Publications
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Drobniewski F, Ashmi M, He C, et al., 2024, Aminoglycosides, deafness, and non-tuberculous mycobacteria, The Lancet Global Health, Vol: 12, Pages: e561-e561, ISSN: 2214-109X
Hedberg P, Parczewski M, Serwin K, et al., 2024, In-hospital mortality during the wild-type, alpha, delta, and omicron SARS-CoV-2 waves: a multinational cohort study in the EuCARE project, The Lancet Regional Health. Europe, Vol: 38, ISSN: 2666-7762
BackgroundInvestigating outcomes of hospitalised COVID-19 patients throughout the pandemic is crucial to understand the impact of different SARS-CoV-2 variants. We compared 28-day in-hospital mortality of Wild-type, Alpha, Delta, and Omicron variant infections. Whether the difference in risk by variant varied by age was also evaluated.MethodsWe conducted a cohort study including patients ≥18 years, hospitalised between 2020 and 02-01 and 2022-10-15 with a SARS-CoV-2 positive test, from nine countries. Variant was classified based on sequenced viruses or from national public metadata. Mortality was compared using the cumulative incidence function and subdistribution hazard ratios (SHR) adjusted for age, sex, calendar time, and comorbidities. Results were shown age-stratified due to effect measure modification (P < 0.0001 for interaction between age and variant).FindingsWe included 38,585 participants: 19,763 Wild-type, 6387 Alpha, 3640 Delta, and 8795 Omicron. The cumulative incidence of mortality decreased throughout the study period. Among participants ≥70 years, the adjusted SHR (95% confidence interval) for Delta vs. Omicron was 1.66 (1.29–2.13). This estimate was 1.66 (1.17–2.36) for Alpha vs. Omicron, and 1.34 (0.92–1.95) for Wild-type vs. Omicron. These were 1.21 (0.81–1.82), 1.21 (0.68–2.17), and 0.98 (0.53–1.82) among unvaccinated participants. When comparing Omicron sublineages, the aSHR for BA.1 was 1.92 (1.43–2.58) compared to BA.2 and 1.52 (1.11–2.08) compared to BA.5.InterpretationThe herein observed decrease in in-hospital mortality seems to reflect a combined effect of immunity from vaccinations and previous infections, although differences in virulence between SARS-CoV-2 variants may also have contributed.FundingEuropean Union’s Horizon Europe Research and Innovation Programme.KeywordsSARS-CoV-2COVID-19Variants of concernIn-hospital mortality
Hedberg P, Varisco B, Bai F, et al., 2023, EuCARE-hospitalised study protocol: a cohort study of patients hospitalised with COVID-19 in the EuCARE project, BMC Infectious Diseases, Vol: 23, ISSN: 1471-2334
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), can lead to hospitalisation, particularly in elderly, immunocompromised, and non-vaccinated or partially vaccinated individuals. Although vaccination provides protection, the duration of this protection wanes over time. Additional doses can restore immunity, but the influence of viral variants, specific sequences, and vaccine-induced immune responses on disease severity remains unclear. Moreover, the efficacy of therapeutic interventions during hospitalisation requires further investigation. The study aims to analyse the clinical course of COVID-19 in hospitalised patients, taking into account SARS-CoV-2 variants, viral sequences, and the impact of different vaccines. The primary outcome is all-cause in-hospital mortality, while secondary outcomes include admission to intensive care unit and length of stay, duration of hospitalisation, and the level of respiratory support required. METHODS: This ongoing multicentre study observes hospitalised adult patients with confirmed SARS-CoV-2 infection, utilising a combination of retrospective and prospective data collection. It aims to gather clinical and laboratory variables from around 35,000 patients, with potential for a larger sample size. Data analysis will involve biostatistical and machine-learning techniques. Selected patients will provide biological material. The study started on October 14, 2021 and is scheduled to end on October 13, 2026. DISCUSSION: The analysis of a large sample of retrospective and prospective data about the acute phase of SARS CoV-2 infection in hospitalised patients, viral variants and vaccination in several European and non-European countries will help us to better understand risk factors for disease severity and the interplay between SARS CoV-2 variants, immune responses and vaccine efficacy. The main strengths of this study are the large sample size, the
Gonzalo X, Yrah S, Broda A, et al., 2023, Performance of lipid fingerprint by routine matrix-assisted laser desorption/ionization time of flight for the diagnosis of Mycobacterium tuberculosis complex species, Clinical Microbiology and Infection, Vol: 29, Pages: 387.e1-387.e6, ISSN: 1198-743X
Objectives:Rapid detection of bacterial pathogens to species and subspecies level is crucial for appropriate treatment, infection control and public health management. Currently, one of the challenges in clinical microbiology is the discrimination of mycobacterial sub-species within the M. tuberculosis complex (MTBC). Our objective was to evaluate the ability of a biosafe mycobacterial-lipid based approach to identify MTBC cultures and subspecies.Methods:A blinded study was performed using 90 mycobacterial clinical isolates strains comprising MTBC strains sub-cultured in Middlebrook 7H11 media supplemented with 10% OADC growth supplement and incubated for up to six weeks at 37°C and using the following 7 reference strains (M. tuberculosis H37Rv, M canettii, M. africanum, M. pinnipedii, M. caprae, M. bovis, M. bovis BCG) grown under the same conditions, in order to set the reference lipid database and test it against the 90 MTBC clinical isolates. Cultured mycobacteria were heat-inactivated and loaded onto the MALDI target followed by addition of the matrix. Acquisition of the data was done using the positive ion mode.Results:Based on the identification of clear and defined lipid signatures from the 7 reference strains, the method we have developed is fast (<10 mins) and produced interpretable profiles for all but four isolates, caused by poor ionization giving an n = 86 with interpretable spectra. The sensitivity and specificity of the MALDI-ToF, were 94.4 (95% CI 86.4-98.5) and 94.4 (95% CI 72.7-99.9) respectively. .Conclusions:Mycobacterial lipid profiling provides for a means of rapid, safe and accurate discrimination of species within the MTBC.
Maurer FP, Shubladze N, Kalmambetova G, et al., 2022, Diagnostic capacities for multidrug-resistant tuberculosis in the World Health Organization European region: action is needed by all member states, The Journal of Molecular Diagnostics, Vol: 24, Pages: 1189-1194, ISSN: 1525-1578
The World Health Organization (WHO) recently revised its guidelines for rapid diagnosis of drug-resistant tuberculosis (TB). This study aimed to investigate if TB reference diagnostic services are prepared to support these revisions. An online survey was performed among 44 TB National Reference Laboratories (NRLs) in the WHO European Region. Questions addressed the use of WHO-recommended molecular techniques for the diagnosis of drug-resistant TB, the techniques applied to investigate antimicrobial resistance, and questions on quality assurance. Among 35 of 44 (80%) participating NRLs, 29 of 35 (83%) reported using the GeneXpert platform as the initial test to detect Mycobacterium tuberculosis complex and rifampicin resistance. Five laboratories reported using another WHO-recommended, moderate-complexity, automated nucleic acid amplification test for detection of Mycobacterium tuberculosis complex and resistance to rifampicin and isoniazid. Most (32 of 35; 91%) NRLs reported the capacity to test second-line drugs that have been in clinical use for many years (fluoroquinolones, linezolid, and injectable agents). Only 23 of 35 (66%) and 21 of 35 (60%) NRLs reported the capacity to test bedaquiline and clofazimine. Further efforts will be needed to improve the availability of quality-controlled testing against WHO Group A and Group B drugs. Earlier considerations on the scale-up of diagnostic capacities should be enforced as part of future approval processes for new antimycobacterial agents.
Gonzalo X, Bielecka MK, Tezera L, et al., 2022, Anti-tuberculosis activity of three carbapenems, clofazimine and nitazoxanide using a novel ex vivo phenotypic drug susceptibility model of human tuberculosis, Antibiotics, Vol: 11, Pages: 1-9, ISSN: 2079-6382
We evaluated a novel physiological 3-D bioelectrospray model of the tuberculosis (TB) granuloma to test the activity of a known anti-TB drug, clofazimine; three carbapenems with potential activity, including one currently used in therapy; and nitazoxanide, an anti-parasitic compound with possible TB activity (all chosen as conventional drug susceptibility was problematical). PBMCs collected from healthy donors were isolated and infected with M. tuberculosis H37Rv lux (i.e., luciferase). Microspheres were generated with the infected cells; the anti-microbial compounds were added and bacterial luminescence was monitored for at least 21 days. Clavulanate was added to each carbapenem to inhibit beta-lactamases. M. tuberculosis (MTB) killing efficacy was dose dependent. Clofazimine was the most effective drug inhibiting MTB growth at 2 mg/L with good killing activity at both concentrations tested. It was the only drug that killed bacteria at the lowest concentration tested. Carbapenems showed modest initial activity that was lost at around day 10 of incubation and clavulanate did not increase killing activity. Of the carbapenems tested, tebipenem was the most efficient in killing MTB, albeit at a high concentration. Nitazoxanide was effective only at concentrations not achievable with current dosing (although this might partly have been an artefact related to extensive protein binding).
Cheong J, Boreland S, Belkarty B, et al., 2022, Implementing tablet-based ototoxicity screening in adult respiratory patients, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Gonzalo X, Drobniewski F, 2022, Are the newer carbapenems of any value against tuberculosis, Antibiotics, Vol: 11, Pages: 1-10, ISSN: 2079-6382
Our aim was to assess whether newer carbapenems with a better administration profile than meropenem (ertapenem, faropenem and tebipenem) were more effective against Mycobacterium tuberculosis including M/XDRTB and determine if there was a synergistic/antagonistic effect with amoxicillin or clavulanate (inhibitor of beta-lactamases that MTB possesses) in vitro. Whilst meropenem is given three times a day intravenously, ertapenem, though given parenterally, is given once a day, faropenem and tebipenem are given orally. Eighty-two clinical drug-sensitive and -resistant MTB strains and a laboratory strain, H37Rv, were assessed by a microdilution methodology against ertapenem, faropenem, tebipenem and meropenem with and without amoxicillin or clavulanic acid. Ertapenem showed a limited activity. The addition of amoxicillin and clavulanate did not translate into significant improvements in susceptibility. Sixty-two isolates (75.6%) exhibited susceptibility to faropenem; the addition of amoxicillin and clavulanate further reduced the MIC in some isolates. Faropenem showed a limited activity (MIC of 8 mg/L or lower) in 21 strains completely resistant to meropenem (MIC of 16 mg/L or higher). Fifteen of the meropenem-resistant strains were susceptible to tebipenem. Carbapenems’ activity has been reported extensively. However, there remains uncertainty as to which of them is most active against TB and what the testing methodology should be.
Simões D, Ehsani S, Stanojevic M, et al., 2022, Integrated use of laboratory services for multiple infectious diseases in the WHO European Region during the COVID-19 pandemic and beyond., Eurosurveillance, Vol: 27, ISSN: 1025-496X
Technical advances in diagnostic techniques have permitted the possibility of multi-disease-based approaches for diagnosis and treatment monitoring of several infectious diseases, including tuberculosis (TB), human immunodeficiency virus (HIV), viral hepatitis and sexually transmitted infections (STI). However, in many countries, diagnosis and monitoring, as well as disease response programs, still operate as vertical systems, potentially causing delay in diagnosis and burden to patients and preventing the optimal use of available resources. With countries facing both human and financial resource constraints, during the COVID-19 pandemic even more than before, it is important that available resources are used as efficiently as possible, potential synergies are leveraged to maximise benefit for patients, continued provision of essential health services is ensured. For the infectious diseases, TB, HIV, hepatitis C (HCV) and STI, sharing devices and integrated services starting with rapid, quality-assured, and complete diagnostic services is beneficial for the continued development of adequate, efficient and effective treatment strategies. Here we explore the current and future potential (as well as some concerns), importance, implications and necessary implementation steps for the use of platforms for multi-disease testing for TB, HIV, HCV, STI and potentially other infectious diseases, including emerging pathogens, using the example of the COVID-19 pandemic.
Khimova E, Gonzalo X, Popova Y, et al., 2022, Urine biomarkers of pulmonary tuberculosis, Expert Review of Respiratory Medicine, Vol: 16, Pages: 615-621, ISSN: 1747-6348
IntroductionSputum-based tuberculosis diagnosis does not address the needs of certain categories of patients. Active development of a noninvasive urine-based diagnosis could provide an alternative approach. We reviewed publications covering more than 30 urine biomarkers proposed as significant for TB diagnosis. Analytical approaches were heterogeneous in design and methods; few studies on diagnostic outcome prediction described a formal specificity and sensitivity analysis.Areas coveredThis review describes studies of non-sputum diagnostic approaches of pulmonary TB based on urine using specific TB biomarkers. The search was performed until December 2021, using terms [Tuberculosis] + [urine] + [biomarkers] in PubMed and Cochrane databases. Publications concerning LAM urine diagnostics were excluded as they have been described elsewhere.Expert opinionMicrobiological culture of sputum is considered to be the ‘gold standard’ diagnostic for pulmonary TB but the methodology is slow due to the slow growth of the TB bacteria. Urine provides a large volume of sample. Investigators have evaluated urine for either TB pathogen biomarkers or host biomarkers with some success as the review demonstrates. Detection sensitivity remains a significant problem. In future, combination of host and pathogen biomarkers could increase the sensitivity and specificity of TB diagnosis.
Drobniewski F, Kusuma D, Broda A, et al., 2022, COVID-19 vaccine hesitancy in diverse groups in the UK — is the driver economic or cultural in student populations, Vaccines, Vol: 10, Pages: 501-501, ISSN: 2076-393X
Studies have identified a greater reluctance for members of the Black, Asian, and minority ethnic communities to be vaccinated against COVID-19 despite a higher probability of greater harm from COVID-19. We conducted an anonymised questionnaire-based study of students (recruiting primarily before first reports of embolic events) at two London universities to identify whether economic or educational levels were primarily responsible for this reluctance: a postgraduate core group (PGCC) n = 860, and a pilot study of undergraduate medical and nursing students (n = 103). Asian and Black students were 2.0 and 3.2 times (PGCC) less likely to accept the COVID vaccine than White British students. Similar findings were noted in the pilot study students. As the students were studying for Master’s or PhD degrees and voluntarily paying high fees, educational and economic reasons were unlikely to be the underlying cause, and wider cultural reservations were more likely. Politicians exerted a strong negative influence, suggesting that campaigns should omit politicians.
Drobniewski F, Keshavjee S, 2021, COVID-19 and Tuberculosis-A global tale of hubris and lessons unlearned?, FRONTIERS IN MEDICINE, Vol: 8, Pages: 1-4
Larrouy-Maumus G, Broda A, Drobniewski F, et al., 2021, An improved method for rapid detection of Mycobacterium abscessus complex based on species-specific lipids fingerprint by routine MALDI-TOF, Frontiers in Chemistry, Vol: 9, Pages: 1-7, ISSN: 2296-2646
Rapid diagnostics of bacterial infection is the key to successful recovery and eradication of the disease. Currently, identification of bacteria is based on the detection of highly abundant proteins, mainly ribosomal proteins, by routine MALDI-TOF mass spectrometry. However, relying solely on proteins is limited in subspecies typing for some pathogens. This is the case for, for example, the mycobacteria belonging to the Mycobacterium abscessus (MABS) complex, which is classified into three subspecies, namely, M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, and M. abscessus subsp. massiliense. Being able to detect bacteria accurately and rapidly at the subspecies level could not only reliably identify the pathogen causing the disease but also enable better antibiotic stewardship. For instance, M. abscessus subsp. abscessus and M. abscessus subsp. bolletii possess a functional erm41 (erythromycin ribosomal methylation gene 41) gene, whilst M. abscessus subsp. massiliense does not, resulting in differences in macrolide antibiotic (e.g., clarithromycin and azithromycin) susceptibilities. This presents a challenge for physicians when designing an appropriate treatment regimen. To address this challenge, in addition to proteins, species-specific lipids have now been considered as a game changer in clinical microbiology diagnostics. However, their extraction can be time-consuming, and analysis requires the use of apolar toxic organic solvents (e.g., chloroform). Here, we present a new method to accurately detect species and subspecies, allowing the discrimination of the mycobacteria within the MABS complex and relying on the use of ethanol. We found that a combination of the matrix named super-DHB with 25% ethanol with a bacterial suspension at McFarland 20 gave robust and reproducible data, allowing the discrimination of the bacteria within the MABS complex strains tested in this study (n = 9). Further investigations have to be conducted to validate the metho
Maurer FP, Shubladze N, Kalmambetova G, et al., 2021, Impact of the COVID-19 pandemic on tuberculosis national reference laboratory services in the WHO European Region, March to November 2020., Eurosurveillance, Vol: 26, Pages: 1-6, ISSN: 1025-496X
We assessed the impact of COVID-19 on diagnostic services for tuberculosis (TB) by national reference laboratories in the WHO European Region. Of 35 laboratories, 30 reported declines in TB sample numbers, amounting up to > 50% of the pre-COVID-19 volumes. Sixteen reported reagent or consumable shortages. Nineteen reallocated ressources to SARS-CoV-2 testing, resulting in an overall increase in workload, largely without a concomitant increase in personnel (n = 14). This poses a risk to meeting the 2025 milestones of the End TB Strategy.
Gonzalo X, Broda A, Drobniewski F, et al., 2021, Performance of lipid fingerprint-based MALDI-ToF for the diagnosis of mycobacterial infections, Clinical Microbiology and Infection, Vol: 27, Pages: 912.e1-912.e5, ISSN: 1198-743X
ObjectivesBacterial diagnosis of mycobacteria is often challenging because of the variability of the sensitivity and specificity of the assay used, and it can be expensive to perform accurately. Although matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) has become the workhorse of clinical laboratories, the current MALDI methodology (which is based on cytosolic protein profiling) for mycobacteria is still challenging due to the number of steps involved (up to seven) and potential biosafety concerns. Knowing that mycobacteria produce surface-exposed species-specific lipids, we here hypothesized that the detection of those molecules could offer a rapid, reproducible and robust method for mycobacterial identification.MethodsWe evaluated the performance of an alternative methodology based on characterized species-specific lipid profiling of intact bacteria, without any sample preparation, by MALDI MS; it uses MALDI-time-of-flight (ToF) MS combined with a specific matrix (super-2,5-dihydroxybenzoic acid solubilized in an apolar solvent system) to analyse lipids of intact heat-inactivated mycobacteria. Cultured mycobacteria are heat-inactivated and loaded directly onto the MALDI target followed by addition of the matrix. Acquisition of the data is done in both positive and negative ion modes. Blinded studies were performed using 273 mycobacterial strains comprising both the Mycobacterium tuberculosis (Mtb) complex and non-tuberculous mycobacteria (NTMs) subcultured in Middlebrook 7H9 media supplemented with 10% OADC (oleic acid/dextrose/catalase) growth supplement and incubated for up to 2 weeks at 37°C.ResultsThe method we have developed is fast (<10 mins) and highly sensitive (<1000 bacteria required); 96.7% of the Mtb complex strains (204/211) were correctly assigned as MTB complex and 91.7% (22/24) NTM species were correctly assigned based only on intact bacteria species-specific lipid profiling by MALDI-ToF MS.ConclusionsIntact bacter
Benet S, Galvez C, Drobniewski F, et al., 2021, Dissemination of Mycobacterium tuberculosis is associated to a SIGLEC1 null variant that limits antigen exchange via trafficking extracellular vesicles, Journal of Extracellular Vesicles, Vol: 10, Pages: 1-17, ISSN: 2001-3078
The identification of individuals with null alleles enables studying how the loss of gene function affects infection. We previously described a non‐functional variant in SIGLEC1, which encodes the myeloid‐cell receptor Siglec‐1/CD169 implicated in HIV‐1 cell‐to‐cell transmission. Here we report a significant association between the SIGLEC1 null variant and extrapulmonary dissemination of Mycobacterium tuberculosis (Mtb) in two clinical cohorts comprising 6,256 individuals. Local spread of bacteria within the lung is apparent in Mtb‐infected Siglec‐1 knockout mice which, despite having similar bacterial load, developed more extensive lesions compared to wild type mice. We find that Siglec‐1 is necessary to induce antigen presentation through extracellular vesicle uptake. We postulate that lack of Siglec‐1 delays the onset of protective immunity against Mtb by limiting antigen exchange via extracellular vesicles, allowing for an early local spread of mycobacteria that increases the risk for extrapulmonary dissemination.
Surkova E, Nikolayevskyy V, Drobniewski F, 2020, False-positive COVID-19 results: hidden problems and costs, LANCET RESPIRATORY MEDICINE, Vol: 8, Pages: 1167-1168, ISSN: 2213-2600
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Nikolayevskyy V, Balabanova Y, Kontsevaya I, et al., 2020, Biomarkers of treatment success in fully sensitive pulmonary tuberculosis patients: a multicenter longitudinal study, Biomarkers in Medicine, Vol: 14, Pages: 1439-1452, ISSN: 1752-0363
Aim: Novel biomarkers that are able to accurately monitor tuberculosis (TB) treatment effectiveness are needed to adjust therapy and identify a need for a regimen change. Materials & methods: In our study, conducted on a cohort comprising 100 pulmonary TB patients, we analyzed the role of plasma cytokines and Toll-like receptors expression as biomarkers of treatment response. Results: Changes in toll-interacting protein (TOLLIP) and lymphocyte antigen 96 (LY96) gene expression as well as nine cytokine levels over the first 2 months were significantly associated with successful treatment outcome. Successful treatment was associated with higher serum concentration of Toll-like receptor-2. Conclusion: Our results suggest that differential expression of specific effector molecules and dynamics of selected cytokines may help to identify those responding to TB treatment early.
Gonzalo X, Satta G, Ortiz Canseco J, et al., 2020, Ertapenem and faropenem against mycobacterium tuberculosis: in vitro testing and comparison by macro and microdilution., BMC Microbiology, Vol: 20, Pages: 1-7, ISSN: 1471-2180
BACKGROUND: Interest in carbapenems has been rising in the last few years due to the emergence of drug resistant tuberculosis. Ertapenem (ETP), given once a day parenteral, and faropenem (FAR), oral, have a better administration profile than meropenem (MEM), imipenem (IPM) and doripenem (DOR). The addition of amoxicillin-clavulanate (AMC) inhibits the hydrolysis by the carbapenemase present in Mycobacterium tuberculosis (MTB). The aim of this study was to determine the in vitro activity of ETP and FAR against susceptible and resistant clinical MTB strains by two widely use methodologies, the BACTEC960 MGIT and microdilution. RESULTS: 19 clinical isolates with different susceptibility profiles and H37Rv were included. Minimal inhibitory concentration (MIC) testing was performed using two methods of different concentrations of ETP and FAR with and without AMC. MIC50 was 2 and 8 for FAR with and without AMC by both methods. MIC90 was > 16 and > 8 by microdilution and MGIT respectively and did not change after AMC addition. 18/20 samples were resistant to the highest concentration of ETP, with and without AMC. Half of the samples had some susceptibility to FAR; addition of AMC further reduced the MIC level in seven isolates. 10/20 isolates showed susceptibility to FAR and the addition of AMC further reduced the MIC in 7 isolates. However, most of the MICs were near the limit of effectiveness (8 μg/mL). Resistance to FAR was associated with resistance to MEM (p = 0.04) but not to resistance profiles of other drugs, including M/XDR status. CONCLUSIONS: The lack of ETP activity may be associated with its degradation, independent of carbapenemase, during incubation. No susceptibility pattern to traditional drugs can predict susceptibility to FAR and susceptibility testing is not routinely available. PK/PD studies are needed as reaching the concentrations tested in these experiments may be challenging. This work highlighted
Wilson DJ, Crook DW, Peto TEA, et al., 2020, GenomegaMap: within-species genome-wide dN/dS estimation from over 10,000 genomes, Molecular Biology and Evolution, Vol: 37, Pages: 2450-2460, ISSN: 0737-4038
The dN/dS ratio provides evidence of adaptation or functional constraint in protein-coding genes by quantifying the relative excess or deficit of amino acid-replacing versus silent nucleotide variation. Inexpensive sequencing promises a better understanding of parameters, such as dN/dS, but analyzing very large data sets poses a major statistical challenge. Here, I introduce genomegaMap for estimating within-species genome-wide variation in dN/dS, and I apply it to 3,979 genes across 10,209 tuberculosis genomes to characterize the selection pressures shaping this global pathogen. GenomegaMap is a phylogeny-free method that addresses two major problems with existing approaches: 1) It is fast no matter how large the sample size and 2) it is robust to recombination, which causes phylogenetic methods to report artefactual signals of adaptation. GenomegaMap uses population genetics theory to approximate the distribution of allele frequencies under general, parent-dependent mutation models. Coalescent simulations show that substitution parameters are well estimated even when genomegaMap’s simplifying assumption of independence among sites is violated. I demonstrate the ability of genomegaMap to detect genuine signatures of selection at antimicrobial resistance-conferring substitutions in Mycobacterium tuberculosis and describe a novel signature of selection in the cold-shock DEAD-box protein A gene deaD/csdA. The genomegaMap approach helps accelerate the exploitation of big data for gaining new insights into evolution within species.
Dara M, Ehsani S, Mozalevskis A, et al., 2020, Tuberculosis, HIV, and viral hepatitis diagnostics in eastern Europe and central Asia: high time for integrated and people-centred services, The Lancet Infectious Diseases, Vol: 20, Pages: e47-e53, ISSN: 1473-3099
Globally, high rates (and in the WHO European region an increasing prevalence) of co-infection with tuberculosis and HIV and HIV and hepatitis C virus exist. In eastern European and central Asian countries, the tuberculosis, HIV, and viral hepatitis programmes, including diagnostic services, are separate vertical structures. In this Personal View, we consider underlying reasons for the poor integration for these diseases, particularly in the WHO European region, and how to address this with an initial focus on diagnostic services. In part, this low integration has reflected different diagnostic development histories, global funding sources, and sample types used for diagnosis (eg, typically sputum for tuberculosis and blood for HIV and hepatitis C). Cooperation between services improved as patients with tuberculosis needed routine testing for HIV and vice versa, but financial, infection control, and logistical barriers remain. Multidisease diagnostic platforms exist, but to be used optimally, appropriate staff training and sensible understanding of different laboratory and infection control risks needs rapid implementation. Technically these ideas are all feasible. Poor coordination between these vertical systems remains unhelpful. There is a need to increase political and operational integration of diagnostic and treatment services and bring them closer to patients.
Katelaris AL, Jackson C, Southern J, et al., 2020, Effectiveness of BCG vaccination against Mycobacterium tuberculosis infection in adults: a cross-sectional analysis of a UK-based cohort, The Journal of Infectious Diseases, Vol: 221, Pages: 146-155, ISSN: 0022-1899
BackgroundBCG appears to reduce acquisition of Mycobacterium tuberculosis (Mtb) infection in children, measured using interferon-gamma release assays (IGRAs). We explored whether BCG vaccination continues to be associated with decreased prevalence of Mtb infection in adults.MethodsWe conducted a cross-sectional analysis of data from adult contacts of tuberculosis cases participating in a UK cohort study. Vaccine effectiveness (VE) of BCG, ascertained based on presence of a scar or vaccination history, against latent tuberculosis infection (LTBI), measured via IGRA, was assessed using multivariable logistic regression. The effects of age at BCG and time since vaccination were also explored.ResultsOf 3453 recent tuberculosis contacts, 27.5% had LTBI. There was strong evidence of an association between BCG and LTBI (aOR=0.70, 95% CI 0.56-0.87, p=0.0017) yielding a VE of 30%. VE declined with time since vaccination, but there was evidence that LTBI prevalence was lower amongst vaccinated individuals even >20 years after vaccination, compared with non-vaccinated participants.ConclusionBCG is associated with lower prevalence of LTBI in adult contacts of tuberculosis. These results contribute to growing evidence that suggests BCG may protect against Mtb infection as well as disease. This has implications for immunisation programmes, vaccine development and tuberculosis control efforts worldwide.
Gupta RK, Lipman M, Jackson C, et al., 2019, Quantitative interferon gamma release assay and tuberculin skin test Results to predict incident tuberculosis: a prospective cohort study., American Journal of Respiratory and Critical Care Medicine, Vol: 208, Pages: 984-991, ISSN: 1073-449X
RATIONALE: Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority. OBJECTIVES: We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB and the tuberculin skin test (TST) might improve prediction of incident TB. METHODS: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by re-linkage to national TB surveillance records (median follow-up 4.7 years). Incidence rates and rate ratios, sensitivities, specificities and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB and TST (with adjustment for prior BCG). MEASUREMENTS AND MAIN RESULTS: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (p<0.0001). Over three years' follow-up, there was a modest increase in positive predictive value (PPV) with the higher thresholds (3.0% for QFT-GIT ≥0.35 IU/mL vs. 3.6% for ≥4.00 IU/mL; 3.4% for T-SPOT.TB ≥5 spots vs. 5.0% for ≥50 spots; and 3.1% for BCG-adjusted TST ≥5mm vs. 4.3% for ≥15mm). As thresholds increased, sensitivity to detect incident TB waned for all tests (61.0% for QFT-GIT ≥0.35 IU/mL vs. 23.2% for ≥4.00 IU/mL; 65.4% for T-SPOT.TB ≥5 spots vs. 27.2% for ≥50 spots; 69.7% for BCG-adjusted TST ≥5mm vs. 28.1% for ≥15mm). CONCLUSIONS: Implementation of higher thresholds for QFT-GIT, T-SPOT.TB and TST modestly increases PPV for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Gupta R, Lipman M, Jackson C, et al., 2019, Do higher quantitative interferon gamma release assay or tuberculin skin test results help to predict incident tuberculosis? Data from the UK PREDICT study, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Kouchaki S, Yang Y, Walker TM, et al., 2019, Application of machine learning techniques to tuberculosis drug resistance analysis, Bioinformatics, Vol: 35, Pages: 2276-2282, ISSN: 1367-4803
Timely identification of Mycobacterium tuberculosis (MTB) resistance to existing drugs is vital to decrease mortality and prevent the amplification of existing antibiotic resistance. Machine learning methods have been widely applied for timely predicting resistance of MTB given a specific drug and identifying resistance markers. However, they have been not validated on a large cohort of MTB samples from multi-centers across the world in terms of resistance prediction and resistance marker identification. Several machine learning classifiers and linear dimension reduction techniques were developed and compared for a cohort of 13 402 isolates collected from 16 countries across 6 continents and tested 11 drugs.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Compared to conventional molecular diagnostic test, area under curve of the best machine learning classifier increased for all drugs especially by 23.11%, 15.22% and 10.14% for pyrazinamide, ciprofloxacin and ofloxacin, respectively (P < 0.01). Logistic regression and gradient tree boosting found to perform better than other techniques. Moreover, logistic regression/gradient tree boosting with a sparse principal component analysis/non-negative matrix factorization step compared with the classifier alone enhanced the best performance in terms of F1-score by 12.54%, 4.61%, 7.45% and 9.58% for amikacin, moxifloxacin, ofloxacin and capreomycin, respectively, as well increasing area under curve for amikacin and capreomycin. Results provided a comprehensive comparison of various techniques and confirmed the application of machine learning for better prediction of the large diverse tuberculosis data. Furthermore, mutation ranking showed the possibility of finding new resistance/susceptible markers.</jats:p> </jats:sec> <jats:sec>
Dixit A, Freschi L, Vargas R, et al., 2019, Whole genome sequencing identifies bacterial factors affecting transmission of multidrug-resistant tuberculosis in a high-prevalence setting, Scientific Reports, Vol: 9, ISSN: 2045-2322
Whole genome sequencing (WGS) can elucidate Mycobacterium tuberculosis (Mtb) transmission patterns but more data is needed to guide its use in high-burden settings. In a household-based TB transmissibility study in Peru, we identified a large MIRU-VNTR Mtb cluster (148 isolates) with a range of resistance phenotypes, and studied host and bacterial factors contributing to its spread. WGS was performed on 61 of the 148 isolates. We compared transmission link inference using epidemiological or genomic data and estimated the dates of emergence of the cluster and antimicrobial drug resistance (DR) acquisition events by generating a time-calibrated phylogeny. Using a set of 12,032 public Mtb genomes, we determined bacterial factors characterizing this cluster and under positive selection in other Mtb lineages. Four of the 61 isolates were distantly related and the remaining 57 isolates diverged ca. 1968 (95%HPD: 1945–1985). Isoniazid resistance arose once and rifampin resistance emerged subsequently at least three times. Emergence of other DR types occurred as recently as within the last year of sampling. We identified five cluster-defining SNPs potentially contributing to transmissibility. In conclusion, clusters (as defined by MIRU-VNTR typing) may be circulating for decades in a high-burden setting. WGS allows for an enhanced understanding of transmission, drug resistance, and bacterial fitness factors.
Hamblion EL, Burkitt A, Lalor MK, et al., 2019, Public health outcome of Tuberculosis Cluster Investigations, England 2010-2013, JOURNAL OF INFECTION, Vol: 78, Pages: 269-274, ISSN: 0163-4453
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Drobniewski FA, jackson C, southern J, et al., 2018, Diabetes mellitus and latent tuberculosis infection: baseline analysis of a large UK cohort, Thorax, Vol: 74, Pages: 91-94, ISSN: 1468-3296
We conducted a cross-sectional analysis of baseline data from a UK cohort study which enrolled participants at risk of latent tuberculosis infection (LTBI, defined as a positive result for either of the two interferon gamma release assays). Binomial regression with a log link was used to estimate crude and adjusted prevalence ratios (PRs) and 95% CIs for the relationship between diabetes mellitus (DM) and LTBI. Adjusted for age, sex, ethnicity, body mass index and the presence of other immunocompromising conditions, DM was associated with a 15% higher prevalence of LTBI (adjusted PR=1.15, 95% CI 1.02 to 1.30, p=0.025).
Allix-Beguec C, Arandjelovic I, Bi L, et al., 2018, Prediction of susceptibility to first-line tuberculosis drugs by DNA sequencing, New England Journal of Medicine, Vol: 379, Pages: 1403-1415, ISSN: 0028-4793
BackgroundThe World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.MethodsWe obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance.ResultsA total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profil
Abubakar I, Drobniewski FA, Southern J, et al., 2018, Prognostic value of interferon gamma release assays and tuberculin skin test in predicting the development of active tuberculosis: The UK PREDICT TB Cohort Study, Lancet Infectious Diseases, Vol: 18, Pages: 1077-1087, ISSN: 1473-3099
BackgroundTackling tuberculosis (TB) requires testing and treatment latenttuberculosis in high-risk groups. The aim of this study was to estimatethe predictive values of the tuberculin skin test (TST) and interferongamma release assays (IGRAs) for development of active TB .MethodA cohort of migrants and contacts of active TB patients wereprospectively recruited in clinics, the community and primary care. Eachparticipant received three tests (Quantiferon Gold In-Tube [QFT-GIT], TSPOT.TBand TST). A positive TST was reported using three thresholds: 5mm(TST5), 10mm (TST10), and 5mm in BCG-naïve or 15mm in vaccinated (TST15).Participants were followed for a median of 2.9 years. Incident TB caseswere identified by national TB databases, telephone interview, andmedical note review. Outcomes were ratio of incidence rate ratios andpredictive values for TB development.FindingsNinety-seven (1.0%) of 9,610 participants developed active TB (77 of6,380 with results for all 3 tests). In all tests, TB incidence was verylow in test-negatives (1.2-1.6 per 1000 per year). Incidence rates intest-positives were highest for T-SPOT.TB (13.2, 95%CI: (9.9,17.4)),TST15 (11.1 (8.3,14.6)) and QFT-GIT (10.1 (7.4,13.4)). Positive resultsfor these tests were significantly more predictive of progression than TST10 and TST5. However, TST5 identified a higher proportion ofprogressors than TST10, TST15, T-SPOT.TB and QFT-GIT.Interpretation IGRA-based or TST15 strategies appear most suited forscreening. Although TST5 and TST10 detect more TB cases, they alsoclassify more individuals who are unlikely to develop TB as testpositive.Funding source: National Institute for Health Research Health TechnologyAssessment Programme 08-68-01.
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