Immune Reconstitution Disease Research Articles

Difficulty in diagnosing intracranial infection caused by Mycobacterium avium in an AIDS patient: case report and review of the literature

BackgroundMycobacterium avium complex (MAC) is an uncommon clinical pathogen, especially in the central nervous system (CNS), and carries a poor prognosis. MAC infections commonly present as immune reconstitution disease (IRD) in HIV patients. Herein, we report a case of intracranial infection caused by MAC in an AIDS patient without disseminated MAC (DMAC) and immune reconstitution inflammatory syndrome (IRIS).Case presentationA 31-year-old HIV-positive male presented us with progressively worsening CNS symptoms, and neuroimaging revealed ring-enhancing lesions. The intracranial lesions worsened after the empirical therapy for toxoplasma encephalitis and fungal infection. Due to the rapid progression of the disease, the patient died. Mycobacterium avium was the only pathogen in brain tissue after cultures and molecular biology tests.ConclusionMAC infection in CNS is challenging to diagnose in HIV patients. Our findings emphasize that obtaining tissue samples and applying molecular biology methods is essential to help diagnose the patient as soon as possible to receive adequate treatment.

Comparison of and Immune Reconstitution and Graft Versus Host Disease in 30mg/Kg Anti-T-Lymphocyte Globuline with 60mg/Kg ATLG As Graft Versus Host Disease Prophylaxis in Matched Unrelated Donor Myeloablative Peripheral Blood Stem Cell Transplantation

Introduction:Data on the influence of different ATLG doses on immune reconstitution (IR) and GvHD in MUD allo-SCT is limited. In this study, we compared the impact of ATLG doses (30mg/kg vs 60 mg/kg) on IR and transplant outcomes.Methods:In this retrospective study we included 289 patients who received MUD allografts (HLA 10/10) between 2005-2019 in the University Cance Center University of Hamburg. All patients received PBSC-allo-SCT with MAC for various hematological malignancies. Seventy-three patients received 30mg/kg ATLG, and 216 patients received 60mg/kg (on days -3.-2 and -1) prior to allo-SCT. Periphereal blood samples were collected on days +30, +100 and +180 and analyzed by flow cytometry for following lymphocyte populations: T-cells (total and activated), T-helper cells (total, naïve and memory), cytotoxic T-cells (total, naïve and memory), B-Lymphocytes (total, naïve and memory), NK-cells, NKT-cells, γδT-cells and regulatory T-cells.Results:Neutrophil and platelet engraftments were significantly delayed after the 60mg/kg compared to 30mg/kg group with medians of 11 days (range, 8-23) vs 12 days (8-27) (p=0.009) for neutrophil and 14 days (range, 9-53) vs 16 days (range, 8-237) for platelets, respectively (p=0.002). We observed a higher incidence of EBV reactivation within the first 100 days in the 60mg/kg group (41% vs 21% in the 30mg/kg group, p=0.049).Higher cumulative incidence of Infections Day +100 was observed in the 60 mg/Kg group with an incidence of 75% vs that of 67% in the 30mg/Kg group respectively (p=0.002). At day +30 we observed a faster reconstitution of naïve-B cells (p<0.0001) and γδ T cells (p=0.045) in the 30mg/kg group. No significant differences in IR were observed at day +100. At day +180 the use of 30mg/Kg was associated with a faster naïve helper T-cell (p=0.046), NK-cells (p=0.035), and naïve B-cell reconstitution (p=0.009).The incidence of aGVHD grade II-IV was comparable between the groups: 63% and 59% in the 30mg/Kg and 60mg/Kg groups, respectively. We observed a higher incidence of grade IV aGvHD in the 30mg/kg group (8%) comparing with the rate of 0.5% in the 60mg/kg group (p=0.0002), this was confirmed in multivariate analysis: RR 0.65 (95%CI 0.005-0.363) p= 0.004.After a median follow up of 21 months (range, 1-161) there were no significant differences in OS, PFS, NRM, RI and cGVHD between the groups.Conclusion:The choice of ATLG dose has significant impact on IR after MUD-allo-SCT. Higher doses are associated with reduced severe aGVHD, however at the cost of delaying engraftment and increasing infections. DisclosuresAyuk: Celgene/BMS: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Miltenyi Biomedicine: Honoraria; Novartis: Honoraria; Takeda: Honoraria.

Differences in Allogeneic Product T-Cell Subsets According to Donor Age: Associations with Immune Reconstitution and Acute Graft Versus Host Disease (aGVHD) in Haploidentical (HI) Hematopoietic Stem Cell Transplantation (HSCT)

▪Numerous analyses have linked increasing donor age with poor outcomes after HSCT. The consequences of using an older donor vary by study with increased relapse, GVHD, non-relapse mortality, decreased overall survival (OS), or a combination of these findings associated with older donors. The age at which donors impact outcomes also varies by analysis with an identified optimal range anywhere from < 30 to < 60 years. Biological age is likely more important than chronological age, affecting allogeneic graft dose and composition at different rates in different donors. Older donors have been found to produce grafts with a higher content of CD3/4 T cells compared to their young counterparts-a possible explanation for differences in HSCT outcomes based on donor age. The goals of this analysis were to 1) assess quantitative differences in donor T cell subsets based on age, 2) identify a transitional donor age range for these differences, and 3) perform a preliminary assessment of the relationship between T cell subsets in the donor graft and early immune reconstitution and the development of aGVHD. Information generated from this analysis would help inform donor selection and serve as the basis for future multivariate analyses testing the effects of donor age on HI HSCT outcomes.Patients underwent HI HSCT using the Jefferson 2 step approach in which after myeloablative (MA-12 Gy TBI) or reduced intensity (RIC-fludarabine-based chemotherapy + 2 Gy TBI) patients receive an unmanipulated donor lymphocyte product (DLI) at a fixed dose of 2 x 108/kg CD3 cells. Cyclophosphamide is given 2-3 days after the DLI for tolerization, followed 2 days later by a CD34 selected product. Because donors provide the DLI product prior to CD34 cell mobilization, the approach provides a unique opportunity to study donor T cell subsets without the influence of growth factor and at identical T cell doses. Bivariate correlation was performed to assess the relationship between age and graft composition. A box plot was used to express the CD3/4 to CD3/8 ratios in the DLI products according to donor age ranges in approximately 10 year increments. Independent samples T Test was used to measure the impact of both graft T cell content and donor age on the incidence of grades 2-4 aGVHD. OS by donor age was tested using Kaplan Meier analysis.179 consecutive HI HSCT donors and recipients, median ages 41 (range 18-68) and 53 (range 19-77) years, respectively, were analyzed. For inclusion, recipients had to be alive and engrafted at day+28. 57% and 43% recipients underwent MA vs RIC HSCT, respectively. There was a positive correlation between donor age and CD3/4 cells/ml/kg (R= .441, p=0.001), a negative correlation between donor age and CD3/8 cells/ml/kg (R= -.331, p=0.001), and a positive correlation between donor age and CD3/4 to CD3/8 ratio (R= .397, p= 0.001). Higher CD3/4 to CD3/8 ratios were associated with donors >46 year old (Figure). In a subset of 130 patients steroid naive at the time of initial immune reconstitution studies at d+28, there was a positive correlation between CD3/4 to CD3/8 ratio in the DLI and recipient CD3/4 count (R= .832. p=0.001) and a negative correlation with recipient CD3/8 count (R= -.875, p= 0.001). In the whole group, older donor age was associated with a higher incidence of grades 2-4 aGVHD (p=0.016), while a higher mean CD3/4 to CD3/8 cell ratio in the DLI product was associated with a higher incidence of grades 2-4 aGVHD, significant in MA recipients only (p=0.044). Neither donor age nor CD3/4 to CD3/8 ratio were significantly associated with OS.In this analysis, older donors produced allogeneic grafts that were higher in CD3/4 and lower in CD3/8 cells than their younger counterparts. This difference was reflected in recipient CD3/4 and CD3/8 counts at d+28. The transition to a higher CD3/4 to CD3/8 ratio began in a donor age range of 46-55 years. Older donor age and CD3/4 to CD3/8 ratio in the DLI product was associated with a greater frequency of grades 2-4 aGVHD but did not significantly affect OS. The results support further studies of the role of age-dependent differences in the T-cell composition of donor grafts in determining HI HSCT outcomes. If confirmed, the results suggest that graft composition, not age, may be a superior method of donor selection. Because the DLI is infused separately from CD34 cells in the 2 step approach, it may be possible to optimize the CD3/4 to CD3/8 ratio in the products of older donors with partial CD3/4 depletion. [Display omitted] DisclosuresWagner:Novartis: Research Funding.

Characteristics of Graves Disease in HIV-Infected Patients on Antiretroviral Therapy

Objective: To demonstrate clinical and laboratory characteristics of Graves disease in human immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART). Methods: This is a single-institution study. All HIV-infected Thai patients who were diagnosed with Graves disease following the initiation of ART between January, 2007, and June, 2018, were retrospectively enrolled. Results: Of the 24 subjects, the mean age was 39.6 ± 10 years at the time of Graves disease diagnosis. The male to female ratio was 1:1.2. Palpitation and weight loss were the most common clinical manifestations. Of the 6 patients (25%) with evidence of Graves orbitopathy, 1 had sight-threatening orbitopathy. Two patients also had other autoimmune diseases (vitiligo and psoriatic arthritis). The median CD4 cell counts at HIV and Graves disease diagnosis were 73.5 (interquartile range [IQR], 15.5 to 189.5) and 525 (IQR, 402.3 to 725) cells/μL, respectively. The median time from ART commencement of the last effective ART regimen to the development of Graves disease was 29.5 (IQR, 13.8 to 48) months with a mean CD4 cell count increment of 328.7 ± 174.9 cells/μL. The median duration of antithyroid therapy was 34.5 (IQR, 23.8 to 51.0) months. Thirteen patients (54.2%) received radioactive iodine ablation. Conclusion: Graves disease should be suspected in HIV-infected patients who present with palpitations and weight loss despite good immunologic response to ART. Awareness of this condition can lead to diagnosis and appropriate management. Unlike immune reconstitution disease associated with infection, Graves disease may develop many years after ART initiation. Abbreviations: AIDS = acquired immunodeficiency syndrome; ART = antiretroviral therapy; HIV = human immunodeficiency virus; IQR = interquartile range; IRD = immune restoration disease; T3 = triiodothyronine; T4 = thyroxine; TgAb = thyroglobulin antibody; TPOAb = thyroid peroxidase antibody; TRAb = thyrotropin receptor antibody; TSH = thyroid-stimulating hormone.

Longitudinal Changes in the Intestinal Microbiome Composition Following Gut Decontamination in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Patients: A Pilot Study

Introduction: Early preclinical studies demonstrating that eradication of intestinal bacteria could prevent the development of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) led many adult and pediatric HSCT programs to practice "gut decontamination" (GD) with non-absorbable oral antibiotics for aGVHD prophylaxis. However, there is insufficient data supporting a clear benefit for GD in HSCT patients. Recent adult HSCT studies show that GVHD-related mortality is associated with decreased bacterial diversity in the gut microbiome, suggesting that certain bacterial species are protective against aGVHD. GD may decrease microbiome diversity and lead to worse post-HSCT outcomes. Methods: We conducted a randomized phase 2 study to examine the impact of GD on intestinal microbiome composition in pediatric allogeneic HSCT patients. 20 patients were enrolled and randomized to receive (GD) or not receive (no GD) oral vancomycin-polymyxin per our institutional standard from day -5 through engraftment. Stool samples were collected pre-transplant, weekly until neutrophil engraftment, monthly through day +100, then at 6 months and 1-year post-HSCT. Our primary endpoint is bacterial diversity, quantified by Shannon diversity index, at 2 weeks post-HSCT. Change in diversity is defined as the delta of diversity before transplantation compared to the minimum diversity seen in a single patient in a one-week window (around 14 days post-transplantation). This change in diversity was then averaged (mean) across each treatment arm. The stool microbiome was characterized using shotgun metagenomic sequencing (Nextera Tagmentation and Illumina HiSeq4000 Sequencing) for 10 patients to date, with median count of 1.4x107 reads per sample (range 1.3x106 to 3.3x107). Following quality control (FastQC, Trim Galore, Super Deduper), reads are assigned taxonomic designations using Kraken2 and GenBank (Oct. 2018) database. Secondary endpoints include the frequency of diarrhea (defined as &gt;3 bowel movements per day in the first 7 days post-HSCT), incidence of aGVHD and bacteremia during the first 100 days post-transplant, immune reconstitution, survival, and malignant disease relapse at 2 years after study entry. Comparisons by treatment group were performed with Fisher's exact test (binary) or Wilcoxon rank-sum test (continuous). Results: Baseline patient characteristics were similar between the two arms (Table 1). At present,5 patients (25%) have completed 2 years of follow up, 4 of 15 patients with malignant disease (27%) have had relapse (3 GD, 1 No GD), and 2 patients (10%) in the No GD arm have died (1 malignant relapse, 1 refractory chronic GVHD). Microbiome analysis in the first 10 patients (4 GD, 6 No GD) demonstrates that the average change in Shannon diversity score at 2 weeks is 1.7 (SD 0.86) in GD and 0.65 (SD 0.61) in No GD (Table 2). Diarrhea occurred in 4/10 patients in GD vs 4/10 patients in no GD (p≥0.99).1/10 patients in GD and 3/10 in No GD developed aGVHD grade II or above(p=0.58). Bacteremia within the first 100 days post-HSCT occurred in 1/10 patient in GD, whereas 5/10 patients in No GD had 8 different bacteremia events (p=0.14) (Table 3). Conclusions: This is the first randomized study of gut decontamination in pediatric patients undergoing HSCT with long-term prospective post-transplant stool sample collection and immune monitoring. Though the small sample size is currently not powered to detect differences in clinical outcomes between the 2 study arms, the descriptive microbiome and immune reconstitution data will inform larger studies. There is no statistical difference in the diarrhea, aGVHD, or bacteremia incidence between the two groups but it is interesting that there was 1 vs 8 bacteremia events in GD vs No GD. Microbiota diversity results from our pilot study with 10 patients indicate a trend toward lower diversity at 2 weeks post-transplant in the GD arm. Microbiome analysis of the remaining samples from the remaining 10 patients is underway as well as longitudinal analysis of samples from all patients. Describing the changes to the microbiota composition over time in two groups will provide insight to practice of GD, potential targets for aGVHD, and will provide preliminary data to understand which microbes and microbial gene-pathways may influence immune reconstitution. Disclosures London: United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Ritz:Draper Labs: Consultancy; Kite Pharma: Research Funding; Avrobio: Consultancy; LifeVault Bio: Consultancy; Merck: Research Funding; TScan Therapeutics: Consultancy; Talaris Therapeutics: Consultancy; Celgene: Consultancy; Aleta Biotherapeutics: Consultancy; Equillium: Research Funding. Bhatt:ArcBio: Other: Scientific Advisory Board; January.ai: Other: Scientific Advisory Board; Caribou Bioscience: Other: Scientific Advisory Board; Kaleido Biosciences: Consultancy, Other: Paid Consultant; Janssen Human Microbiome Institute: Consultancy, Other: Paid Consultant; Illumina: Honoraria; 10x Genomics: Other: Research collaboration without funding support; Illumina: Other: Research collaboration without funding support; Agilent: Research Funding; Global Oncology, Inc: Other: Nonprofit Board.

Lepromatous Leprosy and Human Immunodeficiency Virus: A Rare Co-infection

We report a 23-year-old male with lepromatous leprosy atypically presenting with 5-year history of asymptomatic, verrucous papules, and nodules. Human Immunodeficiency Virus (HIV) testing was positive with depressed CD4 count. In HIV/leprosy co-infection, most of the documented patients were diagnosed with paucibacillary leprosy as immune reconstitution disease (IRD) from treatment-induced immunological recovery. Rarely, multibacillary lepromatous leprosy is encountered in the setting of untreated, severe immunodeficiency. Atypical clinical presentation warrants investigation for concurrent HIV infection.

Improving survival with tuberculosis & HIV treatment integration: A mini-review.

Tuberculosis (TB) is a leading cause of morbidity and mortality among HIV-infected patients while HIV remains a key risk factor for the development of active TB infection. Treatment integration is a key in reducing mortality in patients with HIV-TB co-infection. However, this opportunity to improve outcomes of both infections is often missed or poorly implemented. Challenges in TB-HIV treatment integration range from complexities involving clinical management of co-infected patients to obstacles in health service-organization and prioritization. This is evident in high prevalence settings such as in sub-Saharan Africa where TB-HIV co-infection rates reach up to 80 per cent. This review discusses published literature on clinical trials and cohort studies of strategies for TB-HIV treatment integration aimed at reducing co-infection mortality. Studies published since 2009, when several treatment guidelines recommended treatment integration, were included. A total of 43 articles were identified, of which a total of 23 observational studies and nine clinical trials were informative on TB-HIV treatment integration. The data show that the survival benefit of AIDS therapy in patients infected with TB can be maximized among patients with advanced immunosuppression by starting antiretroviral therapy (ART) soon after TB treatment initiation, i.e. in patients with CD4+ cell counts <50 cells/μl. However, patients with greater CD4+ cell counts should defer initiation of ART to no less than eight weeks after initiation of TB treatment to reduce the occurrence and extent of immune reconstitution disease and subsequent hospitalization. Addressing operational challenges in integrating TB-HIV care can significantly improve patient outcomes, generate substantial public health impact by decreasing morbidity and death in settings with a high burden of HIV and TB.

Novel Findings in HIV, Immune Reconstitution Disease and Strongyloides stercoralis Infection

We report the successful treatment of an HIV-infected patient with progressive strongyloidiasis as a component of immune reconstitution disease and a review of the literature on this topic. In our experience, pre- and post-antiretroviral therapy intestinal biopsies support a novel mechanism of immune reconstitution disease to Strongyloides stercoralis. We conclude that extended, dual antihelminthic therapy and temporary discontinuation of antiretroviral therapy may be effective in similar patients.

PKDL and Other Dermal Lesions in HIV Co-infected Patients with Leishmaniasis: Review of Clinical Presentation in Relation to Immune Responses

BackgroundCo-infection of leishmaniasis and HIV is increasingly reported. The clinical presentation of leishmaniasis is determined by the host immune response to the parasite; as a consequence, this presentation will be influenced by HIV-induced immunosuppression. As leishmaniasis commonly affects the skin, increasing immunosuppression changes the clinical presentation, such as in post-kala-azar dermal leishmaniasis (PKDL) and cutaneous leishmaniasis (CL); dermal lesions are also commonly reported in visceral leishmaniasis (VL) and HIV co-infection.MethodsWe reviewed the literature with regard to dermal manifestations in leishmaniasis and HIV co-infection, in three clinical syndromes, according to the primary presentation: PKDL, VL, or CL.ResultsA wide variety of descriptions of dermal leishmaniasis in HIV co-infection has been reported. Lesions are commonly described as florid, symmetrical, non-ulcerating, nodular lesions with atypical distribution and numerous parasites. Pre-existing, unrelated dermal lesions may become parasitized. Parasites lose their tropism and no longer exclusively cause VL or CL. PKDL in HIV co-infected patients is more common and more severe and is not restricted to Leishmania donovani. In VL, dermal lesions occur in up to 18% of patients and may present as (severe) localized cutaneous leishmaniasis, disseminated cutaneous leishmaniasis (DL) or diffuse cutaneous leishmaniasis (DCL); there may be an overlap with para-kala-azar dermal leishmaniasis. In CL, dissemination in the skin may occur resembling DL or DCL; subsequent spread to the viscera may follow. Mucosal lesions are commonly found in VL or CL and HIV co-infection. Classical mucocutaneous leishmaniasis is more severe. Immune reconstitution disease (IRD) is uncommon in HIV co-infected patients with leishmaniasis on antiretroviral treatment (ART).ConclusionWith increasing immunosuppression, the clinical syndromes of CL, VL, and PKDL become more severe and may overlap. These syndromes may be best described as VL with disseminated cutaneous lesions (before, during, or after VL) and disseminated cutaneous leishmaniasis with or without visceralization.

Improved outcomes from HIV/TB co-infection in Singapore following a switch to earlier anti-retroviral therapy.

IntroductionRecent clinical trials have provided clear evidence to support early anti-retroviral therapy (ART) in patients with HIV/TB co-infection and low CD4 counts. We investigated how this has changed treatment and outcomes in Singapore.Materials and MethodsA retrospective review was performed with inpatient and outpatient records for all subjects diagnosed with HIV/TB co-infection from 2006 to 2011 attending the Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore. Data for subjects with a presenting CD4<200 cell/mm3 were extracted and split into two groups, “Delayed”: ART more than 8/52 after starting TB treatment, and “Early”: ART within 8/52 of starting TB treatment.ResultsOne hundred thirty-four out of 180 subjects in the database met the inclusion criteria for this study, 89 in the delayed group and 45 in the early. No statistically significant differences in baseline demographics between the two groups were identified. Both groups presented with markedly low CD4 counts, with overall 60% <50cells/mm3. Median CD4 counts were lower in the delayed ART group (37 vs 50, p=0.015). Prevalence of other opportunistic infections at TB diagnosis was not significantly different (20%), but TB in the early ART group was more likely to include extra-pulmonary disease (46% vs 57%, p=0.038). Four cases were culture negative, 2 multi-drug resistant and 10 (7.8%) were isoniazid mono-resistant. There was a significant trend to earlier ART with more recent TB diagnosis (p<0.001). In the first 365 days after TB diagnosis, 11 deaths occurred in the delayed ART group, and 0 in the early (p=0.033). A Kaplan-Meier time-to-event analysis demonstrated a clear separation in the frequency of death or opportunistic infections at eight weeks (Figure 1, p<0.001). Immune reconstitution disease was significantly more likely in the early ART group, but did not result in death (9% vs 38%, p<0.001). Treatment interruptions due to adverse drug events (ADE) developed in a median of 25 days (IQR 15–43). Interestingly, early ART was associated with a significantly lower number of treatment interruptions attributed to ADEs, with a higher proportion of patients completing two months of pyrazinamide induction (66% vs 85%, p=0.054) and rifampicin consolidation (79% vs 95%, p=0.03) – after excluding resistance or death. A trend to longer duration TB treatment was observed with delayed ART.ConclusionsSignificant improvements in HIV/TB infection outcomes correlate with the switch to earlier ART.

Graves’ disease as immune reconstitution disease in HIV-positive patients is associated with naive and primary thymic emigrant CD4+ T-cell recovery

Immune restoration disease (IRD) can develop in HIV-infected patients following antiretroviral therapy (ART) initiation as unmasking or paradoxical worsening of opportunistic infections and, rarely, autoimmune phenomena. Although IRD usually occurs in the first months of ART during memory CD4 T-cell recovery, Graves' disease occurs as a distinctive late-onset IRD and its pathogenesis is unclear. Seven patients who developed Graves' disease following ART initiation from the primary HIV care clinic at the National Institutes of Health were retrospectively identified and each was matched with two HIV-infected controls based on age, sex, and baseline CD4 T-cell count. Laboratory evaluations on stored cryopreserved samples were performed. Immunophenotyping of peripheral blood mononuclear cells (PBMCs), T-cell receptor excision circle (TREC) analysis in PBMCs, measurement of serum cytokines, and luciferase immunoprecipitation systems (LIPS) analysis for autoimmune antibodies were performed on stored samples for cases and controls at baseline and longitudinally following ART initiation. TSH/thyrotropin receptor (TSH-R) antibody testing was performed on serum from cases. Data were analyzed using nonparametric testing. In comparison with controls, the proportion of naive CD4 T cells increased significantly (P = 0.0027) in the Graves' disease-IRD patients. TREC/10 PBMCs also increased significantly following ART in Graves' disease-IRD patients compared with controls (P = 0.0071). Similarly, LIPS analysis demonstrated increases in nonthyroid-related autoantibody titers over time following ART in cases compared with controls. Our data suggest that Graves' disease-IRD, in contrast to early-onset IRD, is associated with naive and primary thymic emigrant CD4 T-cell recovery and inappropriate autoantibody production.

T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection

BackgroundHighly active antiretroviral therapy (HAART) restores inflammatory immune responses in AIDS patients which may unmask previous subclinical infections or paradoxically exacerbate symptoms of opportunistic infections. In resource-poor settings, 25% of patients receiving HAART may develop CNS-related immune reconstitution inflammatory syndrome (IRIS). Here we describe a reliable mouse model to study underlying immunopathological mechanisms of CNS-IRIS.MethodsUtilizing our HSV brain infection model and mice with MAIDS, we investigated the effect of immune reconstitution on MAIDS mice harboring opportunistic viral brain infection. Using multi-color flow cytometry, we quantitatively measured the cellular infiltrate and microglial activation.ResultsInfection with the LP-BM5 retroviral mixture was found to confer susceptibility to herpes simplex virus (HSV)-1 brain infection to normally-resistant C57BL/6 mice. Increased susceptibility to brain infection was due to severe immunodeficiency at 8 wks p.i. and a marked increase in programmed death-1 (PD-1) expression on CD4+ and CD8+ T-cells. Both T-cell loss and opportunistic brain infection were associated with high level PD-1 expression because PD-1-knockout mice infected with LP-BM5 did not exhibit lymphopenia and retained resistance to HSV-1. In addition, HSV-infection of MAIDS mice stimulated peripheral immune cell infiltration into the brain and its ensuing microglial activation. Interestingly, while opportunistic herpes virus brain infection of C57BL/6 MAIDS mice was not itself lethal, when T-cell immunity was reconstituted through adoptive transfer of virus-specific CD3+ T-cells, it resulted in significant mortality among recipients. This immune reconstitution-induced mortality was associated with exacerbated neuroinflammation, as determined by MHC class II expression on resident microglia and elevated levels of Th1 cytokines in the brain.ConclusionsTaken together, these results indicate development of an immune reconstitution disease within the central nervous system (CNS-IRD). Experimental immune reconstitution disease of the CNS using T-cell repopulation of lymphopenic murine hosts harboring opportunistic brain infections may help elucidate neuroimmunoregulatory networks that produce CNS-IRIS in patients initiating HAART.

Effect of nutritional factors on adherence to antiretroviral therapy among HIV-infected adults: a case control study in Northern Ethiopia

BackgroundAdherence to antiretroviral treatment is critical for suppression of viral replication, reduced destruction of CD4 cells, prevention of viral resistance, promotion of immune reconstitution and slowed disease progression. This study sought to determine the effect of nutritional factors on adherence to ART among HIV-infected adults on ART.MethodsMatched case control study design (matched by age and sex) was employed. Data was collected from ART registration chart, pre-tested structured data extraction format, anthropometric measurements and by interview. Conditional logistic regression was used to compute the relevant associations among the variables by STATA version 10.ResultsFrom 174 paired subjects participated in the study 80 (46%) pair were males and 94 (54%) pair were females on ART for at least one year prior to the survey. The mean age (±SD) for the non-adherent was 38.4 ± 8.1years and for the adherent subjects was 38.5 ± 8.4 years. Malnutrition with BMI less than 18.5 Kg/m2 in the adherent group was 14 (8%) and that of the non-adherent group was 74 (42.5%) which was associated with non-adherence to ART (AOR 10.0, 95%CI 4.3 – 54.7). Inability to get enough and quality food was also associated with non-adherence to ART (AOR 2.1, 95%CI 1.1 – 11.5).ConclusionsMalnutrition, inability to get enough and/or quality food and consumption pattern which is less than three meals per day were significantly associated with non-adherence to ART. Therefore, the capacity to effectively manage the food and nutrition implications of ART adherence is a critical factor in the success of antiretroviral therapy in resource limited settings.

Encephalitis with Infiltration by CD8+ Lymphocytes in HIV Patients Receiving Combination Antiretroviral Treatment

We report the neuropathological findings in 10 HIV-infected patients treated by combination antiretroviral therapy who developed subacute encephalopathy of rapidly progressive onset. Brain biopsy showed encephalitic lesions variably associated with myelin loss and slight axonal damage. There was inconstant, weak expression of HIV protein p24; tests for other pathogens were negative. The most striking feature was diffuse, perivascular and intraparenchymal infiltration by CD8+ T-lymphocytes. Six patients improved after the treatment. Four had an unfavorable outcome and died within a year. Post-mortem in one case confirmed HIV leukoencephalitis with p24-positive multinucleated giant cells, associated with acute demyelinating encephalomyelitis (ADEM) in the cerebellum. There was diffuse infiltration by CD8+ lymphocytes; CD4+ cells were virtually absent. These cases may represent a specific clinicopathological entity, of which a few comparable cases have been already described. They can be included in the wide framework of immune reconstitution disease. Such syndromes have been described with opportunistic infections, but only seldom with HIV infection of the central nervous system (CNS). Our findings support the hypothesis that CD8+ cytotoxic lymphocytes can be harmful in immune reconstitution disease, particularly in the absence of CD4+ lymphocytes. CD8 cytotoxicity produces an acutization of a smoldering infection and/or an immunopathological reaction similar to ADEM.

Mycobacterium avium-intracellulare brain abscess in HIV-positive patient

Mycobacterial opportunistic infections are a major cause of morbidity and mortality among patients living with HIV (PLHIV) worldwide. Nontuberculous mycobacterial (NTM) infection is one of the leading causes of opportunistic infection in patients with advanced acquired immunodeficiency syndrome i.e., with CD4 count less than 50/cu.mm. Mycobacterium avium complex (MAC) is among the most common opportunistic bacterial infections in those patients with advanced immunodeficiency apart from cryptococcal meningitis, progressive multifocal leukoencephalopathy, etc. Common presentations of mycobacterium avium complex are fever, lymphadenitis and respiratory disease. Immune reconstitution disease is also known to manifest with MAC infections in PLHIV on highly active antiretroviral therapy. Very few cases of central nervous system involvement due to NTM infection have been described. We are reporting a case of advanced acquired immunodeficiency who presented with brain abscess due to Mycobacterium avium intracellulare.

Immune reconstitution disease or mycobacteria other than tuberculosis or both: A dilemma in a patient of AIDS

A 35-year-old male diagnosed as HIV with tuberculous lymphadenopathy, presented with acute increase in size of neck swelling and fever. The patient was on antiretroviral therapy and antitubercular treatment. Investigations revealed raised CD4 counts and the pus from swelling showed mycobacteria other than tuberculosis (MOTT) on bacteriological examination.The patient was started on steroids, azithromycin, and ciprofloxacin to which he responded well. We report this case to highlight the occurrence of immune reconstitution disease in HIV patients and also to bring out the fact that atypical infection like MOTT may confound the diagnosis even in regions like ours where MOTT is rarely reported.

A Morphological Approach to the Diagnosis of Protozoal Infections of the Central Nervous System

Protozoal infections, though endemic to certain regions, can be seen all around the world, because of the increase in travel and migration. In addition, immunosuppression associated with various conditions, particularly with HIV infection, favors the occurrence of more severe manifestations and failure to respond to treatments. The CNS may be the only affected system; when not, it is often the most severely affected. Despite information obtained from clinical, laboratory, and imaging procedures that help to narrow the differential diagnosis of intracranial infections, there are cases that need confirmation with biopsy or autopsy. Predominant presentations are meningoencephalitis (trypanosomiasis), encephalopathy (cerebral malaria), or as single or multiple pseudotumoral enhancing lesions (toxoplasmosis, reactivated Chagas' disease). The immune reconstitution disease, resulting from enhancement of pathogen-specific immune responses after HAART, has altered the typical presentation of toxoplasmosis and microsporidiosis. In this paper, a morphological approach for the diagnosis of protozoal infections affecting the CNS (amoebiasis, cerebral malaria, toxoplasmosis, trypanosomiasis, and microsporidiosis) is presented.

Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy

The risks of unmasking and paradoxical forms of immune reconstitution disease in HIV-infected patients starting antiretroviral therapy (ART) are fuelled by a combination of the late presentation of patients with advanced immunodeficiency, the associated high rates of opportunistic infections (OIs) and the need for rapid initiation of ART to minimize overall mortality risk. We review the risk factors and our current knowledge of the immunopathogenesis of immune reconstitution disease, leading to a discussion of strategies for prevention. Initiation of ART at higher CD4 counts, use of OI-preventive therapies prior to ART eligibility, intensified screening for OIs prior to ART initiation and optimum therapy for OIs are all needed. In addition, use of a range of pharmacological agents with immunosuppressive and immunomodulatory activity is being explored.

A Longitudinal Study of the Effects of ART on Plasma Chemokine Levels in Malaysian HIV Patients

Objectives: Chemokines influence the migration of leukocytes to secondary lymphoid tissue and sites of inflammation. In HIV patients, they are implicated in inflammatory complications of antiretroviral therapy (ART), notably Immune Reconstitution Disease (IRD) and Sensory Neuropathy (SN). However most chemokines have not been monitored as patients begin ART or correlated with IRD and SN.Methods: Plasma chemokine levels were assessed longitudinally using commercial ELISAs in 69 patients treated in Kuala Lumpur, Malaysia. Plasma was available at baseline and after 6, 12, 24 and 48 weeks on ART. Chemokine genotypes were assessed using allele-specific fluorescent probes. IRD were diagnosed in 15 patients. 30 patients were screened for SN using the ACTG BPNS tool after six months on ART. SN was detected in 8 patients.Results: Plasma CXCL10 levels decreased on ART compared to baseline (p= 0.002–0.0001), but remain higher than healthy controls (p≤ 0.0001). The decline was clearer in patients without IRD. CCL5 levels rose on ART but remained similar to controls. CCL2 levels were higher in patients than controls after week 12. Plasma chemokine levels were not affected by CD4+ T-cell counts or any genotypes tested. Several patients with SN displayed higher CCL5 levels throughout therapy compared to patients without neuropathy. Levels of other chemokines and chemokine genotypes were not associated with SN.Conclusions: Chemokines are differentially affected by ART. CXCL10 and CCL5 may influence IRD and CCL5 warrants further investigation for an effect in SN. These trends are not influenced by chemokine genotypes investigated here.

A longitudinal study of the effects of ART on plasma chemokine levels in Malaysian HIV patients.

Objectives: Chemokines influence the migration of leukocytes to secondary lymphoid tissue and sites of inflammation. In HIV patients, they are implicated in inflammatory complications of antiretroviral therapy (ART), notably Immune Reconstitution Disease (IRD) and Sensory Neuropathy (SN). However most chemokines have not been monitored as patients begin ART or correlated with IRD and SN. Methods: Plasma chemokine levels were assessed longitudinally using commercial ELISAs in 69 patients treated in Kuala Lumpur, Malaysia. Plasma was available at baseline and after 6, 12, 24 and 48 weeks on ART. Chemokine genotypes were assessed using allele-specific fluorescent probes. IRD were diagnosed in 15 patients. 30 patients were screened for SN using the ACTG BPNS tool after six months on ART. SN was detected in 8 patients. Results: Plasma CXCL10 levels decreased on ART compared to baseline (p = 0.002–0.0001), but remain higher than healthy controls (p ≤ 0.0001). The decline was clearer in patients without IRD. CCL5 levels rose on ART but remained similar to controls. CCL2 levels were higher in patients than controls after week 12. Plasma chemokine levels were not affected by CD4+ T-cell counts or any genotypes tested. Several patients with SN displayed higher CCL5 levels throughout therapy compared to patients without neuropathy. Levels of other chemokines and chemokine genotypes were not associated with SN. Conclusions: Chemokines are differentially affected by ART. CXCL10 and CCL5 may influence IRD and CCL5 warrants further investigation for an effect in SN. These trends are not influenced by chemokine genotypes investigated here.