immune reconstitution inflammatory syndrome

Background There is limited data on the epidemiology of Immune Reconstitution Inflammatory Syndrome (IRIS) in rural sub-Saharan Africa. A prospective observational cohort study was conducted to assess the incidence, clinical characteristics, outcome and ...

 Kaposi sarcoma (KS) incidence has decreased since combination antiretroviral therapy (cART). However, effects of cART type and duration on KS remain difficult to interpret secondary to KS-associated immune reconstitution inflammatory syndrome (IRIS).  We performed a retrospective study of Veterans Affairs Human Immunodeficiency Virus Clinical Case Registry data from 1985 to 2010. We analyzed the relationship between cART regimens and KS using multivariable Poisson regression, stratified or adjusted for timing around cART initiation. KS was identified by ≥1 inpatient or ≥2 outpatient International Classification of Diseases, Ninth Revision codes (176.0-9). Percent of cART on specific regimen and total duration on specific regimen were examined.  There were 341 KS cases among 25 529 HIV-infected male veterans (incidence rate = 2.02/1000 person-years). Stratified by years after starting cART, every additional 10% time on boosted protease inhibitors (BPIs) was associated with reduced K...

BACKGROUND: About 20–30% of persons with HIV infection, especially those living in countries with limited resources, experience an immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment. The active form of vitamin D, 1,25-dihydroxyvitamin D, is a key player in the clearance of pathogens and influences the level of inflammation and macrophage activation. PRESENTATION OF THE HYPOTHESIS: We hypothesize that

Our objectives were to describe trends in enrolment and clinical outcomes in the open, prospective Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) in the Morogoro region of southern Tanzania, and identify strengths and areas for improvement in the care of HIV-positive individuals in rural Tanzania. We included adults (≥15 years) and children (<15 years) enrolled in the cohort in 2005-2014. The cohort underwent significant changes from autumn 2012 to optimise care. We evaluated mortality and loss to follow-up (LTFU) using competing risks methods, ART usage, opportunistic infections (OI), co-infections and laboratory abnormalities. Overall, 7010 adults and 680 children were enrolled; enrolment peaked in 2008 but has increased steadily since 2011. Among adults (65% female; median age 37 [interquartile range 31-45] years), the proportion referred from hospital wards quadrupled in 2013-14 versus earlier years. 653 (9%) adults died and 2648 (38%) were LTFU; the five-year cumulati...

Cryptococcal meningitis remains a significant opportunistic infection among HIV-infected patients, contributing 15%-20% of HIV-related mortality. A complication of initiating Antiretroviral therapy (ART) following opportunistic infection is Immune Reconstitution Inflammatory Syndrome (IRIS). IRIS afflicts 10-30% of HIV-infected patients with cryptococcal meningitis (CM), but its immunopathogenesis is poorly understood. We compared circulating T cell memory subsets and cytokine responses among 17 HIV-infected Ugandans with CM: 11 with and 6 without CM-IRIS. At meningitis diagnosis, stimulation with cryptococcal capsule component, glucuronoxylomannan (GXM) elicited consistently lower frequencies of CD4+ and CD8+ T cell memory subsets expressing intracellular cytokines (IL-2, IFN-γ and IL-17) among subjects who subsequently developed CM-IRIS. After ART initiation, T cells evolved to show a decreased CD8+ central memory phenotype. At the onset of CM-IRIS, stimulation more frequent...

Pneumocystis is a respiratory fungal pathogen that causes pneumonia (PcP) in immunocompromised patients. Alveolar macrophages are critical effectors for CD4(+) T cell-dependent clearance of Pneumocystis, and prior studies found that alternative macrophage activation accelerates fungal clearance during PcP-related immune reconstitution inflammatory syndrome (IRIS). However, the requirement of either classically or alternatively activated macrophages for Pneumocystis clearance has not been determined. Therefore, RAG2(-/-) mice lacking either the IFNγ receptor or the IL-4 receptor α were infected with Pneumocystis. These mice were then immune reconstituted with wild type lymphocytes to preserve the normal T helper response while preventing downstream effects of Th1 or Th2 effector cytokines on macrophage polarization. As expected, RAG2(-/-) mice developed severe disease, but effectively cleared Pneumocystis and resolved IRIS. Neither RAG/IFNγR(-/-) nor RAG/IL-4Rα(-/-) mice displayed im...

Antiretroviral therapy (ART) has improved the survival of HIV patients but is also associated with unique manifestations of disease in some subjects during the initial months of therapy. Immune reconstitution inflammatory syndrome (IRIS) is a disorder among individuals starting ART, with no evidence-based treatment and management guidelines. We characterized HIV-1 and determined drug resistance among 14 Kenyan patients with suspected IRIS after ART initiation in 2005. Polymerase chain reaction, sequencing, and phylogenetic analysis of viral pol and env showed the following HIV-1 subtypes: A1/A1/A1 (pol-RT/gp41/C2V3), 5; A1/C/A1, 1; A1/D/A1, 2; D/A1/A1, 1; D/C/A1, 1; D/D/A1, 2; D/D/D, 1; and D/A1/A2, 1. Three patients had viruses with major drug resistance-associated mutations. These included nucleoside reverse transcriptase inhibitor (RTI) mutations: M41L, K65R, D67N, K70R, M184V, and K219Q, and nonnucleoside RTI mutations: K101P, L100I, K103N, and Y181C. Twelve patients harbored viruses that are predicted to use chemokine coreceptor 5 (CCR5) whereas two had variant viruses predicted to use the CXCR4 coreceptor. Drug resistance may not be the only cause of ART adverse events. HIV-1 characterization would be important before and during HIV therapy to avoid treatment failure.

Background: The incidence, manifestations, outcome and clinical predictors of paradoxical TB-IRIS in patients with HIV and culture confirmed pulmonary tuberculosis (PTB) in India have not been studied prospectively. Methods: HIV+ patients with culture confirmed PTB started on anti-tuberculosis therapy (ATT) were followed prospectively after anti-retroviral therapy (ART) initiation. Established criteria for IRIS diagnosis were used including decline in plasma HIV RNA at IRIS event. Pre-ART plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) were measured. Univariate and multivariate logistic regression models were used to evaluate associations between baseline variables and IRIS. Results: Of 57 patients enrolled, 48 had complete follow up data. Median ATT-ART interval was 28 days (interquartile range, IQR 14–47). IRIS events occurred in 26 patients (54.2%) at a median of 11 days (IQR: 7–16) after ART initiation. Corticosteroids were required for treatment of most IRIS ev...

Folliculitis, as a manifestation of immune reconstitution inflammatory syndrome (IRIS) during antiretroviral therapy, has only been described in its aseptic form. Here, we describe folliculitis associated with Malassezia spp. as a distinct manifestation of IRIS. The distinction between these two types of IRIS folliculitis is relevant for treatment.

BackgroundAfter the onset of HAART, some HIV-infected individuals under treatment present a exacerbated inflammation in response to a latent or a previously treated opportunistic pathogen termed immune reconstitution inflammatory syndrome (IRIS). Few reports of tegumentary leishmaniasis have been described in association with IRIS. Moreover, the immunopathogenesis of IRIS in association with Leishmania is unclear.Case presentationThe present study reports on a 29-year-old HIV-infected individual who developed mucocutaneous leishmaniasis associated with immune reconstitution inflammatory syndrome (IRIS) five months following highly active antiretroviral therapy (HAART). Severe lesions resulted in the partial destruction of the nasal septum, with improvement observed 15 days after treatment with Amphotericin B and corticosteroids. The immune response of this patient was evaluated before and after the lesions healed. IRIS was diagnosed in association with high levels of TNF-¿ and IL-6....

Immune Reconstitution Inflammatory Syndromes (IRIS) are exaggerated pathological inflammatory reactions occurring after initiation of highly active antiretroviral therapy (HAART) due to exuberant immune responses to occult or apparent opportunistic ...

The simultaneous presence of infectious organisms within cutaneous lesions of Kaposi sarcoma in persons with AIDS has been demonstrated. We describe a patient with concurrent leprosy and Kaposi sarcoma presenting as an immune reconstitution ...

Non-HIV immunocompromised patients may develop immune reconstitution inflammatory syndrome (IRIS) as an abnormal response to invading microorganisms, such as Mycobacterium tuberculosis (MTB). IRIS consists in a sudden change in the dominant T-helper responses to inflammation, which is not balanced by anti-inflammatory response, playing a critical role in microbial pathogenesis. A patient with restoration of host immunity during anti-tuberculosis treatment can become gravely ill with a paradoxical severe form of tuberculosis (TB) disease named TB immune reconstitution disease (IRD).The diagnosis of acute cryptic miliary TB is difficult and requires an accurate histopathology. We report a fatal association between a generalized lymphadenitis tuberculosis and IRD in a 34-year-old male patient, non-smoker, non-HIV immunocompromised, but with a previously co-morbid diabetes mellitus (DM) type I. The purpose of this report is to describe an unusual and rare case of a progressive extrapulm...

Non-HIV immunocompromised patients may develop immune reconstitution inflammatory syndrome (IRIS) as an abnormal response to invading microorganisms, such as Mycobacterium tuberculosis (MTB). IRIS consists in a sudden change in the dominant T-helper responses to inflammation, which is not balanced by anti-inflammatory response, playing a critical role in microbial pathogenesis. A patient with restoration of host immunity during anti-tuberculosis treatment can become gravely ill with a paradoxical severe form of tuberculosis (TB) disease named TB immune reconstitution disease (IRD).The diagnosis of acute cryptic miliary TB is difficult and requires an accurate histopathology. We report a fatal association between a generalized lymphadenitis tuberculosis and IRD in a 34-year-old male patient, non-smoker, non-HIV immunocompromised, but with a previously co-morbid diabetes mellitus (DM) type I. The purpose of this report is to describe an unusual and rare case of a progressive extrapulm...

Fixed dose combination abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) among HIV-1 and tuberculosis (TB)-coinfected patients was evaluated and outcomes between early vs. delayed initiation were compared. In a randomized, pilot study conducted in the Kilimanjaro Region of Tanzania, HIV-infected inpatients with smear-positive TB and total lymphocyte count <1200/mm3 were randomized to initiate ABC/3TC/ZDV either 2 (early) or 8 (delayed) weeks after commencing antituberculosis therapy and were followed for 104 weeks. Of 94 patients screened, 70 enrolled (41% female, median CD4 count 103 cells/mm3), and 33 in each group completed 104 weeks. Two deaths and 12 serious adverse events (SAEs) were observed in the early arm vs. one death, one clinical failure, and seven SAEs in the delayed arm (p = 0.6012 for time to first grade 3/4 event, SAE, or death). CD4 cell increases were +331 and +328 cells/mm3, respectively. TB-immune reconstitution inflammatory syndromes (TB-IRIS) were not observed in any subject. Using intent-to-treat (ITT), missing = failure analyses, 74% (26/35) vs. 89% (31/35) randomized to early vs. delayed therapy had HIV RNA levels <400 copies/ml at 104 weeks (p = 0.2182) and 66% (23/35) vs. 74% (26/35), respectively, had HIV RNA levels <50 copies/ml (p = 0.6026). In an analysis in which switches from ABC/3TC/ZDV = failure, those receiving early therapy were less likely to be suppressed to <400 copies/ml [60% (21/35) vs. 86% (30/35), p = 0.030]. TB-IRIS was not observed among the 70 coinfected subjects beginning antiretroviral treatment. ABC/3TC/ZDV was well tolerated and resulted in steady immunologic improvement. Rates of virologic suppression were similar between early and delayed treatment strategies with triple nucleoside regimens when substitutions were allowed.

OBJECTIVE: To immunophenotype CD4+ and CD8+ T cell sub-populations in HIV-associated immune reconstitution inflammatory syndrome (IRIS). DESIGN: Nested case-control immunological study. METHODS: ART-naïve HIV-infected patients were prospectively observed for IRIS during the first 6 months of ART. Twenty-two IRIS cases and 22 ART-duration matched controls were sampled for T cell immunophenotyping. RESULTS: IRIS cases demonstrated significantly lower CD4 cell counts

HIV-associated tuberculosis can present as extremes, ranging from acute life-threatening disseminated disease to occult asymptomatic infection. Both ends of this spectrum have distinct pathological correlates and require specific diagnostic and treatment approaches. Novel therapeutics, targeting both pathogen and host, are needed to augment pathogen clearance. In latent tuberculosis infection, enhancement of immune activation could be desirable. Antiretroviral therapy augments the beneficial effects of antitubercular therapy. However, in the context of high bacillary burden, antiretroviral therapy can also result in pathology (tuberculosis immune reconstitution inflammatory syndrome). In the immune reconstituting patient, modulation of immune activation controls tissue destruction. Interventions should also be appropriate and sustainable within the programmatic setting.

Abscess formation in the thyroid gland is particularly a rare phenomenon and presents a medical and surgical dilemma especially in HIV seropositive patients. The authors report a case of a paradoxical tuberculous abscess immune reconstitution inflammatory syndrome involving the thyroid gland in a 37-year-old woman who presented 12 weeks after initiation of antiretroviral therapy at the Infectious Diseases Institute, Kampala, Uganda. The patient is still undergoing treatment.

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) frequently complicates combined antiretroviral therapy and antituberculosis therapy in HIV-1-coinfected tuberculosis patients. The immunopathological mechanisms underlying TB-IRIS are incompletely defined, and improved understanding is required to derive new treatments and to reduce associated morbidity and mortality. We performed longitudinal and cross-sectional analyses of human PBMCs from paradoxical TB-IRIS patients and non-IRIS controls (HIV-TB-coinfected patients commencing antiretroviral therapy who did not develop TB-IRIS). Freshly isolated PBMC stimulated with heat-killed Mycobacterium tuberculosis H37Rv (hkH37Rv) were used for IFN-γ ELISPOT and RNA extraction. Stored RNA was used for microarray and RT-PCR, whereas corresponding stored culture supernatants were used for ELISA. Stored PBMC were used for perforin and granzyme B ELISPOT and flow cytometry. There were significantly increased IFN-γ res...

Skin manifestations of immune reconstitution inflammatory syndrome in response to highly active antiretroviral therapy may account for up to 50% of the clinical presentations in this syndrome. Viable or dying infective antigens, host antigens, tumoral antigens, and others may target immune reconstitution inflammatory syndrome, resulting in a wide spectrum of clinical manifestations. We describe a 26-year-old HIV-infected man who had started highly active antiretroviral therapy a few months earlier. He developed multiple linear nodules following the superficial veins in both legs. Histopathologic examination demonstrated a mostly septal panniculitis with features of superficial thrombophlebitis. We propose that superficial thrombophlebitis should be added to the list of clinical manifestations of this newly observed immune restoration disease.

Objectives A proportion of HIV patients beginning antiretroviral therapy (ART) develop immune restoration disease (IRD). Immunological characteristics of IRD were investigated in a cohort of HIV patients beginning therapy in Kuala Lumpur, Malaysia. Methods Peripheral blood mononuclear cells were collected at weeks 0, 6, 12, 24 and 48 of ART from five patients experiencing IRD [two with cryptococcal and three with Mycobacterium tuberculosis (Mtb) disease], eight non-IRD controls who had begun ART with CD4 T-cell counts of &lt; 100 cells/mu L and 17 healthy controls. Leukocytes producing interferon-gamma (IFN gamma) were quantified by enzyme-linked immunospot assay after stimulation with purified protein derivative (PPD), early secretory antigenic target-6 (ESAT-6), Cryptococcus neoformans or Cytomegalovirus antigens. Plasma immunoglobulin (IgG) antibodies reactive with these antigens were assessed by enzyme-linked immunosorbent assay. Proportions of activated (HLA-DRhi) and regulator...

Background &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp; Objective. IRIS is an important complication that occurs during management of HIV-TB coinfection and it poses difficulty in diagnosis. Previous studies have reported variable incidence of IRIS. The present study was undertaken to describe the pattern of TB-associated IRIS using recently proposed consensus case-definitions for TB-IRIS for its use in resource-limited settings.Methods. A prospective analysis of ART-naïve adults started on HAART from November, 2008 to May, 2010 was done in a tertiary care hospital in north India. A total 224 patients divided into two groups, one with HIV-TB and the other with HIV alone, were followedup for a minimum period of 3 months. The diagnosis of TB was categorised as ‘‘definitive’’ and ‘‘probable’’.Results. Out of a total of 224 patients, 203 completed followup. Paradoxical TB-IRIS occurred in 5 of 123 (4%) HIV-TB patients while 6 of 80 (7.5%) HIV patients developed ART-associated TB. A reduction in plasma viral load was significantly (P=.016) associated with paradoxical TB-IRIS. No identifiable risk factors were associated with the development of ART-associated TB.Conclusion. The consensus case-definitions are useful tools in the diagnosis of TB-associated IRIS. High index of clinical suspicion is required for an early diagnosis.

To investigate HIV, its treatment, and hypertension as stroke risk factors in Malawian adults. We performed a case-control study of 222 adults with acute stroke, confirmed by MRI in 86%, and 503 population controls, frequency-matched for age, sex, and place of residence, using Global Positioning System for random selection. Multivariate logistic regression models were used for case-control comparisons. HIV infection (population attributable fraction [PAF] 15%) and hypertension (PAF 46%) were strongly linked to stroke. HIV was the predominant risk factor for young stroke (≤45 years), with a prevalence of 67% and an adjusted odds ratio (aOR) (95% confidence interval) of 5.57 (2.43-12.8) (PAF 42%). There was an increased risk of a stroke in patients with untreated HIV infection (aOR 4.48 [2.44-8.24], p &lt; 0.001), but the highest risk was in the first 6 months after starting antiretroviral therapy (ART) (aOR 15.6 [4.21-46.6], p &lt; 0.001); this group had a lower median CD4(+) T-lymph...