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Purpose: To evaluate the clinical features and management of presumed ocular tuberculosis (OTB). Method: A prospective 3-year follow-up study of patients with ocular inflammation that performed Interferon-gamma release assay (IGRA) and tuberculin skin test (TST) was conducted in a tertiary referral center in Brazil. Patients with clinical signs highly suspect of OTB with a positive TST and/or IGRA with other causes ruled out were prescribed anti-tuberculosis therapy (ATT) during 9 months. Clinical features and treatment outcomes were recorded. Results: Seventy-two patients (mean age 48.3 ± 15.7 years) were included in the study, and most were female (65.3%, n = 47). Posterior uveitis (43.1%, n = 31) was the main clinical feature. Multifocal choroiditis (25%, n = 18) was the most common choroidal involvement. Concomitant oral prednisone (45.8%, n = 33) during ATT was associated with more recurrences ( p = 0.04). A significant difference ( p Conclusion: In our cohort some variation in demographics and ocular phenotypes of presumed OTB was observed. The high rates of cure or remission of our patients strongly support the ATT in presumed OTB. Oral corticosteroids during ATT were associated with higher recurrences rates.

Background The impact of low body mass index (BMI) at initiation of rifampicin-resistant tuberculosis (RR-TB) treatment on outcomes is uncertain. We evaluated the association between BMI at RR-TB treatment initiation and end-of-treatment outcomes. Methods We performed an individual participant data meta-analysis of adults aged ≥18 years with RR-TB whose BMI was documented at treatment initiation. We compared odds of any unfavorable treatment outcome, mortality, or failure/recurrence between patients who were underweight (BMI Results Overall, 5148 patients were included; 1702 (33%) were underweight at treatment initiation. The median (interquartile range) age was 37 years (29 to 47), and 455 (9%) had HIV. Compared with nonunderweight patients, the aOR among underweight patients was 1.7 (95% CI, 1.4–1.9) for any unfavorable outcome, 3.1 (2.4–3.9) for death, and 1.6 (1.2–2.0) for failure/recurrence. Significant effect modification was found for World Health Organization region of treatment. Among HIV-negative patients, 24-month mortality was 14.8% (95% CI, 12.7%–17.3%) for underweight and 5.6% (4.5%–7.0%) for not underweight patients. Among patients with HIV, corresponding values were 33.0% (25.6%–42.6%) and 20.9% (14.1%–27.6%). Conclusions Low BMI at treatment initiation for RR-TB is associated with increased odds of unfavorable treatment outcome, particularly mortality.

Purpose To assess the performance of interferon-gamma release assay (IGRA) associated with tuberculosis skin test (TST) for ocular tuberculosis (OTB) diagnosis and therapeutic decision making. Method One hundred and ninety-one patients with ocular inflammation were prospectively followed-up. Patients with clinical signs highly suspected of OTB, TST >= 10 mm, and/or IGRA >= 0.35 IU/mL received antitubercular therapy (ATT). Sensitivity (Se), specificity (Sp), and area under the curve (AUC) were assessed. Results Seventy-two (37.7%) patients received ATT for presumed OTB. Combining TST and IGRA had Se=89.6%, Sp=99.2%, and AUC (0.98) significantly higher compared to TST (0.85, Z=6.3, p 2.0 IU/mL was associated significantly with more recurrences in ATT patients (p=.01) . Conclusion Considering TST and IGRA together was more effective in assessing OTB diagnosis. The real value of the IGRA test to predict recurrences needs further studies.

Tuberculosis remains a public health problem worldwide, even with the advance in new diagnostic methods...

Purpose: To describe the approach of Brazilian specialists in the diagnosis and treatment of tuberculosis-associated uveitis (TBU).Methods: Members of the Brazilian Uveitis Society received an elec...

Background In developing countries, tuberculosis (TB) is a major public health problem and the leading cause of death among patients with HIV (Human Immunodeficiency Virus). Until 2001, the tuberculin skin test (TST) was the only available tool for the diagnosis of latent tuberculosis infection (LTBI), but false-negative TST results are frequently reported. Recently, the interferon-γ (IFN-γ) release assay (IGRA) has gained ground because it can detect the IFN-γ secreted by circulating lymphocytes T cells when stimulated by specific TB antigens. However, the role of IGRA in the diagnosis of LTBI in HIV-infected patients has not been well established. Methods This cross-sectional study compared the accuracy of TST (performed by the Mantoux method) and IGRA (QuantiFERON-TB Gold In-Tube, Cellestis, Carnegie, Australia) on the diagnosis of LTBI among patients with HIV. LTBI is defined by LTBI risk and at least one positive test (TST or IGRA), without clinical evidence of active TB. We also assessed the accuracy of TST and IGRA among HIV patients with high and low risk for LTBI. Results Among 90 HIV patients, 80 met the study criteria for LTBI, fifty-nine (73.7%) patients were TST positive, 21 (26.2%) were negative, whereas 75 patients (93.7%) were IGRA positive, and five (6.2%) were negative. TST showed poor agreement with the diagnosis of LTBI (Kappa: 0.384), while IGRA demonstrated good agreement (Kappa: 0.769). Among 69 patients with high risk and 21 with low risk for LTBI, TST was positive in 48 (69.5%) and 11 (52.4%), while IGRA was positive in 68 (98.5%) and 7 (33.3%) patients, respectively. There were no association between TST and the level of risk (P = 0,191). Conversely, we observed a strong association between the IGRA and risk for LTBI (p

Hepatitis B virus genotyping was conducted among 11560 healthy blood donors and haemodialysis patients in Brazil and Paraguay. Genotypes A, D and F were found in Brazil and genotypes D and F in Paraguay. This is the first report showing HBV genotype diversity in individuals in Paraguay.

To define the possible impact of T-lymphocyte trafficking parameters on simian immunodeficiency virus (SIV) pathogenesis, we examined migratory profiles of carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled T lymphocytes in acutely SIV mac251 -infected and uninfected macaques within 48 h after autologous transfer. Despite significant upregulation of homeostatic chemokine CCL19/macrophage inflammatory protein 3β and proinflammatory chemokine CXCL9/monokine induced by gamma interferon in secondary lymphoid tissue in SIV infection, no differences in CFSE + T-lymphocyte frequencies or cell compartmentalization in lymph nodes were identified between animal groups. By contrast, a higher frequency of CFSE + T lymphocytes in the small intestine was detected in acute SIV infection. This result correlated with increased numbers of gut CD4 T lymphocytes expressing chemokine receptors CCR9, CCR7, and CXCR3 and high levels of their respective chemokine ligands in the small intestine. The changes in trafficking parameters in SIV-infected macaques occurred concomitantly with acute gut CD4 T-lymphocyte depletion. Here, we present the first in vivo T-lymphocyte trafficking study in SIV infection and a novel approach to delineate T-lymphocyte recruitment into tissues in the nonhuman primate animal model for AIDS. Such studies are likely to provide unique insights into T-lymphocyte sequestration in distinct tissue compartments and possible mechanisms of CD4 T-lymphocyte depletion and immune dysfunction in simian AIDS.

Purpose: To assess interferon gamma release assay (IGRA) and tuberculin skin test (TST) performances in the diagnosis of active tuberculosis (TB) in adults with HIV/AIDS with different degrees of immunodeficiency. Methods: Cross-sectional study conducted with 90 HIV/TB-coinfected adults, Sao Paulo, Brazil. TB diagnosis was established based on the presence of positive sputum smear, culture, or anatomic-pathological examination. The participants responded to a questionnaire and were submitted to physical examination, chest x-ray (CRX), serum CD4+ and CD8+ T cell count, TST, and IGRA (QuantiFERON®-TB Gold In Tube, Cellestis, Carnegie, Australia). Results: Characteristics of 90 HIV/TB-coinfected individuals: male (60.0%), white (54.4%), single (57.3%), and average age 39 (±10.8) years with pulmonary TB (45.6%) and average CD4+ T-cell count (198.92 cells/mm3). TST was positive in 25.56%, and IGRA was positive in 65.56%. IGRA performance was better when compared to TST (p

Three HIV-1-seronegative patients with disseminated tuberculosis presented significant depletion of T-cell counts, in CD4+ and/or CD8+ cells, associated with increased expression of activation marker CD38 on CD8+ T-lymphocytes. This finding raises the question of potential mechanisms involved in the activation or loss of T-cells in disseminated tuberculosis.

BACKGROUND:It is generally accepted that CD8+ T cell responses play an important role in control of immunodeficiency virus replication. The association of HLA-B27 and -B57 with control of viremia supports this conclusion. However, specific correlates of viral control in individuals expressing these alleles have been difficult to define. We recently reported that transient in vivo CD8+ cell depletion in simian immunodeficiency virus (SIV)-infected elite controller (EC) macaques resulted in a brief period of viral recrudescence. SIV replication was rapidly controlled with the reappearance of CD8+ cells, implicating that these cells actively suppress viral replication in ECs. METHODS AND FINDINGS:Here we show that three ECs in that study made at least seven robust CD8+ T cell responses directed against novel epitopes in Vif, Rev, and Nef restricted by the MHC class I molecule Mamu-B*08. Two of these Mamu-B*08-positive animals subsequently lost control of SIV replication. Their breakthrough virus harbored substitutions in multiple Mamu-B*08-restricted epitopes. Indeed, we found evidence for selection pressure mediated by Mamu-B*08-restricted CD8+ T cells in all of the newly identified epitopes in a cohort of chronically infected macaques. CONCLUSIONS:Together, our data suggest that Mamu-B*08-restricted CD8+ T cell responses effectively control replication of pathogenic SIV(mac)239. All seven regions encoding Mamu-B*08-restricted CD8+ T cell epitopes also exhibit amino acid replacements typically seen only in the presence of Mamu-B*08, suggesting that the variation we observe is indeed selected by CD8+ T cell responses. SIV(mac)239 infection of Indian rhesus macaques expressing Mamu-B*08 may therefore provide an animal model for understanding CD8+ T cell-mediated control of HIV replication in humans.

Monocytes and macrophages play a central role in the pathogenesis of human immunodeficiency virus (HIV)-associated dementia. They represent prominent targets for HIV infection and are thought to facilitate viral neuroinvasion and neuroinflammatory processes. However, many aspects regarding monocyte brain recruitment in HIV infection remain undefined. The nonhuman primate model of AIDS is uniquely suited for examination of the role of monocytes in the pathogenesis of AIDS-associated encephalitis. Nevertheless, an approach to monitor cell migration from peripheral blood into the central nervous system (CNS) in primates had been lacking. Here, upon autologous transfer of fluorescein dye-labeled leukocytes, we demonstrate the trafficking of dye-positive monocytes into the choroid plexus stromata and perivascular spaces in the cerebra of rhesus macaques acutely infected with simian immunodeficiency virus between days 12 and 14 postinfection (p.i.). Dye-positive cells that had migrated expressed the monocyte activation marker CD16 and the macrophage marker CD68. Monocyte neuroinvasion coincided with the presence of the virus in brain tissue and cerebrospinal fluid and with the induction of the proinflammatory mediators CXCL9/MIG and CCL2/MCP-1 in the CNS. Prior to neuroinfiltration, plasma viral load levels peaked on day 11 p.i. Furthermore, the numbers of peripheral blood monocytes rapidly increased between days 4 and 8 p.i., and circulating monocytes exhibited increased functional capacity to produce CCL2/MCP-1. Our findings demonstrate acute monocyte brain infiltration in an animal model of AIDS. Such studies facilitate future examinations of the migratory profile of CNS-homing monocytes, the role of monocytes in virus import into the brain, and the disruption of blood-cerebrospinal fluid and blood-brain barrier functions in primates.

CD8 + T lymphocytes appear to play a role in controlling human immunodeficiency virus (HIV) replication, yet routine immunological assays do not measure the antiviral efficacy of these cells. Furthermore, it has been suggested that CD8 + T cells that recognize epitopes derived from proteins expressed early in the viral replication cycle can be highly efficient. We used a functional in vitro assay to assess the abilities of different epitope-specific CD8 + T-cell lines to control simian immunodeficiency virus (SIV) replication. We compared the antiviral efficacies of 26 epitope-specific CD8 + T-cell lines directed against seven SIV epitopes in Tat, Nef, Gag, Env, and Vif that were restricted by either Mamu-A*01 or Mamu-A*02. Suppression of SIV replication varied depending on the epitope specificities of the CD8 + T cells and was unrelated to whether the targeted epitope was derived from an early or late viral protein. Tat 28-35 SL8- and Gag 181-189 CM9-specific CD8 + T-cell lines were consistently superior at suppressing viral replication compared to the other five SIV-specific CD8 + T-cell lines. We also investigated the impact of viral escape on antiviral efficacy by determining if Tat 28-35 SL8- and Gag 181-189 CM9-specific CD8 + T-cell lines could suppress the replication of an escaped virus. Viral escape abrogated the abilities of Tat 28-35 SL8- and Gag 181-189 CM9-specific CD8 + T cells to control viral replication. However, gamma interferon (IFN-γ) enzyme-linked immunospot and IFN-γ/tumor necrosis factor alpha intracellular-cytokine-staining assays detected cross-reactive immune responses against the Gag escape variant. Understanding antiviral efficacy and epitope variability, therefore, will be important in selecting candidate epitopes for an HIV vaccine.

Mycobacterium tuberculosis (MTB) is a leading cause of mortality worldwide from an infectious agent. Natural killer T (NKT) cells recognize mycobacterial antigens and contribute to anti-MTB immunity in mouse models. NKT cells were measured in subjects with pulmonary tuberculosis, MTB-exposed individuals, and healthy controls. NKT cell levels are selectively lower in peripheral blood mononuclear cells from individuals with pulmonary tuberculosis than in both MTB-exposed subjects and healthy control subjects. This apparent loss of NKT cells from the peripheral blood is sustained during the 6 months after the initiation of MTB treatment. These findings indicate that NKT cells may be an important component of antituberculosis immunity.

SummaryTuberculosis (TB) is usually more severe in HIV-infected patients, and the immune derangement found in co-infected patients may differ from that in each isolated disease. Following mitogen stimulation of peripheral blood mononuclear cells (PBMC), interferon (IFN)-γ and tumour necrosis factor (TNF)-α production was evaluated in T cells by flow cytometry, and in culture supernatants by enzyme-linked immunosorbent assay (ELISA) in 33 individuals: 11 AIDS patients with tuberculosis, six asymptomatic HIV-1-infected patients, eight patients with tuberculosis and eight healthy controls. The proportion of CD4+ T lymphocytes expressing IFN-γ did not differ between the groups, whereas a trend towards increased proportions of TNF-α-expression in CD4+ T cells was observed in the TB compared to the HIV group, while intermediate values were observed in co-infected patients. Detection of IFN-γ and TNF-α in CD8+ T lymphocytes was higher in TB than in HIV individuals. Co-infected patients presented intermediate values for IFN-γ, while TNF-α detection was similar to that in HIV mono-infection. In conclusion, the proportion of T cells expressing IFN-γ was relatively preserved in co-infected patients compared to TB patients, while the percentage of T cells expressing TNF-α was decreased, mainly in CD8+ T lymphocytes. However, the marked reduction in T lymphocyte numbers in co-infected patients led to a striking reduction of both cytokines in PBMC supernatants, a finding that is consistent with the impaired response to Mycobacterium tuberculosis.

T-lymphocyte migratory circuits in human and nonhuman primates remain largely unexplored due to the difficulty of defining cell trafficking in vivo. However, this knowledge may reveal critical aspects of immunity and T-lymphocyte homeostasis in both health and disease. Furthermore, in vivo T-lymphocyte trafficking studies may facilitate defining mechanism(s) of immune dysfunction in the nonhuman primate model for acquired immunodeficiency syndrome (AIDS). Here, we developed a model for in vivo T-lymphocyte trafficking in nonhuman primates, and delineated homing characteristics of unstimulated peripheral blood mononuclear cells (PBMCs) to lymphoid and nonlymphoid compartments in healthy rhesus macaques. T-lymphocyte homing of autologous, carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled PBMCs was defined within 48 h of intravenous transfer. The highest relative frequency of CFSE+ T lymphocytes was observed in peripheral blood and spleen. Expression of chemokine receptor CCR7 and its ligands correlated with recirculation of T lymphocytes through the periphery and homing to paracortical regions of lymph node, where cells remained largely excluded from B-cell follicles. T-lymphocyte trafficking was also detected to the liver and bone marrow, and at low levels to the thymus and small intestine. The liver contained the highest proportion of CD45RA- T lymphocytes, consistent with homing of activated/memory T lymphocytes to this nonlymphoid site. Our data suggest that lymphoid and nonlymphoid organs are under continuous immunosurveillance in healthy macaques, and that this model may serve to investigate aberrant patterns in disease.

CD(4)(+) and CD(8)(+) T lymphocyte counts, naive and memory/effector CD(4)(+) T subpopulations, and the expression of CD(38) on CD(8)(+) T lymphocytes were evaluated in four groups: AIDS patients with tuberculosis (HIV/TB, n=14), HIV-1 infected patients (HIV, n=10), HIV-1 negative patients with tuberculosis (TB, n=20) and healthy controls (CTL, n=17). TB and HIV had fewer +CD(4)(+) T cells than CTL, with the lowest values observed in TB/HIV (p0.001). No difference between groups was observed in the percentage of naive and memory/effector subpopulations in +CD(4)(+) T lymphocytes. TB (355 cells/ micro L) and HIV (517 cells/ micro L) had diverging effects on +CD(8)(+) T cell counts, with a marked depletion observed in HIV/TB (196 cells/ micro L). TB and HIV up-regulated CD(38) expression on CD(8)(+) T cells, a finding also present in TB/HIV. While the decrease of +CD(4)(+) T cell counts in HIV/TB may be attributed to HIV and tuberculosis, the decrease of +CD(8)(+) T cell counts is likely to be due to tuberculosis.

The cellular immune response probably plays a pivotal role in determining the clinical outcome after exposure to Mycobacterium tuberculosis. We used multi-parameter flow-cytometry to evaluate the distribution of T-lymphocyte subsets during infection and disease caused by M. tuberculosis. Samples were obtained from 71 volunteers to identify the T CD4(+) and CD8(+) lymphocyte numbers, and the activation plus memory/naive phenotypes, as defined by CD38, HLA-DR, CD45RA and CD27 markers. Subjects were divided into 18 healthy volunteers without detectable reaction to purified protein derivative (PPD-), 18 health care workers with a recent conversion to PPD, 20 patients with active pulmonary tuberculosis (TBC) and 15 patients with treated TBC at 6 months of therapy. By multiple-comparison analyses, the T CD4(+) lymphocyte number of the TBC group was lower than the PPD- group (P < 0.05). Ibis difference was apparently lost after treatment. the higher and the lower number of naive T CD4(+) cells was observed in the PPD- and TB C group, respectively. CD8(+) T lymphocytes were also statistically different among the four groups (P = 0.0002), lower in the TBC group (P < 0.05). CD8(+) T lymphocyte activation was evaluated by the CD38 and HLA-DR surface expression. the percentage distribution of these markers was statistically different between the four groups (P = 0.0055). TBC patients had a higher percentage of CD38(+) cells and mean fluorescence index, suggesting an overall increase of cell activation. These results suggest that peripheral T lymphocytes reflect cellular activation during TBC, along with possible redistribution of naive, memory/effector and late differentiated memory/effector phenotypes in the peripheral blood after infection and disease caused by M. tuberculosis. Universidade Federal de São Paulo, LKab Imunol, Disciplina Doencas Infecc & Parasitarias, Escola Paulista Med,Infect Dis Discipline, BR-04039032 São Paulo, Brazil Univ Rochester, Infect Dis Unit, Rochester, NY 14627 USA Universidade Federal de São Paulo, LKab Imunol, Disciplina Doencas Infecc & Parasitarias, Escola Paulista Med,Infect Dis Discipline, BR-04039032 São Paulo, Brazil Web of Science