Plasma Biomarkers to Detect Prevalent or Predict Progressive Tuberculosis Associated With Human Immunodeficiency Virus–1

Background The risk of HIV-1 infected individuals developing TB is high while both prognostic and diagnostic tools remain insensitive. The predictive performance of plasma biomarkers to identify HIV-1 infected individuals likely to progress to active disease is unknown. Methods Thirteen preselected analytes were determined from QuantiFERON® Gold in-tube (QFT) plasma samples in 421 HIV-1 infected persons recruited within the screening and enrolment phases of a randomised controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomisation. Individuals were classified into prevalent TB, incident TB and controls. Comparisons between groups, supervised learning methods and weighted correlation network analyses were applied utilising the unstimulated and background-corrected plasma analyte concentrations. Results Unstimulated samples showed higher analyte concentrations in prevalent and incident TB compared to controls. The largest differences were seen for CXCL10, IL-2, IL-1 and TGF-. Predictive model analysis using unstimulated analytes discriminated better between controls and prevalent TB (Area Under the Curve AUC= 0·9), reasonably between incident and prevalent TB (AUC > 0·8), but poorly between controls and incident TB. Unstimulated IL-2 and IFN-γ were ranked at or near the top for all comparisons except the comparison between controls vs incident TB. Models using background adjusted values performed poorly. Conclusions Single plasma biomarkers are unlikely to distinguish between disease states in HIV-1 co-infected individuals and combinations of biomarkers are required. The ability to detect prevalent TB is potentially important, as no blood test hitherto has suggested utility to detect prevalent TB amongst HIV-1 co-infected persons

Effect of HIV on the frequency and number of Mycobacterium tuberculosis-specific CD4+ T cells in blood and the airways in latent tuberculosis infection

HIV-1 infection substantially increases the risk of developing tuberculosis (TB). There is extensive depletion of Mycobacterium tuberculosis (M.tuberculosis)-specific CD4+ T cells in blood in early HIV infection, but little is known about responses in the lungs at this stage. Given that mucosal organs are a principal target for HIV-mediated CD4 destruction, we investigated M.tuberculosis-specific responses in bronchoalveolar lavage (BAL), in persons with latent TB infection and untreated HIV-1 co-infection with preserved CD4 counts. M.tuberculosis-specific CD4+ cytokine responses (IFN-, TNF- and IL-2) were discordant in frequency and function between BAL and blood. Responses in BAL were 15-fold lower in HIV-infected compared to uninfected persons (p=0.048), whilst blood responses were 2-fold lower (p=0.006). However, an increase in T cells in the airways in HIV-infected persons resulted in the overall number of M.tuberculosis-specific CD4+ cells in BAL being similar. Our study highlights the important insights gained from studying TB immunity at the site of disease during HIV infection

Theorems on existence and global dynamics for the Einstein equations

This article is a guide to theorems on existence and global dynamics of solutions of the Einstein equations. It draws attention to open questions in the field. The local-in-time Cauchy problem, which is relatively well understood, is surveyed. Global results for solutions with various types of symmetry are discussed. A selection of results from Newtonian theory and special relativity that offer useful comparisons is presented. Treatments of global results in the case of small data and results on constructing spacetimes with prescribed singularity structure or late-time asymptotics are given. A conjectural picture of the asymptotic behaviour of general cosmological solutions of the Einstein equations is built up. Some miscellaneous topics connected with the main theme are collected in a separate section.Comment: Submitted to Living Reviews in Relativity, major update of Living Rev. Rel. 5 (2002)

Effects of tuberculosis and/or HIV-1 infection on COVID-19 presentation and immune response in Africa

Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8% are HIV-1 co-infected. Two or more co-morbidities are present in 57.7% of participants, including HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated (p < 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8% participants overall but undetectable in combined HIV-1 and tuberculosis. Death occurred in 30/104 (29%) of all COVID-19 patients and in 6/15 (40%) of patients with coincident SARS-CoV-2 and tuberculosis. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis

Theorems on existence and global dynamics for the Einstein equations

This article is a guide to theorems on existence and global dynamics of solutions of the Einstein equations. It draws attention to open questions in the field. The local in time Cauchy problem, which is relatively well understood, is surveyed. Global results for solutions with various types of symmetry are discussed. A selection of results from Newtonian theory and special relativity which offer useful comparisons is presented. Treatments of global results in the case of small data and results on constructing spacetimes with prescribed singularity structure are given. A conjectural picture of the asymptotic behaviour of general cosmological solutions of the Einstein equations is built up. Some miscellaneous topics connected with the main theme are collected in a separate section.Comment: 54 pages, submitted to Living Reviews in Relativit

Trilateral overlap between tuberculosis, diabetes and HIV-1 in a high burden African setting: Implications for TB control

Background The diabetes (DM) burden is growing in countries wh ere tuberculosis and HIVB1 remain major challenges, threatening tuberculosis control efforts. This study determined the association between tuberculosis and diabetes / imp aired glucose regulation (IGR) in the context of HIVB1. Methods A crossBsectional study was conducted at a TB clini c in Cape Town. Participants were screened for DM and IGR, using fasting plasma gluco se, oral glucose tolerance test and HbA1c. Results 414 TB and 438 nonBTB participants were enrolled. I n multivariable analysis, diabetes was associated with tuberculosis (Odds ratio: 2.4; 95% CI 1.3 – 4.3 p=0.005); with 14% population attributable risk fraction. but this ass ociation varied by diagnostic test (driven by HbA1c). The association remained significant in HI VB1Binfected (Odds ratio: 2.4; 95% CI 1.1 – 5.2; p=0.030). A high prevalence of IGR (65.2 % amongst tuberculosis cases) and a significant association with tuberculosis (Odds rat io: 2.3; 95% CI: 1.6 – 3.3; p<0.001) was also found. Conclusions Diabetes and IGR prevalence was high and associated with tuberculosis, particularly in HIVB 1Binfected persons, highlighting the importance of DM screening. The variation in findings by diagnostic test highlights the need for better g lycaemia markers to inform screening in the context of tuberculosis and HIVB1

Tuberculosis, HIV and the association with transient hyperglycaemia in peri-urban South Africa

Background Diabetes mellitus (DM) increases tuberculosis (TB) risk. We assessed the prevalence of hyperglycaemia (DM and impaired glucose regulation (IGR)) in TB patients and the association between hyperglycaemia and TB at enrolment and 3 months after TB treatment in the context of HIV-infection. Methods Adults presenting at a Cape Town TB clinic were enrolled. TB cases were defined by South African guidelines, while non-TB participants were those who presented with respiratory symptoms, negative TB tests and resolution of symptoms 3 months later without TB treatment. HIV status was ascertained through medical records or HIV-testing. All participants were screened for DM using HbA1c and fasting plasma glucose at TB treatment and after 3 months. The association between TB and DM was assessed. Results Overall DM prevalence was 11.9% (95% CI: 9.1–15.4) at enrolment and 9.3% (95% CI: 6.4–13) at follow-up; IGR prevalence was 46.9% (95% CI 42.2–51.8) and 21.5% (95% CI 16.9–26.3) at enrolment and follow-up. TB/DM association was significant at enrolment (OR 2.41 (95% CI 1.3–4.3)) and follow-up (OR 3.3 (95% CI 1.5–7.3)), whilst TB/IGR association was only positive at enrolment OR 2.3 (95% CI 1.6–3.3). The TB/DM association was significant at enrolment in both new and pre-existing DM, but only persisted at follow-up in HIV-1-infected pre-existing DM. Conclusion Our study demonstrated high prevalence of transient hyperglycaemia and a significant TB/DM and TB/IGR association at enrolment in newly diagnosed DM, but persistent hyperglycaemia and TB/DM association in HIV-1-infected pre-existing DM, despite TB therapy

The effect of antiretroviral treatment on selected genes in whole blood from HIV-infected adults sensitised by Mycobacterium tuberculosis

HIV-1 co-infection is a leading cause of susceptibility to tuberculosis (TB), with the risk of TB being increased at all stages of HIV-1 infection. Antiretroviral treatment (ART) is the most effective way to reduce the risk of TB in HIV-1 co-infected people. Studying protective, ART-induced, immune restoration in HIV-1 infected individuals sensitised by Mycobacterium tuberculosis (Mtb) can thus help identify mechanisms of protection against TB. In order to understand ART-mediated prevention of TB in HIV-1 infected adults, we investigated the expression of 30 genes in whole blood from HIV-1 infected patients during the first 6 months of ART-induced immune reconstitution. The 30 selected genes were previously described to be differentially expressed between sorted Mtb specific central and effector memory CD4 T cells. HIV-1 infected persons sensitised by Mtb were recruited in Khayelitsha, South Africa, when initiating ART. RNA was extracted from whole blood at initiation and 1, 3 and 6 months of ART. qRT-PCR was used to determine gene expression and three reference ‘housekeeping’ genes were used to calculate the fold change in the expression of each gene relative to day 0 of ART. Results were assessed longitudinally. We observed a decrease in the expression of a number of genes at 6 months of ART, reflecting a decrease in immune activation. However, following correction for multiple comparisons and increasing CD4 counts, only the decrease in CD27 gene expression remained statistically significant. While not statistically significant, a number of genes also showed increased expression at various timepoints, illustrating the broad regeneration of the T cell pool in HIV-1 infected adults on ART. Our findings generate hypotheses underlying ART- induced protective immune reconstitution and may pave the way for future studies to evaluate ART mediated prevention of TB in HIV-1 infected persons

Rapid, simplified whole blood-based multiparameter assay to quantify and phenotype SARS-CoV-2 specific T cells

Rapid tests to evaluate SARS-CoV-2-specific T cell responses are urgently needed to decipher protective immunity and aid monitoring vaccine-induced immunity. Using a rapid whole blood assay requiring minimal amount of blood, we measured qualitatively and quantitatively SARS-38CoV-2-specific CD4 T cell responses in 31 healthcare workers, using flow cytometry. 100% of COVID-19 convalescent participants displayed a detectable SARS-CoV-2-specific CD4 T cell response. SARS-CoV-2-responding cells were also detected in 40.9% of participants with no COVID-19-associated symptoms or who tested PCR negative. Phenotypic assessment indicated that, in COVID-19 convalescent participants, SARS-CoV-2 CD4 responses displayed an early differentiated memory phenotype with limited capacity to produce IFNɣ. Conversely, in participants with no reported symptoms, SARS-CoV-2 CD4 responses were enriched in late differentiated cells, co-expressing IFNɣ and TNFα and also Granzyme B. This proof-of-concept study presents a scalable alternative to PBMC-based assays to enumerate and phenotype SARS-CoV-2-responding T cells, thus representing a practical tool to monitor adaptive immunity due to natural infection or vaccine trials