Dysfunctional effector memory CD8 T cells in the bronchoalveolar compartment of people living with HIV.

Mechanisms by which HIV causes susceptibility to respiratory pathogens remain incompletely understood. We obtained whole blood and bronchoalveolar lavage (BAL) from people with latent TB infection in the presence or absence of antiretroviral-naïve HIV co-infection. Transcriptomic and flow cytometric analyses demonstrated HIV-associated cell proliferation plus type I interferon activity in blood and effector memory CD8 T-cells in BAL. Both compartments displayed reduced induction of CD8 T-cell-derived IL-17A in people with HIV, associated with elevated T-cell regulatory molecule expression. The data suggest that dysfunctional CD8 T-cell responses in uncontrolled HIV contribute to susceptibility to secondary bacterial infections, including tuberculosis.

High sensitivity of ultrasound for the diagnosis of tuberculosis in adults in South Africa: A proof-of-concept study.

BACKGROUND: There are limited data on the performance characteristics of ultrasound for the diagnosis of pulmonary tuberculosis in both HIV-positive and HIV-negative persons. The objective of this proof-of-concept study was to determine the sensitivity and specificity of ultrasound for the diagnosis of tuberculosis in adults. METHODS: Comprehensive thoracic and focused abdominal ultrasound examinations were performed by trained radiologists and pulmonologists on adults recruited from a community multimorbidity survey and a primary healthcare clinic in KwaZulu-Natal Province, South Africa. Sputum samples were systematically collected from all participants. Sensitivity and specificity of ultrasound to detect tuberculosis were calculated compared to a reference standard of i) bacteriologically-confirmed tuberculosis, and ii) either bacteriologically-confirmed or radiologic tuberculosis. RESULTS: Among 92 patients (53 [58%] male, mean age 41.9 [standard deviation 13.7] years, 49 [53%] HIV positive), 34 (37%) had bacteriologically-confirmed tuberculosis, 8 (9%) had radiologic tuberculosis with negative bacteriologic studies, and 50 (54%) had no evidence of active tuberculosis. Ultrasound abnormalities on either thoracic or abdominal exams were detected in 31 (91%) participants with bacteriologic tuberculosis and 27 (54%) of those without tuberculosis. Sensitivity and specificity of any ultrasound abnormality for bacteriologically-confirmed tuberculosis were 91% (95% confidence interval [CI] 76%-98%) and 46% (95% CI 32%-61%). Sensitivity and specificity of any ultrasound abnormality for either bacteriologically-confirmed or radiologic tuberculosis were 86% (95% CI 71%-95%) and 46% (95% CI 32%-61%). Overall performance did not appear to differ markedly between participants with and without HIV. CONCLUSION: A comprehensive ultrasound scanning protocol in adults in a high TB burden setting had high sensitivity but low specificity to identify bacteriologically-confirmed tuberculosis.

MR1-Restricted MAIT Cells From The Human Lung Mucosal Surface Have Distinct Phenotypic, Functional, and Transcriptomic Features That Are Preserved in HIV Infection.

Mucosal associated invariant T (MAIT) cells are a class of innate-like T cells that utilize a semi-invariant αß T cell receptor to recognize small molecule ligands produced by bacteria and fungi. Despite growing evidence that immune cells at mucosal surfaces are often phenotypically and functionally distinct from those in the peripheral circulation, knowledge about the characteristics of MAIT cells at the lung mucosal surface, the site of exposure to respiratory pathogens, is limited. HIV infection has been shown to have a profound effect on the number and function of MAIT cells in the peripheral blood, but its effect on lung mucosal MAIT cells is unknown. We examined the phenotypic, functional, and transcriptomic features of major histocompatibility complex (MHC) class I-related (MR1)-restricted MAIT cells from the peripheral blood and bronchoalveolar compartments of otherwise healthy individuals with latent Mycobacterium tuberculosis (Mtb) infection who were either HIV uninfected or HIV infected. Peripheral blood MAIT cells consistently co-expressed typical MAIT cell surface markers CD161 and CD26 in HIV-negative individuals, while paired bronchoalveolar MAIT cells displayed heterogenous expression of these markers. Bronchoalveolar MAIT cells produced lower levels of pro-inflammatory cytokine IFN-γ and expressed higher levels of co-inhibitory markers PD-1 and TIM-3 than peripheral MAIT cells. HIV infection resulted in decreased frequencies and pro-inflammatory function of peripheral blood MAIT cells, while in the bronchoalveolar compartment MAIT cell frequency was decreased but phenotype and function were not significantly altered. Single-cell transcriptomic analysis demonstrated greater heterogeneity among bronchoalveolar compared to peripheral blood MAIT cells and suggested a distinct subset in the bronchoalveolar compartment. The transcriptional features of this bronchoalveolar subset were associated with MAIT cell tissue repair functions. In summary, we found previously undescribed phenotypic and transcriptional heterogeneity of bronchoalveolar MAIT cells in HIV-negative people. In HIV infection, we found numeric depletion of MAIT cells in both anatomical compartments but preservation of the novel phenotypic and transcriptional features of bronchoalveolar MAIT cells.

Laboratory diagnosis of tuberculous meningitis in human immunodeficiency virus-seropositive patients: Correlation with the uniform case definition.

BACKGROUND: Laboratory confirmation of the diagnosis of tuberculous meningitis (TBM) has always been problematic. Using the uniform case definition suggested by Marais et al., we determined the sensitivity of a variety of laboratory tests. METHODS: Human immunodeficiency virus (HIV)-seropositive patients suspected of having subacute meningitis were included in the study. Using the uniform case definition, patients were divided into possible and probable cases of TBM. The following specific tests were done on the cerebrospinal fluid (CSF): layered Ziehl-Neelsen (ZN) staining, CSF culture and a panel of nucleic acid amplification tests (NAAT) consisting of the GenoType MTBDRplus assay, Cepheid Xpert MTB/RIF, the MTB Q-PCR Alert (Q-PCR) and the loop-mediated isothermal amplification (LAMP) assay. The sensitivity of each test was compared to the case definition and to each other. RESULTS: A total of 68 patients were evaluated. Using the uniform case definition only, without any of the specific laboratory tests, there were 15 probable cases (scores > 12) and 53 possible cases (scores 6-11) of TBM. When the uniform case definition was tested against any laboratory test, 12 of the 15 (80%) probable cases and 26 of the 53 (49.1%) possible cases had laboratory confirmation. When each test was compared to any other test, the sensitivities for the Xpert MTB/RIF, GenoType MTBDRplus, CSF culture, Q-PCR, LAMP and ZN layering were 63.2 (46.0-78.2), 76.3 (59.8-88.6), 65.7 (47.8-80.9), 81.1 (64.8-92.0), 70.3 (53.0-84.1) and 55.6 (38.1-72.1), respectively. CONCLUSION: In this study, the GenoType MTBDRplus and the Q-PCR tests performed better than the Xpert MTB/RIF. Because the Xpert MTB/RIF is not good enough to 'rule out' TBM, a negative result should be followed up by another NAAT, such as the GenoType MTBDRplus or Q-PCR. The LAMP assay may be considered as the first test in resource-poor settings. At the time of the study, we did not have access to the Xpert MTB/RIF Ultra, which has now been recommended by the World Health Organization as the test of first choice. However, even this test has a similar limitation as the Xpert MTB/RIF, with two recent studies showing variable results.

Contrasting Inflammatory Signatures in Peripheral Blood and Bronchoalveolar Cells Reveal Compartment-Specific Effects of HIV Infection.

The mechanisms by which HIV increases susceptibility to tuberculosis and other respiratory infections are incompletely understood. We used transcriptomics of paired whole bronchoalveolar lavage cells (BLCs) and peripheral blood mononuclear cells to compare the effect of HIV at the lung mucosal surface and in peripheral blood. The majority of HIV-induced differentially expressed genes (DEGs) were specific to either the peripheral or lung mucosa compartments (1,307/1,404, 93%). Type I interferon signaling was the dominant signature of DEGs in HIV-positive blood but not in HIV-positive BLCs. DEGs in the HIV-positive BLCs were significantly enriched for infiltration with cytotoxic CD8+ T cells. Higher expression of type 1 interferon transcripts in peripheral CD8+ T cells and representative transcripts and proteins in BLCs-derived CD8+ T cells during HIV infection, including IFNG (IFN-gamma), GZMB (Granzyme B), and PDCD1 (PD-1), was confirmed by cell-subset specific transcriptional analysis and flow cytometry. Thus, we report that a whole transcriptomic approach revealed qualitatively distinct effects of HIV in blood and bronchoalveolar compartments. Further work exploring the impact of distinct type I interferon programs and functional features of CD8+ T cells infiltrating the lung mucosa during HIV infection may provide novel insights into HIV-induced susceptibility to respiratory pathogens.

Risk of healthcare associated infections in HIV positive patients.

HIV positive patients are a high risk population due to the alteration in their immune status. Health-care associated infections (HAI) have not been well described in this population, with some risk factors reported inconsistently in the literature. The aim of this study was to describe the epidemiology as well as the underlying risk factors for HAI, specifically urinary tract infection (UTI), bloodstream infection (BSI) and respiratory tract infection (RTI). This was a retrospective cohort study conducted at an academic health system in New York City which included three hospitals over a two year period from 2006 to 2008. There were 3,877 HIV positive patient discharges in 1,911 patients. There were a total of 142 UTI, 106 BSI, and 100 RTI. The incidence rates were 4.35 for UTI, 3.16 for BSI and 2.98 for RTI. CD4 count and antiretroviral therapy were not associated with HAI. Significant predictors of UTI included urinary catheter, length of stay, female gender, steroids and trimethoprim-sulphamethoxazole (TMP-SMX); of BSI were steroids and TMP-SMX; and RTI were mechanical ventilation, steroids and TMP-SMX. Multivariable analysis indicated that TMP-SMX was significantly associated with an increased risk of infection for all three types of HAI [BSI odds ratio 2.55, 95% confidence interval (1.22-5.34); UTI odds ratio 3.1, 95% confidence interval (1.41-7.22); RTI odds ratio 5.15, 95% confidence interval (1.70-15.62)]. HIV positive patients are at significant risk for developing HAI, but the risk factors differ depending on the specific type of infection. The fact that TMP-SMX is a risk factor in these patients warrants further research as this may have significant health policy implications.

Cutaneous Mycobacterium kansasii infection in a patient with AIDS post initiation of antiretroviral therapy.

The HIV pandemic has resulted in unique clinical presentations in patients, and their diagnosis and management pose challenges to physicians in the developing world. Due to limited resources and difficulties in laboratory diagnosis, most physicians treat according to the most likely etiological agent that might be causing the disease. In South Africa, when acid-fast bacilli are detected, anti-tuberculous treatment is commenced. However, it must be realized that not all acid-fast bacilli are Mycobacterium tuberculosis, and that there are nontuberculous mycobacteria that can cause infections. Clinicians should work closely with the medical microbiologist when unique cases arise to ensure optimal microbial detection, identification, and patient management. This paper describes a very rare case of self-resolving cutaneous Mycobacterium kansasii infection following the initiation of antiretroviral therapy and potentially associated with immune reconstitution inflammatory syndrome.

Disseminated Cryptococcosis in an HIV-negative patient in South Africa: the elusive differential diagnosis.

The presence of an opportunistic infection in a patient in sub-Saharan Africa is assumed to be due to underlying immunosuppression from human immunodeficiency virus (HIV) infection. The presence of disseminated cryptococcosis in a non-HIV-infected patient is interesting as it is unique in our setting because the majority of infections are found in HIV-infected individuals. The protean manifestations of the disease and its predilection for immunosuppressed patients make cryptococcosis a challenging and elusive disease to diagnose in HIV-negative patients in our setting, especially due to limited resources. We present a case of disseminated cryptococcosis in an immunocompetent patient and discuss diagnostic and therapeutic features in this subset of patients.