Medical Abstracts

Keyword: tuberculosis

1. Nat Med. 2019 Feb;25(2):255-262. doi: 10.1038/s41591-018-0319-9. Epub 2019 Jan

21.

Prevention of tuberculosis infection and disease by local BCG in repeatedly

exposed rhesus macaques.

Dijkman K(1), Sombroek CC(2), Vervenne RAW(2), Hofman SO(2), Boot C(2), Remarque

EJ(2), Kocken CHM(2), Ottenhoff THM(3), Kondova I(2), Khayum MA(2), Haanstra

KG(2), Vierboom MPM(2), Verreck FAW(4).

Author information:

(1)Biomedical Primate Research Centre, Rijswijk, the Netherlands.

dijkman@bprc.nl.

(2)Biomedical Primate Research Centre, Rijswijk, the Netherlands.

(3)Department of Infectious Diseases, Leiden University Medical Centre, Leiden,

the Netherlands.

(4)Biomedical Primate Research Centre, Rijswijk, the Netherlands.

verreck@bprc.nl.

Tuberculosis (TB) remains the deadliest infectious disease1, and the widely used

Bacillus Calmette-Guérin (BCG) vaccine fails to curb the epidemic. An improved

vaccination strategy could provide a cost-effective intervention to break the

transmission cycle and prevent antimicrobial resistance2,3. Limited knowledge of

the host responses critically involved in protective immunity hampers the

development of improved TB vaccination regimens. Therefore, assessment of new

strategies in preclinical models to select the best candidate vaccines before

clinical vaccine testing remains indispensable. We have previously established in

rhesus macaques (Macaca mulatta) that pulmonary mucosal BCG delivery reduces TB

disease where standard intradermal injection fails4,5. Here, we show that

pulmonary BCG prevents infection by using a repeated limiting-dose Mycobacterium

tuberculosis challenge model and identify polyfunctional T-helper type 17 (TH17)

cells, interleukin-10 and immunoglobulin A as correlates of local protective

immunity. These findings warrant further research into mucosal immunization

strategies and their translation to clinical application to more effectively

prevent the spread of TB.

DOI: 10.1038/s41591-018-0319-9

PMID: 30664782

2. Am J Respir Crit Care Med. 2019 Jan 29. doi: 10.1164/rccm.201807-1361OC. [Epub

ahead of print]

Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities

Using RNA Sequencing.

Dheda K(1), Lenders L(1), Srivastava S(2), Magombedze G(2), Wainwright H(3), Raj

P(4), Bush SJ(2), Pollara G(5), Steyn R(6), Davids M(7), Pooran A(8), Pennel

T(1), Linegar A(6), McNerney R(6), Moodley L(1), Pasipanodya JG(9), Turner

CT(10), Noursadeghi M(11), Warren RM(12), Wakeland E(4), Gumbo T(13).

Author information:

(1)University of Cape Town, Lung Infection and Immunity Unit, Department of

Medicine, Division of Pulmonology and UCT Lung Institute, Cape Town, Western

Cape, South Africa.

(2)Baylor Institute for Immunology Research, 53620, Dallas, Texas, United States.

(3)Groote Schuur Hospital & University of Cape Town, Department of Pathology,

Cape Town, South Africa.

(4)UT Southwestern Medical Center, Immunology, Dallas, Texas, United States.

(5)University College London, Division of Infection & Immunity, London, United

Kingdom of Great Britain and Northern Ireland.

…

RATIONALE: There is poor understanding about protective immunity and the

pathogenesis of cavitation in tuberculosis patients.

OBJECTIVES: To map pathophysiological pathways at anatomically distinct positions

within the human tuberculosis cavity.

METHODS: Biopsies were obtained from eight pre-determined locations within lung

cavities of multidrug-resistant tuberculosis patients undergoing therapeutic

surgical resection (n=14) and healthy lung tissue from non-tuberculosis controls

(n=10). RNA sequencing, immunohistochemistry, and bacterial load determination

was performed at each cavity position. Differentially expressed genes were

normalized to non-tuberculosis controls, and ontologically mapped to identify a

spatially compartmentalized pathophysiological map of the cavity. In silico

perturbation using a novel distance-dependent dynamical sink model was used to

investigate interactions between immune networks and bacterial burden, and to

integrate these identified pathways.

RESULTS: The median (range) lung cavity volume on PET-CT scans was 50cm3

(15-389cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated

human genes. Multiple pro-inflammatory pathways were upregulated in the cavity

wall, while a downregulation 'sink' in the central caseum-fluid interface

characterized 53% of pathways including neuroendocrine signaling, calcium

signaling, TREM-1, reactive oxygen and nitrogen species production, retinoic

acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical

model demonstrated that neuroendocrine, protein kinase C-θ, and TREM-1 pathways,

as well as macrophage and neutrophil numbers, had the highest correlation with

bacterial burden (r>0.6), while T-helper effector systems did not.

CONCLUSION: These data provide novel insights into host immunity to

drug-resistant Immune Mycobacterium tuberculosis-related cavitation. The pathways

defined may serve as useful targets for the design of host-directed therapies,

and transmission prevention interventions.

DOI: 10.1164/rccm.201807-1361OC

PMID: 30694692

3. Lancet Infect Dis. 2019 Feb;19(2):193-202. doi: 10.1016/S1473-3099(18)30613-3.

Epub 2019 Jan 14.

Clinical utility of existing and second-generation interferon-γ release assays

for diagnostic evaluation of tuberculosis: an observational cohort study.

Whitworth HS(1), Badhan A(2), Boakye AA(2), Takwoingi Y(3), Rees-Roberts M(4),

Partlett C(3), Lambie H(5), Innes J(6), Cooke G(7), Lipman M(8), Conlon C(9),

Macallan D(10), Chua F(11), Post FA(12), Wiselka M(13), Woltmann G(14), Deeks

JJ(3), Kon OM(2), Lalvani A(15); Interferon-γ Release Assays for Diagnostic

Evaluation of Active Tuberculosis study group.

Collaborators: Abdoyeku D, Davidson R, Dedicoat M, Kunst H, Loebingher MR, Lynn

W, Nathani N, O'Connell R, Pozniak A, Menzies S.

Author information:

(1)Tuberculosis Research Centre, National Heart and Lung Institute, Imperial

College London, London, UK; Department of Clinical Research, London School of

Hygiene and Tropical Medicine, London, UK.

(2)Tuberculosis Research Centre, National Heart and Lung Institute, Imperial

College London, London, UK; National Institute for Health Research Health

Protection Research Unit in Respiratory Infections, Imperial College London,

London, UK.

(3)Institute of Applied Health Research, University of Birmingham, Birmingham,

UK.

…

Erratum in

Lancet Infect Dis. 2019 Feb;19(2):e39.

Lancet Infect Dis. 2019 Jan 31;:.

BACKGROUND: The clinical utility of interferon-γ release assays (IGRAs) for

diagnosis of active tuberculosis is unclear, although they are commonly used in

countries with a low incidence of tuberculosis. We aimed to resolve this clinical

uncertainty by determining the accuracy and utility of commercially available and

second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in

a low-incidence setting.

METHODS: We did a prospective cohort study of adults with suspected tuberculosis

in routine secondary care in England. Patients were tested for Mycobacterium

tuberculosis infection at baseline with commercially available (T-SPOT.TB and

QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel

M tuberculosis antigens) IGRAs and followed up for 6-12 months to establish

definitive diagnoses. Sensitivity, specificity, positive and negative likelihood

ratios, and predictive values of the tests were determined.

FINDINGS: Of the 1060 adults enrolled in the study, 845 were included in the

analyses and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for

all tuberculosis diagnosis, including culture-confirmed and highly probable

cases, was 81·4% (95% CI 76·6-85·3), which was higher than QFT-GIT (67·3%

[62·0-72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0-96·4) for culture-confirmed tuberculosis and 89·2% (85·2-92·2) when including highly

probable tuberculosis, giving a negative likelihood ratio for all tuberculosis

cases of 0·13 (95% CI 0·10-0·19). Specificity ranged from 86·2% (95% CI

82·3-89·4) for T-SPOT.TB to 80·0% (75·6-83·8) for second-generation IGRAs.

INTERPRETATION: Commercially available IGRAs do not have sufficient accuracy for

diagnostic evaluation of suspected tuberculosis. Second-generation tests,

however, might have sufficiently high sensitivity, low negative likelihood ratio,

and correspondingly high negative predictive value in low-incidence settings to

facilitate prompt rule-out of tuberculosis.

FUNDING: National Institute for Health Research.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(18)30613-3

PMID: 30655049

4. Sci Transl Med. 2019 Jan 16;11(475). pii: eaat2702. doi:

10.1126/scitranslmed.aat2702.

Tuberculosis following PD-1 blockade for cancer immunotherapy.

Barber DL(1), Sakai S(2), Kudchadkar RR(3), Fling SP(4)(5), Day TA(6), Vergara

JA(6), Ashkin D(7), Cheng JH(8), Lundgren LM(5), Raabe VN(9), Kraft CS(10), Nieva

JJ(8), Cheever MA(4)(5), Nghiem PT(11), Sharon E(12).

Author information:

(1)T Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National

Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.

barberd@niaid.nih.gov sharone@mail.nih.gov.

(2)T Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National

Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.

(3)Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory

University School of Medicine, Atlanta, GA 30322, USA.

…

Because of the well-established therapeutic benefit of boosting antitumor

responses through blockade of the T cell inhibitory receptor PD-1, it has been

proposed that PD-1 blockade could also be useful in infectious disease settings,

including Mycobacterium tuberculosis (Mtb) infection. However, in preclinical

models, Mtb-infected PD-1-/- mice mount exaggerated TH1 responses that drive

lethal immunopathology. Multiple cases of tuberculosis during PD-1 blockade have

been observed in patients with cancer, but in humans little is understood about

Mtb-specific immune responses during checkpoint blockade-associated tuberculosis.

Here, we report two more cases. We describe a patient who succumbed to

disseminated tuberculosis after PD-1 blockade for treatment of nasopharyngeal

carcinoma, and we examine Mtb-specific immune responses in a patient with Merkel

cell carcinoma who developed checkpoint blockade-associated tuberculosis and was

successfully treated for the infection. After anti-PD-1 administration,

interferon-γ-producing Mtb-specific CD4 T cells became more prevalent in the

blood, and a tuberculoma developed a few months thereafter. Mtb-specific TH17

cells, CD8 T cells, regulatory T cells, and antibody abundance did not change

before the appearance of the granuloma. These results are consistent with the

murine model data and suggest that boosting TH1 function with PD-1 blockade may

increase the risk or severity of tuberculosis in humans.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original U.S. Government

Works.

DOI: 10.1126/scitranslmed.aat2702

PMID: 30651320

5. Lancet Infect Dis. 2019 Jan;19(1):46-55. doi: 10.1016/S1473-3099(18)30480-8. Epub 2018 Nov 23.

Substitution of ethambutol with linezolid during the intensive phase of treatment

of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label,

phase 2 trial.

Lee JK(1), Lee JY(2), Kim DK(3), Yoon HI(4), Jeong I(2), Heo EY(1), Park YS(5),

Jo YS(5), Lee JH(4), Park SS(1), Park JS(6), Kim J(2), Lee SM(7), Joh JS(2), Lee

CH(5), Lee J(5), Choi SM(5), Park JH(1), Lee SH(6), Cho YJ(6), Lee YJ(6), Kim

SJ(6), Kwak N(5), Hwang YR(1), Kim H(5), Ki J(2), Lim JN(2), Choi HS(6), Lee

M(8), Song T(8), Kim HS(9), Han J(9), Ahn H(9), Hahn S(10), Yim JJ(11).

Author information:

(1)Division of Pulmonary and Critical Care Medicine, Department of Internal

Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical

Center, Seoul, South Korea.

(2)Division of Pulmonary and Critical Care Medicine, Department of Internal

Medicine, National Medical Center, Seoul, South Korea.

(3)Division of Pulmonary and Critical Care Medicine, Department of Internal

Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical

Center, Seoul, South Korea; Department of Internal Medicine, Seoul National

University College of Medicine, Seoul, South Korea.

…

BACKGROUND: Linezolid improves the treatment outcomes of multidrug-resistant

tuberculosis substantially. We investigated whether use of linezolid instead of

ethambutol increases the proportion of sputum culture conversion at 8 weeks of

treatment in patients with pulmonary tuberculosis.

METHODS: We did a phase 2, multicentre, randomised, open-label trial for patients

with pulmonary tuberculosis at the three affiliated hospitals to Seoul National

University and National Medical Center (Seoul-Seongnam, South Korea). Patients,

aged 20-80 years, with a positive sputum for pulmonary tuberculosis, but without

resistance to rifampicin, and current treatment administered for 7 days or fewer,

were randomly assigned at a 1:1:1 ratio into three groups. The control group

received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The

second group used linezolid (600 mg/day) for 2 weeks and the third group for 4

weeks instead of ethambutol for 2 months. We used a minimisation method to

randomise, and stratified according to institution, cavitation on chest

radiographs, and diabetes. The primary endpoint was the proportion of patients

with negative culture conversion of sputum in liquid media after 8 weeks of

treatment. The results of this trial were analysed primarily in the modified

intention-to-treat population. The trial is registered with ClinicalTrials.gov,

number NCT01994460.

FINDINGS: Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were

enrolled and 428 were randomly assigned into either the control group (142

patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks

group (143 patients). Among them, 401 were eligible for primary efficacy

analyses. In the modified intention-to-treat analyses, negative cultures in

liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control

patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of

132 in the linezolid 4 weeks groups. The difference from the control group was

5.4% (95% CI -4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and -1·1%

(-11·3 to 9·1, p=0·83) for the linezolid 4 weeks group. Numbers of patients who

experienced at least one adverse event were similar across the groups (86 [62·8%]

of 137 in control, 79 [57·2%] of 138 in the linezolid 2 weeks group, and 75

[62·0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not

identified in any patient.

INTERPRETATION: Higher rates of culture conversion at 8 weeks of treatment with

short-term use of linezolid were not observed. However, safety analyses and the

resistance profile suggested the potential role of linezolid in shortening of

treatment for drug-susceptible tuberculosis.

FUNDING: Ministry of Health and Welfare, South Korea.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(18)30480-8

PMID: 30477961

6. Annu Rev Med. 2019 Jan 27;70:105-120. doi: 10.1146/annurev-med-040717-051150.

Epub 2018 Nov 7.

The Global Landscape of Tuberculosis Therapeutics.

Tornheim JA(1), Dooley KE(1)(2)(3).

Author information:

(1)Division of Infectious Diseases, Johns Hopkins University School of Medicine,

Baltimore, Maryland 21287, USA; email: kdooley1@jhmi.edu.

(2)Division of Clinical Pharmacology, Johns Hopkins University School of

Medicine, Baltimore, Maryland 21287, USA.

(3)Center for Tuberculosis Research, Johns Hopkins University School of Medicine,

Baltimore, Maryland 21287, USA.

Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains

the number one infectious disease killer worldwide. Despite decades of experience

treating this disease, TB regimens require months of multidrug therapy, even for

latent infections. There have been important recent advances in treatment options

across the spectrum of TB, from latent infection to extensively drug-resistant

(XDR) TB disease. In addition, new, potent drugs are emerging out of the

development pipeline and are being tested in novel regimens in multiple currently

enrolling trials. Shorter, safer regimens for many forms of TB are now available

or are in our near-term vision. We review recent advances in TB therapeutics and

provide an overview of the upcoming clinical trials landscape that will help

define the future of worldwide TB treatment.

DOI: 10.1146/annurev-med-040717-051150

PMID: 30403551

7. Annu Rev Med. 2019 Jan 27;70:77-90. doi: 10.1146/annurev-med-040717-051502. Epub

2018 Aug 20.

Molecular Diagnostics for Mycobacterium tuberculosis Infection.

Dicks KV(1), Stout JE(1).

Author information:

(1)Division of Infectious Diseases and International Health, Department of

Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA;

email: kristen.dicks@duke.edu , jason.stout@dm.duke.edu.

Resistance to antimycobacterial drugs is a major barrier to effective treatment

of Mycobacterium tuberculosis infection. Molecular diagnostic techniques based on

the association between specific gene mutations and phenotypic resistance to

certain drugs offer the opportunity to rapidly ascertain whether drug resistance

is present and to alter treatment before further resistance develops. Current

barriers to successful implementation of rapid diagnostics include imperfect

knowledge regarding the full spectrum of mutations associated with resistance,

limited utilization of molecular diagnostics where they are most needed, and the

requirement for specialized laboratory facilities to perform molecular testing.

Further understanding of genotypic-phenotypic correlates of resistance and

streamlined implementation platforms will be necessary to optimize the public

health impact of molecular resistance testing for M. tuberculosis.

DOI: 10.1146/annurev-med-040717-051502

PMID: 30125128

8. Am J Respir Crit Care Med. 2019 Jan 15;199(2):220-231. doi:

10.1164/rccm.201802-0366OC.

Dose Optimization of H56:IC31 Vaccine for Tuberculosis-Endemic Populations. A

Double-Blind, Placebo-controlled, Dose-Selection Trial.

Suliman S(1)(2), Luabeya AKK(1)(2), Geldenhuys H(1)(2), Tameris M(1)(2), Hoff

ST(3), Shi Z(4), Tait D(5), Kromann I(3), Ruhwald M(3), Rutkowski KT(4), Shepherd

B(4), Hokey D(4), Ginsberg AM(4), Hanekom WA(1)(2), Andersen P(3), Scriba

TJ(1)(2), Hatherill M(1)(2); H56-035 Trial Group.

Collaborators: Oelofse RE, Stone L, Swarts AM, Onrust R, Jacobs G, Coetzee L,

Khomba G, Diamond B, Companie A, Veldsman A, Mulenga H, Cloete Y, Steyn M, Africa

H, Nkantsu L, Smit E, Botes J, Bilek N, Mabwe S.

Author information:

(1)1 South African Tuberculosis Vaccine Initiative, Institute of Infectious

Disease and Molecular Medicine, and.

(2)2 Division of Immunology, Department of Pathology, University of Cape Town,

Cape Town, South Africa.

(3)3 Statens Serum Institut, Copenhagen, Denmark.

(4)4 Aeras, Rockville, Maryland; and.

(5)5 Aeras, Cape Town, South Africa.

RATIONALE: Global tuberculosis (TB) control requires effective vaccines in

TB-endemic countries, where most adults are infected with Mycobacterium

tuberculosis (M.tb).

OBJECTIVES: We sought to define optimal dose and schedule of H56:IC31, an

experimental TB vaccine comprising Ag85B, ESAT-6, and Rv2660c, for M.tb-infected

and M.tb-uninfected adults.

METHODS: We enrolled 98 healthy, HIV-uninfected, bacillus

Calmette-Guérin-vaccinated, South African adults. M.tb infection was defined by

QuantiFERON-TB (QFT) assay. QFT-negative participants received two vaccinations

of different concentrations of H56 in 500 nmol of IC31 to enable dose selection

for further vaccine development. Subsequently, QFT-positive and QFT-negative

participants were randomized to receive two or three vaccinations to compare

potential schedules. Participants were followed for safety and immunogenicity for

292 days.

MEASUREMENTS AND MAIN RESULTS: H56:IC31 showed acceptable reactogenicity profiles

irrespective of dose, number of vaccinations, or M.tb infection. No

vaccine-related severe or serious adverse events were observed. The three H56

concentrations tested induced equivalent frequencies and functional profiles of

antigen-specific CD4 T cells. ESAT-6 was only immunogenic in QFT-negative

participants who received three vaccinations.

CONCLUSIONS: Two or three H56:IC31 vaccinations at the lowest dose induced

durable antigen-specific CD4 T-cell responses with acceptable safety and

tolerability profiles in M.tb-infected and M.tb-uninfected adults. Additional

studies should validate applicability of vaccine doses and regimens to both

QFT-positive and QFT-negative individuals. Clinical trial registered with

www.clinicaltrials.gov (NCT01865487).

DOI: 10.1164/rccm.201802-0366OC

PMID: 30092143

9. Eur Respir J. 2019 Jan 31. pii: 1801184. doi: 10.1183/13993003.01184-2018. [Epub

ahead of print]

Chronic pulmonary aspergillosis commonly complicates treated pulmonary

tuberculosis with residual cavitation.

Page ID(1)(2), Byanyima R(3), Hosmane S(4), Onyachi N(5), Opira C(6), Richardson

M(1)(7), Sawyer R(4), Sharman A(4), Denning DW(1)(2).

Author information:

(1)Division of Infection, Immunity & Respiratory Medicine, Faculty of Biology,

Medicine & Health, The University of Manchester, Manchester Academic Health

Science Centre, UK.

(2)National Aspergillosis Centre, ECMM Excellence Centre of Medical Mycology,

Manchester University NHS Foundation Trust, UK.

(3)Kampala Imaging Centre, Uganda.

(4)Radiology Department, Manchester University NHS Foundation Trust, UK.

(5)Gulu Regional Referral Hospital, Uganda.

(6)St. Mary's Hospital at Lacor, Gulu, Uganda.

(7)Mycology Reference Centre, ECMM Excellence Centre of Medical Mycology,

Manchester University NHS Foundation Trust, UK.

Chronic pulmonary aspergillosis (CPA) complicates treated pulmonary tuberculosis,

with high 5-year mortality. We measured CPA prevalence in this group.398 Ugandans

with treated pulmonary tuberculosis underwent clinical assessment, chest X-ray

and Aspergillus-specific IgG measurement. 285 were resurveyed 2 years later,

including CT thorax in 73 with suspected CPA. CPA was diagnosed in patients

without active tuberculosis who had raised Aspergillus-specific IgG, radiological

features of CPA and chronic cough or haemoptysis.Author-defined CPA was present

in 14 (4.9%) resurvey patients (95% confidence interval 2.8% - 7.9%). CPA was

significantly more common in those with chest X-ray cavitation (26% versus 0.8%,

p<0.001), but possibly less frequent in HIV co-infected patients (3% versus 6.7%,

p=0.177) The annual rate of new CPA development between surveys was 6.5% in those

with chest X-ray cavitation and 0.2% in those without (p<0.001). Absence of

cavitation and pleural thickening on chest X-ray had 100% negative predictive

value for CPA. The combination of raised Aspergillus-specific IgG, chronic cough

or haemoptysis and chest X-ray cavitation had 85.7% sensitivity and 99.6%

specificity for CPA diagnosis.CPA commonly complicates treated pulmonary

tuberculosis with residual chest X-ray cavitation. Chest X-ray alone can exclude

CPA. Addition of serology can diagnose CPA with reasonable accuracy.

Copyright 漏ERS 2019.

DOI: 10.1183/13993003.01184-2018

PMID: 30705126

10. BMC Biol. 2019 Jan 25;17(1):7. doi: 10.1186/s12915-019-0628-6.

A deletion in the RD105 region confers resistance to multiple drugs in

Mycobacterium tuberculosis.

Qin L(1), Wang J(1), Lu J(1), Yang H(1), Zheng R(1), Liu Z(1), Huang X(1), Feng

Y(1), Hu Z(1), Ge B(2).

Author information:

(1)Shanghai Key Laboratory of Tuberculosis, Clinic and Research Center of

Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine,

Shanghai, 200433, China.

(2)Shanghai Key Laboratory of Tuberculosis, Clinic and Research Center of

Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine,

Shanghai, 200433, China. gebaoxue@sibs.ac.cn.

BACKGROUND: The emergence of drug-resistant strains of Mycobacterium tuberculosis

(Mtb), especially those that are multidrug resistant poses a serious threat to

global tuberculosis control. However, the mechanism underlying the occurrence of

drug resistance against more than one drug is poorly understood. Given that the

Beijing/W strains are associated with outbreaks and multidrug resistance, they

may harbor a genetic advantage and provide useful insight into the disease. One

marker found in all Beijing/W Mtb strains is a deletion of RD105 region that

results in a gene fusion, Rv0071/74, with a variable number (3-9) of VDP (V:

Val, D: Asp; P: Pro) repeats (coded by gtggacccg repeat sequences) at the

N-terminal. Here, we report that this variable number of VDP repeats in Rv0071/74

regulates the development of multidrug resistance.

RESULTS: We collected and analyzed 1255 Beijing/W clinical strains. The results

showed that the number of VDP repeats in Rv0071/74 was related to the development

of multidrug resistance, and the deletion of Rv0071/74-9 from Beijing/W

clinical strain restored drug susceptibility. Rv0071/74-9 also increased

resistance to multiple drugs when transferred to different mycobacterial strains.

Cell-free assays indicate that the domain carrying 4-9 VDP repeats (4-9) showed

a variable binding affinity with peptidoglycan and Rv0071/74 cleaves

peptidoglycan. Furthermore, Rv0071/74-9 increased cell wall thickness and

reduced the intracellular concentration of antibiotics.

CONCLUSIONS: These findings not only identify Rv0071/74 with VDP repeats as a

newly identified multidrug resistance gene but also provide a new model for the

development of multiple drug resistance.

DOI: 10.1186/s12915-019-0628-6

PMCID: PMC6347829

PMID: 30683096

11. Clin Pharmacokinet. 2019 Jan 23. doi: 10.1007/s40262-018-00732-2. [Epub ahead of print]

Personalized Tuberculosis Treatment Through Model-Informed Dosing of Rifampicin.

van Beek SW(1), Ter Heine R(1), Keizer RJ(2), Magis-Escurra C(3), Aarnoutse

RE(1), Svensson EM(4)(5).

Author information:

(1)Department of Pharmacy, Radboud Institute for Health Sciences, Radboud

University Medical Center, Nijmegen, The Netherlands.

(2)InsightRX, San Francisco, CA, USA.

(3)Department of Respiratory Diseases, Radboud University Medical

Center-Dekkerswald, Groesbeek, The Netherlands.

(4)Department of Pharmacy, Radboud Institute for Health Sciences, Radboud

University Medical Center, Nijmegen, The Netherlands.

Elin.Svensson@radboudumc.nl.

(5)Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

Elin.Svensson@radboudumc.nl.

BACKGROUND AND OBJECTIVE: This study proposes a model-informed approach for

therapeutic drug monitoring (TDM) of rifampicin to improve tuberculosis (TB)

treatment.

METHODS: Two datasets from pulmonary TB patients were used: a pharmacokinetic

study (34 patients, 373 samples), and TDM data (96 patients, 391 samples)

collected at Radboud University Medical Center, The Netherlands. Nine suitable

population pharmacokinetic models of rifampicin were identified in the literature

and evaluated on the datasets. A model developed by Svensson et al. was found to

be the most suitable based on graphical goodness of fit, residual diagnostics,

and predictive performance. Prediction of individual area under the

concentration-time curve from time zero to 24 h (AUC24) and maximum concentration

(Cmax) employing various sampling strategies was compared with a previously

established linear regression TDM strategy, using sampling at 2, 4, and 6 h, in

terms of bias and precision (mean error [ME] and root mean square error [RMSE]).

RESULTS: A sampling strategy using 2- and 4-h blood collection was selected to be

the most suitable. The bias and precision of the two strategies were comparable,

except that the linear regression strategy was more biased in prediction of the

AUC24 than the model-informed approach (ME of 9.9% and 1.5%, respectively). A

comparison of resulting dose advice, using predictions on a simulated dataset,

showed no significant difference in sensitivity or specificity between the two

methods. The model was successfully implemented in the InsightRX precision dosing

platform.

CONCLUSION: Blood sampling at 2 and 4 h, combined with model-based prediction,

can be used instead of the currently used linear regression strategy, shortening

the sampling by 2 h and one sampling point without performance loss while

simultaneously offering flexibility in sampling times.

DOI: 10.1007/s40262-018-00732-2

PMID: 30671890

12. J Immunol. 2019 Jan 16. pii: ji1801190. doi: 10.4049/jimmunol.1801190. [Epub

ahead of print]

Coexistent Helminth Infection-Mediated Modulation of Chemokine Responses in

Latent Tuberculosis.

Rajamanickam A(1), Munisankar S(1), Bhootra Y(1), Dolla CK(2), Nutman TB(3), Babu

S(4)(3).

Author information:

(1)National Institutes of Health-National Institute for Research in

Tuberculosis-International Center for Excellence in Research, Chennai, India

600031.

(2)National Institute for Research in Tuberculosis, Chennai, India 600031; and.

(3)Laboratory of Parasitic Diseases, National Institute for Allergy and

Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

(4)National Institutes of Health-National Institute for Research in

Tuberculosis-International Center for Excellence in Research, Chennai, India

600031; sbabu@mail.nih.gov.

Coexistent helminth infections are known to modulate T cell and cytokine

responses in latent infection with Mycobacterium tuberculosis However, their role

in modulating chemokine responses in latent tuberculosis (LTB) has not been

explored. Because chemokines play a vital role in the protective immune responses

in LTB, we postulated that coexistent helminth infection could modulate chemokine

production in helminth-LTB coinfection. To test this, we measured the levels of a

panel of CC and CXC chemokines at baseline and following mycobacterial Ag or

mitogen stimulation in individuals with LTB with (Strongyloides stercoralis

+LTB+) or without S. stercoralis (S. stercoralis -LTB+) infection and in

individuals without both infections, healthy controls (HC). At baseline (in the

absence of a stimulus), S. stercoralis +LTB+ individuals exhibited significantly

diminished production of CCL1, CCL2, CCL4, CCL11, CXCL9, CXCL10, and CXCL11 in

comparison with S. stercoralis -LTB+ and/or HC individuals. Upon mycobacterial Ag

stimulation, S. stercoralis +LTB+ individuals exhibited significantly diminished

production of CCL1, CCL2, CCL4, CCL11, CXCL2, CXCL9, and CXCL10 in comparison

with S. stercoralis -LTB+ and/or HC individuals. No differences were observed

upon mitogen stimulation. Finally, after anthelmintic treatment, the baseline

levels of CCL1, CCL2, CCL4, CCL11, and CXCL11 and mycobacterial Ag-stimulated

levels of CCL1, CCL2, CCL11, CXCL2, and CXCL10 were significantly increased in S.

stercoralis +LTB+ individuals. Thus, our data demonstrate that S. stercoralis

+LTB+ individuals are associated with a compromised ability to express both CC

and CXC chemokines and that this defect is at least partially reversible upon

treatment. Hence, coexistent helminth infection induces downmodulation of

chemokine responses in LTB individuals with likely potential effects on

tuberculosis pathogenesis.

Copyright 2019 by The American Association of Immunologists, Inc.

DOI: 10.4049/jimmunol.1801190

PMID: 30651341

13. Drug Metab Rev. 2018 Nov;50(4):466-481. doi: 10.1080/03602532.2018.1559184. Epub 2019 Jan 7.

Novel insights into the pharmacometabonomics of first-line tuberculosis drugs

relating to metabolism, mechanism of action and drug-resistance.

Du Preez I(1), Loots DT(1).

Author information:

(1)a Human Metabolomics , North-West University , Potchefstroom , South Africa.

The World Health Organization recommends the directly observed therapy

short-course (DOTS) regimen, a combination of four first-line antibiotics

(isoniazid, rifampicin, pyrazinamide and ethambutol), for the treatment of active

pulmonary tuberculosis (TB). However, despite the fact that this treatment

regimen is commonly used worldwide, the metabolism and anti-bacterial mechanisms

of these drugs are not yet fully understood. This lack of information ultimately

contributes to the poor patient compliance and the subsequent treatment failure

and post treatment relapse seen in some TB patients. Pharmacometabonomics, the

latest addition to the omics research domain, focuses on the identification of

drug-induced metabolome variations. The observed metabolite changes can be used

to better understand drug metabolism, drug action and drug-resistance mechanisms.

In this review, we summarize the generally known biological mechanisms of the

first-line TB drugs included in the DOTS program, and we additionally elaborate

on the contribution that pharmacometabonomics has made to the expansion of this

knowledge.

DOI: 10.1080/03602532.2018.1559184

PMID: 30558443

14. Eur Respir J. 2019 Jan 10;53(1). pii: 1801030. doi: 10.1183/13993003.01030-2018.

Print 2019 Jan.

Interventions to improve retention-in-care and treatment adherence among patients

with drug-resistant tuberculosis: a systematic review.

Law S(1), Daftary A(1)(2)(3), O'Donnell M(3)(4), Padayatchi N(3), Calzavara L(5),

Menzies D(1)(2).

Author information:

(1)Department of Epidemiology, Biostatistics and Occupational Health, McGill

University, Montreal, QC, Canada.

(2)McGill International TB Centre, McGill University, Montreal, QC, Canada.

(3)CAPRISA-MRC TB-HIV Pathogenesis and Treatment Unit, Durban, South Africa.

(4)Division of Pulmonary, Allergy and Critical Care Medicine, and Department of

Epidemiology, Mailman School of Public Health, Columbia University Medical

Center, New York, NY, USA.

(5)Dalla Lana School of Public Health, University of Toronto, Toronto, ON,

Canada.

The global loss to follow-up (LTFU) rate among drug-resistant tuberculosis

(DR-TB) patients remains high at 15%. We conducted a systematic review to explore

interventions to reduce LTFU during DR-TB treatment.We searched for studies

published between January 2000 and December 2017 that provided any form of

psychosocial or material support for patients with DR-TB. We estimated point

estimates and 95% confidence intervals of the proportion LTFU. We performed

subgroup analyses and pooled estimates using an exact binomial likelihood

approach.We included 35 DR-TB cohorts from 25 studies, with a pooled proportion

LTFU of 17 (12-23)%. Cohorts that received any form of psychosocial or material

support had lower LTFU rates than those that received standard care. Psychosocial

support throughout treatment, via counselling sessions or home visits, was

associated with lower LTFU rates compared to when support was provided through a

limited number of visits or not at all.Our review suggests that psychosocial

support should be provided throughout DR-TB treatment in order to reduce

treatment LTFU. Future studies should explore the potential of providing

self-administered therapy complemented with psychosocial support during the

continuation phase.

Copyright 漏ERS 2019.

DOI: 10.1183/13993003.01030-2018

PMID: 30309972

15. J Infect Dis. 2019 Jan 9;219(3):459-469. doi: 10.1093/infdis/jiy526.

The MmpS6-MmpL6 Operon Is an Oxidative Stress Response System Providing Selective

Advantage to Mycobacterium tuberculosis in Stress.

Arumugam P(1)(2), Shankaran D(1)(2), Bothra A(1)(2), Gandotra S(1)(2), Rao

V(1)(2).

Author information:

(1)CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.

(2)Academy of Scientific and Innovative Research, New Delhi, India.

Background: The stress response adaptability of Mycobacterium tuberculosis (Mtb)

is still unresolved. In this study, we ascribe an important function to the

MmpS6-MmpL6 (M6) operon in Mtb stress management.

Methods: By using a novel promoter probe in a high-throughput unbiased screen, we

identified several quinones as potent inducers of the M6 operon in addition to

triclosan.

Results: Triclosan and plumbagin effectively altered the intracellular redox

potential in Mtb suggestive of oxidative stress in bacteria. Presence of the

functional M6 operon correlated with an enhanced ability of clinical strains to

survive in the presence of triclosan.

Conclusions: Similar to the addition of a powerful reactive oxygen

species-quenching agent such as N-acetyl cysteine in the medium, introduction of

the complete M6 operon was sufficient to increase tolerance of the M6- strains to

triclosan and plumbagin by effectively ablating the change in intracellular redox

potential of Mtb, signifying the importance of this operon in oxidative stress

survival in mycobacteria.

DOI: 10.1093/infdis/jiy526

PMID: 30203030

16. Biosens Bioelectron. 2019 Jan 1;123:141-151. doi: 10.1016/j.bios.2018.07.053.

Epub 2018 Jul 26.

Electrochemical aptasensor using optimized surface chemistry for the detection of

Mycobacterium tuberculosis secreted protein MPT64 in human serum.

Sypabekova M(1), Jolly P(2), Estrela P(3), Kanayeva D(4).

Author information:

(1)Graduate Program in Science, Engineering, and Technology, School of

Engineering, Nazarbayev University, Astana 010000, Kazakhstan; National

Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan; Department

of Biology, School of Science and Technology, Nazarbayev University, Astana

010000, Kazakhstan.

(2)Centre for Biosensors, Bioelectronics and Biodevices (C3Bio) and Department of

Electronic & Electrical Engineering, University of Bath, Calverton Down, Bath BA2

7AY, United Kingdom.

(3)Centre for Biosensors, Bioelectronics and Biodevices (C3Bio) and Department of

Electronic & Electrical Engineering, University of Bath, Calverton Down, Bath BA2

7AY, United Kingdom. Electronic address: P.Estrela@bath.ac.uk.

(4)Department of Biology, School of Science and Technology, Nazarbayev

University, Astana 010000, Kazakhstan. Electronic address: dkanayeva@nu.edu.kz.

Tuberculosis (TB) remains one of the leading causes of mortality worldwide. There

is a great need for the development of diagnostic tests, which are reliable,

sensitive, stable, and low cost to enable early diagnosis of TB in communities

with scarce resources. This study reports the optimization and evaluation of a

synthetic receptor, an aptamer, for the detection of the secreted protein MPT64,

which is a highly immunogenic polypeptide of Mycobacterium tuberculosis, a

causative agent of TB. The study investigates combinatorial effects of an aptamer

linker and a co-adsorbent onto a gold electrode for optimal binding efficiency

and reduced non-specific interactions for label-free detection of MPT64 using

electrochemical impedance spectroscopy. Two types of co-adsorbents and two types

of aptamer linkers were studied and high specificity and sensitivity to MPT64 was

observed for a surface prepared with a thiol PEGylated aptamer

HS-(CH2)6-OP(O)2O-(CH2CH2O)6-TTTTT-aptamer and 6-mercaptohexanol in a ratio of

1:100. The developed aptamer-based sensor was successfully used with spiked human

serum sample with a limit of detection of 81鈥痯M This work demonstrates the use of the MPT64 aptamer as a lower cost, more sustainable and stable alternative of

antibodies for the development of point-of-care TB biosensors decreasing the

detection time from several days or hours to thirty minutes.

Copyright 漏 2018 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.bios.2018.07.053

PMID: 30078622

17. Clin Infect Dis. 2019 Jan 1;68(1):150-156. doi: 10.1093/cid/ciy544.

What if They Don't Have Tuberculosis? The Consequences and Trade-offs Involved in

False-positive Diagnoses of Tuberculosis.

Houben RMGJ(1)(2), Lalli M(1)(2), Kranzer K(2)(3), Menzies NA(4), Schumacher

SG(5), Dowdy DW(6).

Author information:

(1)Tuberculosis Modelling Group, Tuberculosis Centre and Centre for Mathematical

Modelling of Infectious Diseases.

(2)Infectious Disease Epidemiology Department, Faculty of Epidemiology and Public

Health, London School of Hygiene and Tropical Medicine, United Kingdom.

(3)Research Centre Borstel, National and Supranational Reference Laboratory,

Germany.

(4)Department of Global Health and Population, Harvard T. H. Chan School of

Public Health, Boston, Massachusetts.

(5)Foundation for Innovative New Diagnostics, Geneva, Switzerland.

(6)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,

Baltimore, Maryland.

To find the millions of missed tuberculosis (TB) cases, national TB programs are

under pressure to expand TB disease screening and to target populations with

lower disease prevalence. Together with imperfect performance and application of

existing diagnostic tools, including empirical diagnosis, broader screening risks

placing individuals without TB on prolonged treatment. These false-positive

diagnoses have profound consequences for TB patients and prevention efforts, yet

are usually overlooked in policy decision making. In this article we describe the

pathways to a false-positive TB diagnosis, including trade-offs involved in the

development and application of diagnostic algorithms. We then consider the wide

range of potential consequences for individuals, households, health systems, and

reliability of surveillance data. Finally, we suggest practical steps that the TB

community can take to reduce the frequency and potential harms of false-positive

TB diagnosis and to more explicitly assess the trade-offs involved in the

screening and diagnostic process.

DOI: 10.1093/cid/ciy544

PMCID: PMC6293007

PMID: 29982375