BK病毒感染诊断与治疗的研究现状

doi:10.3969/j.issn.1673-8640.2017.05.021

摘要/Abstract

摘要：

BK病毒（BKV）属于人类多瘤病毒中的一个亚型。BKV在普通人群中隐性感染率高达80%。近年来,随着器官移植术的广泛开展以及强效免疫抑制剂的大量使用,在免疫抑制和免疫低下的人群中,由潜伏于体内的BKV重新被激活而引起的BKV相关肾病（BKVAN）、出血性膀胱炎、输尿管狭窄等疾病越来越受到医学界的关注。目前对BKV感染缺乏明确有效的预防措施及抗病毒药物,因此早期监测器官移植术后患者体内的BKV载量、减少免疫抑制剂的使用量、及时调整免疫抑制剂治疗方案并辅助使用其他抗病毒药物对预防BKV相关疾病的发生尤为重要。文章就BKV感染相关的疾病及其临床症状、生物学特征、感染机制以及当前国内外诊断及治疗研究现状进行综述。

关键词: BK病毒, BK病毒相关肾病, 病毒检测, 诊断, 治疗

Abstract:

：BK virus （BKV） belongs to a subtype of human polyomavirus. Recessive infection rate of BKV in general population is about 80%. With expanded use of organ transplantation in recent years where strong immunosuppression is essential,BKV associated nephropathy（BKVAN）,hemorrhagic cystitis,ureterostenosis and other associated diseases due to the reactivation of latent BKV in immunosuppressed or immunocompromised populations are becoming more of a concern in medical community. Since the prevention measures and effective antiviral drugs for BKV are rather limited,the effective means for reducing BK associated morbidity and mortality due to BKV associated diseases are the early monitoring of viral loads,reducing the usage of immunosuppressant,adjusting immunosuppressant treatment regime and using adjuvant therapies. This review describes the clinical symptoms,biology,mechanisms and the advances in the diagnosis and treatment of BKV at home and abroad.

Key words: BK virus, BK virus associated nephropathy, Virus detection, Diagnosis, Treatment

中图分类号:

R446.5

张志刚, 曹璐, 王鑫, 赵勤俭. BK病毒感染诊断与治疗的研究现状[J]. 检验医学, 2017, 32(5): 440-445.

ZHANG Zhigang, CAO Lu, WANG Xin, ZHAO Qinjian. Status on the diagnosis and treatment of BK virus infection[J]. Laboratory Medicine, 2017, 32(5): 440-445.

图/表 3

参考文献 33

[1]	GARDNER S D,FIELD A M,COLEMAN D V,et al.New human popovavirus(B.K.) isolated from urine after renal transplantation[J]. Lancet,1971,1(7712):1253-1257.
[2]	STOLT A,SASNAUSKAS K,KOSKELA P,et al.Seroepidemiology of the human polyomaviruses[J]. J Gen Virol,2003,84(Pt 6):1499-1504.
[3]	吴蓓颖,蔡刚,林佳菲,等. 移植患者BK病毒监测的临床意义[J]. 检验医学,2014,29(5):493-497.
[4]	BALBA G P,JAVAID B,TIMPONE JG Jr.BK polyomavirus infection in the renal transplant recipient[J]. Infect Dis Clin North Am,2013,27(2): 271-283.
[5]	杨晓勇,任亮,王玮,等. 肾移植受者BK病毒感染的单中心回顾性研究[J]. 首都医科大学学报,2015,36(3):459-464.
[6]	屠国伟,朱同玉. 肾移植术后BK病毒感染的研究进展[J]. 国际泌尿系统杂志,2008,28(1):40-44.
[7]	HIRSCH H H,RANDHAWA P,AST Infectious Diseases Community of Practice. BK virus in solid organ transplant recipients[J]. Am J Transplant,2009,9(Suppl 4):S136-S146.
[8]	GONZALEZ S,ESCOBAR-SERNA D P,SUAREZ O,et al. BK virus nephropathy in kidney transplantation:an approach proposal and update on risk factors,diagnosis,and treatment[J]. Transplant Proc,2015,47(6): 1777-1785.
[9]	TROND F,HENRIK P,ANNE H,et al.BK virus infection in patients with AIDS[J]. Scandinavian J Infect Dis,2015,20(2):145-150.
[10]	GUPTA N,LAWRENCE R M,NGUYEN C,et al.Review article:BK virus in systemic lupus erythematosus[J]. Pediatr Rheumatol Online J,2015,13:34.
[11]	HENDRIX K M.BK virus in recipients of kidney transplants[J]. Nephrol Nurs J,2014,41(6):593-601.
[12]	KRAUTKRÄMER E,KLEIN T M,SOMMERER C,et al. Mutations in the BC-loop of the BKV VP1 region do not influence viral load in renal transplant patients[J]. J Med Virol,2009, 81(1):75-81.
[13]	HUANG J,DANOVITCH G,PHAM P T,et al.Kidney retransplantation for BK virus nephropathy with active viremia without allograft nephrectomy[J]. J Nephrol,2015,28(6): 773-777.
[14]	YEO F E,YUAN C M,SWANSON S J,et al.The prevalence of BK polyomavirus infection in outpatient kidney transplant recipients followed in a single center[J]. Clin Transplant,2008,22(5): 532-541.
[15]	SINGH H K,ANDREONI K A,MADDEN V,et al.Presence of urinary Haufen accurately predicts polyomavirus nephropathy[J]. J Am Soc Nephrol,2009,20(2):416-427.
[16]	SAWINSKI D,GORAL S.BK virus infection: an update on diagnosis and treatment[J]. Nephrol Dial Transplant,2015,30(2):209-217.
[17]	DING R,MEDEIROS M,DADHANIA D,et al.Noninvasive diagnosis of BK virus nephritis by measurement of messenger RNA for BK virus VP1 in urine[J]. Transplantation,2002,74(7): 987-994.
[18]	ASTEGIANO S,BERGALLO M,TERLIZZI M E,et al.Combined measurement of serum DNA and urine VP1 messenger RNA in monitoring BK virus replication in kidney graft recipients[J]. Transplant Proc,2011,43(4):1052-1054.
[19]	NICKELEIT V,KLIMKAIT T,BINET I F,et a1. Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy[J]. N Engl J Med,2000,342(18):1309-1315.
[20]	BUCSA C,STEFAN G,TACU G,et al.Does the KDIGO CKD risk stratification based on GFR and proteinuria predict kidney graft failure?[J]. Int Urol Nephrol,2014,46(9):1857-1865.
[21]	FERREIRA-GONZALEZ A,SIDIQUI R.BK virus in the transplant patient[J]. Clin Microbiol Newslett,2007,29(16):121-128.
[22]	Kidney Disease:Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients[J]. Am J Transplant,2009,9(Suppl 3):S1-S155.
[23]	HARDINGER K L,KOCH M J,BOHL D J,et al.BK-virus and the impact of pre-emptive immunosuppression reduction:5-year results[J]. Am J Transplant,2010,10(2):407-415.
[24]	SCHWARZ A,LINNENWEBER-HELD S,HEIM A,et al.Factors influence viral clearing and renal function during polyomavirus BK-associated nephropathy after renal transplantation[J]. Transplantation,2012,94(4):396-402.
[25]	TESCHNER S,GERKE P,GEYER M,et al.Leflunomide therapy for polyomavirus-induced allograft nephropathy:efficient BK virus elimination without increased risk of rejection[J]. Transplant Proc,2009,41(6):2533-2538.
[26]	KRISL J C,TABER D J,PILCH N,et al.Leflunomide efficacy and pharmacodynamics for the treatment of BK viral infection[J]. Clin J Am Soc Nephrol,2012,7(6):1003-1009.
[27]	REISMAN L,HABIB S,MCCLURE G B,et al.Treatment of BK virus-associated nephropathy with CMX001 after kidney transplantation in a young child[J]. Pediatr Transplant,2014,18(7):E227-E231.
[28]	JOHNSTON O,JASWAL D,GILL J S,et al.Treatment of polyomavirus infection in kidney transplant recipients:a systematic review[J]. Transplantation,2010,89(9):1057-1070.
[29]	LEE S S,AHN J S,JUNG S H,et al.Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation[J]. Korean J Intern Med,2015,30(2):212-218.
[30]	KNOLL G A,HUMAR A,FERGUSSON D,et al.Levofloxacin for BK virus prophylaxis following kidney transplantation:a randomized clinical trial[J]. JAMA,2014,312(20):2106-2114.
[31]	HUMAR A,GILL J,JOHNSTON O,et al.Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation:study protocol for a randomized controlled trial[J]. Trials,2013,14:185.
[32]	ANYAEGBU E L,ALMOND P S,MILLIGAN T,et al.Intravenous immunglobulin therapy in the treatment of BK viremia and nephropathy in pediatric renal transplant recipients[J]. Pediatr Transplant,2012,16(1):E19-E24.
[33]	MBIANDA D,EL-MEANAWY A,SOROKIN A.Mechanisms of BK virus infection of renal cells and therapeutic implications[J]. J Clin Virol,2015,71:59-62.

检测和诊断方法	优点	缺点	临床应用情况
基于尿液Decoy 细胞检测	敏感性、阴性预测值均较高（>99%）	阳性预测值较低（25%~30%）	用于器官移植后BKV感染的筛查
基于电镜的 Haufen检测	阳性预测值、阴性预测值均较高（>90%）	未经大规模临床试验证实	作为候选的BKVAN非侵入性诊断方法
基于VP1 mRNA 的分子检测	敏感性、特异性均高（>90%）	成本较高,操作难度大,样本预处理较难	辅助监测体内BKV复制程度
定量PCR	敏感性100%,特异性88%~98%	尚无统一的病毒临界载量标准	作为肾移植后BKV监测的首选方法
肾组织活检	阳性预测值100%	有创性检查,容易出现假阴性的检测结果	作为诊断BKVAN的金标准

检测和诊断方法	优点	缺点	临床应用情况
基于尿液Decoy 细胞检测	敏感性、阴性预测值均较高（>99%）	阳性预测值较低（25%~30%）	用于器官移植后BKV感染的筛查
基于电镜的 Haufen检测	阳性预测值、阴性预测值均较高（>90%）	未经大规模临床试验证实	作为候选的BKVAN非侵入性诊断方法
基于VP1 mRNA 的分子检测	敏感性、特异性均高（>90%）	成本较高,操作难度大,样本预处理较难	辅助监测体内BKV复制程度
定量PCR	敏感性100%,特异性88%~98%	尚无统一的病毒临界载量标准	作为肾移植后BKV监测的首选方法
肾组织活检	阳性预测值100%	有创性检查,容易出现假阴性的检测结果	作为诊断BKVAN的金标准