Imperial College London

Professor Francis Drobniewski

Faculty of MedicineDepartment of Infectious Disease

Chair in Global Health and Tuberculosis
 
 
 
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f.drobniewski

 
 
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Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
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290 results found

Gonzalo X, Yrah S, Broda A, Laurenson I, Claxton P, Kostrzewa M, Drobniewski F, Larrouy-Maumus Get al., 2022, Performance of lipid fingerprint by routine MALDI-ToF for the diagnosis of Mycobacterium tuberculosis complex species, Clinical Microbiology and Infection, ISSN: 1198-743X

ObjectivesRapid 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.MethodsA 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.ResultsBased 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. .ConclusionsMycobacterial lipid profiling provides for a means of rapid, safe and accurate discrimination of species within the MTBC.

Journal article

Gonzalo X, Bielecka MK, Tezera L, Elkington P, Drobniewski Fet 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).

Journal article

Maurer FP, Shubladze N, Kalmambetova G, Felker I, Kuchukhidze G, Köser CU, Cirillo DM, Drobniewski F, Yedilbayev A, Ehsani S, European Laboratory Initiative on TB, HIV and Viral Hepatitiset 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, 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.

Journal article

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.

Journal article

Simões D, Ehsani S, Stanojevic M, Shubladze N, Kalmambetova G, Paredes R, Cirillo DM, Avellon A, Felker I, Maurer FP, Yedilbayev A, Drobniewski F, Vojnov L, Johansen AS, Seguy N, Dara M, European Laboratory Initiative on TB, HIV and viral hepatitis core group memberset 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.

Journal article

Khimova E, Gonzalo X, Popova Y, Eliseev P, Andrey M, Nikolayevskyy V, Broda A, Drobniewski Fet 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.

Journal article

Drobniewski F, Kusuma D, Broda A, Castro-Sánchez E, Ahmad Ret 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.

Journal article

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

Journal article

Larrouy-Maumus G, Broda A, Drobniewski F, Khor MJ, kostrzewaet 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

Journal article

Maurer FP, Shubladze N, Kalmambetova G, Felker I, Kuchukhidze G, Drobniewski F, Yedilbayev A, Ehsani S, European Laboratory Initiative on TB, HIV and Viral Hepatitis, Additional members of the European Laboratory Initiative on TB, HIV and Viral Hepatitis core group in alphabetical orderet 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.

Journal article

Gonzalo X, Broda A, Drobniewski F, Larrouy-Maumus Get 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

Journal article

Benet S, Galvez C, Drobniewski F, Kontsevaya I, Arias L, Monguio-Tortajada M, Erkizia I, Urrea V, Ong R-Y, Luquin M, Dupont M, Chojnacki J, Dalmau J, Cardona P, Neyrolles O, Lugo-Villarino G, Verollet C, Julian E, Furrer H, Gunthard HF, Crocker PR, Tapia G, Borras FE, Fellay J, McLaren PJ, Telenti A, Cardona P-J, Clotet B, Vilaplana C, Martinez-Picado J, Izquierdo-Useros Net 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.

Journal article

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

Journal article

Nikolayevskyy V, Balabanova Y, Kontsevaya I, Ignatyeva O, Skenders G, Vasiliauskiene E, Bockel DV, Drobniewski Fet 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.

Journal article

Gonzalo X, Satta G, Ortiz Canseco J, McHugh TD, Drobniewski Fet 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

Journal article

Wilson DJ, Crook DW, Peto TEA, Walker AS, Hoosdally SJ, Gibertoni Cruz AL, Carter J, Grazian C, Earle SG, Kouchaki S, Lachapelle A, Yang Y, Clifton DA, Fowler PW, Iqbal Z, Hunt M, Knaggs J, Smith EG, Rathod P, Jarrett L, Matias D, Cirillo DM, Borroni E, Battaglia S, Ghodousi A, Spitaleri A, Cabibbe A, Tahseen S, Nilgiriwala K, Shah S, Rodrigues C, Kambli P, Surve U, Khot R, Niemann S, Kohl TA, Merker M, Hoffmann H, Todt K, Plesnik S, Ismail N, Omar SV, Joseph L, Thwaites G, Thuong TNT, Ngoc NH, Srinivasan V, Walker TM, Moore D, Coronel J, Solano W, Gao GF, He G, Zhao Y, Liu C, Ma A, Zhu B, Laurenson I, Claxton P, Koch A, Wilkinson R, Lalvani A, Posey J, Gardy J, Werngren J, Paton N, Jou R, Wu M-H, Lin W-H, Ferrazoli L, de Oliveira RS, Arandjelovic I, Chaiprasert A, Comas I, Roig CJ, Drobniewski FA, Farhat MR, Gao Q, Hee ROT, Sintchenko V, Supply P, van Soolingen Det 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.

Journal article

Dara M, Ehsani S, Mozalevskis A, Vovc E, Simões D, Avellon Calvo A, Casabona i Barbarà J, Chokoshvili O, Felker I, Hoffner S, Kalmambetova G, Noroc E, Shubladze N, Skrahina A, Tahirli R, Tsertsvadze T, Drobniewski Fet 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.

Journal article

Katelaris AL, Jackson C, Southern J, Gupta RK, Drobniewski F, Lalvani A, Lipman M, Mangtani P, Abubakar Iet 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.

Journal article

Gupta RK, Lipman M, Jackson C, Sitch A, Southern J, Drobniewski F, Deeks JJ, Tsou C-Y, Griffiths C, Davidson J, Campbell C, Stirrup O, Noursadeghi M, Kunst H, Haldar P, Lalvani A, Abubakar Iet 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/).

Journal article

Gupta R, Lipman M, Jackson C, Sitch A, Southern J, Drobniewski F, Deeks J, Tsou C-Y, Griffiths C, Davidson J, Campbell C, Stirrup O, Noursadeghi M, Kunst H, Haldar P, Lalvani A, Abubakar Iet 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

Conference paper

Kouchaki S, Yang Y, Walker TM, Sarah Walker A, Wilson DJ, Peto TEA, Crook DW, Clifton DAet 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 &lt; 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>

Journal article

Dixit A, Freschi L, Vargas R, Calderon R, Sacchettini J, Drobniewski F, Galea JT, Contreras C, Yataco R, Zhang Z, Lecca L, Kolokotronis S-O, Mathema B, Farhat MRet 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.

Journal article

Hamblion EL, Burkitt A, Lalor MK, Anderson LF, Thomas HL, Abubakar I, Morton S, Maguire H, Anderson SR, Watson J, Monk P, Drobniewski F, Magee J, Smith G, Catherall C, Reshat S, Ratna Net al., 2019, Public health outcome of Tuberculosis Cluster Investigations, England 2010-2013, JOURNAL OF INFECTION, Vol: 78, Pages: 269-274, ISSN: 0163-4453

Journal article

Drobniewski FA, jackson C, southern J, Lalvani A, grifiths C, lipman M, bothamley G, deeks J, Imran A, Kon O, Sithembinkosi M, Nikolayevsky V, Rees-Roberts M, Sitch A, Tsou C-Y, Whitworth H, Abubakar Iet 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).

Journal article

Allix-Beguec C, Arandjelovic I, Bi L, Beckert P, Bonnet M, Bradley P, Cabibbe AM, Cancino-Munoz I, Caulfield MJ, Chaiprasert A, Cirillo DM, Clifton D, Comas I, Crook DW, De Filippo MR, de Neeling H, Diel R, Drobniewski FA, Faksri K, Farhat MR, Fleming J, Fowler P, Fowler TA, Gao Q, Gardy J, Gascoyne-Binzi D, Gibertoni-Cruz A-L, Gil-Brusola A, Golubchik T, Gonzalo X, Grandjean L, He G, Guthrie JL, Hoosdally S, Hunt M, Iqbal Z, Ismail N, Johnston J, Khanzada FM, Khor CC, Kohl TA, Kong C, Lipworth S, Liu Q, Maphalala G, Martinez E, Mathys V, Merker M, Miotto P, Mistry N, Moore DAJ, Murray M, Niemann S, Ong RT-H, Peto TEA, Posey JE, Prammananan T, Pym A, Rodrigues C, Rodrigues M, Rodwell T, Rossolini GM, Padilla ES, Schito M, Shen X, Shendure J, Sintchenko V, Sloutsky A, Smith EG, Snyder M, Soetaert K, Starks AM, Supply P, Suriyapol P, Tahseen S, Tang P, Teo Y-Y, Thuong TNT, Thwaites G, Tortoli E, Omar S, van Soolingen D, Walker AS, Walker TM, Wilcox M, Wilson DJ, Wyllie D, Yang Y, Zhang H, Zhao Y, Zhu Bet 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

Journal article

Abubakar I, Drobniewski FA, Southern J, Sitch A, Jackson C, Lipman M, Deeks J, Griffiths C, Bothamley G, Lynn W, Burgess H, Mann B, Imran A, Sridhar S, Tsou C, Nikolayevskyy V, Roberts R, Whitworth H, Kon O, Kunst K, Anderson S, Watson J, Haldar P, Milburn H, Lalvani Aet 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.

Journal article

Abubakar I, Lalvani A, Southern J, Sitch A, Jackson C, Onyimadu O, Lipman M, Deeks JJ, Griffiths C, Bothamley G, Kon OM, Hayward A, Lord J, Drobniewski Fet al., 2018, Two interferon gamma release assays for predicting active tuberculosis: the UK PREDICT TB prognostic test study, Health Technology Assessment, Vol: 22, Pages: 1-95, ISSN: 1366-5278

BACKGROUND: Despite a recent decline in the annual incidence of tuberculosis (TB) in the UK, rates remain higher than in most Western European countries. The detection and treatment of latent TB infection (LTBI) is an essential component of the UK TB control programme. OBJECTIVES: To assess the prognostic value and cost-effectiveness of the current two interferon gamma release assays (IGRAs) compared with the standard tuberculin skin test (TST) for predicting active TB among untreated individuals at increased risk of TB: (1) contacts of active TB cases and (2) new entrants to the UK from high-TB-burden countries. DESIGN: A prospective cohort study and economic analysis. PARTICIPANTS AND SETTING: Participants were recruited in TB clinics, general practices and community settings. Contacts of active TB cases and migrants who were born in high-TB-burden countries arriving in the UK were eligible to take part if they were aged ≥ 16 years. MAIN OUTCOME MEASURES: Outcomes include incidence rate ratios comparing the incidence of active TB in those participants with a positive test result and those with a negative test result for each assay, and combination of tests and the cost per quality-adjusted life-year (QALY) for each screening strategy. RESULTS: A total of 10,045 participants were recruited between May 2010 and July 2015. Among 9610 evaluable participants, 97 (1.0%) developed active TB. For the primary analysis, all test data were available for 6380 participants, with 77 participants developing active TB. A positive result for TSTa (positive if induration is ≥ 5 mm) was a significantly poorer predictor of progression to active TB than a positive result for any of the other tests. Compared with TSTb [positive if induration is ≥ 6 mm without prior bacillus Calmette-Guérin (BCG) alone, T-SPOT®.TB (Oxford Immunotec Ltd, Oxford, UK), TSTa + T-SPOT.TB, TSTa + IGRA and the three combination

Journal article

Broda A, Nikolayevskyy V, Casali N, Khan H, Bowker R, Blackwell G, Patel B, Hume J, Hussain W, Drobniewski Fet al., 2018, Experimental platform utilising melting curve technology for detection of mutations in Mycobacterium tuberculosis isolates, European Journal of Clinical Microbiology and Infectious Diseases, Vol: 37, Pages: 1273-1279, ISSN: 0934-9723

Tuberculosis (TB) remains one of the most deadly infections with approximately a quarter of cases not being identified and/or treated mainly due to a lack of resources. Rapid detection of TB or drug-resistant TB enables timely adequate treatment and is a cornerstone of effective TB management. We evaluated the analytical performance of a single-tube assay for multidrug-resistant TB (MDR-TB) on an experimental platform utilising RT-PCR and melting curve analysis that could potentially be operated as a point-of-care (PoC) test in resource-constrained settings with a high burden of TB. Firstly, we developed and evaluated the prototype MDR-TB assay using specimens extracted from well-characterised TB isolates with a variety of distinct rifampicin and isoniazid resistance conferring mutations and nontuberculous Mycobacteria (NTM) strains. Secondly, we validated the experimental platform using 98 clinical sputum samples from pulmonary TB patients collected in high MDR-TB settings. The sensitivity of the platform for TB detection in clinical specimens was 75% for smear-negative and 92.6% for smear-positive sputum samples. The sensitivity of detection for rifampicin and isoniazid resistance was 88.9 and 96.0% and specificity was 87.5 and 100%, respectively. Observed limitations in sensitivity and specificity could be resolved by adjusting the sample preparation methodology and melting curve recognition algorithm. Overall technology could be considered a promising PoC methodology especially in resource-constrained settings based on its combined accuracy, convenience, simplicity, speed, and cost characteristics.

Journal article

Lalor MK, Casali N, Walker TM, Anderson LF, Davidson JA, Ratna N, Mullarkey C, Gent M, Foster K, Brown T, Magee J, Barrett A, Crook DW, Drobniewski F, Thomas HL, Abubakar Iet al., 2018, The use of whole-genome sequencing in cluster investigation of an MDR-TB outbreak, European Respiratory Journal, Vol: 51, ISSN: 0903-1936

We used whole-genome sequencing to delineate transmission networks and investigate the benefits of whole-genome sequencing during cluster investigation.We included clustered cases of M/XDR-TB linked by MIRU-VNTR, or epidemiological information in the national cluster B1006, notified between 2007-2013 in the UK. We excluded cases whose isolates differed by >12 SNPs from further investigation. Data relating to patients’ social networks were collected.Twenty-seven cases were investigated, 22 had whole-genome sequencing; 8 (36%) of which were excluded as their isolates differed by >12 SNPs to other cases. Eighteen cases were ruled into the transmission network based on genomic and epidemiological information. Evidence of transmission was inconclusive in 39% (7/18) of cases in the transmission network following whole-genome sequencing and epidemiological investigation. This investigation of a drug resistant TB cluster illustrates the opportunities and limitations of whole-genome sequencing in understanding transmission in a setting with a high proportion of migrant cases. The use of WGS should be combined with classical epidemiological methods. However not every cluster will be solvable, regardless of the quality of genomic data.

Journal article

Black AT, Hamblion EL, Buttivant H, Anderson SR, Stone M, Casali N, Drobniewski F, Nwoguh F, Marshall BG, Booth Let al., 2018, Tracking and responding to an outbreak of tuberculosis using MIRU-VNTR genotyping and whole genome sequencing as epidemiological tools, JOURNAL OF PUBLIC HEALTH, Vol: 40, Pages: E66-E73, ISSN: 1741-3842

Journal article

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