Balabanova Yanina, Nikolayevskyy Vladyslav, Ignatyeva Olga, Kontsevaya Irina, Mironova Svetlana, Kovalyov Alexander, Kritsky Andrey, Rodionova Yulia, Fedorin Ivan, Casali Nicola, Hooper Richard, Horstmann Rolf D, Nejentsev Sergey, Hoffner Sven, Nuernberg Peter, Drobniewski Francis
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.
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.
Infect Genet Evol. 2015 Dec;36:517-523. doi: 10.1016/j.meegid.2015.08.028. Epub 2015 Aug 28.
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.
我们开展了一项前瞻性研究，以确定俄罗斯结核病患者生存的相关因素，包括社会、临床和病原体相关的基因参数。具体而言，我们希望确定北京家族的不同菌株/进化枝是否对生存产生不同影响。2008年至2010年期间，在萨马拉州招募了HIV阴性且培养确诊的病例，并于2011年12月进行审查。通过 spoligotyping、多位点VNTR分型和全基因组测序（WGS）相结合的方法进行分子特征分析。我们分析了2602株菌株，检测到北京家族的高流行率（n=1933；74%），主要由两个高度同质的优势进化枝A（n=794）和B（n=402）以及非A/非B（n=737）组成。对1366例有完整临床和基因分型数据的患者进行多变量分析显示，多重和广泛耐药（HR=1.86；95%CI：1.52，2.28和HR=2.19；95%CI：1.55，3.11）对生存的影响最大。此外，年龄较大、广泛的肺部损伤、呼吸急促、既往治疗和酗酒会缩短生存时间。在对临床和人口统计学预测因素进行调整后，有证据表明，进化枝A和B合并在一起与比其他北京菌株更差的生存相关（HR=0.48；95%CI 0.34，0.67）。所有其他病原体相关因素（plcA、plcB、plcC、lipR、dosT和pks15/1基因中的多态性）对生存没有影响。总之，耐药性对结核病患者的生存影响最大。然而，我们提供了证据，证明即使在同一特定地理人群中，不同北京家族菌株对生存也有独立的生物学效应。更好地理解不同菌株因素在活动性疾病中的作用及其对结局的影响至关重要。
