2019年
No.23
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]