Distinct serum biosignatures are associated with different tuberculosis treatment outcomes (original) (raw)
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Determinants of tuberculosis treatment outcomes
2016
support and valuable insights whilst at the Francis Crick Institute, Mill Hill Laboratory. I acknowledge Dr. Lizma Streicher and Dr. Ronnett Seldon for collaborating with me in carrying out of spoligotyping work. I am grateful to Dr. Bruno Andrade and Professor Katalin Wilkinson who supervised carrying out luminex and Elisa assay of plasma and serum bioanlytes. I thank Dr. Bruno Andrade for his valuable insights.
EBioMedicine, 2017
More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8 weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.
A metabolic biosignature of early response to anti-tuberculosis treatment
BMC Infectious Diseases, 2014
The successful treatment of tuberculosis (TB) requires long-term multidrug chemotherapy. Clinical trials to evaluate new drugs and regimens for TB treatment are protracted due to the slow clearance of Mycobacterium tuberculosis (Mtb) infection and the lack of early biomarkers to predict treatment outcome. Advancements in the field of metabolomics make it possible to identify metabolic profiles that correlate with disease states or successful chemotherapy. However, proof-of-concept of this approach has not been provided for a TBearly treatment response biosignature (TB-ETRB).
Immune markers measured before treatment predict outcome of intensive phase tuberculosis therapy
Clinical and Experimental Immunology, 2006
The development of a statistical model based on simple immunological markers which could predict the response to tuberculosis treatment would facilitate clinical trials of new anti-tuberculosis drugs. We have examined the ability of immunological biomarkers, measured at diagnosis and after 4 weeks of treatment, to predict sputum smear status at week 8. Eighteen tuberculosis patients with positive Ziehl-Nielsen (ZN)-stained sputum smears 8 weeks after initiation of treatment (slow response) were matched for age, gender, sputum smear grade and extent of disease on chest radiograph to 18 patients with negative sputum smears at week 8 (fast response). In addition to total white blood cell (WBC) counts and absolute lymphocyte, monocyte and neutrophil numbers, concentrations of six serum markers were measured by enzyme-linked immunosorbent assay (ELISA) in all patients (soluble interleukin-2 receptor alpha (sIL-2Ra), granzyme B, soluble tumour necrosis factor alpha receptors 1 and 2 (sTNF-R1 and-2), nitrotyrosine and interferongamma (IFN-g). At diagnosis, 4 biomarkers (sTNF-R1, total WBC, absolute monocyte and absolute neutrophil numbers) were significantly higher in slow response patients. At week 4, total WBC count and absolute monocyte and neutrophil numbers remained significantly higher in slow responders. Discriminant analysis of the diagnosis and week 4 data provided models for classification of slow response patients with 67% and 83% predictive accuracy. We suggest that treatment response phenotypes can be determined before the start of treatment. Reliable predictive models would allow targeted interventions for patients at risk for slow treatment response to standard tuberculosis therapy.
Scandinavian Journal of Immunology, 2009
Mycobacterium tuberculosis (MTB) is a slow growing bacterium. Therefore, the immune responses associated with resolution of infection or development of disease post-exposure may take several months to evolve. We have carried out a prospective longitudinal study in a high TB transmission setting to determine the evolution of biomarkers in a recently exposed household contact (HC = 77) and their respective sputum positive index cases (TB = 17). Mycobacterium-induced cytokines [interferon-γ (IFN-γ), tumour necrosis factor-α, interleukin-6 (IL-6) and IL-10)] were assessed in whole blood cultures and immunoglobulin G (IgG1) antibodies in plasma. When compared with non-exposed community controls (endemic controls = 59) the HC group at intake showed changes in biomarkers commensurate with recent exposure. The HC group showed significant increases in IFN-γ between 0 and 6 months (paired t-test; P = 0.001) and IL-0 between 6 and 12 months (P = 0.001), most likely reflecting the role of these cytokines in resolution and immune recovery from infection as this HC cohort remained symptom-free for 4 years without prophylactic treatment. When the TB group post-treatment was compared with the HC group, the best discriminators (ANOVA; repeated measures) were IL-10 responses at 0 (P = 0.004) and 6 months (P = 0.001) and IgG1 at 6 (P = 0.004) and 12 months (P = 0.014) with a 3–4 fold higher responses in the TB group. Therefore, within each group, biomarkers show unique profile of responses. These studies highlighted the importance of assessing multiple biomarkers in longitudinal studies for providing better understanding of protective biomarker profiles associated with resolution of clinical and subclinical infections in TB.
Journal of Infectious Diseases, 2014
See the editorial commentary by Khan and Behr on pages 1682-4.) Background. Patients with multidrug-resistant (MDR) tuberculosis may have phenotypic heterogeneity in results of drug-susceptibility tests (DSTs). However, the impact of this on clinical outcomes among patients treated for MDR tuberculosis is unknown. Methods. Phenotypic DST heterogeneity was defined as presence of at least 1 Mycobacterium tuberculosis isolate susceptible to rifampicin and isoniazid recovered <3 months after MDR tuberculosis treatment initiation from a patient with previous documented tuberculosis due to M. tuberculosis resistant to at least rifampicin and isoniazid. The primary outcome was defined as good (ie, cure or treatment completion) or poor (ie, treatment failure, treatment default, or death). A secondary outcome was time to culture conversion. Cox proportional hazard models were used to determine the association between phenotypic DST heterogeneity and outcomes. Results. Phenotypic DST heterogeneity was identified in 33 of 475 patients (7%) with MDR tuberculosis. Poor outcome occurred in 126 patients (28%). Overall, patients with MDR tuberculosis who had phenotypic DST heterogeneity were at greater risk of poor outcome than those with MDR tuberculosis but no phenotypic DST heterogeneity (adjusted hazard ratio [aHR], 2.1; 95% confidence interval [CI], 1.2-3.6). Among HIV-infected patients with MDR tuberculosis, the adjusted hazard for a poor outcome for those with phenotypic DST heterogeneity was 2.4 (95% CI, 1.3-4.2) times that for those without phenotypic DST heterogeneity, whereas among HIV-negative patients with MDR tuberculosis, the adjusted hazard for those with phenotypic DST heterogeneity was 1.5 (95% CI, .5-4.3) times that for those without phenotypic DST heterogeneity. HIV-infected patients with MDR tuberculosis with phenotypic DST heterogeneity also had a longer time to culture conversion than with HIV-infected patients with MDR tuberculosis without phenotypic DST heterogeneity (aHR, 2.9; 95% CI, 1.4-6.0). Conclusions. Phenotypic DST heterogeneity among persons with HIV infection who are being treated for MDR tuberculosis is associated with poor outcomes and longer times to culture conversion.
Exploratory Study on Plasma Immunomodulator and Antibody Profiles in Tuberculosis Patients
Clinical and Vaccine Immunology, 2013
ABSTRACTHost immune responses toMycobacterium tuberculosisare generally able to contain infection and maintain a delicate balance between protection and immunopathology. A shift in this balance appears to underlie active disease observed in about 10% of infected individuals. Effects of local inflammation, combined with anti-M. tuberculosissystemic immune responses, are directly detectable in peripheral circulation, withoutex vivostimulation of blood cells or biopsy of the affected organs. We studied plasma immunomodulator and antibody biomarkers in patients with active pulmonary tuberculosis (TB) by a combination of multiplex microbead immunoassays and computational tools for data analysis. Plasma profiles of 10 immunomodulators and antibodies against eightM. tuberculosisantigens (previously reported by us) were examined in active pulmonary TB patients in a country where TB is endemic, Pakistan. Multiplex analyses were performed on samples from apparently healthy individuals without...