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Brief Report: Pulmonary Tuberculosis Is Associated With Persistent Systemic Inflammation and Decreased HIV-1 Reservoir Markers in Coinfected Ugandans.

ABSTRACT: BACKGROUND:Mycobacterium tuberculosis (TB) infection induces systemic inflammation that could impact HIV-1 persistence. SETTING:HIV-1-seropositive individuals either with or without pulmonary TB disease were recruited in Kampala, Uganda. METHODS:Plasma cytokines, HIV-1 DNA, and cell-associated (ca)-RNA were compared among those coinfected with TB (cases) to those without TB (controls). TB-coinfected cases and controls were compared at presentation (n = 15 and n = 16, respectively) and at around 6 months after HIV-1 treatment initiation among those who had achieved virologic suppression (n = 6 and n = 8, respectively). At follow-up, the TB-coinfected cases had also finished TB treatment. RESULTS:Before treatment, the TB-coinfected cases as compared to the controls had higher levels of soluble(s)-CD163 (P = 0.0002) and interleukin-6 (P = 0.006) but lower levels of macrophage chemoattractant protein-1 (P = 0.04). After treatment, the TB-coinfected cases as compared to controls still had higher plasma s-CD163 levels (P = 0007). Controls as compared to the coinfected cases had higher ca-RNA per DNA template both at baseline (P = 0.03) and at follow-up (P = 0.07). Levels of ca-RNA per DNA copy at follow-up showed a negative correlation with baseline plasma s-CD163 (P = 0.008) and interleukin-6 (P = 0.05) levels. CONCLUSIONS:TB disease is associated with inflammation and decreased HIV-1 RNA expression relative to the number of infected cells, both before and after viral suppression. Infections present before antiretroviral initiation impact HIV-1 latency.

SUBMITTER: Olson A

PROVIDER: S-EPMC6506856 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Brief Report: Pulmonary Tuberculosis Is Associated With Persistent Systemic Inflammation and Decreased HIV-1 Reservoir Markers in Coinfected Ugandans.

Olson Alex A Ragan Elizabeth J EJ Nakiyingi Lydia L Lin Nina N Jacobson Karen R KR Ellner Jerrold J JJ Manabe Yukari C YC Sagar Manish M

Journal of acquired immune deficiency syndromes (1999) 20181101 3

<h4>Background</h4>Mycobacterium tuberculosis (TB) infection induces systemic inflammation that could impact HIV-1 persistence.<h4>Setting</h4>HIV-1-seropositive individuals either with or without pulmonary TB disease were recruited in Kampala, Uganda.<h4>Methods</h4>Plasma cytokines, HIV-1 DNA, and cell-associated (ca)-RNA were compared among those coinfected with TB (cases) to those without TB (controls). TB-coinfected cases and controls were compared at presentation (n = 15 and n = 16, respec ...[more]

PMID: 30063648

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Project description:BackgroundThe incidence of tuberculosis (TB) is high among human immunodeficiency virus (HIV) infected Ugandans. Recent evidence suggests that Chronic Pulmonary Aspergillosis and Aspergillus sensitisation might be responsible for significant mortality in patients treated for tuberculosis in Uganda.MethodsWe retrieved and tested paired serum aliquots for 101 HIV-TB co-infected patients at the beginning and week 24 of TB treatment. We tested samples for Aspergillus-specific immunoglobulin G (IgG) and immunoglobulin E (IgE) using ImmunoCAP®; and Aspergillus-specific IgG and total serum IgE using Immulite® immunoassays. We compared antibody levels between baseline and week 24, relating them to selected baseline characteristics.Results10% of the patients had elevated Aspergillus-specific IgE (Aspergillus sensitization) and Aspergillus-specific IgG antibodies were elevated in 9% of the patients at the end of TB treatment. There was a significant fall in the Aspergillus-specific IgG antibody levels between baseline and week 24 (P = 0.02). Patients with cluster of differentiation 4 (CD4) T-cell count <100 cells/μl and those who were not on anti-retroviral therapy at baseline had more elevated Aspergillus-specific IgG antibodies (P = 0.01, P = 0.03). The ImmunoCAP® Aspergillus-specific IgG antibody titres were higher at week 24 than baseline with more positives at week 24; even though the difference in means was small. However, this difference was statistically significant (P = 0.02). Pulmonary infiltrates were the commonest x-ray abnormality and only 5% of the patients had pulmonary cavities on chest x-ray at week 24.ConclusionThese results suggest that Aspergillus infection may complicate active pulmonary TB and further studies including fungal culture and thoracic imaging may now be indicated to measure the prevalence of pulmonary aspergillosis complicating tuberculosis.Trial registrationThe SOUTH trial was registered prospectively. ClinicalTrials.gov Identifier: NCT01782950 ; Registration date: 4th February 2013; Last verified: 13th April 2015.

Project description:BACKGROUND:Lung remodeling and pulmonary fibrosis are serious, life-threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients. METHODS:The JNK inhibitor CC-930 was evaluated in the house dust mite-induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF (n = 28), with a 4-week, placebo-controlled, double-blind, sequential ascending-dose period (50 mg QD, 100 mg QD, 100 mg BID) and a 52-week open-label treatment-extension period. RESULTS:In the preclinical model, CC-930 attenuated collagen 1A1 gene expression, peribronchiolar collagen deposition, airway mucin MUC5B expression in club cells, and MMP-7 expression in lung, bronchoalveolar lavage fluid, and serum. In the phase I study, CC-930 reduced c-Jun phosphorylation induced by UV radiation in skin. In the phase II IPF study, there was a CC-930 dose-dependent trend in reduction of MMP-7 and SP-D plasma protein levels. The most commonly reported adverse events were increased ALT, increased AST, and upper respiratory tract infection (six subjects each, 21.4 %). A total of 13 subjects (46.4 %) experienced adverse events that led to discontinuation of study drug. Nine out of 28 subjects experienced progressive disease in this study. The mean FVC (% predicted) declined after 26-32 weeks at doses of 100 mg QD and 100 mg BID. Changes in MMP-7, SP-D, and tenascin-C significantly correlated with change in FVC (% predicted). CONCLUSIONS:These results illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support systemic biomarker use for tracking disease progression and the potential clinical benefit of this novel intervention in IPF. Trial registration ClinicalTrials.gov NCT01203943.

Project description:BackgroundThe current understanding of airborne tuberculosis (TB) transmission is based on classic 1950s studies in which guinea pigs were exposed to air from a tuberculosis ward. Recently we recreated this model in Lima, Perú, and in this paper we report the use of molecular fingerprinting to investigate patient infectiousness in the current era of HIV infection and multidrug-resistant (MDR) TB.Methods and findingsAll air from a mechanically ventilated negative-pressure HIV-TB ward was exhausted over guinea pigs housed in an airborne transmission study facility on the roof. Animals had monthly tuberculin skin tests, and positive reactors were removed for autopsy and organ culture for M. tuberculosis. Temporal exposure patterns, drug susceptibility testing, and DNA fingerprinting of patient and animal TB strains defined infectious TB patients. Relative patient infectiousness was calculated using the Wells-Riley model of airborne infection. Over 505 study days there were 118 ward admissions of 97 HIV-positive pulmonary TB patients. Of 292 exposed guinea pigs, 144 had evidence of TB disease; a further 30 were tuberculin skin test positive only. There was marked variability in patient infectiousness; only 8.5% of 118 ward admissions by TB patients were shown by DNA fingerprinting to have caused 98% of the 125 characterised cases of secondary animal TB. 90% of TB transmission occurred from inadequately treated MDR TB patients. Three highly infectious MDR TB patients produced 226, 52, and 40 airborne infectious units (quanta) per hour.ConclusionsA small number of inadequately treated MDR TB patients coinfected with HIV were responsible for almost all TB transmission, and some patients were highly infectious. This result highlights the importance of rapid TB drug-susceptibility testing to allow prompt initiation of effective treatment, and environmental control measures to reduce ongoing TB transmission in crowded health care settings. TB infection control must be prioritized in order to prevent health care facilities from disseminating the drug-resistant TB that they are attempting to treat.

Dataset Information

Brief Report: Pulmonary Tuberculosis Is Associated With Persistent Systemic Inflammation and Decreased HIV-1 Reservoir Markers in Coinfected Ugandans.

Publications

Brief Report: Pulmonary Tuberculosis Is Associated With Persistent Systemic Inflammation and Decreased HIV-1 Reservoir Markers in Coinfected Ugandans.

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