome (IRIS). Previous studies have shown that GM2 is overexpressed on HIV‐1 infected T lymphocytes.Case presentationA 71‐year‐old patient diagnosed with HIV‐1 infection developed neurological symptoms congruent with meningoradiculitis 1 month after initiation of antiretroviral therapy. Concurrent syphilitic seroconversion raised the hypothesis of neurosyphilis, which was later infirmed. Serum antiganglioside immunoglobulin M antibodies were highly positive. Treatment with intravenous immunoglobulins was effective.ConclusionWe postulate that meningoradiculitis in this patient was a consequence of anti‐GM2 antibodies produced as part of an anti‐HIV‐1 immune response, and that this case falls within the scope of autoimmune manifestations linked to HIV IRIS.

Worsening Guillain-Barré syndrome: harbinger of IRIS in HIV?

We report an HIV patient aged 38 years with acute inflammatory demyelinating polyradiculoneuropathy subtype of Guillain-Barré syndrome (GBS) as the only manifestation of seroconversion and worsening of GBS being the...

TB-HIV co-infection: a catastrophic comradeship.

The symbiotic association of tuberculosis (TB) and HIV poses a challenge to human survival. HIV complicates every aspect of TB including presentation, diagnosis and treatment. HIV-TB patients encounter unique problems like drug-drug interactions, cumulative toxicity, immune reconstitution inflammatory syndrome (IRIS), lower plasma drug levels and emergence of drug resistance during treatment despite adherence. TB may also be overdiagnosed in HIV due to a number of diseases that closely resemble TB. Notable among them are non-tuberculous mycobacteria, Pneumocystis Jirovecii and Nocardia. Even though diagnostic procedures have improved over the years, patients in developing countries usually seek health care at later stage of the disease. Research data ascertains the duration of therapy for TB to be 6months with rifampicin and isoniazid, reinforced with ethambutol and pyrazinamide in the first 2months. The schedule of therapy is still debatable with daily regimens being preferred in the context of HIV. Many reasons exist for persistence of Mycobacterium Tuberculosis (M.TB) in sputum, or delayed-clearance of TB from sputum smears in HIV, apart from emergence of drug resistance and non-compliance. Acquired rifampicin resistance (ARR) is a unique phenomenon complicating HIV-associated TB when an intermittent regimen of antituberculosis therapy (ATT) is used without timely initiation of highly active antiretroviral therapy (HAART), especially in patients harbouring isoniazid-resistant strains Immune restoration is often incomplete ('swiss cheese' pattern) even with effective HAART if not started early. Immune reconstitution inflammatory syndrome (IRIS) is the paradoxical worsening of the patient's condition often with radiological deterioration, due to an enhanced immune response with HAART. IRIS occurs despite an effective virological suppression and a favourable response to ATT. The incidence of IRIS in HIV has reached up to 54%, requiring utilization of experts and tertiary care which forms an obstacle to the decentralization of patients in the ART programme. Research in HIV-TB immunology and management needs further exploration in order to understand thediseases and offer appropriate treatment. The following paragraphs provide scientific evidences generated through research that could potentially guide management.

Neurological immune reconstitution inflammatory response: riding the tide of immune recovery.

This manuscript reviews current reports about clinical aspects of immune reconstitution inflammatory syndrome (IRIS), with a particular emphasis on IRIS in the setting of progressive multifocal leukoencephalopathy (PML) and to a lesser extent on cryptococcal meningitis and HIV. PML prognosis has been radically improved, as it has become possible to provide immune reconstitution, although some remaining morbidity and mortality results from excess inflammation. Similar pathologic responses are seen less often, but remain clinically important in cryptococcal meningitis, and HIV. Early diagnosis and active management of PML results in optimal outcomes with survival of 75% or higher in multiple recent series. These finding apply both to natalizumab and HIV-associated PML. Cryptococcal meningitis is frequently complicated by IRIS, and early treatment with antifungal therapy preceding HIV therapy provides optimal outcomes. HIV IRIS is reduced by early therapy, which is now recommended, but even on therapy, chronic dysregulated immune responses may play important roles in ongoing HIV-associated neurocognitive disease (HAND), which is common, as well as rare but more dramatic subacute encephalopathies. The clinician must actively monitor and treat both opportunistic infection and the inflammatory response that is essential to recovery but may itself augment disease and injury.

A non-synonymous polymorphism in IL-23R Gene (rs1884444) is associated with reduced risk to schistosomiasis-associated Immune Reconstitution Inflammatory Syndrome in a Kenyan population.

BackgroundHuman Immunodeficiency Virus (HIV) and Schistosomiasis co-infection is common among residents at the shores of Lake Victoria in Kenya. About 36% of this population initiating antiretroviral therapy (ART) experience Immune Reconstitution Inflammatory Syndrome (IRIS) that complicates recovery. Several IL-23R alleles have been associated with susceptibility to both autoimmune and inflammatory diseases through T-helper type 17 (TH17) cells. However, whether or not variants within the IL-23R increase susceptibility to IRIS in western Kenya is unknown. The objective of the current study was to determine the association between IL-23R gene polymorphisms, CD4+ cell counts and HIV RNA levels and IRIS in HIV and Schistosoma mansoni co-infected patients undergoing highly active anti-retroviral therapy (HAART).MethodsA three-month case–control study was conducted on antiretroviral naïve schistosomiasis/HIV co-infected fishermen starting HAART in Uyoma Rarieda, Siaya County, Kenya. Seventy one patients were sampled at baseline and followed up for three months, to establish if they developed Schistosoma-related IRIS. In addition, the CD4+ cell counts and HIV RNA levels were determined in pre- and post-administration of HAART. Variations at five polymorphic sites of IL-23R (rs1884444, rs11465754, rs6682925, rs7530511 and rs7539625) based on >10% minor allele frequency in Yoruban reference population was determined using Allelic Discrimination Assay. The association between the five variants and susceptibility to IRIS was determined using logistic regression while controlling for potential confounders. In addition, the functional differences between the baseline CD4 + Cell counts and viral loads were determined using medians while across IL-23R genotypes were determined using Kruskal-Wallis tests.ResultsOverall, 26 (36.6%) patients developed schistosomiasis-associated IRIS at a median age of 35.5 years. Carriage of the TT genotype at the non-synonymous rs1884444 T > G relative to GG, was associated with a decreased risk of schistosomiasis-associated IRIS (OR, 0.25, 95% CI, 0.07-0.96, P = 0.043) while both baseline CD4+ cell counts and viral loads had no association with IRIS.ConclusionThese findings indicate that the non-synonymous variant rs1884444 T > G of IL-23R is associated with a decreased risk to schistosomiasis-associated IRIS. However, additional studies in a larger cohort and with an all inclusive polymorphic variants in the synonymous and non-synonymous regions need to be evaluated.

Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study

Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible. We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1-5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p≤0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7-25.6, p<0.001). Pre-ART increases in Th(17) and Th(2) responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-α, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions.

Pericardial Large B-Cell Lymphoma as a Manifestation of HIV Immune Reconstitution Inflammatory Syndrome

Pericardial Large B-Cell Lymphoma as a Manifestation of HIV Immune Reconstitution Inflammatory Syndrome

Biomarkers of HIV Immune Reconstitution Inflammatory Syndrome

Dysregulation of the immune system drives HIV pathogenesis. As we develop new ways to treat HIV and AIDS, we encounter new clinical ramifications of our treatment on regulatory components of the immune system. HIV-associated Immune Reconstitution Inflammatory Syndrome (IRIS) occurs after initiation of anti-retroviral therapy (ART) with inappropriate and dysbalanced restoration of the immune system resulting in pathologic inflammatory reactions with significant morbidity. IRIS is most commonly associated with latent, occult, or past infections, including tuberculosis, Cryptococcus neoformans, and Mycobacterium avium-complex. We discuss common clinical presentations, new diagnostic modalities, current hypotheses of IRIS pathogenesis, and future directions of IRIS-related research, focusing on the identification of biomarkers that can be used to predict and diagnose IRIS.

Pediatric HIV immune reconstitution inflammatory syndrome

Little is known regarding HIV immune reconstitution inflammatory syndrome in children. As the antiretroviral therapy roll out has gathered pace since 2004 in resource-limited settings, pediatric immune reconstitution inflammatory syndrome has emerged as a clinical challenge. The incidence of immune reconstitution inflammatory syndrome appears to be between 10 and 20%. The commonest causes are mostly mycobacterial, including tuberculosis, atypical mycobacteria and bacillus Calmette-Guérin related. In many pediatric cohorts, however, a marked early mortality within the first 90 days of antiretroviral therapy occurs. This mortality is poorly understood, and the contribution of immune reconstitution inflammatory syndrome to this mortality is unknown. Children after starting antiretroviral therapy may have paradoxical worsening of previously treated opportunistic infections. Due to the differences, however, in children's immunology with vertical HIV transmission, children are probably at greater risk of unmasking occult, subclinical infections during immune reconstitution.