title: Beijing clades of Mycobacterium tuberculosis are associated with differential survival in HIV-negative Russian patients.
abstract: We conducted a prospective study to establish factors associated with survival in tuberculosis patients in Russia including social, clinical and pathogen-related genetic parameters. Specifically we wished to determine whether different strains/clades of the Beijing lineage exerted a differential effect of survival. HIV-negative culture-confirmed cases were recruited during 2008-2010 across Samara Oblast and censored in December 2011. Molecular characterization was performed by a combination of spoligotyping, multilocus VNTR typing and whole genome sequencing (WGS). We analyzed 2602 strains and detected a high prevalence of Beijing family (n=1933; 74%) represented largely by two highly homogenous dominant clades A (n=794) and B (n=402) and non-A/non-B (n=737). Multivariable analysis of 1366 patients with full clinical and genotyping data showed that multi- and extensive drug resistance (HR=1.86; 95%CI: 1.52, 2.28 and HR=2.19; 95%CI: 1.55, 3.11) had the largest impact on survival. In addition older age, extensive lung damage, shortness of breath, treatment in the past and alcohol abuse reduced survival time. After adjustment for clinical and demographic predictors there was evidence that clades A and B combined were associated with poorer survival than other Beijing strains (HR=0.48; 95%CI 0.34, 0.67). All other pathogen-related factors (polymorphisms in genes plcA, plcB, plcC, lipR, dosT and pks15/1) had no effect on survival. In conclusion, drug resistance exerted the greatest effect on survival of TB patients. Nevertheless we provide evidence for the independent biological effect on survival of different Beijing family strains even within the same defined geographical population. Better understanding of the role of different strain factors in active disease and their influence on outcome is essential.
authors: Clinical TB and HIV Group, Blizard Institute, Queen Mary, University of London, 2 Newark Street, London E12AT, UK; Department of Infectious Diseases, Imperial College London, DuCane Road, London W12 ONN, UK; Robert Koch Institute, Seestraße 10, 13353 Berlin, Germany. Electronic address: yanina.lenz@imperial.ac.uk.
authors: Yanina
authors: Y
authors: Balabanova
authors: Clinical TB and HIV Group, Blizard Institute, Queen Mary, University of London, 2 Newark Street, London E12AT, UK; Department of Infectious Diseases, Imperial College London, DuCane Road, London W12 ONN, UK.
authors: Vladyslav
authors: V
authors: Nikolayevskyy
authors: N.V. Postnikov Samara Region Clinical Tuberculosis Dispensary, Novosadovaya str 154, Samara 443086, Russia.
authors: Olga
authors: O
authors: Ignatyeva
authors: N.V. Postnikov Samara Region Clinical Tuberculosis Dispensary, Novosadovaya str 154, Samara 443086, Russia.
authors: Irina
authors: I
authors: Kontsevaya
authors: N.V. Postnikov Samara Region Clinical Tuberculosis Dispensary, Novosadovaya str 154, Samara 443086, Russia.
authors: Svetlana
authors: S
authors: Mironova
authors: N.V. Postnikov Samara Region Clinical Tuberculosis Dispensary, Novosadovaya str 154, Samara 443086, Russia.
authors: Alexander
authors: A
authors: Kovalyov
authors: N.V. Postnikov Samara Region Clinical Tuberculosis Dispensary, Novosadovaya str 154, Samara 443086, Russia.
authors: Andrey
authors: A
authors: Kritsky
authors: N.V. Postnikov Samara Region Clinical Tuberculosis Dispensary, Novosadovaya str 154, Samara 443086, Russia.
authors: Yulia
authors: Y
authors: Rodionova
authors: N.V. Postnikov Samara Region Clinical Tuberculosis Dispensary, Novosadovaya str 154, Samara 443086, Russia.
authors: Ivan
authors: I
authors: Fedorin
authors: Department of Infectious Diseases, Imperial College London, DuCane Road, London W12 ONN, UK.
authors: Nicola
authors: N
authors: Casali
authors: Centre for Primary Care & Public Health, Blizard Institute, Queen Mary, University of London, 2 Newark Street, London E12AT, UK.
authors: Richard
authors: R
authors: Hooper
authors: Department of Molecular Medicine, Bernhard Nocht Institute for Topical Medicine, Bernhard-Nocht-Straße 74, 20259 Hamburg, Germany.
authors: Rolf D
authors: RD
authors: Horstmann
authors: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0SP, UK.
authors: Sergey
authors: S
authors: Nejentsev
authors: Public Health Agency of Sweden, Swedish Institute for Infectious Disease Control, Department of Clinical Microbiology, Karolinska Institute, Solnavägen 1, 171 77 Solna, Sweden.
authors: Sven
authors: S
authors: Hoffner
authors: Cologne Center for Genomics (CCG), University of Cologne, D-50931 Köln, Germany.
authors: Peter
authors: P
authors: Nuernberg
authors: Clinical TB and HIV Group, Blizard Institute, Queen Mary, University of London, 2 Newark Street, London E12AT, UK; Department of Infectious Diseases, Imperial College London, DuCane Road, London W12 ONN, UK.
authors: Francis
authors: F
authors: Drobniewski
mesh_terms: D005260:Female; D008040:Genetic Linkage; D016680:Genome, Bacterial; D005838:Genotype; D018023:HIV Seronegativity; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D012426:Russia / Q000453:epidemiology; D014376:Tuberculosis / Q000453:epidemiology / Q000382:microbiology* / Q000401:mortality*
keywords: Beijing family of strains; Clades; Russia; Survival; Tuberculosis