Medical Abstracts

Keyword: tuberculosis

1. Lancet. 2019 Apr 20;393(10181):1642-1656. doi: 10.1016/S0140-6736(19)30308-3.

Epub 2019 Mar 20.

Tuberculosis.

Furin J(1), Cox H(2), Pai M(3).

Author information:

(1)Department of Global Health and Social Medicine, Harvard Medical School,

Boston, MA, USA. Electronic address: jennifer_furin@hms.harvard.edu.

(2)Division of Medical Microbiology and the Institute of Infectious Disease and

Molecular Medicine, University of Cape Town, Cape Town, South Africa.

(3)McGill International Tuberculosis Centre, McGill University, Montreal, QC,

Canada; Manipal McGill Centre for Infectious Diseases, Manipal Academy of Higher

Education, Manipal, India.

Tuberculosis remains the leading cause of death from an infectious disease among

adults worldwide, with more than 10 million people becoming newly sick from

tuberculosis each year. Advances in diagnosis, including the use of rapid

molecular testing and whole-genome sequencing in both sputum and non-sputum

samples, could change this situation. Although little has changed in the

treatment of drug-susceptible tuberculosis, data on increased efficacy with new

and repurposed drugs have led WHO to recommend all-oral therapy for

drug-resistant tuberculosis for the first time ever in 2018. Studies have shown

that shorter latent tuberculosis prevention regimens containing rifampicin or

rifapentine are as effective as longer, isoniazid-based regimens, and there is a

promising vaccine candidate to prevent the progression of infection to the

disease. But new tools alone are not sufficient. Advances must be made in

providing high-quality, people-centred care for tuberculosis. Renewed political

will, coupled with improved access to quality care, could relegate the morbidity,

mortality, and stigma long associated with tuberculosis, to the past.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S0140-6736(19)30308-3

PMID: 30904262 [Indexed for MEDLINE]

2. N Engl J Med. 2019 Mar 14;380(11):1001-1011. doi: 10.1056/NEJMoa1806808.

One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis.

Swindells S(1), Ramchandani R(1), Gupta A(1), Benson CA(1), Leon-Cruz J(1),

Mwelase N(1), Jean Juste MA(1), Lama JR(1), Valencia J(1), Omoz-Oarhe A(1),

Supparatpinyo K(1), Masheto G(1), Mohapi L(1), da Silva Escada RO(1), Mawlana

S(1), Banda P(1), Severe P(1), Hakim J(1), Kanyama C(1), Langat D(1), Moran L(1),

Andersen J(1), Fletcher CV(1), Nuermberger E(1), Chaisson RE(1); BRIEF TB/A5279

Study Team.

Author information:

(1)From the University of Nebraska Medical Center, Omaha (S.S., C.V.F.); Harvard

T.H. Chan School of Public Health, Boston (R.R., J.L.-C., J.A.); Johns Hopkins

University School of Medicine, Baltimore (A.G., E.N., R.E.C.), and Social and

Scientific Systems, Silver Spring (L. Moran) - both in Maryland; University of

California, San Diego, School of Medicine, La Jolla (C.A.B.); GHESKIO,

Port-au-Prince, Haiti (M.A.J.J., P.S.); …

Comment in

N Engl J Med. 2019 Mar 14;380(11):1073-1074.

BACKGROUND: Tuberculosis is the leading killer of patients with human

immunodeficiency virus (HIV) infection. Preventive therapy is effective, but

current regimens are limited by poor implementation and low completion rates.

METHODS: We conducted a randomized, open-label, phase 3 noninferiority trial

comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus

isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in

HIV-infected patients who were living in areas of high tuberculosis prevalence or

who had evidence of latent tuberculosis infection. The primary end point was the

first diagnosis of tuberculosis or death from tuberculosis or an unknown cause.

Noninferiority would be shown if the upper limit of the 95% confidence interval

for the between-group difference in the number of events per 100 person-years was

less than 1.25.

RESULTS: A total of 3000 patients were enrolled and followed for a median of 3.3

years. Of these patients, 54% were women; the median CD4+ count was 470 cells per

cubic millimeter, and half the patients were receiving antiretroviral therapy.

The primary end point was reported in 32 of 1488 patients (2%) in the 1-month

group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65

per 100 person-years and 0.67 per 100 person-years, respectively (rate difference

in the 1-month group, -0.02 per 100 person-years; upper limit of the 95%

confidence interval, 0.30). Serious adverse events occurred in 6% of the patients

in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The

percentage of treatment completion was significantly higher in the 1-month group

than in the 9-month group (97% vs. 90%, P<0.001).

CONCLUSIONS: A 1-month regimen of rifapentine plus isoniazid was noninferior to 9

months of isoniazid alone for preventing tuberculosis in HIV-infected patients.

The percentage of patients who completed treatment was significantly higher in

the 1-month group. (Funded by the National Institute of Allergy and Infectious

Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.).

Copyright © 2019 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1806808

PMID: 30865794 [Indexed for MEDLINE]

3. N Engl J Med. 2019 Mar 28;380(13):1201-1213. doi: 10.1056/NEJMoa1811867. Epub

2019 Mar 13.

A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis.

Nunn AJ(1), Phillips PPJ(1), Meredith SK(1), Chiang CY(1), Conradie F(1), Dalai

D(1), van Deun A(1), Dat PT(1), Lan N(1), Master I(1), Mebrahtu T(1), Meressa

D(1), Moodliar R(1), Ngubane N(1), Sanders K(1), Squire SB(1), Torrea G(1), Tsogt

B(1), Rusen ID(1); STREAM Study Collaborators.

Collaborators: Teferi M, Ali O, Aseffa A, Bantubani N, Gama E, Girma M, Langley

I, Abubakar I, Ahmed S, Cook C, Dodds W, Lambiase P, Moodley R, Murphy B,

Rauchenberger M, Spittle B, Teera J, Tweed C, Adilaa O, Rash B, Zagd C, Nyamdavaa

N, Nguyen TTV, Tang SN, Howell P, Hailu M, Abseno M, Duckworth L, Aucock S, Madan

J, Komrska J, Ornstein T.

Author information:

(1)From the Medical Research Council (MRC) Clinical Trials Unit at University

College London (UCL), London (A.J.N, P.P.J.P., S.K.M., K.S.), and the Liverpool

School of Tropical Medicine, Liverpool (S.B.S.) - both in the United Kingdom;

International Union against Tuberculosis and Lung Disease (the Union), Paris

(C.-Y.C., A.D., I.D.R.);…

Comment in

N Engl J Med. 2019 Mar 28;380(13):1279-1280.

BACKGROUND: Cohort studies in Bangladesh showed promising cure rates among

patients with multidrug-resistant tuberculosis who received existing drugs in

regimens shorter than that recommended by the World Health Organization (WHO) in

2011.

METHODS: We conducted a phase 3 noninferiority trial in participants with

rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and

aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive

a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long

regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy

outcome was a favorable status at 132 weeks, defined by cultures negative for

Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no

intervening positive culture or previous unfavorable outcome. An upper 95%

confidence limit for the between-group difference in favorable status that was 10

percentage points or less was used to determine noninferiority.

RESULTS: Of 424 participants who underwent randomization, 383 were included in

the modified intention-to-treat population. Favorable status was reported in

79.8% of participants in the long-regimen group and in 78.8% of those in the

short-regimen group - a difference, with adjustment for human immunodeficiency

virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5)

(P = 0.02 for noninferiority). The results with respect to noninferiority were

consistent among the 321 participants in the per-protocol population (adjusted

difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of

grade 3 or higher occurred in 45.4% of participants in the long-regimen group and

in 48.2% in the short-regimen group. Prolongation of either the QT interval or

the corrected QT interval (calculated with Fridericia's formula) to 500 msec

occurred in 11.0% of participants in the short-regimen group, as compared with

6.4% in the long-regimen group (P = 0.14); because of the greater incidence in

the short-regimen group, participants were closely monitored and some received

medication adjustments. Death occurred in 8.5% of participants in the

short-regimen group and in 6.4% in the long-regimen group, and acquired

resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%,

respectively.

CONCLUSIONS: In persons with rifampin-resistant tuberculosis that was susceptible

to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a

long regimen with respect to the primary efficacy outcome and was similar to the

long regimen in terms of safety. (Funded by the U.S. Agency for International

Development and others; Current Controlled Trials number, ISRCTN78372190;

ClinicalTrials.gov number, NCT02409290.).

Copyright © 2019 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1811867

PMID: 30865791 [Indexed for MEDLINE]

4. Lancet. 2019 Mar 23;393(10177):1216-1224. doi: 10.1016/S0140-6736(18)32993-3.

Epub 2019 Feb 21.

Smartphone-enabled video-observed versus directly observed treatment for

tuberculosis: a multicentre, analyst-blinded, randomised, controlled superiority

trial.

Story A(1), Aldridge RW(2), Smith CM(2), Garber E(3), Hall J(3), Ferenando G(3),

Possas L(3), Hemming S(3), Wurie F(2), Luchenski S(2), Abubakar I(4), McHugh

TD(5), White PJ(6), Watson JM(7), Lipman M(8), Garfein R(9), Hayward AC(10).

Author information:

(1)Institute of Health Informatics, University College London, London, UK; Find

and Treat, University College Hospitals NHS Foundation Trust, London, UK.

(2)Institute of Health Informatics, University College London, London, UK.

(3)Institute of Health Informatics, University College London, London, UK; Royal

Free London NHS Foundation Trust, London, UK.

(4)Institute for Global Health, University College London, London, UK.

…

Comment in

Lancet. 2019 Mar 23;393(10177):1180-1181.

BACKGROUND: Directly observed treatment (DOT) has been the standard of care for

tuberculosis since the early 1990s, but it is inconvenient for patients and

service providers. Video-observed therapy (VOT) has been conditionally

recommended by WHO as an alternative to DOT. We tested whether levels of

treatment observation were improved with VOT.

METHODS: We did a multicentre, analyst-blinded, randomised controlled superiority

trial in 22 clinics in England (UK). Eligible participants were patients aged at

least 16 years with active pulmonary or non-pulmonary tuberculosis who were

eligible for DOT according to local guidance. Exclusion criteria included

patients who did not have access to charging a smartphone. We randomly assigned

participants to either VOT (daily remote observation using a smartphone app) or

DOT (observations done three to five times per week in the home, community, or

clinic settings). Randomisation was done by the SealedEnvelope service using

minimisation. DOT involved treatment observation by a health-care or lay worker,

with any remaining daily doses self-administered. VOT was provided by a

centralised service in London. Patients were trained to record and send videos of

every dose ingested 7 days per week using a smartphone app. Trained treatment

observers viewed these videos through a password-protected website. Patients were

also encouraged to report adverse drug events on the videos. Smartphones and data

plans were provided free of charge by study investigators. DOT or VOT observation

records were completed by observers until treatment or study end. The primary

outcome was completion of 80% or more scheduled treatment observations over the

first 2 months following enrolment. Intention-to-treat (ITT) and restricted

(including only patients completing at least 1 week of observation on allocated

arm) analyses were done. Superiority was determined by a 15% difference in the

proportion of patients with the primary outcome (60% vs 75%). This trial is

registered with the International Standard Randomised Controlled Trials Number

registry, number ISRCTN26184967.

FINDINGS: Between Sept 1, 2014, and Oct 1, 2016, we randomly assigned 226

patients; 112 to VOT and 114 to DOT. Overall, 131 (58%) patients had a history of

homelessness, imprisonment, drug use, alcohol problems or mental health problems.

In the ITT analysis, 78 (70%) of 112 patients on VOT achieved ≥80% scheduled

observations successfully completed during the first 2 months compared with 35

(31%) of 114 on DOT (adjusted odds ratio [OR] 5·48, 95% CI 3·10-9·68; p<0·0001).

In the restricted analysis, 78 (77%) of 101 patients on VOT achieved the primary

outcome compared with 35 (63%) of 56 on DOT (adjusted OR 2·52; 95% CI 1·17-5·54;

p=0·017). Stomach pain, nausea, and vomiting were the most common adverse events

reported (in 16 [14%] of 112 on VOT and nine [8%] of 114 on DOT).

INTERPRETATION: VOT was a more effective approach to observation of tuberculosis

treatment than DOT. VOT is likely to be preferable to DOT for many patients

across a broad range of settings, providing a more acceptable, effective, and

cheaper option for supervision of daily and multiple daily doses than DOT.

FUNDING: National Institute for Health Research.

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/S0140-6736(18)32993-3

PMCID: PMC6429626

PMID: 30799062 [Indexed for MEDLINE]

5. 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]

6. FEMS Microbiol Rev. 2019 Mar 27. pii: fuz006. doi: 10.1093/femsre/fuz006. [Epub

ahead of print]

Mycobacterium tuberculosis infection of host cells in space and time.

Bussi C(1), Gutierrez MG(1).

Author information:

(1)Host-pathogen interactions in tuberculosis laboratory, The Francis Crick

Institute, 1 Midland Road, London, NW1 1AT, United Kingdom.

Tuberculosis (TB) caused by the bacterial pathogen M. tuberculosis (Mtb) remains

one of the deadliest infectious diseases with over a billion deaths in the past

two hundred years (Paulson, 2013). TB causes more deaths worldwide than any other

single infectious agent, with 10.4 million new cases and close to 1.7 million

deaths in 2017. The obstacles that make TB hard to treat and eradicate are

intrinsically linked to the intracellular lifestyle of Mtb. Mtb needs to

replicate within human cells to disseminate to other individuals and cause

disease. However, we still do not completely understand how Mtb manages to

survive within eukaryotic cells and why some cells are able to eradicate this

lethal pathogen. Here, we summarise the current knowledge of the complex host

cell-pathogen interactions in TB and review the cellular mechanisms operating at

the interface between Mtb and the human host cell, highlighting the technical and

methodological challenges to investigating the cell biology of human host

cell-Mtb interactions.

© FEMS 2019.

DOI: 10.1093/femsre/fuz006

PMID: 30916769

7. Sci Transl Med. 2019 Mar 13;11(483). pii: eaau6267. doi:

10.1126/scitranslmed.aau6267.

A gastric resident drug delivery system for prolonged gram-level dosing of

tuberculosis treatment.

Verma M(1)(2)(3), Vishwanath K(2), Eweje F(2)(4)(5), Roxhed N(2)(6), Grant

T(2)(7), Castaneda M(2), Steiger C(2)(5)(7), Mazdiyasni H(2)(7), Bensel T(2)(7),

Minahan D(2)(7), Soares V(2)(7), Salama JAF(2), Lopes A(2)(7), Hess K(2)(7),

Author information:

(1)Department of Biological Engineering, Massachusetts Institute of Technology,

Cambridge, MA 02139, USA.

(2)Koch Institute for Integrative Cancer Research, Massachusetts Institute of

Technology, Cambridge, MA 02139, USA.

(3)Tata Center for Technology and Design, Massachusetts Institute of Technology,

Cambridge, MA 02139, USA.

…

Multigram drug depot systems for extended drug release could transform our

capacity to effectively treat patients across a myriad of diseases. For example,

tuberculosis (TB) requires multimonth courses of daily multigram doses for

treatment. To address the challenge of prolonged dosing for regimens requiring

multigram drug dosing, we developed a gastric resident system delivered through

the nasogastric route that was capable of safely encapsulating and releasing

grams of antibiotics over a period of weeks. Initial preclinical safety and drug

release were demonstrated in a swine model with a panel of TB antibiotics. We

anticipate multiple applications in the field of infectious diseases, as well as

for other indications where multigram depots could impart meaningful benefits to

patients, helping maximize adherence to their medication.

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

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

Works.

DOI: 10.1126/scitranslmed.aau6267

PMID: 30867322

8. Clin Infect Dis. 2019 Mar 28. pii: ciz256. doi: 10.1093/cid/ciz256. [Epub ahead

of print]

Dolutegravir-Based Antiretroviral Therapy for Patients Co-Infected with

Tuberculosis and Hiv: A Multicenter, Noncomparative, Open-Label, Randomized

Trial.

Dooley KE(1), Kaplan R(2), Mwelase N(3), Grinsztejn B(4), Ticona E(5), Lacerda

M(6), Sued O(7), Belonosova E(8), Ait-Khaled M(9), Angelis K(10), Brown D(11),

Singh R(12), Talarico CL(13), Tenorio AR(13), Keegan MR(9), Aboud M(9); INSPIRING

study group.

Author information:

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

N. Wolfe Street, Baltimore, MD, USA.

(2)Desmond Tutu HIV Foundation, Cape Town, South Africa.

(3)Clinical HIV Research Unit, Johannesburg, South Africa.

…

BACKGROUND: Concurrent treatment of tuberculosis and HIV is challenging owing to

drug interactions, overlapping toxicities, and immune reconstitution inflammatory

syndrome (IRIS). The efficacy and safety of dolutegravir were assessed in adults

with HIV and drug-susceptible tuberculosis.

METHODS: INSPIRING (NCT02178592) is a non-comparative, active-control,

randomised, open-label study in HIV-1-infected ART-naïve adults (CD4+ 50

cells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were

randomised (3:2) to receive dolutegravir (50 mg twice-daily during and 2 weeks

post-tuberculosis therapy, then 50 mg once-daily) or efavirenz (600 mg daily),

with two NRTIs for 52 weeks. The primary endpoint was the proportion of

dolutegravir-arm participants with plasma HIV-1-RNA <50 copies/mL (responders) by

FDA Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study

was not powered to compare arms.

RESULTS: For dolutegravir (N=69), Baseline HIV-1-RNA was >100,000 copies/mL in

64%, with median CD4+ 208 cells/mm3; for efavirenz (N=44), 55% had HIV-1-RNA

>100,000 copies/mL, median CD4+ count was 202 cells/mm3. Week 48 response rate

was 75% (52/69) (95% CI: 65%, 86%) for dolutegravir and 82% (36/44) (95% CI: 70%,

93%) for efavirenz. Dolutegravir non-response was driven by non-treatment-related

discontinuations (n=10 lost-to-follow-up). There were no deaths or study drug

switches. There were two discontinuations for toxicity (efavirenz). There were

three protocol-defined virological failures (2 dolutegravir, no acquired

resistance; 1 efavirenz, NRTI and NNRTI emergent resistance). Tuberculosis

treatment success was high. TB-associated IRIS was uncommon (4/arm), with no

discontinuations for IRIS.

CONCLUSIONS: Among adults with HIV receiving rifampicin-based tuberculosis

treatment, twice-daily dolutegravir was effective and well-tolerated.

© 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/ciz256

PMID: 30918967

9. J Infect Dis. 2019 Mar 15. pii: jiz116. doi: 10.1093/infdis/jiz116. [Epub ahead

of print]

BCG overexpressing an endogenous STING agonist provides enhanced protection

against pulmonary tuberculosis.

Dey RJ(1)(2), Dey B(1)(3), Singh AK(1), Praharaj M(1)(4), Bishai W(1).

Author information:

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

Baltimore, Maryland, USA.

(2)Department of Biological Sciences, BITS Pilani-Hyderabad, Hyderabad,

Telangana, India.

(3)National Institute of Animal Biotechnology, Hyderabad, Telangana, India.

(4)Department of Microbiology and Molecular Immunology, Johns Hopkins Bloomberg

School of Public Health, Baltimore, Maryland, USA.

BACKGROUND: STING is a key cytosolic receptor for small nucleotides and plays a

key role in anti-cancer and antiviral immunity. Cyclic dinucleotide STING

agonists may comprise a novel class of vaccine adjuvants capable of inducing

cellular immune responses and protective efficacy against intracellular

pathogens.

METHODS: We generated a recombinant BCG (BCG-disA-OE) that overexpresses the

endogenous mycobacterial diadenylate cyclase gene and releases high levels of the

STING agonist c-di-AMP. We used a 24-week guinea pig vaccination-M.tb. challenge

model to test the protective efficacy of BCG-disA-OE versus wild-type BCG and

measured lung weights, pathology scores, and M.tb. organ CFU counts.

RESULTS: BCG-disA-OE elicited statistically significantly stronger TNF-α, IL-6,

IL-1β, IRF3, and IFN-β levels than BCG-WT in vitro in murine macrophages. In vivo

in guinea pigs we found that BCG-disA-OE reduced lung weights, pathology scores,

and M.tb. CFU counts in lungs by 28% (p<0.05), 34%, and 2.0 log10 CFU units (p <

0.5) compared with BCG-WT, respectively.

CONCLUSION: We report a strategy of delivering a STING agonist from within live

BCG. Overproduction of the STING agonist c-di-AMP significantly enhanced the

protective efficacy of BCG against pulmonary and extrapulmonary tuberculosis. Our

findings support the development of BCG-vectored STING agonists as a TB vaccine

strategy.

© 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/jiz116

PMID: 30901058

10. Clin Infect Dis. 2019 Mar 18. pii: ciz219. doi: 10.1093/cid/ciz219. [Epub ahead

of print]

Building the framework for standardized clinical laboratory reporting of next

generation sequencing data for resistance-associated mutations in Mycobacterium

tuberculosis complex.

Tornheim JA(1), Starks AM(2), Rodwell TC(3)(4), Gardy JL(5)(6), Walker TM(7),

Cirillo DM(8), Jayashankar L(9), Miotto P(8), Zignol M(10), Schito M(11).

Author information:

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

Baltimore, MD, USA.

(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)Foundation for Innovative New Diagnostics, Geneva Switzerland.

…

Tuberculosis is the primary infectious disease killer worldwide, with a growing

threat from multidrug- resistant cases. Unfortunately, classic growth-based

phenotypic drug susceptibility testing (DST) remains difficult, costly and

time-consuming, while current rapid molecular testing options are limited by the

diversity of antimicrobial resistant genotypes that can be detected at once. Next

generation sequencing (NGS) offers the opportunity for rapid, comprehensive DST

without the time or cost burden of phenotypic tests and can provide useful

information for global surveillance. As access to NGS expands, it will be

important to ensure that results are communicated clearly, are consistent, are

comparable between laboratories, and are associated with clear guidance on

clinical interpretation of results. This viewpoint summarizes two expert

workshops regarding a standardized report format, focusing on relevant variables,

terminology, and required minimal elements for clinical and laboratory reports

with a proposed standardized template for clinical reporting of NGS results for

Mycobacterium tuberculosis.

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

Diseases Society of America.

DOI: 10.1093/cid/ciz219

PMID: 30883637

11. Emerg Infect Dis. 2019 Mar;25(3):482-488. doi: 10.3201/eid2503.180894.

SNP-IT Tool for Identifying Subspecies and Associated Lineages of Mycobacterium

tuberculosis Complex.

Lipworth S, Jajou R, de Neeling A, Bradley P, van der Hoek W, Maphalala G, Bonnet

M, Sanchez-Padilla E, Diel R, Niemann S, Iqbal Z, Smith G, Peto T, Crook D,

Walker T, van Soolingen D.

The clinical phenotype of zoonotic tuberculosis and its contribution to the

global burden of disease are poorly understood and probably underestimated. This

shortcoming is partly because of the inability of currently available laboratory

and in silico tools to accurately identify all subspecies of the Mycobacterium

tuberculosis complex (MTBC). We present SNPs to Identify TB (SNP-IT), a

single-nucleotide polymorphism-based tool to identify all members of MTBC,

including animal clades. By applying SNP-IT to a collection of clinical genomes

from a UK reference laboratory, we detected an unexpectedly high number of M.

orygis isolates. M. orygis is seen at a similar rate to M. bovis, yet M. orygis

cases have not been previously described in the United Kingdom. From an

international perspective, it is possible that M. orygis is an underestimated

zoonosis. Accurate identification will enable study of the clinical phenotype,

host range, and transmission mechanisms of all subspecies of MTBC in greater

detail.

DOI: 10.3201/eid2503.180894

PMCID: PMC6390766

PMID: 30789126

12. Eur Respir J. 2019 Mar 18;53(3). pii: 1801184. doi: 10.1183/13993003.01184-2018.

Print 2019 Mar.

Chronic pulmonary aspergillosis commonly complicates treated pulmonary

tuberculosis with residual cavitation.

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

M(7)(8), Sawyer R(4), Sharman A(4), Denning DW(7)(2).

Author information:

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

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

Science Centre, Manchester, UK iain.page@manchester.ac.uk.

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

Manchester University NHS Foundation Trust, Manchester, UK.

(3)Kampala Imaging Centre, Kampala, Uganda.

…

Chronic pulmonary aspergillosis (CPA) complicates treated pulmonary tuberculosis

(TB), with high 5-year mortality. We measured CPA prevalence in this group.398

Ugandans with treated pulmonary TB underwent clinical assessment, chest

radiography and Aspergillus-specific IgG measurement. 285 were resurveyed 2?years

later, including computed tomography of the thorax in 73 with suspected CPA. CPA

was diagnosed in patients without active TB who had raised Aspergillus-specific

IgG, radiological features of CPA and chronic cough or haemoptysis.Author-defined

CPA was present in 14 (4.9%, 95% CI 2.8-7.9%) resurvey patients. CPA was

significantly more common in those with chest radiography cavitation (26% versus

0.8%; p<0.001), but possibly less frequent in HIV co-infected patients (3% versus

6.7%; p=0.177) The annual rate of new CPA development between surveys was 6.5% in

those with chest radiography cavitation and 0.2% in those without (p<0.001).

Absence of cavitation and pleural thickening on chest radiography had 100%

negative predictive value for CPA. The combination of raised Aspergillus-specific

IgG, chronic cough or haemoptysis and chest radiography cavitation had 85.7%

sensitivity and 99.6% specificity for CPA diagnosis.CPA commonly complicates

treated pulmonary TB with residual chest radiography cavitation. Chest

radiography alone can exclude CPA. Addition of serology can diagnose CPA with

reasonable accuracy.

Copyright ©ERS 2019.

DOI: 10.1183/13993003.01184-2018

PMCID: PMC6422837

PMID: 30705126

13. J Immunol. 2019 Mar 1;202(5):1494-1500. doi: 10.4049/jimmunol.1801190. Epub 2019 Jan 16.

Coexistent Helminth Infection-Mediated Modulation of Chemokine Responses in

Latent Tuberculosis.

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

S(4)(3).

Author information:

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

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

600031.

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

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

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

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

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

600031; sbabu@mail.nih.gov.

Coexistent helminth infections are known to modulate T cell and cytokine

responses in latent infection with Mycobacterium tuberculosis However, their role

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

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

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

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

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

mitogen stimulation in individuals with LTB with (Strongyloides stercoralis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

treatment. Hence, coexistent helminth infection induces downmodulation of

chemokine responses in LTB individuals with likely potential effects on

tuberculosis pathogenesis.

Copyright © 2019 by The American Association of Immunologists, Inc.

DOI: 10.4049/jimmunol.1801190

PMCID: PMC6382527 [Available on 2020-03-01]

PMID: 30651341

14. Biosens Bioelectron. 2019 Mar 1;128:76-82. doi: 10.1016/j.bios.2018.11.045. Epub 2018 Dec 7.

E-DNA detection of rpoB gene resistance in Mycobacterium tuberculosis in real

samples using Fe3O4/polypyrrole nanocomposite.

Haddaoui M(1), Sola C(2), Raouafi N(3), Korri-Youssoufi H(4).

Author information:

(1)Univ. Paris Sud, Université Paris-Saclay, LCBB, Institut de Chimie Moléculaire

et des Matériaux d'Orsay(UMR -CNRS 8182), Bât 420, 2 Rue du Doyen Georges Poitou,

91400 Orsay, France; Université de Tunis El Manar, Faculté des Sciences,

Laboratoire de Chimie Analytique et Electrochimie (LR99ES15), Campus

universitaire de Tunis El Manar, 2092 Tunis El-Manar, Tunisia.

(2)Institute of Integrative Cell Biology(I2BC), CEA, ?CNRS, Univ. Paris-Sud,

Université Paris-Saclay, 91198, Gif-sur-Yvette, France.

(3)Université de Tunis El Manar, Faculté des Sciences, Laboratoire de Chimie

Analytique et Electrochimie (LR99ES15), Campus universitaire de Tunis El Manar,

2092 Tunis El-Manar, Tunisia. Electronic address: noureddine.raouafi@fst.utm.tn.

(4)Univ. Paris Sud, Université Paris-Saclay, LCBB, Institut de Chimie Moléculaire

et des Matériaux d'Orsay(UMR -CNRS 8182), Bât 420, 2 Rue du Doyen Georges Poitou,

91400 Orsay, France. Electronic address: hafsa.korri-youssoufi@u-psud.fr.

In this work, we achieved the selective detection of wild and mutated rpoB gene

in M. tuberculosis using an electrochemical DNA (E-DNA) sensor based on

polypyrrole/Fe3O4 nanocomposite bearing redox naphthoquinone tag on PAMAM

(spaNQ/PAMAM/PPy/Fe3O4). The hybridization between a given probe and the

complementary DNA target induced a large decrease in the naphthoquinone redox

signal as measured by SWV and no cross-hybridization with single nucleotide

mismatch DNA target occurred. Thanks to the catalytic properties of iron oxide

nanoparticles combined with conducting properties of polypyrrole platform, we

demonstrated that the transducing system allowed the detection of 1 fM of DNA

target in a 50-µL drop corresponding to 3?×?104 copies of DNA. The sensor was

able to detect the rpoB gene in PCR-amplified samples of genomic DNA and could

also discriminate between the wild type rpoB gene and a single nucleotide mutated

rpoB gene that provides resistance? to rifampicin. Furthermore, the sensor could

selectively detect the wild and mutant DNA in genomic samples without PCR

amplification.

Copyright © 2018. Published by Elsevier B.V.

DOI: 10.1016/j.bios.2018.11.045

PMID: 30640123