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高分SCI文摘

2019年

No.23

来源:tushuguan 发布时间:2020-03-13 浏览次数:
字号: + - 14

Medical Abstracts

Keyword: tuberculosis

1. N Engl J Med. 2019 Dec 19;381(25):2429-2439. doi: 10.1056/NEJMoa1909953. Epub

2019 Oct 29.

Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

Tait DR(1), Hatherill M(1), Van Der Meeren O(1), Ginsberg AM(1), Van Brakel E(1),

Author information:

(1)From the International AIDS Vaccine Initiative (IAVI) (D.R.T.), the South

African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and

Molecular Medicine and Division of Immunology, Department of Pathology (M.H.,

T.J.S., M.T.),…

Comment in

Nature. 2020 Jan;577(7789):145.

BACKGROUND: Results of an earlier analysis of a trial of the M72/AS01E candidate

vaccine against Mycobacterium tuberculosis showed that in infected adults, the

vaccine provided 54.0% protection against active pulmonary tuberculosis disease,

without evident safety concerns. We now report the results of the 3-year final

analysis of efficacy, safety, and immunogenicity.

METHODS: From August 2014 through November 2015, we enrolled adults 18 to 50

years of age with M. tuberculosis infection (defined by positive results on

interferon-γ release assay) without evidence of active tuberculosis disease at

centers in Kenya, South Africa, and Zambia. Participants were randomly assigned

in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered

1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to

prevent active pulmonary tuberculosis disease according to the first case

definition (bacteriologically confirmed pulmonary tuberculosis not associated

with human immunodeficiency virus infection). Participants were followed for 3

years after the second dose. Participants with clinical suspicion of tuberculosis

provided sputum samples for polymerase-chain-reaction assay, mycobacterial

culture, or both. Humoral and cell-mediated immune responses were evaluated until

month 36 in a subgroup of 300 participants. Safety was assessed in all

participants who received at least one dose of M72/AS01E or placebo.

RESULTS: A total of 3575 participants underwent randomization, of whom 3573

received at least one dose of M72/AS01E or placebo, and 3330 received both

planned doses. Among the 3289 participants in the according-to-protocol efficacy

cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26

of the 1663 participants in the placebo group, had cases of tuberculosis that met

the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years).

The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to

71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the

concentrations of M72-specific antibodies and the frequencies of M72-specific

CD4+ T cells increased after the first dose and were sustained throughout the

follow-up period. Serious adverse events, potential immune-mediated diseases, and

deaths occurred with similar frequencies in the two groups.

CONCLUSIONS: Among adults infected with M. tuberculosis, vaccination with

M72/AS01E elicited an immune response and provided protection against progression

to pulmonary tuberculosis disease for at least 3 years. (Funded by

GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598.).

Copyright © 2019 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1909953

PMID: 31661198 [Indexed for MEDLINE]

2. Lancet Infect Dis. 2020 Mar;20(3):318-329. doi: 10.1016/S1473-3099(19)30575-4.

Epub 2019 Dec 19.

Adverse events in adults with latent tuberculosis infection receiving daily

rifampicin or isoniazid: post-hoc safety analysis of two randomised controlled

trials.

Campbell JR(1), Trajman A(2), Cook VJ(3), Johnston JC(4), Adjobimey M(5), Ruslami

R(6), Eisenbeis L(7), Fregonese F(8), Valiquette C(8), Benedetti A(1), Menzies

D(9).

Author information:

(1)Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute,

McGill International TB Centre, McGill University Health Centre Research

Institute, McGill University, Montréal, QC, Canada; Department of Epidemiology

and Biostatistics, McGill University, Montréal, QC, Canada.

(2)Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute,

McGill International TB Centre, McGill University Health Centre Research

Institute, McGill University, Montréal, QC, Canada; Federal University of Rio de

Janeiro, Rio de Janeiro, Brazil.

(3)Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada;

Provincial TB Services, British Columbia Centre for Disease Control, Vancouver,

BC, Canada.

BACKGROUND: An important problem limiting treatment of latent tuberculosis

infection is the occurrence of adverse events with isoniazid. We combined

populations from phase 2 and phase 3 open-label, randomised controlled trials, to

establish risk factors for adverse events during latent tuberculosis infection

treatment.

METHODS: We did a post-hoc safety analysis based on data from two open-label,

randomised controlled trials done in health-care facilities in Australia, Benin,

Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea.

Participants were consenting adults (aged ≥18 years) with a positive latent

tuberculosis infection diagnostic test, indication for treatment, and without

contraindications to rifampicin or isoniazid. Patients were centrally randomly

assigned 1:1 to 4 months of daily 10 mg/kg rifampicin or 9 months of daily 5

mg/kg isoniazid. The primary outcome evaluated was adverse events (including

grade 1-2 rash and all events of grade 3-5) resulting in permanent

discontinuation of study medication and judged possibly or probably related to

study drug by a masked, independent, three-member adjudication panel (trial

registration: NCT00170209; NCT00931736).

FINDINGS: Participants were recruited from April 27, 2004, up until Jan 31, 2007

(phase 2), and Oct 1, 2009, up until Dec 31, 2014 (phase 3). The safety

populations for each group comprised 3205 individuals receiving isoniazid and

3280 receiving rifampicin. Among those receiving isoniazid, 86 (2·7%) of 3205 had

grade 1-2 rash or any grade 3-5 adverse events, more than the 50 (1·5%) of 3280

who had these events with rifampicin (risk difference -1·2%, 95% CI -1·9 to

-0·5). Age was associated with adverse events in adults receiving isoniazid.

Compared with individuals aged 18-34 years, the adjusted odds ratio (OR) for

adverse events was 1·8 (95% CI 1·1-3·0) for individuals aged 35-64 years and 3·0

(1·2-6·8) for individuals aged 65-90 years. With rifampicin, adverse events were

associated with inconsistent medication adherence (adjusted OR 2·0, 1·1-3·6) and

concomitant medication use (2·8, 1·5-5·2), but not age, with an adjusted OR of

1·1 (0·6-2·1) for individuals aged 35-64 years and 1·7 (0·5-4·7) for individuals aged 65-90 years. One treatment-related death occurred in the isoniazid group.

INTERPRETATION: In patients without a contraindication, rifampicin is likely to

be the safest latent tuberculosis infection treatment option. With more

widespread use of rifampicin, rare, but serious adverse events might be seen.

However, within these randomised trials, rifampicin was safer than isoniazid and

adverse events were not associated with older age. Therefore, rifampicin should

become a primary treatment option for latent tuberculosis infection based on its

safety.

FUNDING: Canadian Institutes of Health Research.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(19)30575-4

PMID: 31866327

3. Am J Respir Crit Care Med. 2019 Dec 11. doi: 10.1164/rccm.201905-0969OC. [Epub

ahead of print]

Quantitative Interferon Gamma Release Assay and Tuberculin Skin Test Results to

Predict Incident Tuberculosis: A Prospective Cohort Study.

Gupta RK(1), Lipman M(2)(3), Jackson C(4), Sitch A(5)(6), Southern J(7),

Drobniewski F(8), Deeks JJ(6)(5), Tsou CY(7), Griffiths C(9), Davidson J(7),

Campbell C(7), Stirrup O(4), Noursadeghi M(10), Kunst H(11)(12), Haldar P(13),

Lalvani A(14), Abubakar I(4).

Author information:

(1)University College London, 4919, Institute for Global Health, London, United

Kingdom of Great Britain and Northern Ireland; r.gupta@ucl.ac.uk.

(2)University College London, UCL-TB and UCL Respiratory, London, United Kingdom

of Great Britain and Northern Ireland.

(3)Royal Free London NHS Foundation Trust, 4965, London, United Kingdom of Great

Britain and Northern Ireland.

RATIONALE: Development of diagnostic tools with improved predictive value for

tuberculosis (TB) is a global research priority.

OBJECTIVES: We evaluated whether implementing higher diagnostic thresholds than

currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB and the

tuberculin skin test (TST) might improve prediction of incident TB.

METHODS: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants

was extended by re-linkage to national TB surveillance records (median follow-up

4.7 years). Incidence rates and rate ratios, sensitivities, specificities and

predictive values for incident TB were calculated according to ordinal strata for

quantitative results of QFT-GIT, T-SPOT.TB and TST (with adjustment for prior

BCG).

MEASUREMENTS AND MAIN RESULTS: For all tests, incidence rates and rate ratios

increased with the magnitude of the test result (p<0.0001). Over three years'

follow-up, there was a modest increase in positive predictive value (PPV) with

the higher thresholds (3.0% for QFT-GIT ≥0.35 IU/mL vs. 3.6% for ≥4.00 IU/mL;

3.4% for T-SPOT.TB ≥5 spots vs. 5.0% for ≥50 spots; and 3.1% for BCG-adjusted TST

≥5mm vs. 4.3% for ≥15mm). As thresholds increased, sensitivity to detect incident

TB waned for all tests (61.0% for QFT-GIT ≥0.35 IU/mL vs. 23.2% for ≥4.00 IU/mL;

65.4% for T-SPOT.TB ≥5 spots vs. 27.2% for ≥50 spots; 69.7% for BCG-adjusted TST

≥5mm vs. 28.1% for ≥15mm).

CONCLUSIONS: Implementation of higher thresholds for QFT-GIT, T-SPOT.TB and TST

modestly increases PPV for incident TB, but markedly reduces sensitivity. Novel

biomarkers or validated multivariable risk algorithms are required to improve

prediction of incident TB. This article is open access and distributed under the

terms of the Creative Commons Attribution Non-Commercial No Derivatives License

4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

DOI: 10.1164/rccm.201905-0969OC

PMID: 31825645

4. Clin Microbiol Rev. 2019 Oct 30;33(1). pii: e00100-19. doi: 10.1128/CMR.00100-19.

Print 2019 Dec 18.

Tuberculosis Vaccine Development: Progress in Clinical Evaluation.

Sable SB(1), Posey JE(2), Scriba TJ(3)(4)(5).

Author information:

(1)Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral

Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention,

Atlanta, Georgia, USA SSable@cdc.gov.

(2)Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral

Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention,

Atlanta, Georgia, USA.

(3)South African Tuberculosis Vaccine Initiative, Cape Town, South Africa.

Tuberculosis (TB) is the leading killer among all infectious diseases worldwide

despite extensive use of the Mycobacterium bovis bacille Calmette-Guérin (BCG)

vaccine. A safer and more effective vaccine than BCG is urgently required. More

than a dozen TB vaccine candidates are under active evaluation in clinical trials

aimed to prevent infection, disease, and recurrence. After decades of extensive

research, renewed promise of an effective vaccine against this ancient airborne

disease has recently emerged. In two innovative phase 2b vaccine clinical trials,

one for the prevention of Mycobacterium tuberculosis infection in healthy

adolescents and another for the prevention of TB disease in M.

tuberculosis-infected adults, efficacy signals were observed. These

breakthroughs, based on the greatly expanded knowledge of the M. tuberculosis

infection spectrum, immunology of TB, and vaccine platforms, have reinvigorated

the TB vaccine field. Here, we review our current understanding of natural

immunity to TB, limitations in BCG immunity that are guiding vaccinologists to

design novel TB vaccine candidates and concepts, and the desired attributes of a

modern TB vaccine. We provide an overview of the progress of TB vaccine

candidates in clinical evaluation, perspectives on the challenges faced by

current vaccine concepts, and potential avenues to build on recent successes and

accelerate the TB vaccine research-and-development trajectory.

This is a work of the U.S. Government and is not subject to copyright protection

in the United States. Foreign copyrights may apply.

DOI: 10.1128/CMR.00100-19

PMCID: PMC6822991 [Available on 2020-10-30]

PMID: 31666281

5. J Clin Invest. 2019 Dec 2;129(12):5254-5260. doi: 10.1172/JCI125810.

Mechanisms of reactivation of latent tuberculosis infection due to SIV

coinfection.

Buc?an AN(1), Chatterjee A(2), Singh DK(2), Foreman TW(1), Lee TH(2), Threeton

B(1), Kirkpatrick MG(1), Ahmed M(3), Golden N(1), Alvarez X(1), Hoxie JA(4),

Mehra S(1), Rengarajan J(5)(6), Khader SA(3), Kaushal D(1)(2).

Author information:

(1)Tulane National Primate Research Center, Covington, Louisiana, USA.

(2)Southwest National Primate Research Center, Texas Biomedical Research

Institute, San Antonio, Texas, USA.

(3)Department of Molecular Microbiology, Washington University in St. Louis

School of Medicine, St. Louis, Missouri, USA.

HIV is a major driver of tuberculosis (TB) reactivation. Depletion of CD4+ T

cells is assumed to be the basis behind TB reactivation in individuals with

latent tuberculosis infection (LTBI) coinfected with HIV. Nonhuman primates

(NHPs) coinfected with a mutant simian immunodeficiency virus (SIVΔGY) that does

not cause depletion of tissue CD4+ T cells during infection failed to reactivate

TB. To investigate the contribution of CD4+ T cell depletion relative to other

mechanisms of SIV-induced reactivation of LTBI, we used CD4R1 antibody to deplete

CD4+ T cells in animals with LTBI without lentiviral infection. The mere

depletion of CD4+ T cells during LTBI was insufficient in generating reactivation

of LTBI. Instead, direct cytopathic effects of SIV resulting in chronic immune

activation, along with the altered effector T cell phenotypes and dysregulated T

cell homeostasis, were likely mediators of reactivation of LTBI. These results

revealed important implications for TB control in HIV-coinfected individuals.

DOI: 10.1172/JCI125810

PMCID: PMC6877319

PMID: 31479428

6. Lancet Infect Dis. 2019 Dec;19(12):e437-e443. doi: 10.1016/ S1473-3099(19) 30420-7. Epub 2019 Aug 22.

Improving the cascade of global tuberculosis care: moving from the "what" to the

"how" of quality improvement.

Agins BD(1), Ikeda DJ(2), Reid MJA(3), Goosby E(3), Pai M(4), Cattamanchi A(5).

Author information:

(1)HEALTHQUAL, Institute for Global Health Sciences, University of California,

San Francisco, CA, USA; Division of Global Epidemiology, University of

California, San Francisco, CA, USA; Institute for Implementation Science in

Population Health, City University of New York, NY, USA. Electronic address:

bruce.agins@ucsf.edu.

(2)HEALTHQUAL, Institute for Global Health Sciences, University of California,

San Francisco, CA, USA; Harvard Medical School, Boston, MA, USA.

(3)Division of HIV, Infectious Diseases and Global Medicine, University of

California, San Francisco, CA, USA.

Tuberculosis is preventable, treatable, and curable, yet it has the highest

mortality rate of infectious diseases worldwide. Over the past decade, services

to prevent, screen, diagnose, and treat tuberculosis have been developed and

scaled up globally, but progress to end the disease as a public health threat has

been slow, particularly in low-income and middle-income countries. In these

settings, low-quality tuberculosis prevention, diagnostic, and treatment services

frustrate efforts to translate use of existing tools, approaches, and treatment

regimens into improved individual and public health outcomes. Increasingly

sophisticated methods have been used to identify gaps in quality of tuberculosis

care, but inadequate work has been done to apply these findings to activities

that generate population-level improvements. In this Personal View, we contend

that shifting the focus from the "what" to the "how" of quality improvement will

require National Tuberculosis Programmes to change the way they organise, use

data, implement, and respond to the needs and preferences of people with

tuberculosis and at-risk communities.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(19)30420-7

PMID: 31447305

7. Am J Respir Crit Care Med. 2019 Dec 15;200(12):1531-1538. doi:

10.1164/rccm.201904-0772OC.

Tuberculosis Diagnosis in Children Using Xpert Ultra on Different Respiratory

Specimens.

Zar HJ(1), Workman LJ(1), Prins M(1), Bateman LJ(1), Mbhele SP(2), Whitman CB(1),

Denkinger CM(3)(4), Nicol MP(2)(5).

Author information:

(1)Department of Paediatrics and Child Health, Red Cross War Memorial Children's

Hospital and South African Medical Research Council Unit on Child and Adolescent

Health and.

(2)Division of Medical Microbiology, University of Cape Town, Cape Town, South

Africa.

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

Comment in

Am J Respir Crit Care Med. 2019 Dec 15;200(12):1464-1465.

Rationale: Microbiological confirmation of pulmonary tuberculosis in children is

desirable.Objectives: To investigate the diagnostic accuracy and incremental

yield of Xpert MTB/RIF Ultra (Ultra; Cepheid), a new rapid test, on repeated

induced sputum, nasopharyngeal aspirates, and combinations of specimens.Methods:

Consecutive South African children hospitalized with suspected pulmonary

tuberculosis were enrolled.Measurements and Main Results: Induced sputum (IS) and

nasopharyngeal aspirates (NPAs) were obtained. NPAs were frozen; IS underwent

liquid culture, and an aliquot was frozen. Ultra was performed on thawed NPAs and

IS specimens individually. Children were categorized as confirmed, unconfirmed,

or unlikely tuberculosis according to NIH consensus case definitions. The

diagnostic accuracy of Ultra was compared with liquid culture on IS. In total,

195 children (median age: 23.3 mo; 32 [16.4%] HIV-infected) had one IS and NPA,

and 130 had two NPAs. There were 40 (20.5%) culture-confirmed cases. Ultra was

positive on NPAs in 26 (13.3%) and on IS in 31 (15.9%). Sensitivity and

specificity of Ultra on one NPA were 46% and 98%, respectively, and similar by

HIV status. Sensitivity and specificity of Ultra on one IS were 74.3% and 96.9%

respectively. Combining one NPA and one IS increased sensitivity to 80%.

Sensitivity using Ultra on two NPAs was 54.2%, increasing to 87.5% with an IS

Ultra.Conclusions: IS provides a better specimen than repeated NPA for rapid

diagnosis using Ultra. However, Ultra testing of combinations of specimens

provides a novel strategy that can be adapted to identify most children with

confirmed pulmonary tuberculosis.

DOI: 10.1164/rccm.201904-0772OC

PMCID: PMC6909828

PMID: 31381861

8. J Immunol. 2020 Feb 1;204(3):671-681. doi: 10.4049/jimmunol.1900919. Epub 2019

Dec 23.

Mycobacterium tuberculosis Lipoarabinomannan Activates Human Neutrophils via a

TLR2/1 Mechanism Distinct from Pam3CSK4.

Hook JS(1), Cao M(1), Weng K(1), Kinnare N(1), Moreland JG(2)(3).

Author information:

(1)Department of Pediatrics, University of Texas Southwestern Medical Center,

Dallas, TX 75390; and.

(2)Department of Pediatrics, University of Texas Southwestern Medical Center,

Dallas, TX 75390; and Jessica.Moreland@UTSouthwestern.edu.

(3)Department of Microbiology, University of Texas Southwestern Medical Center,

Dallas, TX 75390.

Neutrophils, polymorphonuclear (PMN) leukocytes, play an important role in the

early innate immune response to Mycobacterium tuberculosis infection in the lung.

Interactions between PMN and mycobacterial lipids impact the activation state of

these migrated cells with consequences for the surrounding tissue in terms of

resolution versus ongoing inflammation. We hypothesized that lipoarabinomannan

from M. tuberculosis (Mtb LAM) would prime human PMN in a TLR2-dependent manner

and investigated this with specific comparison with the purified synthetic TLR2

agonists, Pam3CSK4 and FSL-1. In contrast to Pam3CSK4 and FSL-1, we found Mtb LAM

did not induce any of the classical PMN priming phenotypes, including enhancement

of NADPH oxidase activity, shedding of l-selectin, or mobilization of CD11b.

However, exposure of PMN to Mtb LAM did elicit pro- and anti-inflammatory

cytokine production and release in a TLR2/1-dependent manner, using the TLR1

single-nucleotide polymorphism rs5743618 (1805G/T) as a marker for TLR2/1

specificity. Moreover, Mtb LAM did not elicit p38 MAPK phosphorylation or

endocytosis, although these processes occurred with Pam3CSK4 stimulation, and

were necessary for the early priming events to occur. Interestingly, Mtb LAM did

not abrogate priming responses elicited by Pam3CSK4 Notably, subfractionation of

light membranes from Pam3CSK4 versus Mtb LAM-stimulated cells demonstrated

differential patterns of exocytosis. In summary, Mtb LAM activates PMN via

TLR2/1, resulting in the production of cytokines but does not elicit early PMN

priming responses, as seen with Pam3CSK4 We speculate that the inability of Mtb

LAM to prime PMN may be due to differential localization of TLR2/1 signaling.

Copyright © 2020 by The American Association of Immunologists, Inc.

DOI: 10.4049/jimmunol.1900919

PMID: 31871022

9. Euro Surveill. 2019 Dec;24(50). doi: 10.2807/1560-7917.ES.2019.24.50.1900130.

Towards standardisation: comparison of five whole genome sequencing (WGS)

analysis pipelines for detection of epidemiologically linked tuberculosis cases.

Jajou R(1)(2)(3), Kohl TA(4)(5)(1), Walker T(6), Norman A(7), Cirillo DM(8),

Tagliani E(8), Niemann S(9)(5), de Neeling A(3), Lillebaek T(10)(7), Anthony

RM(3), van Soolingen D(3).

Author information:

(1)These authors contributed equally.

(2)Center of Epidemiology and Surveillance of infectious diseases, National

Institute for Public Health and the Environment (RIVM), Bilthoven, the

Netherlands.

(3)Tuberculosis Reference Laboratory, National Institute for Public Health and

the Environment (RIVM), Bilthoven, the Netherlands.

BackgroundWhole genome sequencing (WGS) is a reliable tool for studying

tuberculosis (TB) transmission. WGS data are usually processed by custom-built

analysis pipelines with little standardisation between them.AimTo compare the

impact of variability of several WGS analysis pipelines used internationally to

detect epidemiologically linked TB cases.MethodsFrom the Netherlands, 535

Mycobacterium tuberculosis complex (MTBC) strains from 2016 were included.

Epidemiological information obtained from municipal health services was available

for all mycobacterial interspersed repeat unit-variable number of tandem repeat

(MIRU-VNTR) clustered cases. WGS data was analysed using five different

pipelines: one core genome multilocus sequence typing (cgMLST) approach and four

single nucleotide polymorphism (SNP)-based pipelines developed in Oxford, United

Kingdom; Borstel, Germany; Bilthoven, the Netherlands and Copenhagen, Denmark.

WGS clusters were defined using a maximum pairwise distance of 12

SNPs/alleles.ResultsThe cgMLST approach and Oxford pipeline clustered all

epidemiologically linked cases, however, in the other three SNP-based pipelines

one epidemiological link was missed due to insufficient coverage. In general, the

genetic distances varied between pipelines, reflecting different clustering

rates: the cgMLST approach clustered 92 cases, followed by 84, 83, 83 and 82

cases in the SNP-based pipelines from Copenhagen, Oxford, Borstel and Bilthoven

respectively.ConclusionConcordance in ruling out epidemiological links was high

between pipelines, which is an important step in the international validation of

WGS data analysis. To increase accuracy in identifying TB transmission clusters,

standardisation of crucial WGS criteria and creation of a reference database of

representative MTBC sequences would be advisable.

DOI: 10.2807/1560-7917.ES.2019.24.50.1900130

PMCID: PMC6918587

PMID: 31847944

10. J Infect Dis. 2019 Dec 13. pii: jiz663. doi: 10.1093/infdis/jiz663. [Epub ahead

of print]

Mycobacterium tuberculosis HN878 infection induces human-like B cell follicles in

mice.

Alberto Choreño-Parra J(1)(2), Bobba S(1), Rangel-Moreno J(3), Ahmed M(1), Mehra

S(4)(5)(6), Rosa B(7), Martin J(7), Mitreva M(7), Kaushal D(4)(8)(9), Zúñiga

J(10)(11), Khader SA(1).

Author information:

(1)Department of Molecular Microbiology, Washington University School of Medicine

in St Louis, St. Louis, MO, USA.

(2)Escuela Nacional de Ciencias Bilógicas, Instituto Politécnico Nacional, Mexico

City, Mexico.

(3)Division of Allergy/Immunology and Rheumatology, University of Rochester

School of Medicine and Dentistry, Rochester, NY, USA.

Specific spatial organization of granulomas within the lungs is crucial for

protective anti-tuberculosis (TB) immune responses. However, only large animal

models such as macaques are thought to reproduce the morphological hallmarks of

human TB granulomas. In this study, we show that infection of mice with clinical

"hypervirulent" Mycobacterium tuberculosis (Mtb) HN878 induces human-like

granulomas composed of bacilli-loaded macrophages surrounded by lymphocytes and

organized localization of germinal centers and B cell follicles. Conversely,

infection with lab-adapted Mtb H37Rv resulted in granulomas that are

characterized by unorganized clusters of macrophages scattered between

lymphocytes. An in-depth exploration of the functions of B cells within these

follicles suggested diverse roles and the activation of signaling pathways

associated with antigen presentation and immune cell recruitment. These findings

support the use of clinical Mtb HN878 strain for infection in mice as an

appropriate model to study immune parameters associated with human TB granulomas.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America. All rights reserved. For permissions, e-mail:

journals.permissions@oup.com.

DOI: 10.1093/infdis/jiz663

PMID: 31832640

11. Clin Infect Dis. 2019 Dec 9. pii: ciz1179. doi: 10.1093/cid/ciz1179. [Epub ahead

of print]

Clinical impact of rapid drug susceptibility testing to accompany

fluoroquinolone-containing universal tuberculosis regimens: a Markov model.

Kendall EA(1), Malhotra S(2), Cook-Scalise S(2), Dowdy DW(3), Denkinger CM(4)(5).

Author information:

(1)Division of Infectious Diseases and Center for Tuberculosis Research, Johns

Hopkins University School of Medicine, Baltimore, Maryland, USA.

(2)Global Alliance for TB Drug Development, New York, NY USA.

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

Baltimore, Maryland, USA.

BACKGROUND: Many candidate regimens for universal treatment of tuberculosis

combine novel and existing, widely-used drugs. Appropriate implementation

requires evidence-based, context-specific drug-susceptibility testing (DST)

strategies.

METHODS: We created a Markov state-transition model of 100,000 adults with TB

receiving a novel, fluoroquinolone (FQ)-containing regimen. We estimated clinical

outcomes and resource utilization with no FQ-DST, universal use of FQ-DST, or

FQ-DST only in patients with rifampin-resistant TB ('targeted FQ-DST'). We

considered scenarios of stronger (South Africa) and weaker (Southeast Asia)

correlation of fluoroquinolone resistance with rifampin resistance.

RESULTS: Relative to no FQ-DST, targeted FQ-DST increased cure of FQ-resistant TB

by 7.5% (interquartile range 6.7-9.2%) in South Africa and 1.7% (0.7 -2.5%) in

Southeast Asia. However, rare FQ resistance among the more-prevalent

rifampin-susceptible TB accounted for 50% of FQ-resistant TB in South Africa and

83% in Southeast Asia. As a result, universal FQ-DST further increased cure of

FQ-resistant TB by 3.4% (2.3-5.4%) in South Africa and 5.8% (5.1-6.3%) in

Southeast Asia. With targeted FQ-DST, one additional patient was cured per 50

(42-70) tests in South Africa and 44 (37-51) in Southeast Asia. When expanding

from targeted to universal FQ-DST, one additional cure required 3500 (2300-5500)

tests in South Africa and 410 (370-450) in Southeast Asia. The impact of FQ-DST

was sensitive to overall treatment effectiveness, regimen robustness to loss of

fluoroquinolone activity, and prevalence of both moxifloxacin and pyrazinamide

resistance.

CONCLUSIONS: FQ-DST improved patient outcomes and was particularly important for

high-risk patient groups and less-robust regimens. A universal strategy was

favored in generalized epidemics of fluoroquinolone resistance.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America. All rights reserved. For permissions, e-mail:

journals.permissions@oup.com.

DOI: 10.1093/cid/ciz1179

PMID: 31813958

12. Clin Infect Dis. 2019 Dec 4. pii: ciz1138. doi: 10.1093/cid/ciz1138. [Epub ahead

of print]

Tuberculosis disease in children and adolescents on therapy with anti-tumor

necrosis factor-alpha agents: a collaborative, multi-centre ptbnet study.

Noguera-Julian A(1)(2)(3)(4), Calzada-HernÁndez J(1), Brinkmann F(5), …

Author information:

(1)Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat

d´Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Hospital Sant

Joan de Déu, Barcelona, Spain.

(2)Departament de Pediatria, Universitat de Barcelona, Barcelona, Spain.

(3)CIBER de Epidemiología y Salud Pública, CIBERESP, Madrid, Spain.

BACKGROUND: In adults, anti-tumor-necrosis-factor (TNF)-α therapy is associated

with progression of latent tuberculosis infection (LTBI) to tuberculosis (TB)

disease. The existing paediatric data are very limited.

METHODS: Retrospective multi-centre study within the Paediatric Tuberculosis

Network European Trials Group, capturing patients <18 years who developed TB

disease during anti-TNF-α therapy.

RESULTS: Sixty-six tertiary healthcare institutions providing care for children

with TB participated. Nineteen cases were identified; Crohn´s disease (n=8;42%)

and juvenile idiopathic arthritis (n=6;32%) were the commonest underlying

conditions. Immune-based TB screening (tuberculin skin test and/or

interferon-gamma release assay) was performed in 15 patients before commencing

anti-TNF-α therapy, but only identified one LTBI case; 13 patients were already

receiving immunosuppressants at the time of screening. The median interval

between starting anti-TNF-α therapy and TB diagnosis was 13.1 (IQR:7.1-20.3)

months. All cases presented with severe disease, predominately miliary TB

(n=14;78%). One case was diagnosed post-mortem. TB was microbiologically

confirmed in 15 cases (79%). The median duration of anti-TB treatment was 50

(IQR:46-66) weeks. Five of 15 (33%) cases who had completed TB treatment had

long-term sequelae.

CONCLUSIONS: The data indicate that LTBI screening is frequently false-negative

in this patient population, likely due to immunosuppressants impairing test

performance. Therefore, patients with immune-mediated diseases should be screened

for LTBI at the point of diagnosis, before commencing immunosuppressive

medication. Children on anti-TNF-α therapy are prone to severe TB disease, and

significant long-term morbidity. Those observations underscore the need for

robust LTBI screening programs in this high-risk patient population, even in low

TB prevalence settings.

© The Author(s) 2019. Published by Oxford University Press for the Infectious

Diseases Society of America. All rights reserved. For permissions, e-mail:

journals.permissions@oup.com.

DOI: 10.1093/cid/ciz1138

PMID: 31796965

13. Thorax. 2019 Dec;74(12):1161-1167. doi: 10.1136/thoraxjnl-2018-212557. Epub 2019 Oct 14.

Biomarkers of iron metabolism facilitate clinical diagnosis in M ycobacterium

tuberculosis infection.

Dai Y(1)(2), Shan W(3), Yang Q(3), Guo J(1), Zhai R(4), Tang X(2), Tang L(5), Tan

Y(6), Cai Y(1), Chen X(7).

Author information:

(1)Guangdong Key Laboratory of Regional Immunity and Diseases, Department of

Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China.

(2)Research Institute of Infectious Diseases, Guangzhou Eighth People's Hospital,

Guangzhou Medical University, Guangzhou, China.

(3)Shenzhen Key Laboratory of Infection & Immunity, Shenzhen Third People's

Hospital, Shenzhen University School of Medicine, Shenzhen, China.

BACKGROUND: Perturbed iron homeostasis is a risk factor for tuberculosis (TB)

progression and an indicator of TB treatment failure and mortality. Few studies

have evaluated iron homeostasis as a TB diagnostic biomarker.

METHODS: We recruited participants with TB, latent TB infection (LTBI), cured TB

(RxTB), pneumonia (PN) and healthy controls (HCs). We measured serum levels of

three iron biomarkers including serum iron, ferritin and transferrin, then

established and validated our prediction model.

RESULTS: We observed and verified that the three iron biomarker levels correlated

with patient status (TB, HC, LTBI, RxTB or PN) and with the degree of lung damage

and bacillary load in patients with TB. We then built a TB prediction model,

neural network (NNET), incorporating the data of the three iron biomarkers. The

model showed good performance for diagnosis of TB, with 83% (95% CI 77 to 87)

sensitivity and 86% (95% CI 83 to 89) specificity in the training data set

(n=663) and 70% (95% CI 58 to 79) sensitivity and 92% (95% CI 86 to 96)

specificity in the test data set (n=220). The area under the curves (AUCs) of the

NNET model to discriminate TB from HC, LTBI, RxTB and PN were all >0.83.

Independent validation of the NNET model in a separate cohort (n=967) produced an

AUC of 0.88 (95% CI 0.85 to 0.91) with 74% (95% CI 71 to 77) sensitivity and 92%

(95% CI 87 to 96) specificity.

CONCLUSIONS: The established NNET TB prediction model discriminated TB from HC,

LTBI, RxTB and PN in a large cohort of patients. This diagnostic assay may

augment current TB diagnostics.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No

commercial re-use. See rights and permissions. Published by BMJ.

DOI: 10.1136/thoraxjnl-2018-212557

PMCID: PMC6902069

PMID: 31611342

Conflict of interest statement: Competing interests: None declared.

14. Eur Respir J. 2019 Dec 19;54(6). pii: 1901522. doi: 10.1183/13993003.01522-2019.

Print 2019 Dec.

Surveillance of adverse events in the treatment of drug-resistant tuberculosis:

first global report.

Borisov S(1)(2), Danila E(3), Maryandyshev A(4), Dalcolmo M(5), Miliauskas S(6),

Author information:

(1)Moscow Research and Clinical Center for TB Control, Moscow Government's Health

Department, Moscow, Russian Federation.

(2)These authors contributed equally.

(3)Clinic of Chest Diseases, Immunology and Allergology, Vilnius University

Medical Faculty, Centre of Pulmonology and Allergology, Vilnius University

Hospital Santaros Klinikos, Vilnius, Lithuania.

The World Health Organization (WHO) recommends that countries implement

pharmacovigilance and collect information on active drug safety monitoring (aDSM)

and management of adverse events.The aim of this prospective study was to

evaluate the frequency and severity of adverse events to anti-tuberculosis (TB)

drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline,

delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO

aDSM project. Adverse events were collected prospectively after attribution to a

specific drug together with demographic, bacteriological, radiological and

clinical information at diagnosis and during therapy. This interim analysis

included patients who completed or were still on treatment at time of data

collection.Globally, 45 centres from 26 countries/regions reported 658 patients

(68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline,

18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with

clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were

classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The

majority of the 57 serious adverse events reported by 55 patients (51 out of 57,

89.5%) ultimately resolved. Among patients reporting serious adverse events, some

drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577),

delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and

clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were

reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one

out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid

and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided

valuable information, but implementation needs scaling-up to support

patient-centred care.

Copyright ©ERS 2019.

DOI: 10.1183/13993003.01522-2019

PMID: 31601711

15. Crit Rev Biotechnol. 2019 Dec;39(8):1056-1077. doi:

10.1080/07388551.2019.1668348. Epub 2019 Sep 25.

Electrochemical-based biosensors for detection of Mycobacterium tuberculosis and

tuberculosis biomarkers.

Golichenari B(1)(2), Nosrati R(3), Farokhi-Fard A(4), Faal Maleki M(5), Gheibi

Hayat SM(6), Ghazvini K(7), Vaziri F(8)(9), Behravan J(1)(9)(10).

Author information:

(1)Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad

University of Medical Sciences , Mashhad , Iran.

(2)Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad

University of Medical Sciences , Mashhad , Iran.

(3)Cellular and Molecular Research Center, Faculty of Medicine, Guilan University

of Medical Sciences , Rasht , Iran.

Early detection of tuberculosis (TB) reduces the interval between infection and

the beginning of treatment. However, commercially available tests cannot

discriminate between BCG-vaccinated healthy persons and patients. Also, they are

not suitable to be used for immunocompromised persons. In recent years,

biosensors have attracted great attention due to their simple utility,

accessibility, and real-time outputs. These sensors are increasingly being

considered as pioneering tools for point-of-care diagnostics in communities with

a high burden of TB and limited accessibility to reference laboratories. Among

other types of biosensors, the electrochemical sensors have the advantages of

low-cost operation, fast processing, simultaneous multi-analyte analyzing,

operating with turbid samples, comparable sensitivity and readily available

miniaturization. Electrochemical biosensors are sub-divided into several

categories including: amperometric, impedimetric, potentiometric, and

conductometric biosensors. The biorecognition element in electrochemical

biosensors is usually based on antibodies (immunosensors), DNAs or PNAs

(genosensors), and aptamers (aptasensors). In either case, whether an interaction

of the antigen-antibody/aptamer or the hybridization of probe with target

mycobacterial DNA is detected, a change in the electrical current occurs that is

recorded and displayed as a plot. Therefore, impedimetric-based methods evaluate

resistance to electron transfer toward an electrode by a Nyquist plot and

amperometric/voltammetric-based methods weigh the electrical current by means of

cyclic voltammetry, square wave voltammetry, and differential pulse voltammetry.

Electrochemical biosensors provide a promising scope for the new era of

diagnostics. As a consequence, they can improve detection of Mycobacterium

tuberculosis traces even in attomolar scales.

DOI: 10.1080/07388551.2019.1668348

PMID: 31550916 [Indexed for MEDLINE]

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