2019年
No.9
Keyword: tuberculosis
1. Nat Med. 2019 Jun;25(6):977-987. doi: 10.1038/s41591-019-0441-3. Epub 2019 May
20.
IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure.
Lu LL(1)(2), Smith MT(3), Yu KKQ(3), Luedemann C(2), Suscovich TJ(2), Grace
PS(2), Cain A(2), Yu WH(2)(4), McKitrick TR(5), Lauffenburger D(4), Cummings
RD(5), Mayanja-Kizza H(6), Hawn TR(3), Boom WH(7), Stein CM(7)(8), Fortune
SM(1)(2), Seshadri C(9), Alter G(10).
Author information:
(1)Department of Immunology and Infectious Diseases, Harvard TH Chan School of
Public Health, Boston, MA, USA.
(2)Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
(3)Department of Medicine, University of Washington, Seattle, WA, USA.
…
Erratum in
Nat Med. 2019 Jun 20;:.
Exposure to Mycobacterium tuberculosis (Mtb) results in heterogeneous clinical
outcomes including primary progressive tuberculosis and latent Mtb infection
(LTBI). Mtb infection is identified using the tuberculin skin test and
interferon-γ (IFN-γ) release assay IGRA, and a positive result may prompt
chemoprophylaxis to prevent progression to tuberculosis. In the present study, we
report on a cohort of Ugandan individuals who were household contacts of patients
with TB. These individuals were highly exposed to Mtb but tested negative disease
by IFN-γ release assay and tuberculin skin test, 'resisting' development of
classic LTBI. We show that 'resisters' possess IgM, class-switched IgG antibody
responses and non-IFN-γ T cell responses to the Mtb-specific proteins ESAT6 and
CFP10, immunologic evidence of exposure to Mtb. Compared to subjects with classic
LTBI, 'resisters' display enhanced antibody avidity and distinct Mtb-specific IgG
Fc profiles. These data reveal a distinctive adaptive immune profile among
Mtb-exposed subjects, supporting an expanded definition of the host response to
Mtb exposure, with implications for public health and the design of clinical
trials.
DOI: 10.1038/s41591-019-0441-3
PMCID: PMC6559862 [Available on 2019-11-20]
PMID: 31110348 [Indexed for MEDLINE]
2. Nat Rev Immunol. 2019 May 21. doi: 10.1038/s41577-019-0174-z. [Epub ahead of
print]
Moving tuberculosis vaccines from theory to practice.
Andersen P(1)(2), Scriba TJ(3).
Author information:
(1)Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark.
pa@ssi.dk.
(2)Department of Immunology and Microbiology, University of Copenhagen,
Copenhagen, Denmark. pa@ssi.dk.
(3)South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease
and Molecular Medicine and Division of Immunology, Department of Pathology,
University of Cape Town, Cape Town, South Africa. thomas.scriba@uct.ac.za.
Tuberculosis (TB) vaccine research has reached a unique point in time.
Breakthrough findings in both the basic immunology of Mycobacterium tuberculosis
infection and the clinical development of TB vaccines suggest, for the first time
since the discovery of the Mycobacterium bovis bacillus Calmette-Guérin (BCG)
vaccine more than a century ago, that a novel, efficacious TB vaccine is
imminent. Here, we review recent data in the light of our current understanding
of the immunology of TB infection and discuss the identification of biomarkers
for vaccine efficacy and the next steps in the quest for an efficacious vaccine
that can control the global TB epidemic.
DOI: 10.1038/s41577-019-0174-z
PMID: 31114037
3. Lancet Infect Dis. 2019 May 30. pii: S1473-3099(19)30001-5. doi:
10.1016/S1473-3099(19)30001-5. [Epub ahead of print]
Novel lipoarabinomannan point-of-care tuberculosis test for people with HIV: a
diagnostic accuracy study.
Broger T(1), Sossen B(2), du Toit E(3), Kerkhoff AD(4), Schutz C(2), Ivanova
Reipold E(1), Ward A(2), Barr DA(5), Macé A(1), Trollip A(6), Burton R(7),
Ongarello S(1), Pinter A(8), Lowary TL(9), Boehme C(1), Nicol MP(3), Meintjes
G(10), Denkinger CM(11).
Author information:
(1)FIND, Geneva, Switzerland.
(2)Department of Medicine, Faculty of Health Sciences, University of Cape Town,
Cape Town, South Africa; Wellcome Center for Infectious Diseases Research in
Africa, Institute of Infectious Disease and Molecular Medicine, University of
Cape Town, Cape Town, South Africa.
(3)Division of Medical Microbiology, University of Cape Town, Cape Town, South
Africa; National Health Laboratory Service, Cape Town, South Africa.
…
BACKGROUND: Most tuberculosis-related deaths in people with HIV could be
prevented with earlier diagnosis and treatment. The only commercially available
tuberculosis point-of-care test (Alere Determine TB LAM Ag [AlereLAM]) has
suboptimal sensitivity, which restricts its use in clinical practice. The novel
Fujifilm SILVAMP TB LAM (FujiLAM) assay has been developed to improve the
sensitivity of AlereLAM. We assessed the diagnostic accuracy of the FujiLAM assay
for the detection of tuberculosis in hospital inpatients with HIV compared with
the AlereLAM assay.
METHODS: For this diagnostic accuracy study, we assessed biobanked urine samples
obtained from the FIND Specimen Bank and the University of Cape Town Biobank,
which had been collected from hospital inpatients (aged ≥18 years) with HIV
during three independent prospective cohort studies done at two South African
hospitals. Urine samples were tested using FujiLAM and AlereLAM assays. The
conduct and reporting of each test was done blind to other test results. The
primary objective was to assess the diagnostic accuracy of FujiLAM compared with
AlereLAM, against microbiological and composite reference standards (including
clinical diagnoses).
FINDINGS: Between April 18, 2018, and May 3, 2018, urine samples from 968
hospital inpatients with HIV were evaluated. The prevalence of
microbiologically-confirmed tuberculosis was 62% and the median CD4 count was 86
cells per μL. Using the microbiological reference standard, the estimated
sensitivity of FujiLAM was 70·4% (95% CI 53·0 to 83·1) compared with 42·3% (31·7
to 51·8) for AlereLAM (difference 28·1%) and the estimated specificity of FujiLAM
was 90·8% (86·0 to 94·4) and 95·0% (87·7-98·8) for AlereLAM (difference -4·2%).Against the composite reference standard, the specificity of both assays was
higher (95·7% [92·0 to 98·0] for FujiLAM vs 98·2% [95·7 to 99·6] for AlereLAM;
difference -2·5%), but the sensitivity of both assays was lower (64·9% [50·1 to
76·7] for FujiLAM vs 38·2% [28·1 to 47·3] for AlereLAM; difference 26·7%).
INTERPRETATION: In comparison to AlereLAM, FujiLAM offers superior diagnostic
sensitivity, while maintaining specificity, and could transform rapid
point-of-care tuberculosis diagnosis for hospital inpatients with HIV. The
applicability of FujiLAM for settings of intended use requires prospective
assessment.
FUNDING: Global Health Innovative Technology Fund, UK Department for
International Development, Dutch Ministry of Foreign Affairs, Bill & Melinda
Gates Foundation, German Federal Ministry of Education and Research, Australian
Department of Foreign Affairs and Trade, Wellcome Trust, Department of Science
and Technology and National Research Foundation of South Africa, and South
African Medical Research Council.
Copyright © 2019 Author(s). Published by Elsevier Ltd. This is an Open Access
article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights
reserved.
DOI: 10.1016/S1473-3099(19)30001-5
PMID: 31155318
4. Nat Commun. 2019 May 27;10(1):2329. doi: 10.1038/s41467-019-10065-8.
Heterogeneous GM-CSF signaling in macrophages is associated with control of
Mycobacterium tuberculosis.
Bryson BD(1)(2), Rosebrock TR(1)(2), Tafesse FG(3), Itoh CY(1)(2), Nibasumba
A(1)(2), Babunovic GH(1)(2), Corleis B(2), Martin C(1)(2), Keegan C(4), Andrade
P(4), Realegeno S(4), Kwon D(2), Modlin RL(4), Fortune SM(5)(6).
Author information:
(1)Harvard T. H. Chan School of Public Health, 655 Huntington Avenue Boston,
Boston, MA, 02115, USA.
(2)Ragon Institute of MGH, MIT, and Harvard, 400 Technology Square Cambridge,
Cambridge, MA, 02139, USA.
(3)Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland,
OR, 97239, USA.
…
Variability in bacterial sterilization is a key feature of Mycobacterium
tuberculosis (Mtb) disease. In a population of human macrophages, there are
macrophages that restrict Mtb growth and those that do not. However, the sources
of heterogeneity in macrophage state during Mtb infection are poorly understood.
Here, we perform RNAseq on restrictive and permissive macrophages and reveal that
the expression of genes involved in GM-CSF signaling discriminates between the
two subpopulations. We demonstrate that blocking GM-CSF makes macrophages more
permissive of Mtb growth while addition of GM-CSF increases bacterial control. In
parallel, we find that the loss of bacterial control that occurs in HIV-Mtb
coinfected macrophages correlates with reduced GM-CSF secretion. Treatment of
coinfected cells with GM-CSF restores bacterial control. Thus, we leverage the
natural variation in macrophage control of Mtb to identify a critical cytokine
response for regulating Mtb survival and identify components of the antimicrobial
response induced by GM-CSF.
DOI: 10.1038/s41467-019-10065-8
PMCID: PMC6536549
PMID: 31133636 [Indexed for MEDLINE]
5. Nat Commun. 2019 May 13;10(1):2128. doi: 10.1038/s41467-019-10110-6.
GWAS for quantitative resistance phenotypes in Mycobacterium tuberculosis reveals
resistance genes and regulatory regions.
Farhat MR(1)(2), Freschi L(3), Calderon R(4), Ioerger T(5), Snyder M(6), Meehan
CJ(7), de Jong B(7), Rigouts L(7), Sloutsky A(8), Kaur D(9), Sunyaev S(3)(10),
van Soolingen D(11), Shendure J(6)(12)(13), Sacchettini J(5), Murray M(14).
Author information:
(1)Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Maha_Farhat@hms.harvard.edu.
(2)Division of Pulmonary and Critical Care, Massachusetts General Hospital,
Boston, MA, USA. Maha_Farhat@hms.harvard.edu.
(3)Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
…
Drug resistance diagnostics that rely on the detection of resistance-related
mutations could expedite patient care and TB eradication. We perform minimum
inhibitory concentration testing for 12 anti-TB drugs together with Illumina
whole-genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB)
isolates. We evaluate genome-wide associations between mutations in MTB genes or
non-coding regions and resistance, followed by validation in an independent data
set of 792 patient isolates. We confirm associations at 13 non-canonical loci,
with two involving non-coding regions. Promoter mutations are measured to have
smaller average effects on resistance than gene body mutations. We estimate the
heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower
than expected contribution from known resistance genes. This study highlights the
complexity of the genomic mechanisms associated with the MTB resistance
phenotype, including the relatively large number of potentially causal loci, and
emphasizes the contribution of the non-coding portion of the genome.
DOI: 10.1038/s41467-019-10110-6
PMCID: PMC6513847
PMID: 31086182 [Indexed for MEDLINE]
6. PLoS Biol. 2019 May 13;17(5):e3000265. doi: 10.1371/journal.pbio.3000265.
eCollection 2019 May.
Transition bias influences the evolution of antibiotic resistance in
Mycobacterium tuberculosis.
Payne JL(1)(2), Menardo F(3)(4), Trauner A(3)(4), Borrell S(3)(4), Gygli
SM(3)(4), Loiseau C(3)(4), Gagneux S(3)(4), Hall AR(1).
Author information:
(1)Institute of Integrative Biology, ETH Zurich, Switzerland.
(2)Swiss Institute of Bioinformatics, Lausanne, Switzerland.
(3)Swiss Tropical and Public Health Institute, Basel, Switzerland.
(4)University of Basel, Basel, Switzerland.
Transition bias, an overabundance of transitions relative to transversions, has
been widely reported among studies of the rates and spectra of spontaneous
mutations. However, demonstrating the role of transition bias in adaptive
evolution remains challenging. In particular, it is unclear whether such biases
direct the evolution of bacterial pathogens adapting to treatment. We addressed
this challenge by analyzing adaptive antibiotic-resistance mutations in the major
human pathogen Mycobacterium tuberculosis (MTB). We found strong evidence for
transition bias in two independently curated data sets comprising 152 and 208
antibiotic-resistance mutations. This was true at the level of mutational paths
(distinct adaptive DNA sequence changes) and events (individual instances of the
adaptive DNA sequence changes) and across different genes and gene promoters
conferring resistance to a diversity of antibiotics. It was also true for
mutations that do not code for amino acid changes (in gene promoters and the 16S
ribosomal RNA gene rrs) and for mutations that are synonymous to each other and
are therefore likely to have similar fitness effects, suggesting that transition
bias can be caused by a bias in mutation supply. These results point to a central
role for transition bias in determining which mutations drive adaptive antibiotic
resistance evolution in a key pathogen.
DOI: 10.1371/journal.pbio.3000265
PMCID: PMC6532934
PMID: 31083647
Conflict of interest statement: The authors have declared that no competing
interests exist.
7. Microbiol Mol Biol Rev. 2019 Mar 27;83(2). pii: e00062-18. doi:
10.1128/MMBR.00062-18. Print 2019 May 15.
Deciphering Within-Host Microevolution of Mycobacterium tuberculosis through
Whole-Genome Sequencing: the Phenotypic Impact and Way Forward.
Ley SD(1), de Vos M(1), Van Rie A(#)(2), Warren RM(#)(3).
Author information:
(1)DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South
African Medical Research Council Centre for Tuberculosis Research; Division of
Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences,
Stellenbosch University, Cape Town, South Africa.
(2)Department of Epidemiology and Social Medicine, Faculty of Medicine and Health
Sciences, University of Antwerp, Antwerp, Belgium.
(3)DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South
African Medical Research Council Centre for Tuberculosis Research; Division of
Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences,
Stellenbosch University, Cape Town, South Africa rw1@sun.ac.za.
(#)Contributed equally
The Mycobacterium tuberculosis genome is more heterogenous and less genetically
stable within the host than previously thought. Currently, only limited data
exist on the within-host microevolution, diversity, and genetic stability of M.
tuberculosis As a direct consequence, our ability to infer M. tuberculosis
transmission chains and to understand the full complexity of drug resistance
profiles in individual patients is limited. Furthermore, apart from the
acquisition of certain drug resistance-conferring mutations, our knowledge on the
function of genetic variants that emerge within a host and their phenotypic
impact remains scarce. We performed a systematic literature review of
whole-genome sequencing studies of serial and parallel isolates to summarize the
knowledge on genetic diversity and within-host microevolution of M. tuberculosis
We identified genomic loci of within-host emerged variants found across multiple
studies and determined their functional relevance. We discuss important remaining
knowledge gaps and finally make suggestions on the way forward.
Copyright © 2019 American Society for Microbiology.
DOI: 10.1128/MMBR.00062-18
PMID: 30918049 [Indexed for MEDLINE]
8. Lancet Infect Dis. 2019 May;19(5):519-528. doi: 10.1016/S1473-3099(18)30753-9.
Epub 2019 Mar 22.
Active and passive case-finding in tuberculosis-affected households in Peru: a
10-year prospective cohort study.
Saunders MJ(1), Tovar MA(2), Collier D(3), Baldwin MR(4), Montoya R(5), Valencia
TR(6), Gilman RH(7), Evans CA(2).
Author information:
(1)Infectious Diseases and Immunity, Imperial College London, and Wellcome Trust
Imperial College Centre for Global Health Research, London, UK; Innovation for
Health and Development (IFHAD), Laboratory of Research and Development,
Universidad Peruana Cayetano Heredia, Lima, Peru; Innovación Por la Salud Y
Desarrollo (IPSYD), Asociación Benéfica PRISMA, Lima, Peru. Electronic address:
matthew.saunders@ifhad.org.
(2)Infectious Diseases and Immunity, Imperial College London, and Wellcome Trust
Imperial College Centre for Global Health Research, London, UK; Innovation for
Health and Development (IFHAD), Laboratory of Research and Development,
Universidad Peruana Cayetano Heredia, Lima, Peru; Innovación Por la Salud Y
Desarrollo (IPSYD), Asociación Benéfica PRISMA, Lima, Peru.
(3)Innovation for Health and Development (IFHAD), Laboratory of Research and
Development, Universidad Peruana Cayetano Heredia, Lima, Peru; Innovación Por la
Salud Y Desarrollo (IPSYD), Asociación Benéfica PRISMA, Lima, Peru.
BACKGROUND: Active case-finding among contacts of patients with tuberculosis is a
global health priority, but the effects of active versus passive case-finding are
poorly characterised. We assessed the contribution of active versus passive
case-finding to tuberculosis detection among contacts and compared sex and
disease characteristics between contacts diagnosed through these strategies.
METHODS: In shanty towns in Callao, Peru, we identified index patients with
tuberculosis and followed up contacts aged 15 years or older for tuberculosis.
All patients and contacts were offered free programmatic active case-finding
entailing sputum smear microscopy and clinical assessment. Additionally, all
contacts were offered intensified active case-finding with sputum smear and
culture testing monthly for 6 months and then once every 4 years. Passive
case-finding at local health facilities was ongoing throughout follow-up.
FINDINGS: Between Oct 23, 2002, and May 26, 2006, we identified 2666 contacts,
who were followed up until March 1, 2016. Median follow-up was 10·0 years (IQR
7·5-11·0). 232 (9%) of 2666 contacts were diagnosed with tuberculosis. The 2-year
cumulative risk of tuberculosis was 4·6% (95% CI 3·5-5·5), and overall incidence
was 0·98 cases (95% CI 0·86-1·10) per 100 person-years. 53 (23%) of 232 contacts
with tuberculosis were diagnosed through active case-finding and 179 (77%) were
identified through passive case-finding. During the first 6 months of the study,
23 (45%) of 51 contacts were diagnosed through active case-finding and 28 (55%)
were identified through passive case-finding. Contacts diagnosed through active
versus passive case-finding were more frequently female (36 [68%] of 53 vs 85
[47%] of 179; p=0·009), had a symptom duration of less than 15 days (nine [25%]
of 36 vs ten [8%] of 127; p=0·03), and were more likely to be sputum
smear-negative (33 [62%] of 53 vs 62 [35%] of 179; p=0·0003).
INTERPRETATION: Although active case-finding made an important contribution to
tuberculosis detection among contacts, passive case-finding detected most of the
tuberculosis burden. Compared with passive case-finding, active case-finding was
equitable, helped to diagnose tuberculosis earlier and usually before a positive
result on sputum smear microscopy, and showed a high burden of undetected
tuberculosis among women.
FUNDING: Wellcome Trust, Department for International Development Civil Society
Challenge Fund, Joint Global Health Trials consortium, Bill & Melinda Gates
Foundation, Imperial College National Institutes of Health Research Biomedical
Research Centre, Foundation for Innovative New Diagnostics, Sir Halley Stewart
Trust, WHO, TB REACH, and IFHAD: Innovation for Health and Development.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access
article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights
reserved.
DOI: 10.1016/S1473-3099(18)30753-9
PMCID: PMC6483977
PMID: 30910427
9. J Antimicrob Chemother. 2019 May 22. pii: dkz215. doi: 10.1093/jac/dkz215. [Epub
ahead of print]
WGS more accurately predicts susceptibility of Mycobacterium tuberculosis to
first-line drugs than phenotypic testing.
Jajou R(1), van der Laan T(1), de Zwaan R(1), Kamst M(1), Mulder A(1), de Neeling
A(1), Anthony R(1), van Soolingen D(1).
Author information:
(1)National Tuberculosis Reference Laboratory, Centre for Infectious Disease
Control, National Institute for Public Health and the Environment (RIVM),
Bilthoven, The Netherlands.
BACKGROUND: Drug-susceptibility testing (DST) of Mycobacterium tuberculosis
complex (MTBC) isolates by the Mycobacteria Growth Indicator Tube (MGIT) approach
is the most widely applied reference standard. However, the use of WGS is
increasing in many developed countries to detect resistance and predict
susceptibility. We investigated the reliability of WGS in predicting drug
susceptibility, and analysed the discrepancies between WGS and MGIT against the
first-line drugs rifampicin, isoniazid, ethambutol and pyrazinamide.
METHODS: DST by MGIT and WGS was performed on MTBC isolates received in
2016/2017. Nine genes and/or their promotor regions were investigated for
resistance-associated mutations: rpoB, katG, fabG1, ahpC, inhA, embA, embB, pncA
and rpsA. Isolates that were discrepant in their MGIT/WGS results and a control
group with concordant results were retested in the MGIT, at the critical
concentration and a lower concentration, and incubated for up to 45 days after
the control tube became positive in the MGIT.
RESULTS: In total, 1136 isolates were included, of which 1121 were routine MTBC
isolates from the Netherlands. The negative predictive value of WGS was ≥99.3%
for all four first-line antibiotics. The majority of discrepancies for isoniazid
and ethambutol were explained by growth at the lower concentrations, and for
rifampicin by prolonged incubation in the MGIT, both indicating low-level
resistance.
CONCLUSIONS: Applying WGS in a country like the Netherlands, with a low TB
incidence and low prevalence of resistance, can reduce the need for phenotypic
DST for ∼90% of isolates and accurately detect mutations associated with
low-level resistance, often missed in conventional DST.
© The Author(s) 2019. Published by Oxford University Press on behalf of the
British Society for Antimicrobial Chemotherapy. All rights reserved. For
permissions, please email: journals.permissions@oup.com.
DOI: 10.1093/jac/dkz215
PMID: 31119271
10. Eur Respir J. 2019 May 16. pii: 1802242. doi: 10.1183/13993003.02242-2018. [Epub
ahead of print]
IL-4 subverts mycobacterial containment in M. tuberculosis-infected human
macrophages.
Pooran A(1), Davids M(1), Nel A(2), Shoko A(3), Blackburn J(2), Dheda K(4)(5).
Author information:
(1)Division of Pulmonology, Department of Medicine and UCT Lung Institute,
University of Cape Town, Cape Town, South Africa.
(2)Department of Integrative Biomedical Sciences; Institute for Infectious
Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
(3)Centre for Proteomics and Genomics Research, Cape Town, South Africa.
(4)Division of Pulmonology, Department of Medicine and UCT Lung Institute,
University of Cape Town, Cape Town, South Africa keertan.dheda@uct.ac.za.
(5)Faculty of Infectious and Tropical Diseases, Department of Immunology and
Infection, London School of Hygiene and Tropical Medicine, London, UK.
Protective immunity against Mycobacterium tuberculosis is poorly understood. The
role of interleukin-4 (IL-4), the archetypal T-helper-2 (Th2) cytokine, in the
immunopathogenesis of human tuberculosis remains unclear.Blood and/or
broncho-alveolar lavage fluid (BAL) were obtained from participants with
pulmonary TB (TB; n=23) and presumed latent TB infection (LTBI; n=22). Messenger
RNA expression levels of interferon-gamma (IFN-γ), IL-4, and its splice variant
IL-4δ2 were determined by real-time PCR. The effect of human recombinant IL-4
(hrIL-4) on mycobacterial survival/containment [colony-forming-units (CFU·mL-1]
was evaluated in M. tuberculosis-infected macrophages co-cultured with
mycobacterial antigen-primed effector T-cells. Regulatory T-cell (Treg) and Th1
cytokine levels were evaluated using flow cytometry.In blood, but not BAL, IL-4
mRNA levels (p=0.02) and the IL-4/IFN-γ ratio (p=0.01) was higher in TB versus
LTBI. hrIL-4 reduced mycobacterial containment in infected macrophages (p<0.008)
in a dose-dependent manner and was associated with an increase in Tregs (p<0.001)
but decreased CD4+Th1 cytokine levels (CD4+IFN-γ+: p<0.001; CD4+TNFα+: p=0.01).
Blocking IL-4 significantly neutralised mycobacterial containment (p=0.03),
CD4+IFNγ+ levels (p=0.03) and Treg expression (p=0.03).IL-4 can subvert
mycobacterial containment in human macrophages, likely via perturbations in Treg
and Th1-linked pathways. These data may have implications in the design of
effective TB vaccines and host-directed therapies.
Copyright ©ERS 2019.
DOI: 10.1183/13993003.02242-2018
PMID: 31097521
11. Clin Infect Dis. 2019 May 10. pii: ciz380. doi: 10.1093/cid/ciz380. [Epub ahead
of print]
Sub-therapeutic rifampicin concentration is associated with unfavourable
tuberculosis treatment outcomes.
Ramachandran G(1), Chandrasekaran P(1), Gaikwad S(2), Hemanth Kumar AK(1),
Thiruvengadam K(1), Gupte N(3)(4), Paradkar M(4), Dhanasekaran K(1),
Sivaramakrishnan GN(1), Kagal A(2), Thomas B(1), Pradhan N(4), Kadam D(2), Hanna
LE(1), Balasubramanian U(4), Kulkarni V(4), Murali L(5), Golub J(3)(6), Gupte
A(3), Shivakumar SVBY(7), Swaminathan S(8), Dooley KE(3), Gupta A(3)(4)(6), Mave
V(3)(4); C-TRIUMPh team.
Author information:
(1)National Institute for Research in Tuberculosis (ICMR), Chennai, Tamil Nadu,
India.
(2)Byramjee Jeejeebhoy Government Medical College, Pune, Maharashtra, India.
(3)Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
…
BACKGROUND: The relationships between first-line drug concentrations and
clinically-important outcomes among patients with tuberculosis (TB) remain poorly
understood.
METHODS: We enrolled a prospective cohort of patients with new pulmonary TB
receiving thrice-weekly treatment in India. Maximum plasma concentration of each
drug was determined at month 1 and 5 using blood samples drawn 2 hours post-dose.
Sub-therapeutic cut-offs were: rifampicin <8µg/mL; isoniazid <3µg/mL;
pyrazinamide <20µg/mL. Factors associated with lower log-transformed drug
concentrations, unfavourable outcomes (composite of treatment failure, all-cause
mortality, and recurrence) as well as individual outcomes were examined using
Poisson regression models.
RESULTS: Among 404 participants, rifampicin, isoniazid, and pyrazinamide
concentrations were sub-therapeutic in 85%, 29%, and 12% at month 1 (with similar
results for rifampicin and isoniazid at month 5). Rifampicin concentrations were
lower with HIV co-infection (1.6 µg/ml vs 4.6 µg/ml; p = 0.015). Unfavourable
outcome was observed in 19%; a 1 ug/ml decrease in rifampicin concentration was
independently associated with unfavourable outcome (aIRR 1.21, 95% CI: 1.01 -
1.47) and treatment failure (aIRR: 1.16; 95% CI: 1.05 - 1.28). A 1 ug/ml decrease
in pyrazinamide concentration was associated with recurrence (aIRR: 1.05; 95% CI:
1.01-1.11).
CONCLUSIONS: Rifampicin concentrations were sub-therapeutic in most Indian
patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide
concentrations were associated with poor outcomes. Higher or more frequent dosing
is needed to improve TB treatment outcomes in India.
© 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/ciz380
PMID: 31075166
12. Proc Natl Acad Sci U S A. 2019 May 21;116(21):10430-10434. doi:
10.1073/pnas.1903561116. Epub 2019 May 8.
Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a
cohort of European ancestry.
Kerner G(1)(2), Ramirez-Alejo N(3), Seeleuthner Y(1)(2), Yang R(3), Ogishi M(3),
Cobat A(1)(2), Patin E(4), Quintana-Murci L(4), Boisson-Dupuis S(1)(2)(3),
Casanova JL(5)(2)(3)(6)(7), Abel L(1)(2)(3).
Author information:
(1)Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR
1163, Necker Hospital for Sick Children, 75015 Paris, France.
(2)Imagine Institute, Paris Descartes University, 75015 Paris, France.
(3)St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller
Branch, The Rockefeller University, New York, NY 10065.
(4)Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR2000, 75015 Paris,
France.
(5)Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR
1163, Necker Hospital for Sick Children, 75015 Paris, France;
…
The human genetic basis of tuberculosis (TB) has long remained elusive. We
recently reported a high level of enrichment in homozygosity for the common TYK2
P1104A variant in a heterogeneous cohort of patients with TB from non-European
countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans
and ∼1/5,000 people from other countries outside East Asia and sub-Saharan
Africa. We report a study of this variant in the UK Biobank cohort. The frequency
of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in
controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of
5.0 [95% confidence interval (CI): 1.96-10.31, P = 2 × 10-3]. Conversely, we did
not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F
homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of
controls were infected with Mycobacterium tuberculosis, as 97% were of European
genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom.
Had all of them been infected, the OR for developing TB upon infection would be
higher. These findings suggest that homozygosity for TYK2 P1104A may account for
∼1% of TB cases in Europeans.
DOI: 10.1073/pnas.1903561116
PMCID: PMC6534977 [Available on 2019-11-08]
PMID: 31068474
13. Proc Natl Acad Sci U S A. 2019 May 21;116(21):10510-10517. doi:
10.1073/pnas.1818009116. Epub 2019 May 6.
Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis.
Flentie K(1), Harrison GA(1), Tükenmez H(2), Livny J(3), Good JAD(4)(5), Sarkar
S(4)(5), Zhu DX(1), Kinsella RL(1), Weiss LA(1), Solomon SD(1), Schene ME(1),
Hansen MR(4)(5), Cairns AG(4)(5), Kulén M(4)(5), Wixe T(4)(5), Lindgren
AEG(4)(5), Chorell E(1)(4)(5), Bengtsson C(4)(5), Krishnan KS(4)(5), Hultgren
SJ(1)(6), Larsson C(2)(5), Almqvist F(7)(5), Stallings CL(8).
Author information:
(1)Department of Molecular Microbiology, Washington University School of
Medicine, St. Louis, MO 63110.
(2)Department of Molecular Biology, Umeå University, SE-90187 Umeå, Sweden.
(3)Infectious Disease and Microbiome Program, Broad Institute, Cambridge, MA
02142.
…
Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single
infectious agent. This dangerous pathogen is able to withstand stresses imposed
by the immune system and tolerate exposure to antibiotics, resulting in
persistent infection. The global tuberculosis (TB) epidemic has been exacerbated
by the emergence of mutant strains of Mtb that are resistant to frontline
antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are
major obstacles to successful TB therapy. Using a chemical approach to identify
compounds that block stress and drug tolerance, as opposed to traditional screens
for compounds that kill Mtb, we identified a small molecule, C10, that blocks
tolerance to oxidative stress, acid stress, and the frontline antibiotic
isoniazid (INH). In addition, we found that C10 prevents the selection for
INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb
strains harboring mutations in the katG gene, which encodes the enzyme that
converts the prodrug INH to its active form. Through mechanistic studies, we
discovered that C10 inhibits Mtb respiration, revealing a link between
respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect
Mtb persistence, we discovered that INH resistance is not absolute and can be
reversed.
DOI: 10.1073/pnas.1818009116
PMCID: PMC6535022 [Available on 2019-11-06]
PMID: 31061116
Conflict of interest statement: Conflict of interest statement: C.L.S., S.J.H.,
and F.A. have ownership interests in Quretech Bio AB, which licenses C10.
14. Clin Pharmacokinet. 2019 May 3. doi: 10.1007/s40262-019-00764-2. [Epub ahead of print]
Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human
Tuberculosis.
Abulfathi AA(1), Decloedt EH(2), Svensson EM(3)(4), Diacon AH(5)(6), Donald P(7),
Reuter H(2).
Author information:
(1)Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine
and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South
Africa. aaabulfathi@sun.ac.za.
(2)Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine
and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South
Africa.
(3)Department of Pharmacy, Radboud Institute for Health Sciences, Radboud
University Medical Center, Nijmegen, The Netherlands.
…
The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five
decades ago was critical for shortening the treatment duration for patients with
pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months.
Resistance or hypersensitivity to rifampicin effectively condemns a patient to
prolonged, less effective, more toxic, and expensive regimens. Because of cost
and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg
(8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates
of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure
rates that might be the consequence of increased emergence of resistance. Several
lines of evidence suggest that higher rifampicin doses, if tolerated and safe,
could shorten treatment duration even further. We conducted a narrative review of
rifampicin pharmacokinetics and pharmacodynamics in adults across a range of
doses and highlight variables that influence its
pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter-
and intra-individual variability that could be reduced by administration during
fasting. Several factors including malnutrition, HIV infection, diabetes
mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and
substandard medicinal products alter rifampicin exposure and/or efficacy. Renal
impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg.
Rifampicin maximum (peak) concentration (Cmax) > 8.2 μg/mL is an independent
predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and
6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin
concentration of ≥ 8 µg/mL. A higher rifampicin Cmax is required for severe forms
TB such as TB meningitis, with Cmax ≥ 22 μg/mL and area under the
concentration-time curve (AUC) from time zero to 6 h (AUC6) ≥ 70 μg·h/mL
associated with reduced mortality. More studies are needed to confirm whether
doses achieving exposures higher than the current standard dosage could translate
into faster sputum conversion, higher cure rates, lower relapse rates, and less
mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were
found to be safe and well-tolerated over a period of 12 weeks. High-dose
rifampicin should thus be considered in future studies when constructing
potentially shorter regimens. The studies should be adequately powered to
determine treatment outcomes and should include surrogate markers of efficacy
such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.
DOI: 10.1007/s40262-019-00764-2
PMID: 31049868
15. Emerg Infect Dis. 2019 May;25(5):936-943. doi: 10.3201/eid2505.181823.
Outcomes of Bedaquiline Treatment in Patients with Multidrug-Resistant
Tuberculosis.
Mbuagbaw L, Guglielmetti L, Hewison C, Bakare N, Bastard M, Caumes E,
Fréchet-Jachym M, Robert J, Veziris N, Khachatryan N, Kotrikadze T, Hayrapetyan
A, Avaliani Z, Schünemann HJ, Lienhardt C.
Bedaquiline is recommended by the World Health Organization for the treatment of
multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB).
We pooled data from 5 cohorts of patients treated with bedaquiline in France,
Georgia, Armenia, and South Africa and in a multicountry study. The rate of
culture conversion to negative at 6 months (by the end of 6 months of treatment)
was 78% (95% CI 73.5%-81.9%), and the treatment success rate was 65.8% (95% CI
59.9%-71.3%). Death rate was 11.7% (95% CI 7.0%-19.1%). Up to 91.1% (95% CI
82.2%-95.8%) of the patients experienced >1 adverse event, and 11.2% (95% CI
5.0%-23.2%) experienced a serious adverse event. Lung cavitations were
consistently associated with unfavorable outcomes. The use of bedaquiline in MDR
and XDR TB treatment regimens appears to be effective and safe across different
settings, although the certainty of evidence was assessed as very low.
DOI: 10.3201/eid2505.181823
PMCID: PMC6478224
PMID: 31002070
