New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the ...blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations.
To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases.
We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations.
An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls.
Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.
A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood ...RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test.
Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis M.TB from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI 87-100; specificity 90%, 95% CI 80-97) and TB from OD (sensitivity 93%, 95% CI 83-100; specificity 88%, 95% CI 74-97). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI 85-100; specificity 94%, 95% CI 84-100) and OD patients (sensitivity 100%, 95% CI 100-100; specificity 96%, 95% CI 93-100). Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group.
In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions. Please see later in the article for the Editors' Summary.
Globally there are approximately 9 million new active tuberculosis cases and 1.4 million deaths annually. Effective antituberculosis treatment monitoring is difficult as there are no existing ...biomarkers of poor adherence or inadequate treatment earlier than 2 months after treatment initiation. Inadequate treatment leads to worsening disease, disease transmission and drug resistance.
To determine if blood transcriptional signatures change in response to antituberculosis treatment and could act as early biomarkers of a successful response.
Blood transcriptional profiles of untreated active tuberculosis patients in South Africa were analysed before, during (2 weeks and 2 months), at the end of (6 months) and after (12 months) antituberculosis treatment, and compared to individuals with latent tuberculosis. An active-tuberculosis transcriptional signature and a specific treatment-response transcriptional signature were derived. The specific treatment response transcriptional signature was tested in two independent cohorts. Two quantitative scoring algorithms were applied to measure the changes in the transcriptional response. The most significantly represented pathways were determined using Ingenuity Pathway Analysis.
An active tuberculosis 664-transcript signature and a treatment specific 320-transcript signature significantly diminished after 2 weeks of treatment in all cohorts, and continued to diminish until 6 months. The transcriptional response to treatment could be individually measured in each patient.
Significant changes in the transcriptional signatures measured by blood tests were readily detectable just 2 weeks after treatment initiation. These findings suggest that blood transcriptional signatures could be used as early surrogate biomarkers of successful treatment response.
Summary Background We aimed to assess whether interferon-γ release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than ...that of the tuberculin skin test (TST). Methods Longitudinal studies of the predictive value for active tuberculosis of in-house or commercial IGRAs were identified through searches of PubMed, Embase, Biosis, and Web of Science and complementary manual searches up to June 30, 2011. Eligible studies included adults or children, with or without HIV, who were free of active tuberculosis at study baseline. We summarised incidence rates in forest plots and pooled data with random-effects models when appropriate. We calculated incidence rate ratios (IRR) for rates of disease progression in IGRA-positive versus IGRA-negative individuals. Findings 15 studies had a combined sample size of 26 680 participants. Incidence of tuberculosis during a median follow-up of 4 years (IQR 2–6), even in IGRA-positive individuals, was 4–48 cases per 1000 person-years. Seven studies with no possibility of incorporation bias and reporting baseline stratification on the basis of IGRA results showed a moderate association between positive results and subsequent tuberculosis (pooled unadjusted IRR 2·10, 95% CI 1·42–3·08). Compared with test-negative results, IGRA-positive and TST-positive results were much the same with regard to the risk of tuberculosis (pooled IRR in the five studies that used both was 2·11 95% CI 1·29–3·46 for IGRA vs 1·60 0·94–2·72 for TST at the 10 mm cutoff). However, the proportion of IGRA-positive individuals in seven of 11 studies that assessed both IGRAs and TST was generally lower than TST-positive individuals. Interpretation Neither IGRAs nor the TST have high accuracy for the prediction of active tuberculosis, although use of IGRAs in some populations might reduce the number of people considered for preventive treatment. Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients' preferences rather than on predictive ability alone. Funding Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian Institutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership.
Vitamin D was used to treat tuberculosis (TB) in the preantibiotic era. Prospective studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been ...performed.
To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status.
A double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London, United Kingdom. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks.
The primary outcome measure was assessed with a functional whole blood assay (BCG-lux assay), which measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the readout is expressed as a luminescence ratio (luminescence postinfection/baseline luminescence). IFN-gamma responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared with placebo (mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for difference, 0.01-0.25; p=0.03) but did not affect antigen-stimulated IFN-gamma secretion.
A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection. Clinical trial registered with www.clinicaltrials.gov (NCT 00157066).
Summary Background Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid ...preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy. Methods For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov , number NCT00463086. Findings 1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6–3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8–4·7; hazard ratio HR 0·63, 95% CI 0·41–0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90–4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 0·21–0·86 and 0·43 0·20–0·96; for positive tests 0·86 0·37–2·00 and 0·55 0·26–1·24, respectively). Interpretation Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status. Funding Department of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town).
In high-burden settings, case fatality rates are reported to be between 11% and 32% in hospitalized patients with HIV-associated tuberculosis, yet the underlying causes of mortality remain poorly ...characterized. Understanding causes of mortality could inform the development of novel management strategies to improve survival. We aimed to assess clinical and microbiologic determinants of mortality and to characterize the pathophysiological processes underlying death by evaluating host soluble inflammatory mediators and determined the relationship between these mediators and death as well as biomarkers of disseminated tuberculosis.
Adult patients with HIV hospitalized with a new diagnosis of HIV-associated tuberculosis were enrolled in Cape Town between 2014 and 2016. Detailed tuberculosis diagnostic testing was performed. Biomarkers of tuberculosis dissemination and host soluble inflammatory mediators at baseline were assessed. Of 682 enrolled participants, 576 with tuberculosis (487/576, 84.5% microbiologically confirmed) were included in analyses. The median age was 37 years (IQR = 31-43), 51.2% were female, and the patients had advanced HIV with a median cluster of differentiation 4 (CD4) count of 58 cells/L (IQR = 21-120) and a median HIV viral load of 5.1 log10 copies/mL (IQR = 3.3-5.7). Antituberculosis therapy was initiated in 566/576 (98.3%) and 487/576 (84.5%) started therapy within 48 hours of enrolment. Twelve-week mortality was 124/576 (21.5%), with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Clinical and microbiologic determinants of mortality included disseminated tuberculosis (positive urine lipoarabinomannan LAM, urine Xpert MTB/RIF, or tuberculosis blood culture in 79.6% of deaths versus 60.7% of survivors, p = 0.001), sepsis syndrome (high lactate in 50.8% of deaths versus 28.9% of survivors, p < 0.001), and rifampicin-resistant tuberculosis (16.9% of deaths versus 7.2% of survivors, p = 0.002). Using non-supervised two-way hierarchical cluster and principal components analyses, we describe an immune profile dominated by mediators of the innate immune system and chemotactic signaling (interleukin-1 receptor antagonist IL-1Ra, IL-6, IL-8, macrophage inflammatory protein-1 beta MIP-1β/C-C motif chemokine ligand 4 CCL4, interferon gamma-induced protein-10 IP-10/C-X-C motif chemokine ligand 10 CXCL10, MIP-1 alpha MIP-1α/CCL3), which segregated participants who died from those who survived. This immune profile was associated with mortality in a Cox proportional hazards model (adjusted hazard ratio aHR = 2.2, 95%CI = 1.9-2.7, p < 0.001) and with detection of biomarkers of disseminated tuberculosis. Clinicians attributing causes of death identified tuberculosis as a cause or one of the major causes of death in 89.5% of cases. We did not perform longitudinal sampling and did not have autopsy-confirmed causes of death.
In this study, we did not identify a major contribution from coinfections to these deaths. Disseminated tuberculosis, sepsis syndrome, and rifampicin resistance were associated with mortality. An immune profile dominated by mediators of the innate immune system and chemotactic signaling was associated with both tuberculosis dissemination and mortality. These findings provide pathophysiologic insights into underlying causes of mortality and could be used to inform the development of novel treatment strategies and to develop methods to risk stratify patients to appropriately target novel interventions. Causal relationships cannot be established from this study.
The immune response in tuberculosis O'Garra, Anne; Redford, Paul S; McNab, Finlay W ...
Annual review of immunology,
01/2013, Letnik:
31
Journal Article
Recenzirano
There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of ...these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.
Strains of Mycobacterium tuberculosis vary in virulence. Strains that have caused outbreaks in the United States and United Kingdom have been shown to subvert the innate immune response as a ...potential immune evasion mechanism. There is, however, little information available as to whether these patterns of immune subversion are features of individual strains or characteristic of broad clonal lineages of M. tuberculosis.
Strains from two major modern lineages (lineage 2 East-Asian and lineage 4 Euro-American) circulating in the Western Cape in South Africa as well as a comparator modern lineage (lineage 3 CAS/Delhi) were identified. We assessed two virulence associated characteristics: mycobacterial growth (in liquid broth and monocyte derived macrophages) and early pro-inflammatory cytokine induction.
In liquid culture, Lineage 4 strains grew more rapidly and reached higher plateau levels than other strains (lineage 4 vs. lineage 2 p=0.0024; lineage 4 vs. lineage 3 p=0.0005). Lineage 3 strains were characterized by low and early plateau levels, while lineage 2 strains showed an intermediate growth phenotype. In monocyte-derived macrophages, lineage 2 strains grew faster than lineage 3 strains (p<0.01) with lineage 4 strains having an intermediate phenotype. Lineage 2 strains induced the lowest levels of pro-inflammatory TNF and IL-12p40 as compared to other lineages (lineage 2: median TNF 362 pg/ml, IL-12p40 91 pg/ml; lineage 3: median TNF 1818 pg/ml, IL-12p40 123 pg/ml; lineage 4: median TNF 1207 pg/ml, IL-12p40 205 pg/ml;). In contrast, lineage 4 strains induced high levels of IL-12p40 and intermediate level of TNF. Lineage 3 strains induced high levels of TNF and intermediate levels of IL-12p40.
Strains of M. tuberculosis from the three major modern strain lineages possess distinct patterns of growth and cytokine induction. Rapid growth and immune subversion may be key characteristics to the success of these strains in different human populations.
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