2021年
No.10
Medical Abstracts
Filters applied: from 2021/8/1 - 2021/8/31
Key words: tuberculosis ; lung cancer
1. Lancet. 2021 Oct 9;398(10308):1344-1357. doi: 10.1016/S0140-6736(21)02098-5.
Epub 2021 Sep 20.
Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA
non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label,
phase 3 trial.
Felip E(1), Altorki N(2), Zhou C(3), Csőszi T(4), Vynnychenko I(5), Goloborodko
O(6), Luft A(7), Akopov A(8), Martinez-Marti A(9), Kenmotsu H(10), Chen YM(11),
Chella A(12), Sugawara S(13), Voong D(14), Wu F(15), Yi J(14), Deng Y(14),
McCleland M(14), Bennett E(14), Gitlitz B(14), Wakelee H(16); IMpower010
Investigators.
Author information:
(1)Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital,
Barcelona, Spain. Electronic address: efelip@vhio.net.
(2)Division of Thoracic Surgery, Weill Cornell Medicine, New York-Presbyterian
Hospital, New York, NY, USA.
(3)Department of Oncology, Tongji University Affiliated Shanghai Pulmonary
Hospital, Shanghai, China.
…
Erratum in
Lancet. 2021 Sep 23;:
BACKGROUND: Novel adjuvant strategies are needed to optimise outcomes after
complete surgical resection in patients with early-stage non-small-cell lung
cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best
supportive care after adjuvant platinum-based chemotherapy in these patients.
METHODS: IMpower010 was a randomised, multicentre, open-label, phase 3 study
done at 227 sites in 22 countries and regions. Eligible patients were 18 years
or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the
Union Internationale Contre le Cancer and American Joint Committee on Cancer
staging system (7th edition). Patients were randomly assigned (1:1) by a
permuted-block method (block size of four) to receive adjuvant atezolizumab
(1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care
(observation and regular scans for disease recurrence) after adjuvant
platinum-based chemotherapy (one to four cycles). The primary endpoint,
investigator-assessed disease-free survival, was tested hierarchically first in
the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or
more of tumour cells (SP263), then all patients in the stage II-IIIA population,
and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was
evaluated in all patients who were randomly assigned and received atezolizumab
or best supportive care. IMpower010 is registered with ClinicalTrials.gov,
NCT02486718 (active, not recruiting).
FINDINGS: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled
after complete resection. 1269 received adjuvant chemotherapy, of whom 1005
patients were eligible for randomisation to atezolizumab (n=507) or best
supportive care (n=498); 495 in each group received treatment. After a median
follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population,
atezolizumab treatment improved disease-free survival compared with best
supportive care in patients in the stage II-IIIA population whose tumours
expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88;
p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81
(0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%).
INTERPRETATION: IMpower010 showed a disease-free survival benefit with
atezolizumab versus best supportive care after adjuvant chemotherapy in patients
with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose
tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety
signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment
option for patients with resected early-stage NSCLC.
FUNDING: F Hoffmann-La Roche and Genentech.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(21)02098-5
PMID: 34555333
2. N Engl J Med. 2021 Sep 18. doi: 10.1056/NEJMoa2112431. Online ahead of print.
Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer.
Li BT(1), Smit EF(1), Goto Y(1), Nakagawa K(1), Udagawa H(1), Mazières J(1),
Nagasaka M(1), Bazhenova L(1), Saltos AN(1), Felip E(1), Pacheco JM(1), Pérol
M(1), Paz-Ares L(1), Saxena K(1), Shiga R(1), Cheng Y(1), Acharyya S(1), Vitazka
P(1), Shahidi J(1), Planchard D(1), Jänne PA(1); DESTINY-Lung01 Trial
Investigators.
Author information:
(1)From Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New
York (B.T.L.); the Netherlands Cancer Institute, Amsterdam (E.F.S); the National
Cancer Center Hospital, Tokyo (Y.G.), Kindai University Hospital, Osaka (K.N.),
and the National Cancer Center East, Kashiwa (H.U.) - all in Japan; Centre
Hospitalier Universitaire, Toulouse (J.M.), Centre Léon Bérard, Lyon (M.P.), and
the Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif
(D.P.) - all in France; Karmanos Cancer Institute, Detroit (M.N.); the
University of California, San Diego, Moores Cancer Center, San Diego (L.B.);
Moffitt Cancer Center, Tampa, FL (A.N.S.); Vall d'Hebron University Hospital and
Vall d'Hebron Institute of Oncology, Barcelona (E.F.); University of Colorado,
Aurora (J.M.P.); Hospital Universitario 12 de Octubre, H12O-Centro Nacional de
Investigaciones Oncológicas (CNIO) Lung Cancer Clinical Research Unit, and
Complutense University, Madrid (L.P.-A.); Daiichi Sankyo, Basking Ridge, NJ
(K.S., R.S., Y.C., S.A., P.V., J.S.); and Dana-Farber Cancer Institute and the
Belfer Center for Applied Cancer Science, Boston (P.A.J.).
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies
have not been approved for patients with non-small-cell lung cancer (NSCLC). The
efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2
antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been
investigated extensively.
METHODS: We conducted a multicenter, international, phase 2 study in which
trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to
patients who had metastatic HER2-mutant NSCLC that was refractory to standard
treatment. The primary outcome was objective response as assessed by independent
central review. Secondary outcomes included the duration of response,
progression-free survival, overall survival, and safety. Biomarkers of HER2
alterations were assessed.
RESULTS: A total of 91 patients were enrolled. The median duration of follow-up
was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response
occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The
median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median
progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median
overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was
generally consistent with those from previous studies; grade 3 or higher
drug-related adverse events occurred in 46% of patients, the most common event
being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease
occurred in 26% of patients and resulted in death in 2 patients. Responses were
observed across different HER2 mutation subtypes, as well as in patients with no
detectable HER2 expression or HER2 amplification.
CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in
patients with previously treated HER2-mutant NSCLC. The safety profile included
interstitial lung disease that was fatal in two cases. Observed toxic effects
were generally consistent with those in previously reported studies. (Funded by
Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number,
NCT03505710.).
Copyright © 2021 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2112431
PMID: 34534430
3. Nature. 2021 Sep;597(7878):732-737. doi: 10.1038/s41586-021-03898-1. Epub 2021
Sep 15.
Structure-based classification predicts drug response in EGFR-mutant NSCLC.
Robichaux JP(1), Le X(1), Vijayan RSK(2), Hicks JK(3), Heeke S(1), Elamin YY(1),
Lin HY(4), Udagawa H(1), Skoulidis F(1), Tran H(1), Varghese S(1), He J(1),
Zhang F(1), Nilsson MB(1), Hu L(1), Poteete A(1), Rinsurongkawong W(5), Zhang
X(6), Ren C(6), Liu X(1)(7), Hong L(1), Zhang J(1), Diao L(8), Madison R(9),
Schrock AB(9), Saam J(10), Raymond V(10), Fang B(6), Wang J(8), Ha MJ(4), Cross
JB(2), Gray JE(11), Heymach JV(12).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer
Center, Houston, TX, USA.
(2)Institute for Applied Cancer Science, MD Anderson Cancer Center, Houston, TX,
USA.
(3)Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa,
FL, USA.
…
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21
and are established driver mutations in non-small cell lung cancer (NSCLC)1-3.
Targeted therapies are approved for patients with 'classical' mutations and a
small number of other mutations4-6. However, effective therapies have not been
identified for additional EGFR mutations. Furthermore, the frequency and effects
of atypical EGFR mutations on drug sensitivity are unknown1,3,7-10. Here we
characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC,
and establish the structure-function relationship of EGFR mutations on drug
sensitivity. We found that EGFR mutations can be separated into four distinct
subgroups on the basis of sensitivity and structural changes that
retrospectively predict patient outcomes following treatment with EGFR
inhibitors better than traditional exon-based groups. Together, these data
delineate a structure-based approach for defining functional groups of EGFR
mutations that can effectively guide treatment and clinical trial choices for
patients with EGFR-mutant NSCLC and suggest that a structure-function-based
approach may improve the prediction of drug sensitivity to targeted therapies in
oncogenes with diverse mutations.
© 2021. The Author(s).
DOI: 10.1038/s41586-021-03898-1
PMCID: PMC8481125
PMID: 34526717
4. Annu Rev Pharmacol Toxicol. 2021 Sep 30. doi:
10.1146/annurev-pharmtox-041921-074800. Online ahead of print.
Emerging Therapeutics, Technologies, and Drug Development Strategies to Address
Patient Nonadherence and Improve Tuberculosis Treatment.
Garcia-Cremades M(1), Solans BP(1), Strydom N(1), Vrijens B(2)(3), Pillai
GC(4)(5), Shaffer C(1), Thomas B(6), Savic RM(1).
Author information:
(1)Department of Bioengineering and Therapeutic Sciences, University of
California San Francisco, San Francisco, California 94158, USA; email:
rada.savic@ucsf.edu.
(2)AARDEX Group, B-4102 Liège Science Park, Belgium.
(3)Department of Public Health, University of Liège, B-4000 Liège, Belgium.
(4)Division of Clinical Pharmacology, University of Cape Town, Observatory 7925,
South Africa.
(5)CP+ Associates GmbH, Basel 4102, Switzerland.
(6)The Arcady Group, Richmond, Virginia 23226, USA.
Imperfect medication adherence remains the biggest predictor of treatment
failure for patients with tuberculosis. Missed doses during treatment lead to
relapse, tuberculosis resistance, and further spread of disease. Understanding
individual patient phenotypes, population pharmacokinetics, resistance
development, drug distribution to tuberculosis lesions, and pharmacodynamics at
the site of infection is necessary to fully measure the impact of adherence on
patient outcomes. To decrease the impact of expected variability in drug intake
on tuberculosis outcomes, an improvement in patient adherence and new forgiving
regimens that protect against missed doses are needed. In this review, we
summarize emerging technologies to improve medication adherence in clinical
practice and provide suggestions on how digital adherence technologies can be
incorporated in clinical trials and practice and the drug development pipeline
that will lead to more forgiving regimens and benefit patients suffering from
tuberculosis. Expected final online publication date for the Annual Review of
Pharmacology and Toxicology, Volume 62 is January 2022. Please see
http://www.annualreviews.org/page/journal/pubdates for revised estimates.
DOI: 10.1146/annurev-pharmtox-041921-074800
PMID: 34591605
5. Lancet Oncol. 2021 Oct;22(10):1448-1457. doi: 10.1016/S1470-2045(21)00401-0.
Epub 2021 Sep 13.
Stereotactic ablative radiotherapy for operable stage I non-small-cell lung
cancer (revised STARS): long-term results of a single-arm, prospective trial
with prespecified comparison to surgery.
Chang JY(1), Mehran RJ(2), Feng L(3), Verma V(4), Liao Z(4), Welsh JW(4), Lin
SH(4), O'Reilly MS(4), Jeter MD(4), Balter PA(5), McRae SE(6), Berry D(3),
Heymach JV(7), Roth JA(2); STARS Lung Cancer Trials Group.
Collaborators: Antonoff M, Hofstetter W, Rajaram R, Rice D, Sepesi B, Swisher S,
Vaporciyan A, Walsh G, DeGraaf C, Correa A, Chen A, Gandhi S, Komaki R, Lee P,
Nguyen QN, Ning M, Gao S, Pollard-Larkin J, Nitsch P, Sadagopan R, Wang X.
Author information:
(1)Department of Radiation Oncology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA. Electronic address: jychang@mdanderson.org.
(2)Department of Thoracic and Cardiovascular Surgery, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA.
(3)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA.
…
BACKGROUND: A previous pooled analysis of the STARS and ROSEL trials showed
higher survival after stereotactic ablative radiotherapy (SABR) than with
surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that
analysis had notable limitations. This study reports long-term results of the
revised STARS trial, in which the SABR group was re-accrued with a larger sample
size, along with a protocol-specified propensity-matched comparison with a
prospectively registered, contemporary institutional cohort of patients who
underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph
node dissection (VATS L-MLND).
METHODS: This single-arm prospective trial was done at the University of Texas
MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years
or older with a Zubrod performance status of 0-2, newly diagnosed and
histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma,
large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or
less. This trial did not include patients from the previous pooled analysis.
SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in
four fractions (for central tumours; simultaneous integrated boost to gross
tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival.
For the propensity-matching analysis, we used a surgical cohort from the MD
Anderson Department of Thoracic and Cardiovascular Surgery's prospectively
registered, institutional review board-approved database of all patients with
clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment
in this trial. Non-inferiority could be claimed if the 3-year overall survival
rate after SABR was lower than that after VATS L-MLND by 12% or less and the
upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965.
Propensity matching consisted of determining a propensity score using a
multivariable logistic regression model including several covariates (age,
tumour size, histology, performance status, and the interaction of age and sex);
based on the propensity scores, one patient in the SABR group was randomly
matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match
algorithm. This study is registered with ClinicalTrials.gov, NCT02357992.
FINDINGS: Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and
included in efficacy and safety analyses. Median follow-up time was 5·1 years
(IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87%
(79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one
(1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung
fibrosis. No serious adverse events were recorded. Overall survival in the
propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84%
(76-93) at 5 years. Non-inferiority was claimed since the 3-year overall
survival after SABR was not lower than that observed in the VATS L-MLND group.
There was no significant difference in overall survival between the two patient
cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable
analysis.
INTERPRETATION: Long-term survival after SABR is non-inferior to VATS L-MLND for
operable stage IA NSCLC. SABR remains promising for such cases but
multidisciplinary management is strongly recommended.
FUNDING: Varian Medical Systems and US National Cancer Institute (National
Institutes of Health).
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(21)00401-0
PMCID: PMC8521627
PMID: 34529930 [Indexed for MEDLINE]
6. Cancer Cell. 2021 Sep 13;39(9):1279-1291.e3. doi: 10.1016/j.ccell.2021.07.005.
Epub 2021 Aug 12.
Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated,
advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study.
Zhou Q(1), Xu CR(1), Cheng Y(2), Liu YP(3), Chen GY(4), Cui JW(5), Yang N(6),
Song Y(7), Li XL(8), Lu S(9), Zhou JY(10), Ma ZY(11), Yu SY(12), Huang C(13),
Shu YQ(14), Wang Z(1), Yang JJ(1), Tu HY(1), Zhong WZ(1), Wu YL(15).
Author information:
(1)Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer,
Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and
Guangdong Academy of Medical Sciences, Guangzhou, China.
(2)Department of Thoracic Oncology, Jilin Provincial Tumor Hospital, Changchun,
China.
(3)Department of Medical Oncology, First Hospital of China Medical University,
Shenyang, China.
…
Dual inhibition of epidermal growth factor receptor (EGFR) and vascular
endothelial growth factor (VEGF) pathways may delay therapeutic resistance in
advanced non-small cell lung cancer (NSCLC). This phase 3 study investigated the
efficacy and safety of an erlotinib plus bevacizumab regimen in untreated
patients with advanced NSCLC. In total, 311 patients received bevacizumab plus
erlotinib (n = 157) or erlotinib only (n = 154). Progression-free survival (PFS)
was 17.9 months (95% confidence interval [CI], 15.2-19.9) for bevacizumab plus
erlotinib and 11.2 months (95% CI, 9.7-13.8) for erlotinib only (hazard ratio
[HR] = 0.55; 95% CI, 0.41-0.73; p < 0.001). A brain metastases subgroup treated
with bevacizumab plus erlotinib also showed improved PFS (HR = 0.48; 95% CI,
0.27-0.84; p = 0.008). Grade ≥3 treatment-related adverse events occurred in 86 (54.8%) and 40 (26.1%) patients, respectively. Bevacizumab plus erlotinib
significantly improved PFS in patients with untreated metastatic EGFR-mutated
NSCLC, including those with brain metastases at baseline.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2021.07.005
PMID: 34388377
7. Nat Med. 2021 Sep;27(9):1646-1654. doi: 10.1038/s41591-021-01388-5. Epub 2021
Jun 28.
Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.
Ogishi M(1)(2), Yang R(3), Aytekin C(4), Langlais D(5), Bourgey M(6), Khan T(7),
Ali FA(7), Rahman M(7), Delmonte OM(8), Chrabieh M(9)(10), Zhang P(3), Gruber
C(11)(12)(13)(14), Pelham SJ(3), Spaan AN(3), Rosain J(9)(10), Lei WT(3),
Drutman S(3), Hellmann MD(15)(16), Callahan MK(15)(16), Adamow M(17)(18), Wong
P(17), Wolchok JD(15)(16)(18)(19), Rao G(20), Ma CS(20)(21), Nakajima Y(22),
Yaguchi T(22), Chamoto K(22), Williams SC(23)(24), Emile JF(25), Rozenberg
F(26), Glickman MS(27), Rapaport F(3), Kerner G(9)(10), Allington G(28)(29)(30),
Tezcan I(31), Cagdas D(31), Hosnut FO(32), Dogu F(33), Ikinciogullari A(33), Rao
VK(34), Kainulainen L(35), Béziat V(3)(9)(10), Bustamante J(3)(9)(10)(36),
Vilarinho S(#)(28)(29)(30), Lifton RP(#)(28)(37), Boisson B(#)(3)(9)(10), Abel
L(#)(3)(9)(10), Bogunovic D(#)(11)(12)(13)(14), Marr N(#)(7)(38), Notarangelo
LD(#)(8), Tangye SG(#)(20)(21), Honjo T(#)(22), Gros P(#)(39)(40),
Boisson-Dupuis S(#)(41)(42)(43), Casanova JL(#)(44)(45)(46)(47).
Author information:
(1)St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller
Branch, Rockefeller University, New York, NY, USA. mogishi@rockefeller.edu.
(2)The David Rockefeller Graduate Program, Rockefeller University, New York, NY,
USA. mogishi@rockefeller.edu.
(3)St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller
Branch, Rockefeller University, New York, NY, USA.
…
The pathophysiology of adverse events following programmed cell death protein 1
(PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly
characterized. We studied a patient with inherited PD-1 deficiency and TB who
died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or
respond to PD-1-mediated suppression. The patient's lymphocytes produced only
small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to
patients with inborn errors of IFN-γ production who are vulnerable to TB. This
phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated
invariant T and CD56bright natural killer lymphocytes and dysfunction of other T
lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an
expansion of total, activated and RORγT+ CD4-CD8- double-negative αβ T cells,
similar to patients with STAT3 gain-of-function mutations who display
lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts
of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated
T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by
activated T lymphocytes. Our work highlights the indispensable role of human
PD-1 in governing both antimycobacterial immunity and self-tolerance, while
identifying potentially actionable molecular targets for the diagnostic and
therapeutic management of TB and autoimmunity in patients on PD-1 blockade.
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41591-021-01388-5
PMCID: PMC8446316
PMID: 34183838 [Indexed for MEDLINE]
8. J Clin Invest. 2021 Sep 1;131(17):e137407. doi: 10.1172/JCI137407.
TREM-2 promotes Th1 responses by interacting with the CD3ζ-ZAP70 complex
following Mycobacterium tuberculosis infection.
Wu Y(1)(2)(3)(4), Wu M(1), Ming S(1)(2)(5), Zhan X(1), Hu S(1), Li X(1)(2), Yin
H(1)(2), Cao C(1)(2), Liu J(1)(2), Li J(1)(2), Wu Z(6), Zhou J(6), Liu L(5),
Gong S(4), He D(7), Huang X(1)(2)(3)(4)(5).
Author information:
(1)Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun
Yat-sen University, Zhuhai, Guangdong Province, China.
(2)Guangdong Provincial Engineering Research Center of Molecular Imaging,
Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of
Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University,
Zhuhai, China.
(3)Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai,
Guangdong Province, China.
(4)Department of Gastroenterology, Guangzhou Women and Children's Medical
Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University,
Guangzhou, Guangdong Province, China.
(5)National Clinical Research Center for Infectious Disease, Shenzhen Third
People's Hospital, The Second Affiliated Hospital of the Southern University of
Science and Technology, Shenzhen, Guangdong Province, China.
(6)The Fourth People's Hospital of Foshan, Foshan, China.
(7)Shantou No. 3 People's Hospital, Shantou, Guangdong Province, China.
Triggering receptor expressed on myeloid cells 2 (TREM-2) is a modulator of
pattern recognition receptors on innate immune cells that regulates the
inflammatory response. However, the role of TREM-2 in in vivo models of
infection and inflammation remains controversial. Here, we demonstrated that
TREM-2 expression on CD4+ T cells was induced by Mycobacterium tuberculosis
infection in both humans and mice and positively associated with T cell
activation and an effector memory phenotype. Activation of TREM-2 in CD4+ T
cells was dependent on interaction with the putative TREM-2 ligand expressed on
DCs. Unlike the observation in myeloid cells that TREM-2 signals through DAP12,
in CD4+ T cells, TREM-2 interacted with the CD3ζ-ZAP70 complex as well as with
the IFN-γ receptor, leading to STAT1/-4 activation and T-bet transcription. In
addition, an infection model using reconstituted Rag2-/- mice (with TREM-2-KO
vs. WT cells or TREM-2+ vs. TREM-2-CD4+ T cells) or CD4+ T cell-specific TREM-2
conditional KO mice demonstrated that TREM-2 promoted a Th1-mediated host
defense against M. tuberculosis infection. Taken together, these findings reveal
a critical role of TREM-2 in evoking proinflammatory Th1 responses that may
provide potential therapeutic targets for infectious and inflammatory diseases.
DOI: 10.1172/JCI137407
PMCID: PMC8409584
PMID: 34623322 [Indexed for MEDLINE]
9. Lancet Infect Dis. 2021 Sep 23:S1473-3099(21)00449-7. doi:
10.1016/S1473-3099(21)00449-7. Online ahead of print.
Global, regional, and national sex differences in the global burden of
tuberculosis by HIV status, 1990-2019: results from the Global Burden of Disease
Study 2019.
GBD 2019 Tuberculosis Collaborators.
BACKGROUND: Tuberculosis is a major contributor to the global burden of disease,
causing more than a million deaths annually. Given an emphasis on equity in
access to diagnosis and treatment of tuberculosis in global health targets,
evaluations of differences in tuberculosis burden by sex are crucial. We aimed
to assess the levels and trends of the global burden of tuberculosis, with an
emphasis on investigating differences in sex by HIV status for 204 countries and
territories from 1990 to 2019.
METHODS: We used a Bayesian hierarchical Cause of Death Ensemble model (CODEm)
platform to analyse 21 505 site-years of vital registration data, 705 site-years
of verbal autopsy data, 825 site-years of sample-based vital registration data,
and 680 site-years of mortality surveillance data to estimate mortality due to
tuberculosis among HIV-negative individuals. We used a population attributable
fraction approach to estimate mortality related to HIV and tuberculosis
coinfection. A compartmental meta-regression tool (DisMod-MR 2.1) was then used
to synthesise all available data sources, including prevalence surveys, annual
case notifications, population-based tuberculin surveys, and tuberculosis
cause-specific mortality, to produce estimates of incidence, prevalence, and
mortality that were internally consistent. We further estimated the fraction of
tuberculosis mortality that is attributable to independent effects of risk
factors, including smoking, alcohol use, and diabetes, for HIV-negative
individuals. For individuals with HIV and tuberculosis coinfection, we assessed
mortality attributable to HIV risk factors including unsafe sex, intimate
partner violence (only estimated among females), and injection drug use. We
present 95% uncertainty intervals for all estimates.
FINDINGS: Globally, in 2019, among HIV-negative individuals, there were 1·18
million (95% uncertainty interval 1·08-1·29) deaths due to tuberculosis and 8·50 million (7·45-9·73) incident cases of tuberculosis. Among HIV-positive
individuals, there were 217 000 (153 000-279 000) deaths due to tuberculosis and
1·15 million (1·01-1·32) incident cases in 2019. More deaths and incident cases
occurred in males than in females among HIV-negative individuals globally in
2019, with 342 000 (234 000-425 000) more deaths and 1·01 million (0·82-1·23)
more incident cases in males than in females. Among HIV-positive individuals,
6250 (1820-11 400) more deaths and 81 100 (63 300-100 000) more incident cases
occurred among females than among males in 2019. Age-standardised mortality
rates among HIV-negative males were more than two times greater in 105 countries
and age-standardised incidence rates were more than 1·5 times greater in 74
countries than among HIV-negative females in 2019. The fraction of global
tuberculosis deaths among HIV-negative individuals attributable to alcohol use,
smoking, and diabetes was 4·27 (3·69-5·02), 6·17 (5·48-7·02), and 1·17
(1·07-1·28) times higher, respectively, among males than among females in 2019.
Among individuals with HIV and tuberculosis coinfection, the fraction of
mortality attributable to injection drug use was 2·23 (2·03-2·44) times greater
among males than females, whereas the fraction due to unsafe sex was 1·06
(1·05-1·08) times greater among females than males.
INTERPRETATION: As countries refine national tuberculosis programmes and
strategies to end the tuberculosis epidemic, the excess burden experienced by
males is important. Interventions are needed to actively communicate, especially
to men, the importance of early diagnosis and treatment. These interventions
should occur in parallel with efforts to minimise excess HIV burden among women
in the highest HIV burden countries that are contributing to excess HIV and
tuberculosis coinfection burden for females. Placing a focus on tuberculosis
burden among HIV-negative males and HIV and tuberculosis coinfection among
females might help to diminish the overall burden of tuberculosis. This strategy
will be crucial in reaching both equity and burden targets outlined by global
health milestones.
FUNDING: Bill & Melinda Gates Foundation.
Copyright © 2021 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(21)00449-7
PMID: 34563275
10. J Clin Oncol. 2021 Sep 22:JCO2101113. doi: 10.1200/JCO.21.01113. Online ahead of print.
Poziotinib for Patients With HER2 Exon 20 Mutant Non-Small-Cell Lung Cancer:
Results From a Phase II Trial.
Elamin YY(1), Robichaux JP(1), Carter BW(2), Altan M(1), Gibbons DL(1), Fossella
FV(1), Lam VK(1)(3), Patel AB(4), Negrao MV(1), Le X(1), Mott FE(1), Zhang J(1),
Feng L(5), Blumenschein G Jr(1), Tsao AS(1), Heymach JV(1).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX.
(2)Department of Thoracic Imaging, The University of Texas MD Anderson Cancer
Center, Houston, TX.
(3)Department of Medicine, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore,
MD.
(4)Department of Dermatology, The University of Texas MD Anderson Cancer Center,
Houston, TX.
(5)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, TX.
PURPOSE: Targeted therapies against non-small-cell lung cancer (NSCLC) harboring
HER2 mutations remain an unmet need. In this study, we assessed the efficacy and
safety of poziotinib in patients with HER2 exon 20 mutant advanced NSCLC in a
single-arm, open-label, phase II study.
PATIENTS AND METHODS: Patients with advanced HER2 exon 20 mutant NSCLC were
enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The
primary end point was objective response rate per RECIST version 1.1.
Confirmatory scans were performed at least 28 days from initial radiologic
response.
RESULTS: Thirty patients received poziotinib treatment. At baseline, 90% of
patients received prior platinum-based chemotherapy and 53% had two lines or
more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed
objective response rate was 27% (95% CI, 12 to 46). Responses were observed
across HER2 exon 20 mutation subtypes. The median duration of response was 5.0
months (95% CI, 4.0 to not estimable). The median progression-free survival was
5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95%
CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse
events were skin rash (47%) and diarrhea (20%). There was one possible
treatment-related death because of pneumonitis.
CONCLUSION: Poziotinib showed promising antitumor activity in patients with HER2
exon 20 mutant NSCLC including patients who had previously received
platinum-based chemotherapy.
DOI: 10.1200/JCO.21.01113
PMID: 34550757
11. Nat Commun. 2021 Sep 20;12(1):5548. doi: 10.1038/s41467-021-25867-y.
Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line
drug isoniazid.
Jiang Y(1), Li Y(1), Liu C(1), Zhang L(1), Lv D(1), Weng Y(2), Cheng Z(2), Chen
X(3), Zhan J(1), Zhang H(4).
Author information:
(1)Program for Cancer and Cell Biology, Department of Human Anatomy, Histology
and Embryology, PKU International Cancer Institute, MOE Key Laboratory of
Carcinogenesis and Translational Research and State Key Laboratory of Natural
and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR
China.
(2)Jingjie PTM BioLab Co. Ltd., Hangzhou Economic and Technological Development
Area, Hangzhou, PR China.
(3)Department of Microbiology & Infectious Disease Center, Peking University
Health Science Center, Beijing, PR China.
(4)Program for Cancer and Cell Biology, Department of Human Anatomy, Histology
and Embryology, PKU International Cancer Institute, MOE Key Laboratory of
Carcinogenesis and Translational Research and State Key Laboratory of Natural
and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR
China. Hongquan.Zhang@bjmu.edu.cn.
Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years.
However, the mechanism underlying the side effects of INH has remained elusive.
Here, we report that INH and its metabolites induce a post-translational
modification (PTM) of histones, lysine isonicotinylation (Kinic), also called
4-picolinylation, in cells and mice. INH promotes the biosynthesis of
isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation.
Mass spectrometry reveals 26 Kinic sites in histones in HepG2 cells.
Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone Kinic,
while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase
sensitivity assay and RNA-seq analysis show that histone Kinic relaxes chromatin
structure and promotes gene transcription. INH-mediated histone Kinic
upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling
pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We
demonstrate that Kinic is a histone acylation mark with a pyridine ring, which
may have broad biological effects. Therefore, INH-induced isonicotinylation
potentially accounts for the side effects in patients taking INH long-term for
anti-tuberculosis therapy, and this modification may increase the risk of cancer
in humans.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-25867-y
PMCID: PMC8452692
PMID: 34545082 [Indexed for MEDLINE]
12. PLoS Med. 2021 Sep 14;18(9):e1003712. doi: 10.1371/journal.pmed.1003712.
eCollection 2021 Sep.
Economic and modeling evidence for tuberculosis preventive therapy among people
living with HIV: A systematic review and meta-analysis.
Uppal A(1)(2)(3), Rahman S(1)(2)(3), Campbell JR(1)(2)(3), Oxlade O(3), Menzies
D(1)(2)(3).
Author information:
(1)Montréal Chest Institute, Montréal, Québec, Canada.
(2)Respiratory Epidemiology and Clinical Research Unit, Centre for Outcomes
Research and Evaluation, Research Institute of McGill University Health Centre,
Montréal, Québec, Canada.
(3)McGill International Tuberculosis Centre, Montréal, Québec, Canada.
Comment in
Tuberculosis preventive treatment in people living with HIV - is the glass
half empty, or half full?
The Latent Tuberculosis Cascade-of-Care Among People Living with HIV: A
Systematic Review and Meta-Analysis.
Tuberculosis Preventive Therapy for People Living with HIV: A Systematic
Review and Network Meta-analysis.
BACKGROUND: Human immunodeficiency virus (HIV) is the strongest known risk
factor for tuberculosis (TB) through its impairment of T-cell immunity.
Tuberculosis preventive treatment (TPT) is recommended for people living with
HIV (PLHIV) by the World Health Organization, as it significantly reduces the
risk of developing TB disease. We conducted a systematic review and
meta-analysis of modeling studies to summarize projected costs, risks, benefits,
and impacts of TPT use among PLHIV on TB-related outcomes.
METHODS AND FINDINGS: We searched MEDLINE, Embase, and Web of Science from
inception until December 31, 2020. Two reviewers independently screened titles,
abstracts, and full texts; extracted data; and assessed quality. Extracted data
were summarized using descriptive analysis. We performed quantile regression and
random effects meta-analysis to describe trends in cost, effectiveness, and
cost-effectiveness outcomes across studies and identified key determinants of
these outcomes. Our search identified 6,615 titles; 61 full texts were included
in the final review. Of the 61 included studies, 31 reported both cost and
effectiveness outcomes. A total of 41 were set in low- and middle-income
countries (LMICs), while 12 were set in high-income countries (HICs); 2 were set
in both. Most studies considered isoniazid (INH)-based regimens 6 to 2 months
long (n = 45), or longer than 12 months (n = 11). Model parameters and
assumptions varied widely between studies. Despite this, all studies found that
providing TPT to PLHIV was predicted to be effective at averting TB disease. No
TPT regimen was substantially more effective at averting TB disease than any
other. The cost of providing TPT and subsequent downstream costs (e.g. post-TPT
health systems costs) were estimated to be less than $1,500 (2020 USD) per
person in 85% of studies that reported cost outcomes (n = 36), regardless of
study setting. All cost-effectiveness analyses concluded that providing TPT to
PLHIV was potentially cost-effective compared to not providing TPT. In
quantitative analyses, country income classification, consideration of
antiretroviral therapy (ART) use, and TPT regimen use significantly impacted
cost-effectiveness. Studies evaluating TPT in HICs suggested that TPT may be
more effective at preventing TB disease than studies evaluating TPT in LMICs;
pooled incremental net monetary benefit, given a willingness-to-pay threshold of
country-level per capita gross domestic product (GDP), was $271 in LMICs (95%
confidence interval [CI] -$81 to $622, p = 0.12) and was $2,568 in HICs
(-$32,115 to $37,251, p = 0.52). Similarly, TPT appeared to be more effective at
averting TB disease in HICs; pooled percent reduction in active TB incidence was
20% (13% to 27%, p < 0.001) in LMICs and 37% (-34% to 100%, p = 0.13) in HICs.
Key limitations of this review included the heterogeneity of input parameters
and assumptions from included studies, which limited pooling of effect
estimates, inconsistent reporting of model parameters, which limited sample
sizes of quantitative analyses, and database bias toward English publications.
CONCLUSIONS: The body of literature related to modeling TPT among PLHIV is large
and heterogeneous, making comparisons across studies difficult. Despite this
variability, all studies in all settings concluded that providing TPT to PLHIV
is potentially effective and cost-effective for preventing TB disease.
DOI: 10.1371/journal.pmed.1003712
PMCID: PMC8439468
PMID: 34520463
13. Am J Respir Crit Care Med. 2021 Sep 14. doi: 10.1164/rccm.202103-0548OC. Online ahead of print.
Longitudinal Dynamics of a Blood Transcriptomic Signature of Tuberculosis.
Mulenga H(1), Musvosvi M(2), Mendelsohn SC(3), Penn-Nicholson A(4), Kimbung
Mbandi S(4), Gartland AF(5), Tameris M(6), Mabwe S(7), Africa H(8), Bilek N(7),
Kafaar F(4), Khader SA(9), Carstens B(4), Hadley K(4), Hikuam C(4), Erasmus
M(7), Jaxa L(4), Raphela R(4), Nombida O(4), Kaskar M(4), Nicol MP(10), Mbhele
S(10), Van Heerden J(10), Innes C(11), Brumskine W(11), Hiemstra A(12), Malherbe
ST(13), Hassan-Moosa R(14), Walzl G(13), Naidoo K(15), Churchyard G(16),
Hatherill M(17), Scriba TJ(18); CORTIS Study Team.
Author information:
(1)University of Cape Town Faculty of Health Sciences, 63726, Pathology,
Observatory, South Africa.
(2)University of Cape Town, Institute of Infectious Diseases and Molecular
Medicine, Observatory, South Africa.
(3)University of Cape Town, 37716, South African Tuberculosis Vaccine
Initiative, Cape Town, South Africa.
…
Objectives We evaluated longitudinal kinetics of an 11-gene blood transcriptomic
tuberculosis (TB) signature, RISK11, and effects of TB preventative therapy
(TPT) and respiratory organisms on RISK11 signature score, in HIV-uninfected and
HIV-infected individuals. Methods RISK11 was measured in a longitudinal study of
RISK11-guided TPT in HIV-uninfected adults, a cross-sectional respiratory
organisms cohort or a longitudinal study in people living with HIV (PLHIV).
HIV-uninfected RISK11+ participants were randomised to TPT or no TPT; RISK11-
participants received no TPT. PLHIV received standard-of-care ART and TPT. In
the cross-sectional respiratory organisms cohort, viruses and bacteria in
nasopharyngeal and oropharyngeal swabs were quantified by RT-qPCR. Measurements
and Main Results RISK11+ status was transient in most of the 128 HIV-negative
participants with longitudinal samples; >70% of RISK11+ participants reverted to
RISK11- by 3 months, irrespective of TPT. By comparison, reversion from a
RISK11-positive state was less common in 645 PLHIV (42.1%). Non-HIV viral and
non-tuberculous bacterial organisms were detected in 7.2% and 38.9% of the 1,000
respiratory organisms cohort participants, respectively, and among those
investigated for TB, 3.8% had prevalent disease. Median RISK11 scores (%) were
higher in participants with viral organisms alone (46.7%), viral and bacterial
organisms (42.8%), or prevalent TB (85.7%), than those with bacterial organisms
other than TB (13.4%), or no organisms (14.2%). RISK11 could not discriminate
between prevalent TB and viral organisms. Conclusions Positive RISK11 signature
status is often transient, possibly due to intercurrent viral infection,
highlighting potentially important challenges for implementation of these
biomarkers as new tools for TB control. This article is open access and
distributed under the terms of the Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/).
DOI: 10.1164/rccm.202103-0548OC
PMID: 34520313
14. Lancet Infect Dis. 2021 Sep 7:S1473-3099(21)00403-5. doi:
10.1016/S1473-3099(21)00403-5. Online ahead of print.
100 years of Mycobacterium bovis bacille Calmette-Guérin.
Lange C(1), Aaby P(2), Behr MA(3), Donald PR(4), Kaufmann SHE(5), Netea MG(6),
Mandalakas AM(7).
Author information:
(1)Division of Clinical Infectious Diseases, Medical Clinic, Research Center
Borstel, Borstel, Germany; German Center for Infection Research (DZIF)
Tuberculosis Unit, Borstel, Germany; Respiratory Medicine and International
Health, University of Lübeck, Lübeck, Germany; Global TB Program, Baylor College
of Medicine and Texas Children's Hospital, Houston, TX, USA. Electronic address:
clange@fz-borstel.de.
(2)Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau; Bandim Health
Project, Southern Danish University, Copenhagen, Denmark.
(3)McGill International TB Centre and Department of Medicine, McGill University,
Montreal, QC, Canada.
…
Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine
designed to protect cattle from bovine tuberculosis, was administered for the
first time to a newborn baby in Paris in 1921. Over the past century, BCG has
saved tens of millions of lives and has been given to more humans than any other
vaccine. It remains the sole tuberculosis vaccine licensed for use in humans.
BCG provides long-lasting strong protection against miliary and meningeal
tuberculosis in children, but it is less effective for the prevention of
pulmonary tuberculosis, especially in adults. Evidence mainly from the past two
decades suggests that BCG has non-specific benefits against non-tuberculous
infections in newborn babies and in older adults, and offers immunotherapeutic
benefit in certain malignancies such as non-muscle invasive bladder cancer.
However, as a live attenuated vaccine, BCG can cause localised or disseminated
infections in immunocompromised hosts, which can also occur following
intravesical installation of BCG for the treatment of bladder cancer. The legacy
of BCG includes fundamental discoveries about tuberculosis-specific and
non-specific immunity and the demonstration that tuberculosis is a
vaccine-preventable disease, providing a foundation for new vaccines to hasten
tuberculosis elimination.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(21)00403-5
PMID: 34506734
15. Lancet Infect Dis. 2021 Sep 6:S1473-3099(21)00145-6. doi:
10.1016/S1473-3099(21)00145-6. Online ahead of print.
Comparison of three tests for latent tuberculosis infection in high-risk people
in the USA: an observational cohort study.
Ho CS(1), Feng PI(2), Narita M(3), Stout JE(4), Chen M(2), Pascopella L(5),
Garfein R(6), Reves R(7), Katz DJ(2); Tuberculosis Epidemiologic Studies
Consortium.
Collaborators: Flood J, Pascopella L, Higashi J, Moser K, Moore M, Garfein R,
Benson C, Belknap R, Reves R, Stout JE, Ahmed A, Sterling T, Pettit A, Blumberg
HM, Oladele A, Lauzardo M, Seraphin MN, Brostrom R, Khurana R, Cronin W, Dorman
S, Narita M, Horne D, Miller T.
Author information:
(1)Division of Tuberculosis Elimination, US Centers for Disease Control and
Prevention, Atlanta, GA, USA. Electronic address: gtb9@cdc.gov.
(2)Division of Tuberculosis Elimination, US Centers for Disease Control and
Prevention, Atlanta, GA, USA.
(3)TB Control Program, Public Health-Seattle and King County, Seattle, WA, USA.
(4)Division of Infectious Diseases and International Health, Department of
Medicine, Duke University Medical Center, Durham, NC, USA.
(5)Tuberculosis Control Branch, Division of Communicable Disease Control, Center
for Infectious Diseases, California Department of Public Health, Richmond, CA,
USA.
(6)Division of Global Public Health, School of Medicine, University of
California, San Diego, CA, USA.
(7)Denver Health and Hospital Authority, Denver, CO, USA.
BACKGROUND: Treatment of latent tuberculosis infection is an important strategy
to prevent tuberculosis disease. In the USA, three tests are used to identify
latent tuberculosis infection: the tuberculin skin test (TST) and two IFN-γ
release assays (T-SPOT.TB and QuantiFERON). To our knowledge, few large studies
have compared all three tests among people at high risk of latent tuberculosis
infection or progression to tuberculosis disease. We aimed to assess test
agreement between IFN-γ release assays and TST to provide guidance on their use
in important risk groups.
METHODS: In this observational cohort study, we enrolled participants at high
risk of latent tuberculosis infection or progression to tuberculosis disease at
ten US sites with 18 affiliated clinics, including close contacts of infectious
tuberculosis cases, people born in countries whose populations in the USA have
high (≥100 cases per 100 000 people) or moderate (10-99 cases per 100 000
people) tuberculosis incidence, and people with HIV. Participants were
interviewed about demographics and medical risk factors, and all three tests
were administered to each participant. The primary endpoints for this study were
the proportions of positive test results by test type stratified by risk group
and test concordance by risk group for participants with valid results for all
three test types. The study is registered at ClinicalTrials.gov, NCT01622140.
FINDINGS: Between July 12, 2012, and May 5, 2017, 26 292 people were approached
and 22 131 (84·2%) were enrolled in the study. Data from 21 846 (98·7%)
participants were available for analysis, including 3790 (17·3%) born in the USA
and 18 023 (82·5%) born outside the USA. Among non-US-born participants overall,
the RR comparing the proportions of TST-positive results (7476 [43·2%] of 17 306 participants) to QuantiFERON-positive results (4732 [26·5%] of 17 882
participants) was 1·6 (95% CI 1·6-1·7). The risk ratio (RR) for the comparison
with the proportion of T-SPOT.TB-positive results (3693 [21·6%] of 17 118
participants) was 2·0 (95% CI 1·9-2·1). US-born participants had less variation
in the proportions of positive results across all tests. The RRs for the
proportion of TST-positive results (391 [10·9%] of 3575 participants) compared
with the proportion of QuantiFERON-positive results (445 [12·0%] of 3693
participants) and T-SPOT.TB-positive results (295 [8·1%] of 3638 participants)
were 0·9 (95% CI 0·8-1·0) and 1·3 (1·2-1·6), respectively. 20 149 (91·0%) of 21 846 participants had results for all three tests, including 16 712 (76%)
non-US-born participants. Discordance between TST and IFN-γ release assay
results varied by age among non-US-born participants and was greatest among the
848 non-US-born children younger than 5 years. 204 (87·2%) of 234 non-US-born
children younger than 5 years with at least one positive test were TST-positive
and IFN-γ release assay-negative. The proportion of non-US-born participants who
were TST-negative but IFN-γ release assay-positive ranged from one (0·5%) of 199 children younger than 2 years to 86 (14·5%) of 594 participants aged 65 years
and older (ptrend<0·0001). Test agreement was higher between the two IFN-γ
release assays than between TST and either IFN-γ release assay, regardless of
birthplace. κ agreement was particularly low between TST and IFN-γ release
assays in non-US-born children younger than 5 years.
INTERPRETATION: Our findings support the preferential use of IFN-γ release
assays for the diagnosis of latent tuberculosis in high-risk populations,
especially in very young and older people born outside the USA.
FUNDING: US Centers for Disease Control and Prevention.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(21)00145-6
PMID: 34499863
16. Nat Commun. 2021 Sep 2;12(1):5236. doi: 10.1038/s41467-021-25537-z.
The cryo-EM structure of the bd oxidase from M. tuberculosis reveals a unique
structural framework and enables rational drug design to combat TB.
Safarian S(1), Opel-Reading HK(2), Wu D(3), Mehdipour AR(4), Hards K(5), Harold
LK(5), Radloff M(3), Stewart I(6), Welsch S(7), Hummer G(4)(8), Cook GM(5),
Krause KL(2), Michel H(9).
Author information:
(1)Department of Molecular Membrane Biology, Max Planck Institute of Biophysics,
Frankfurt/Main, Germany. schara.safarian@biophys.mpg.de.
(2)Department of Biochemistry, University of Otago, Dunedin, New Zealand.
(3)Department of Molecular Membrane Biology, Max Planck Institute of Biophysics,
Frankfurt/Main, Germany.
…
New drugs are urgently needed to combat the global TB epidemic. Targeting
simultaneously multiple respiratory enzyme complexes of Mycobacterium
tuberculosis is regarded as one of the most effective treatment options to
shorten drug administration regimes, and reduce the opportunity for the
emergence of drug resistance. During infection and proliferation, the cytochrome
bd oxidase plays a crucial role for mycobacterial pathophysiology by maintaining
aerobic respiration at limited oxygen concentrations. Here, we present the
cryo-EM structure of the cytochrome bd oxidase from M. tuberculosis at 2.5 Å. In
conjunction with atomistic molecular dynamics (MD) simulation studies we
discovered a previously unknown MK-9-binding site, as well as a unique disulfide
bond within the Q-loop domain that defines an inactive conformation of the
canonical quinol oxidation site in Actinobacteria. Our detailed insights into
the long-sought atomic framework of the cytochrome bd oxidase from M.
tuberculosis will form the basis for the design of highly specific drugs to act
on this enzyme.
© 2021. The Author(s).
DOI: 10.1038/s41467-021-25537-z
PMCID: PMC8413341
PMID: 34475399 [Indexed for MEDLINE]
17. J Clin Invest. 2021 Sep 2:148013. doi: 10.1172/JCI148013. Online ahead of print.
Alveolar macrophages from persons living with HIV show impaired epigenetic
response to Mycobacterium tuberculosis.
Correa-Macedo W(1), Fava VM(2), Orlova M(2), Cassart P(2), Olivenstein R(3),
Sanz J(4), Xu YZ(2), Dumaine A(5), Sindeaux RH(6), Yotova V(6), Pacis A(7),
Girouard J(8), Kalsdorf B(9), Lange C(9), Routy JP(2), Barreiro LB(5), Schurr
E(2).
Author information:
(1)Department of Biochemistry, McGill University, Montréal, Canada.
(2)Program in Infectious Diseases and Global Health, The Research Institute of
the McGill University Health Centre, Montréal, Canada.
(3)Translational Research in Respiratory Diseases Program, The Research
Institute of the McGill University Health Centre, Montréal, Canada.
…
Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB).
HIV-associated TB is often the result of recent infection with Mycobacterium
tuberculosis (Mtb) followed by rapid progression to disease. Alveolar
macrophages (AM) are the first cells of the innate immune system that engage
Mtb, but how HIV and antiretroviral therapy (ART) impact on the
anti-mycobacterial response of AM is not known. To investigate the impact of HIV
and ART on the transcriptomic and epigenetic response of AM to Mtb, we obtained
AM by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who
were HIV-free (HC), and 14 subjects who received ART as pre-exposure prophylaxis
(PrEP) to prevent HIV infection. Following in-vitro challenge with Mtb, AM from
each group displayed overlapping but distinct profiles of significantly up- and
down-regulated genes in response to Mtb. Comparatively, AM isolated from both
PLWH and PrEP subjects presented a substantially weaker transcriptional
response. In addition, AM from HC subjects challenged with Mtb responded with
pronounced chromatin accessibility changes while AM obtained from PLWH and PrEP
subjects displayed no significant changes in their chromatin state.
Collectively, these results revealed a stronger adverse effect of ART than HIV
on the epigenetic landscape and transcriptional responsiveness of AM.
DOI: 10.1172/JCI148013
PMID: 34473646
18. Lancet Infect Dis. 2021 Sep;21(9):e272-e280. doi: 10.1016/S1473-3099(21)00077-3.
Barriers and enablers to implementing tuberculosis control strategies in EU and
European Economic Area countries: a systematic review.
Conroy O(1), Wurie F(2), Collin SM(2), Edmunds M(2), de Vries G(3), Lönnroth
K(4), Abubakar I(5), Anderson SR(2), Zenner D(6).
Author information:
(1)TB Unit, National Infection Service, Public Health England, London, UK.
Electronic address: olivia.conroy@PHE.gov.uk.
(2)TB Unit, National Infection Service, Public Health England, London, UK.
(3)KNCV Tuberculosis Foundation, The Hague, Netherlands.
(4)Department of Public Health Sciences, Karolinska Institute, Stockholm,
Sweden.
(5)Institute for Global Health, University College London, London, UK.
(6)TB Unit, National Infection Service, Public Health England, London, UK;
Institute for Global Health, University College London, London, UK.
Meeting the 2035 WHO targets of reducing tuberculosis incidence by 90% from 2015
levels requires the implementation of country-specific tuberculosis control
strategies. This systematic review aims to identify factors that facilitate or
impede the implementation of such strategies in EU and European Economic Area
(EEA) settings. Focusing on providers of care, health system constraints, and
social and political factors, this Review complements available evidence on the
accessibility of tuberculosis services to recipients of care. Databases were
searched for EU and EEA articles published between Jan 1, 1997, and Nov 6, 2020,
that presented empirical data on tuberculosis policies, strategies, guidelines,
or interventions. 2061 articles were screened and 65 were included. The most
common barrier to tuberculosis control strategies described the divergence of
health-care practices from guidelines, often related to inadequate knowledge or
perceived usefulness of the guidelines by clinicians. The most commonly
identified enabler to tuberculosis control strategies was the documented
positive attitudes of health-care workers towards tuberculosis programmes.
Divergence between clinical practice and guidelines was described in most EU and
EEA settings, indicating the need for a focused review of guideline adherence.
Strengths of this study involve its broad inclusion criteria and wide range of
tuberculosis control strategies analysed.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(21)00077-3
PMID: 34450080 [Indexed for MEDLINE]
19. J Exp Med. 2021 Sep 6;218(9):e20210615. doi: 10.1084/jem.20210615. Epub 2021 Jul 22.
Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the
infected lung.
Pisu D(1), Huang L(1)(2), Narang V(3), Theriault M(1), Lê-Bury G(1), Lee B(3),
Lakudzala AE(4), Mzinza DT(4), Mhango DV(4), Mitini-Nkhoma SC(4), Jambo
KC(4)(5), Singhal A(3)(6), Mwandumba HC(4)(5), Russell DG(1).
Author information:
(1)Microbiology and Immunology, College of Veterinary Medicine, Cornell
University, Ithaca, NY.
(2)Microbiology and Immunology, University of Arkansas for Medical Sciences,
Little Rock, AR.
(3)Singapore Immunology Network, Agency for Science, Technology and Research,
Singapore.
(4)Malawi Liverpool Wellcome Trust Clinical Research Program, University of
Malawi College of Medicine, Blantyre, Malawi.
(5)Department of Clinical Sciences, Liverpool School of Tropical Medicine,
Liverpool, UK.
(6)A*STAR Infectious Diseases Laboratories, Agency for Science, Technology and
Research, Singapore.
In this study, we detail a novel approach that combines bacterial fitness
fluorescent reporter strains with scRNA-seq to simultaneously acquire the host
transcriptome, surface marker expression, and bacterial phenotype for each
infected cell. This approach facilitates the dissection of the functional
heterogeneity of M. tuberculosis-infected alveolar (AMs) and interstitial
macrophages (IMs) in vivo. We identify clusters of pro-inflammatory AMs
associated with stressed bacteria, in addition to three different populations of
IMs with heterogeneous bacterial phenotypes. Finally, we show that the main
macrophage populations in the lung are epigenetically constrained in their
response to infection, while inter-species comparison reveals that most AMs
subsets are conserved between mice and humans. This conceptual approach is
readily transferable to other infectious disease agents with the potential for
an increased understanding of the roles that different host cell populations
play during the course of an infection.
© 2021 Pisu et al.
DOI: 10.1084/jem.20210615
PMCID: PMC8302446
PMID: 34292313
20. J Exp Med. 2021 Sep 6;218(9):e20210332. doi: 10.1084/jem.20210332. Epub 2021 Jul 16.
Genetic models of latent tuberculosis in mice reveal differential influence of
adaptive immunity.
Su H(1), Lin K(1), Tiwari D(1), Healy C(1), Trujillo C(1), Liu Y(1), Ioerger
TR(2), Schnappinger D(1), Ehrt S(1).
Author information:
(1)Department of Microbiology and Immunology, Weill Cornell Medicine, New York,
NY.
(2)Department of Computer Science and Engineering, Texas A&M University, College
Station, TX.
Studying latent Mycobacterium tuberculosis (Mtb) infection has been limited by
the lack of a suitable mouse model. We discovered that transient depletion of
biotin protein ligase (BPL) and thioredoxin reductase (TrxB2) results in latent
infections during which Mtb cannot be detected but that relapse in a subset of
mice. The immune requirements for Mtb control during latency, and the frequency
of relapse, were strikingly different depending on how latency was established.
TrxB2 depletion resulted in a latent infection that required adaptive immunity
for control and reactivated with high frequency, whereas latent infection after
BPL depletion was independent of adaptive immunity and rarely reactivated. We
identified immune signatures of T cells indicative of relapse and demonstrated
that BCG vaccination failed to protect mice from TB relapse. These reproducible
genetic latency models allow investigation of the host immunological
determinants that control the latent state and offer opportunities to evaluate
therapeutic strategies in settings that mimic aspects of latency and TB relapse
in humans.
© 2021 Su et al.
DOI: 10.1084/jem.20210332
PMCID: PMC8289691
PMID: 34269789
21. J Clin Oncol. 2021 Sep 10;39(26):2872-2880. doi: 10.1200/JCO.21.00276. Epub 2021 Jul 12.
SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With
Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II
Trial.
Rothschild SI(1), Zippelius A(1), Eboulet EI(2), Savic Prince S(3), Betticher
D(4), Bettini A(4), Früh M(5)(6), Joerger M(5), Lardinois D(7), Gelpke H(8),
Mauti LA(9), Britschgi C(10), Weder W(11), Peters S(12), Mark M(13), Cathomas
R(13), Ochsenbein AF(6), Janthur WD(14), Waibel C(15), Mach N(16), Froesch
P(17), Buess M(18), Bohanes P(19), Godar G(2), Rusterholz C(2), Gonzalez M(20),
Pless M(9); Swiss Group for Clinical Cancer Research (SAKK).
Author information:
(1)Department of Medical Oncology and Comprehensive Cancer Center, University
Hospital Basel, Basel, Switzerland.
(2)SAKK Coordinating Center, Bern, Switzerland.
(3)Pathology, Institute of Medical Genetics and Pathology, University Hospital
Basel, Basel, Switzerland.
…
PURPOSE: For patients with resectable stage IIIA(N2) non-small-cell lung cancer,
neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery
resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00
trial and is an accepted standard of care. We investigated the additional
benefit of perioperative treatment with durvalumab.
METHODS: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m2
and docetaxel 85 mg/m2 once every 3 weeks followed by two doses of durvalumab
750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery.
The primary end point was 1-year EFS. The hypothesis for statistical
considerations was an improvement of 1-year EFS from 48% to 65%.
RESULTS: Sixty-eight patients were enrolled, 67 were included in the full
analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after
neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant
immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a
major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among
them a complete pathologic response. Postoperative nodal downstaging (ypN0-1)
was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0
resection. There was no significant effect of pretreatment PD-L1 expression on
MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to
82). Median EFS and overall survival were not reached after 28.6 months of
median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3
including two fatal adverse events that were judged not to be treatment-related.
CONCLUSION: The addition of perioperative durvalumab to neoadjuvant chemotherapy
in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds
historical data of chemotherapy alone with a high MPR and an encouraging 1-year
EFS rate of 73%.
DOI: 10.1200/JCO.21.00276
PMID: 34251873
22. Am J Respir Crit Care Med. 2021 Sep 15;204(6):713-722. doi:
10.1164/rccm.202009-3527OC.
Evidence-based Definition for Extensively Drug-Resistant Tuberculosis.
Roelens M(1), Battista Migliori G(2), Rozanova L(1), Estill J(1)(3), Campbell
JR(4)(5), Cegielski JP(6), Tiberi S(7)(8), Palmero D(9), Fox GJ(10),
Guglielmetti L(11)(12), Sotgiu G(13), Brust JCM(14), Bang D(15)(16), Lienhardt
C(17)(18), Lange C(19)(20)(21), Menzies D(4)(5), Keiser O(1), Raviglione M(22).
Author information:
(1)Institute of Global Health, Faculty of Medicine, University of Geneva,
Geneva, Switzerland.
(2)Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere
Scientifico, Tradate, Italy.
(3)Institute of Mathematical Statistics and Actuarial Science, University of
Bern, Bern, Switzerland.
…
Comment in
Am J Respir Crit Care Med. 2021 Sep 15;204(6):629-631.
Rationale: Until 2020, extensively drug-resistant tuberculosis (XDR-TB) was
defined as TB with resistance to rifampicin and isoniazid (multidrug-resistant
TB [MDR-TB]), any fluoroquinolone (FQ), and any second-line injectable drug
(SLID). In 2019, the World Health Organization issued new recommendations for
treating patients with drug-resistant TB, substantially limiting the role of
SLIDs in MDR-TB treatment and thus putting the definition of XDR-TB into
question. Objectives: To propose an up-to-date definition for XDR-TB. Methods:
We used a large data set to assess treatment outcomes for patients with MDR-TB
exposed to any type of longer regimen. We included patients with
bacteriologically confirmed MDR-TB and known FQ and SLID resistance results. We
performed logistic regression to estimate the adjusted odds ratios (aORs) for an
unfavorable treatment outcome (failure, relapse, death, loss to follow-up), and
estimates were stratified by the resistance pattern (FQ and/or SLID) and group A
drug use (moxifloxacin/levofloxacin, linezolid, and/or bedaquiline).
Measurements and Main Results: We included 11,666 patients with MDR-TB; 4,653
(39.9%) had an unfavorable treatment outcome. Resistance to FQs increased the
odds of an unfavorable treatment outcome (aOR, 1.91; 95% confidence interval
[CI], 1.63-2.23). Administration of bedaquiline and/or linezolid improved
treatment outcomes regardless of resistance to FQs and/or SLIDs. Among patients
with XDR-TB, compared with persons receiving no group A drug, aORs for an
unfavorable outcome were 0.37 (95% CI, 0.20-0.69) with linezolid only, 0.40 (95%
CI, 0.21-0.77) with bedaquiline only, and 0.21 (95% CI, 0.12-0.38) with both.
Conclusions: Our study supports a new definition of XDR-TB as MDR-TB and
additional resistance to FQ plus bedaquiline and/or linezolid and helps assess
the adequacy of this definition for surveillance and treatment choice.
DOI: 10.1164/rccm.202009-3527OC
PMID: 34107231 [Indexed for MEDLINE]
23. Autophagy. 2021 Sep;17(9):2629-2638. doi: 10.1080/15548627.2020.1825273. Epub 2020 Oct 4.
Neutrophil autophagy during human active tuberculosis is modulated by SLAMF1.
Pellegrini JM(1)(2), Sabbione F(3), Morelli MP(1)(2), Tateosian NL(1)(2),
Castello FA(1)(2), Amiano NO(1)(2), Palmero D(4), Levi A(4), Ciallella L(4),
Colombo MI(5), Trevani AS(3), García VE(1)(2).
Author information:
(1)Departamento de Química Biológica. Facultad de Ciencias Exactas y Naturales,
UBA, Buenos Aires, Argentina.
(2)Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales
(IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos
Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires,
Argentina.
(3)Laboratorio de Inmunidad Innata, Instituto de Medicina Experimental
(IMEX)-CONICET,Academia Nacional de Medicina, Buenos Aires, Argentina.
(4)Hospital F.J. Muñiz, Uspallata 2272, (C1282AEN) Buenos Aires, Argentina.
(5)Instituto de Histología y Embriología de Mendoza, Facultad de Ciencias
Médicas, Universidad Nacional de Cuyo-CONICET, Mendoza, Argentina.
Neutrophils infected with Mycobacterium tuberculosis (Mtb) predominate in
tuberculosis patients' lungs. Neutrophils phagocytose the pathogen, but the
mechanism of pathogen elimination is controversial. Macroautophagy/autophagy, a
crucial mechanism for several neutrophil functions, can be modulated by
immunological mediators. The costimulatory molecule SLAMF1 can act as a
microbial sensor in macrophages being also able to interact with
autophagy-related proteins. Here, we demonstrate for the first time that human
neutrophils express SLAMF1 upon Mtb-stimulation. Furthermore, SLAMF1 was found
colocalizing with LC3B+ vesicles, and activation of SLAMF1 increased neutrophil
autophagy induced by Mtb. Finally, tuberculosis patients' neutrophils displayed
reduced levels of SLAMF1 and lower levels of autophagy against Mtb as compared
to healthy controls. Altogether, these results indicate that SLAMF1 participates
in neutrophil autophagy during active tuberculosis.Abbreviations: AFB: acid-fast
bacilli; BafA1: bafilomycin A1; CLL: chronic lymphocytic leukemia; DPI:
diphenyleneiodonium; EVs: extracellular vesicles; FBS: fetal bovine serum; HD:
healthy donors; HR: high responder (tuberculosis patient); IFNG: interferon
gamma; IL1B: interleukin 1 beta; IL17A: interleukin 17A; IL8: interleukin 8; LR:
low responder (tuberculosis patient); mAb: monoclonal antibody; MAP1LC3/LC3:
microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein
kinase; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK14/p38:
mitogen-activated protein kinase 14; Mtb: Mycobacterium tuberculosis; Mtb-Ag:
Mycobacterium tuberculosis, Strain H37Rv, whole cell lysate; NETs: neutrophils
extracellular traps; PPD: purified protein derivative; ROS: reactive oxygen
species; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3;
SLAMF1: signaling lymphocytic activation molecule family member 1; TB:
tuberculosis; TLR: toll like receptor.
DOI: 10.1080/15548627.2020.1825273
PMCID: PMC8496709
PMID: 32954947
