Plasma Levels of Cytokines (IL-10, IFN-γ and TNF-α) in Multidrug Resistant Tuberculosis and Drug Responsive Tuberculosis Patients in Ghana

The emergence of multidrug-resistant tuberculosis (MDR–TB) and more recently, extensively drug-resistant (XDR) TB has intensified the need for studies aimed at identifying factors associated with TB drug resistance. This study determined the differences in plasma concentrations of pro-inflammatory (IFN-γ and TNF-α) and anti-inflammatory (IL-10) cytokines in MDR-TB and drug-susceptible (DS) TB patients, in addition to some socio-economic factors. Plasma levels of IL-10, IFN-γ and TNF-α were measured in 83 participants (comprising 49 MDR-TB and 34 DS-TB patients) using sandwich ELISA. Levels of the three cytokines were elevated in MDR-TB patients compared to DS-TB patients. The mean level of IL-10 (7.8 ± 3.61 ρg/mL) measured in MDR-TB cases was relatively higher than those of TNF-α and IFN-γ, and statistically significant (p = 0.0022) when compared to the level of IL-10 (4.8 ± 4.94 ρg/mL) in the DS-TB cases. There were statistically significant associations between MDR-TB and factors such as education level (X2 = 9.895, p = 0.043), employment status (X2 = 19.404, p = 0.001) and alcoholism (X2 = 3.971, p = 0.046). This study adds to the knowledge that IFN-γ, TNF-α and IL-10 play a role in the host response to Mycobacterium tuberculosis (MTB). Alcohol intake can be considered as an important MDR-TB risk factor.

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Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01608-21 ◽

2021 ◽

Author(s):

Tomohiro Sasaki ◽

Elin M. Svensson ◽

Xiaofeng Wang ◽

Yanlin Wang ◽

Jeffrey Hafkin ◽

...

Keyword(s):

Plasma Concentrations ◽

Population Pharmacokinetic Analysis ◽

Apparent Volume ◽

Multidrug Resistant ◽

Volume Of Distribution ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 to 17 years old, enrolled in 2 clinical trials, were utilized for the analysis. The final dataset contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two compartment models for each component with linear elimination were selected to characterize the disposition of delamanid and DM-6705, respectively. The covariates included in the model were body weight on apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible vs film coated tablet) on mean absorption time; age, formulation, and dose on bioavailability of delamanid; age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB, QT corrected by Bazett’s' formula) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc value were less than 10 ms at the simulated Cmax of DM-6705 following administration of maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive delamanid.

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Differential Gene Expression in Response to Adjunctive Recombinant Human Interleukin-2 Immunotherapy in Multidrug-Resistant Tuberculosis Patients

Infection and Immunity ◽

10.1128/iai.66.6.2426-2433.1998 ◽

1998 ◽

Vol 66 (6) ◽

pp. 2426-2433 ◽

Cited By ~ 14

Author(s):

Barbara J. Johnson ◽

Iris Estrada ◽

Zhu Shen ◽

Stan Ress ◽

Paul Willcox ◽

...

Keyword(s):

Differential Display ◽

Interleukin 2 ◽

Multidrug Resistant ◽

Rt Pcr ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Ifn Γ ◽

Baseline Levels

ABSTRACT Administration of low-dose recombinant human interleukin 2 (rhuIL-2) in combination with multidrug chemotherapy to patients with multidrug-resistant tuberculosis (MDR TB) induces measurable changes in in vitro immune response parameters which are associated with changes in the clinical and bacteriologic status of the patients. To determine the molecular basis of these changes, we have used semiquantitative reverse transcriptase-initiated PCR (RT-PCR) and differential display technology. During rhuIL-2 treatment of MDR TB patients, decreased levels of gamma interferon (IFN-γ) mRNA in peripheral blood mononuclear cells (PBMC) relative to baseline levels were observed. However, at the site of a delayed-type hypersensitivity (DTH) response to purified protein derivative of tuberculin (PPD), the expression of cellular IFN-γ and IL-2 mRNAs was increased during rhuIL-2 therapy. Levels of other cytokine mRNAs were not significantly affected by rhuIL-2 administration. Using differential-display RT-PCR, we identified several genes expressed at the DTH skin test site which were up- or down-regulated during rhuIL-2 treatment. Cytochrome oxidase type I mRNA was increased in response to rhuIL-2 therapy relative to baseline levels, as was heterogeneous nuclear ribonuclear protein G mRNA. CD63, clathrin heavy chain, and β-adaptin mRNAs, all of which encode proteins associated with the endocytic vacuolar pathway of cells, were also differentially regulated by rhuIL-2 administration. The differential effects of IL-2 were confirmed in vitro by using PBMC obtained from PPD-positive individuals stimulated withMycobacterium tuberculosis and IL-2. The differential expression of genes may provide a surrogate marker for leukocyte activation at a mycobacterial antigen-specific response site and for the development of an enhanced antimicrobial response which may result in improved outcomes in MDR TB patients.

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Patients with Multidrug-Resistant Tuberculosis Display Impaired Th1 Responses and Enhanced Regulatory T-Cell Levels in Response to an Outbreak of Multidrug-Resistant Mycobacterium tuberculosis M and Ra Strains

Infection and Immunity ◽

10.1128/iai.00224-09 ◽

2009 ◽

Vol 77 (11) ◽

pp. 5025-5034 ◽

Cited By ~ 42

Author(s):

Laura Geffner ◽

Noemí Yokobori ◽

Juan Basile ◽

Pablo Schierloh ◽

Luciana Balboa ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Mononuclear Cells ◽

Multidrug Resistant ◽

Interleukin 4 ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Ifn Γ ◽

Ctl Activity

ABSTRACT In Argentina, multidrug-resistant tuberculosis (MDR-TB) outbreaks emerged among hospitalized patients with AIDS in the early 1990s and thereafter disseminated to the immunocompetent community. Epidemiological, bacteriological, and genotyping data allowed the identification of certain MDR Mycobacterium tuberculosis outbreak strains, such as the so-called strain M of the Haarlem lineage and strain Ra of the Latin America and Mediterranean lineage. In the current study, we evaluated the immune responses induced by strains M and Ra in peripheral blood mononuclear cells from patients with active MDR-TB or fully drug-susceptible tuberculosis (S-TB) and in purified protein derivative-positive healthy controls (group N). Our results demonstrated that strain M was a weaker gamma interferon (IFN-γ) inducer than H37Rv for group N. Strain M induced the highest interleukin-4 expression in CD4+ and CD8+ T cells from MDR- and S-TB patients, along with the lowest cytotoxic T-lymphocyte (CTL) activity in patients and controls. Hence, impairment of CTL activity is a hallmark of strain M and could be an evasion mechanism employed by this strain to avoid the killing of macrophages by M-specific CTL effectors. In addition, MDR-TB patients had an increased proportion of circulating regulatory T cells (Treg cells), and these cells were further expanded upon in vitro M. tuberculosis stimulation. Experimental Treg cell depletion increased IFN-γ expression and CTL activity in TB patients, with M- and Ra-induced CTL responses remaining low in MDR-TB patients. Altogether, these results suggest that immunity to MDR strains might depend upon a balance between the individual host response and the ability of different M. tuberculosis genotypes to drive Th1 or Th2 profiles.

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Faculty Opinions recommendation of Development and evaluation of a pilot nurse case management model to address multidrug-resistant tuberculosis (MDR-TB) and HIV in South Africa.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725239549.793504303 ◽

2015 ◽

Author(s):

Rannakoe Lehloenya

Keyword(s):

South Africa ◽

Case Management ◽

Multidrug Resistant ◽

Management Model ◽

Nurse Case Management ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

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Multidrug-Resistant Tuberculosis (MDR-TB) Control Activities in Kano State, North West Nigeria: Progress so Far

TEXILA INTERNATIONAL JOURNAL OF PUBLIC HEALTH ◽

10.21522/tijph.2013.se.19.02.art002 ◽

2019 ◽

pp. 6-12

Author(s):

Musa K. Bawa

Keyword(s):

Multidrug Resistant ◽

North West ◽

Tb Control ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

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The epidemiologic impact and cost-effectiveness of new tuberculosis vaccines on multidrug-resistant tuberculosis in India and China

BMC Medicine ◽

10.1186/s12916-021-01932-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Chathika K Weerasuriya ◽

Rebecca C Harris ◽

C Finn McQuaid ◽

Fiammetta Bozzani ◽

Yunzhou Ruan ◽

...

Keyword(s):

Cost Effectiveness ◽

Cost Effective ◽

Multidrug Resistant ◽

Second Line ◽

Second Line Therapy ◽

China And India ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Line Therapy ◽

Mdr Tb

Abstract Background Despite recent advances through the development pipeline, how novel tuberculosis (TB) vaccines might affect rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is unknown. We investigated the epidemiologic impact, cost-effectiveness, and budget impact of hypothetical novel prophylactic prevention of disease TB vaccines on RR/MDR-TB in China and India. Methods We constructed a deterministic, compartmental, age-, drug-resistance- and treatment history-stratified dynamic transmission model of tuberculosis. We introduced novel vaccines from 2027, with post- (PSI) or both pre- and post-infection (P&PI) efficacy, conferring 10 years of protection, with 50% efficacy. We measured vaccine cost-effectiveness over 2027–2050 as USD/DALY averted-against 1-times GDP/capita, and two healthcare opportunity cost-based (HCOC), thresholds. We carried out scenario analyses. Results By 2050, the P&PI vaccine reduced RR/MDR-TB incidence rate by 71% (UI: 69–72) and 72% (UI: 70–74), and the PSI vaccine by 31% (UI: 30–32) and 44% (UI: 42–47) in China and India, respectively. In India, we found both USD 10 P&PI and PSI vaccines cost-effective at the 1-times GDP and upper HCOC thresholds and P&PI vaccines cost-effective at the lower HCOC threshold. In China, both vaccines were cost-effective at the 1-times GDP threshold. P&PI vaccine remained cost-effective at the lower HCOC threshold with 49% probability and PSI vaccines at the upper HCOC threshold with 21% probability. The P&PI vaccine was predicted to avert 0.9 million (UI: 0.8–1.1) and 1.1 million (UI: 0.9–1.4) second-line therapy regimens in China and India between 2027 and 2050, respectively. Conclusions Novel TB vaccination is likely to substantially reduce the future burden of RR/MDR-TB, while averting the need for second-line therapy. Vaccination may be cost-effective depending on vaccine characteristics and setting.

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PP581 Catastrophic Costs Of Multidrug-Resistant Tuberculosis: Estimation Based On The Cost Of Treatment In China

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462320002032 ◽

2020 ◽

Vol 36 (S1) ◽

pp. 43-43

Author(s):

Lijun Shen ◽

Shangshang Gu ◽

Fan Zhang ◽

Zhao Liu ◽

Yuehua Liu

Keyword(s):

Market Price ◽

Multidrug Resistant ◽

Policy Support ◽

World Health ◽

Chinese Patients ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Drug Affordability ◽

The Cost

IntroductionChina bears a considerably high burden of multidrug-resistant tuberculosis (MDR-TB). Second-line anti-TB drugs are urgently needed yet domestic MDR-TB drugs are expensive and lack policy support. Patients’ living conditions are closely related to the drug affordability. The national TB prevention programs should play a critical role. The purpose of this study is to measure the cost of treating MDR-TB patients under different treatment schemes and price sources. The results of this study are expected to inform the relevant drug protection policies and provide inputs for further cost-effectiveness analyses.MethodsBased on the treatment plan of China's Multidrug-Resistant Pulmonary Tuberculosis Clinical Path (2012 edition) and the World Health Organization (WHO) Drug-Resistant Tuberculosis Treatment Guide (2018 edition), the treatment costs of MDR-TB were measured under different scenarios. Catastrophic health expenditure was then calculated if the treatment cost exceeds 40 percent of the household's non-subsistence income. National, rural and disposable income per capita in 2018, were used to represent Chinese patients’ affordability.ResultsUnder varied treatment schemes and market price sources in China, the total costs for MDR-TB patients range from 19,401 to 126,703 CNY [2,853 to 18,633 USD] per person. Under current prices, all treatment schemes recommended by the WHO will incur catastrophic costs for Chinese MDR-TB patients. Significant differences were found between rural and urban areas as 52.8 percent of the treatment listed in the 2012 China Guideline would lead to catastrophic cost for rural patients but not urban ones.ConclusionsOur study concludes that the domestic drugs are more expensive than the international purchase price and the treatment of MDR-TB imposes substantial economic burden on patients, especially in the rural areas. The results of the study also indicate that it is urgent for the state to emphasize government responsibility and initiate centralized procurement for price negotiations to reduce the market price of MDR-TB drugs. The urban-rural gap should also be addressed in the design of future policies to ensure the drug affordability for all patients in need.

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Outcomes of Community-Based Systematic Screening of Household Contacts of Patients with Multidrug-Resistant Tuberculosis in Myanmar

Tropical Medicine and Infectious Disease ◽

10.3390/tropicalmed5010002 ◽

2019 ◽

Vol 5 (1) ◽

pp. 2

Author(s):

Nang Thu Thu Kyaw ◽

Aung Sithu ◽

Srinath Satyanarayana ◽

Ajay M. V. Kumar ◽

Saw Thein ◽

...

Keyword(s):

Chest Radiography ◽

Multidrug Resistant ◽

Sputum Smear ◽

Community Based ◽

Household Contacts ◽

Resistant Tuberculosis ◽

Symptom Screening ◽

Multidrug Resistant Tuberculosis ◽

Screening Algorithm ◽

Mdr Tb

Screening of household contacts of patients with multidrug-resistant tuberculosis (MDR-TB) is a crucial active TB case-finding intervention. Before 2016, this intervention had not been implemented in Myanmar, a country with a high MDR-TB burden. In 2016, a community-based screening of household contacts of MDR-TB patients using a systematic TB-screening algorithm (symptom screening and chest radiography followed by sputum smear microscopy and Xpert-MTB/RIF assays) was implemented in 33 townships in Myanmar. We assessed the implementation of this intervention, how well the screening algorithm was followed, and the yield of active TB. Data collected between April 2016 and March 2017 were analyzed using logistic and log-binomial regression. Of 620 household contacts of 210 MDR-TB patients enrolled for screening, 620 (100%) underwent TB symptom screening and 505 (81%) underwent chest radiography. Of 240 (39%) symptomatic household contacts, 71 (30%) were not further screened according to the algorithm. Children aged <15 years were less likely to follow the algorithm. Twenty-four contacts were diagnosed with active TB, including two rifampicin- resistant cases (yield of active TB = 3.9%, 95% CI: 2.3%–6.5%). The highest yield was found among children aged <5 years (10.0%, 95% CI: 3.6%–24.7%). Household contact screening should be strengthened, continued, and scaled up for all MDR-TB patients in Myanmar.

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