On December 31, 2019, the Chinese government officially announced the identification of a new type of coronavirus (SARS‐CoV‐2) as the etiological cause of a severe acute respiratory syndrome in Wuhan city, Hubei Province. Over the next weeks, SARS‐CoV‐2 caused a global pandemic as officially declared by the WHO on March 11, 2020, with confirmed cases and deaths in more than 166 countries. We are experiencing a worldwide phenomenon of unprecedented social and economic consequences. Since the beginning of the COVID‐19 outbreak, there have been fears that the epidemic could strongly impact weaker healthcare systems in poor‐resource settings, especially in Sub‐Saharan Africa (SSA). The 2 million Chinese nationals that live and work in Africa could potentially contribute to the spread of COVID‐19 on the continent.
The taxonomic position of members of the Mycobacterium abscessus complex has been the subject of intensive investigation and, in some aspects confusion, in recent years as a result of varying approaches to genetic data interpretation. Currently, the former species Mycobacterium massiliense and Mycobacterium bolletii are grouped together as Mycobacterium abscessus subsp. bolletii. They differ greatly, however, as the former M. bolletii has a functional erm(41) gene that confers inducible resistance to macrolides, the primary therapeutic antimicrobials for M. abscessus, while in the former M. massiliense the erm(41) gene is non-functional. Furthermore, previous whole genome studies of the M. abscessus group support the separation of M. bolletii and M. massiliense. To shed further light on the population structure of Mycobacterium abscessus, 43 strains and three genomes retrieved from GenBank were subjected to pairwise comparisons using three computational approaches: verage ucleotide dentity, enome to enome istance and single nucleotide polymorphism analysis. The three methods produced overlapping results, each demonstrating three clusters of strains corresponding to the same number of taxonomic entities. The distances were insufficient to warrant distinction at the species level, but met the criteria for differentiation at the subspecies level. Based on prior erm(41)-related phenotypic data and current genomic data, we conclude that the species M. abscessus encompasses, in adjunct to the presently recognized subspecies M. abscessus subsp. abscessus and M. abscessus subsp. bolletii, a third subspecies for which we suggest the name M. abscessus subsp. massiliense comb. nov. (type strain CCUG 48898(T) =CIP 108297(T) =DSM 45103(T) = KCTC 19086(T)). ; research grants FFC from Fondazione Ricerca Fibrosi Cistica ; European Union PathoNgen-Trace project ; German Center for Infection Research (DZIF) ; Ist Sci San Raffaele, Emerging Bacterial Pathogens Unit, Milan, Italy ; Leibniz Zentrum Med & Biowissensch, Mol & Expt Mycobacteriol, Borstel, Germany ; Univ Texas Hlth Ctr Tyler, Dept Microbiol, Mycobact Nocardia Res Lab, Tyler, TX USA ; Univ Fed Sao Paulo, Escol Paulista Med, Dept Microbiol Imunol & Parasiotol, Sao Paulo, SP, Brazil ; Univ Madrid, Dept Prevent Med Publ Hlth & Microbiol, Madrid, Spain ; Diagnost Serv Manitoba, Winnipeg, MB, Canada ; Univ Texas Hlth Sci Ctr Tyler, Dept Pulm Med, Tyler, TX USA ; Meyer Univ Hosp, Reg Reference Ctr Cyst Fibrosis, Florence, Italy ; IRCCS Ca Granda, Cyst Fibrosis Microbiol Lab, Milan, Italy ; IRCCS Ca Granda, Cyst Fibrosis Ctr, Milan, Italy ; Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil ; research grants FFC from Fondazione Ricerca Fibrosi Cistica: 27/2014 ; European Union PathoNgen-Trace project: FP7-278864-2 ; Web of Science
BACKGROUND: The risk of tuberculosis outbreaks among people fleeing hardship for refuge in Europe is heightened. We describe the cross-border European response to an outbreak of multidrug-resistant tuberculosis among patients from the Horn of Africa and Sudan. METHODS: On April 29 and May 30, 2016, the Swiss and German National Mycobacterial Reference Laboratories independently triggered an outbreak investigation after four patients were diagnosed with multidrug-resistant tuberculosis. In this molecular epidemiological study, we prospectively defined outbreak cases with 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) profiles; phenotypic resistance to isoniazid, rifampicin, ethambutol, pyrazinamide, and capreomycin; and corresponding drug resistance mutations. We whole-genome sequenced all Mycobacterium tuberculosis isolates and clustered them using a threshold of five single nucleotide polymorphisms (SNPs). We collated epidemiological data from host countries from the European Centre for Disease Prevention and Control. FINDINGS: Between Feb 12, 2016, and April 19, 2017, 29 patients were diagnosed with multidrug-resistant tuberculosis in seven European countries. All originated from the Horn of Africa or Sudan, with all isolates two SNPs or fewer apart. 22 (76%) patients reported their travel routes, with clear spatiotemporal overlap between routes. We identified a further 29 MIRU-VNTR-linked cases from the Horn of Africa that predated the outbreak, but all were more than five SNPs from the outbreak. However all 58 isolates shared a capreomycin resistance-associated tlyA mutation. INTERPRETATION: Our data suggest that source cases are linked to an M tuberculosis clone circulating in northern Somalia or Djibouti and that transmission probably occurred en route before arrival in Europe. We hypothesise that the shared mutation of tlyA is a drug resistance mutation and phylogenetic marker, the first of its kind in M tuberculosis sensu stricto. FUNDING: The Swiss Federal Office of Public Health, the University of Zurich, the Wellcome Trust, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), the Medical Research Council, BELTA-TBnet, the European Union, the German Center for Infection Research, and Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG).
10 Pages, 1 Figure, 3 Tables. Supplementary information: http://dx.doi.org/10.1038/s41598-018-33731-1 ; Drug-resistant tuberculosis poses a persistent public health threat. The ReSeqTB platform is a collaborative, curated knowledgebase, designed to standardize and aggregate global Mycobacterium tuberculosis complex (MTBC) variant data from whole genome sequencing (WGS) with phenotypic drug susceptibility testing (DST) and clinical data. We developed a unified analysis variant pipeline (UVP) ( https://github.com/CPTR-ReSeqTB/UVP ) to identify variants and assign lineage from MTBC sequence data. Stringent thresholds and quality control measures were incorporated in this open source tool. The pipeline was validated using a well-characterized dataset of 90 diverse MTBC isolates with conventional DST and DNA Sanger sequencing data. The UVP exhibited 98.9% agreement with the variants identified using Sanger sequencing and was 100% concordant with conventional methods of assigning lineage. We analyzed 4636 publicly available MTBC isolates in the ReSeqTB platform representing all seven major MTBC lineages. The variants detected have an above 94% accuracy of predicting drug based on the accompanying DST results in the platform. The aggregation of variants over time in the platform will establish confidence-graded mutations statistically associated with phenotypic drug resistance. These tools serve as critical reference standards for future molecular diagnostic assay developers, researchers, public health agencies and clinicians working towards the control of drug-resistant tuberculosis. ; This study was supported by the Bill & Melinda Gates Foundation under grant agreement OPP1115887 to C-Path for developing the ReSeqTB drug resistance data sharing platform and under grant agreement FIND OPP1115209 to address how to score mutations in the ReSeqTB data sharing platform initiative. The South African MRC and the EDCTP support K. Dheda. I. Comas is supported by the Ministerio de Economía y Competitividad (Spanish Government) research grant SAF2016-77346-R and the European Research Council (ERC) (638553-TB-ACCELERATE). L. Chindelevitch acknowledges support by NSERC, Genome Canada, and the Sloan Foundation. Use of trade names is for identification only and does not constitute endorsement by the US Department of Health and Human Services, the US Public Health Service, or the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency. ; Peer reviewed
This paper describes an action framework for countries with low tuberculosis (TB) incidence (<100 TB cases per million population) that are striving for TB elimination. The framework sets out priority interventions required for these countries to progress first towards "pre-elimination" (<10 cases per million) and eventually the elimination of TB as a public health problem (less than one case per million). TB epidemiology in most low-incidence countries is characterised by a low rate of transmission in the general population, occasional outbreaks, a majority of TB cases generated from progression of latent TB infection (LTBI) rather than local transmission, concentration to certain vulnerable and hard-to-reach risk groups, and challenges posed by cross-border migration. Common health system challenges are that political commitment, funding, clinical expertise and general awareness of TB diminishes as TB incidence falls. The framework presents a tailored response to these challenges, grouped into eight priority action areas: 1) ensure political commitment, funding and stewardship for planning and essential services; 2) address the most vulnerable and hard-to-reach groups; 3) address special needs of migrants and cross-border issues; 4) undertake screening for active TB and LTBI in TB contacts and selected high-risk groups, and provide appropriate treatment; 5) optimise the prevention and care of drug-resistant TB; 6) ensure continued surveillance, programme monitoring and evaluation and case-based data management; 7) invest in research and new tools; and 8) support global TB prevention, care and control. The overall approach needs to be multisectorial, focusing on equitable access to high-quality diagnosis and care, and on addressing the social determinants of TB. Because of increasing globalisation and population mobility, the response needs to have both national and global dimensions.
13 Pages, 1 Figure, 4 tables. The authors' affiliations are listed in the Supplementary Appendix, available at NEJM.org. Supplementary Material, available at http://dx.doi.org/10.1056/NEJMoa1800474 ; BACKGROUND: The 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. METHODS: We 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. RESULTS: A 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 profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.). ; Supported by grants from the Bill and Melinda Gates Foundation (OPP1133541, to CRyPTIC, plus separate support to Dr. Rodwell), a Wellcome Trust/Newton Fund–MRC Collaborative Award (200205/Z/15/Z, to CRyPTIC), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, the NIHR Biomedical Research Centre at Barts, the NIHR Biomedical Research Centre at Imperial, the NIHR and NHS England (to the 100,000 Genomes Project, which is managed by Genomics England, a wholly owned company of the U.K. Department of Health), the Wellcome Trust, the Medical Research Council, Public Health England, a grant from the National Science and Technology Key Program of China (2014ZX10003002), a grant from the National Basic Research program of China (2014CB744403), a grant from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29020000), a grant from the European Commission Seventh Framework Program (FP7/2007-2013, to Borstel under grant agreement 278864 in the framework of the Patho-NGen-Trace project), the German Center for Infection Research (to Borstel), Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG), the Belgian Ministry of Social Affairs (to the Belgian Reference Center for Tuberculosis and Mycobacteria from Bacterial Diseases Service through a fund within the Health Insurance System), the French governmental program "Investing for the Future" (to Genoscreen), a grant from the European Commission Seventh Framework Program (FP7/2007-2013, to Genoscreen under grant agreement 278864 in the framework of the Patho-NGen-Trace project), grants from the Drug Resistant Tuberculosis Fund (R015833003, to Dr. Chaiprasert), the Faculty of Medicine, Siriraj Hospital, Mahidol University (to Dr. Chaiprasert), a grant from the Ministry of Economy and Competitiveness (MINECO), Spain (SAF2016-77346-R, to Dr. Comas), a grant from the European Research Council (638553-TB-ACCELERATE, to Dr. Comas), a grant from the BC Centre for Disease Control Foundation for Population and Public Health (to Dr. Gardy), a grant from the British Colombia Lung Association (to Dr. Gardy), grants from the Wellcome Trust and the Royal Society (101237/Z/13/Z and 102541/A/13/Z, to Drs. Wilson and Iqbal [Sir Henry Dale Fellows]), a grant from the National University of Singapore Yong Loo Lin School of Medicine Aspiration Fund (NUHSRO/2014/069/AF-New Idea/04, to Drs. Ong and Teo), a European Commission Seventh Framework Program European Genetic Network (EUROGEN) grant (201483, to Dr. Drobniewski), and the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to Dr. Rodwell). Dr. T. Walker is an NIHR Academic Clinical Lecturer, and Drs. Crook, Peto, and Caulfield are NIHR Senior Investigators. No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Stéphanie Duthoy, Carina Hahn, Alamdar Hussain, Yannick Laurent, Mathilde Mairey, Vanessa Mohr, and Mahmood Qadir for technical assistance and George F. Gao, Director of the Chinese Center for Disease Control and Prevention, for directing the Chinese grant and sequencing program ; Peer reviewed
