Intravenous immunoglobulin therapy for severe arthritis associated with human parvovirus B19 infection

Symptoms caused by acute human parvovirus B19 (HPV-B19) infection can vary considerably, from asymptomatic to severely symptomatic. A 39-year-old Japanese woman complained of sudden, severe arthralgia with edematous limbs coincident with an outbreak of HPV-B19 infection at the elementary school attended by her daughter. A diagnosis of acute HPV-B19 infection was made by the detection of serum antibody to HPV-B19 IgM and HPV-B19 DNA. Magnetic resonance imaging revealed bilateral synovitis of the cubital joints. The patient was immunocompetent and suffered from severe arthralgia associated with persistent HPV-B19 viremia for more than 4 months after the diagnosis of acute HPV-B19 infection. The administration of high-dose intravenous immunoglobulin resulted in remission, with little change in the serum HPV-B19 DNA level. Even in our immunocompetent patient, severe and prolonged arthritis was found to be associated with persistent viremia.     

细小病毒B19宫内感染与新生儿贫血的相关性研究

目的探讨细小病毒B19宫内感染与新生儿贫血的相关性。方法收集138例贫血新生儿和85例未贫血新生儿的脐血,应用酶联免疫吸附试验检测两组患儿脐血中的人细小病毒B19IgM抗体水平。结果两组患儿脐血检测结果差异具有统计学意义(P0.05)。结论 B19病毒宫内感染与新生儿贫血具有一定的相关性。     

Hepatic dysfunction due to parvovirus B19 infection

Parvovirus B19 has been associated with different diseases. However, hepatic involvement has rarely been reported in adult patients with parvovirus B19 infection. Herein, we report two adult patients with hepatic dysfunction associated with acute parvovirus B19 infection. We believe that hepatic involvement in the setting of parvovirus B19 infection is more common than suspected, and that antibodies against this agent should be routinely measured in patients with hepatic dysfunction of unclear etiology. Received: August 1, 1999 / Accepted: November 29, 1999     

流产胚胎组织中人类微小病毒B19的检测分析

目的 通过对三组不同妊娠民政部组别胚胎组织标本检测人类微小病毒Ｂ１９（Ｂ１９Ｖ）结果的分析。探讨Ｂ１９Ｖ感染与人类自然流产之间的关系。方法 实验对象由７２例不明原因自然流产的病人、３２例妊娠情况正常的人工流产者、３６例足月分娩新生儿正常的产妇组织,计１４０例,惧订流产组织和正常产妇胎盘组织为检测标本。应用聚合酶链反应（ＰＣＲ）方法检测Ｂ１９Ｖ。结果 ７２份自然流产病人流产组织标本Ｂ１９Ｖ的检出率为２７．８％（２０／７２）,３６份正常产妇胎盘组织标本Ｂ１９Ｖ的检出率为５．６％（２／３６）,３２份人工流产者的流产组织标本未检测出Ｂ１９Ｖ,自然流产者与人工流产者、正常分娩者组织标本ＰＣＲ－Ｂ１９Ｖ结果的差别有显著性（卡方检验。Ｐ〈０．０５）。结论 自然流产病人流产组织ＰＣＲ－Ｂ１９Ｖ的检出率显著性高于人工流产者和正常     

Quantitative real-time PCR for differential diagnostics of parvovirus B19 infection in acute liver failure patients

Background: Human Parvovirus B19 (B19V) is a common pathogen worldwide. After primary infection, B19V-DNA may permanently persist in non-erythroid tissues, including the liver of patients with acute liver failure (ALF).

Objective: To validate a real-time PCR (qPCR) for the quantification of B19V-DNA, in order to establish a differential diagnosis for B19V infection in ALF patients.

Methods: The qPCR techniques were based on Sybr Green® and TaqMan® methodologies. To evaluate the quality parameters of both methods, samples from patients with or without B19V infection were tested. The diagnostic utility of qPCR in the detection B19V-DNA in patients with ALF was evaluated by testing archived serum and hepatic tissue explants from 10 patients.

Results: The Sybr Green® methodology showed 97% efficiency, the limits of detection and quantification were 62.6 and 53,200 copies/mL, respectively. The TaqMan® methodology showed 95% efficiency, the limits of detection and quantification were 4.48 and 310 copies/mL, respectively. A false positive result was found only with the Sybr Green® methodology. Among ALF patients without defined etiology, three (30%) were positive for B19V DNA in serum and liver.

Conclusion: The qPCR methods validated here were effective in clarifying uncommon cases of B19V-related ALF and are fit for differential diagnosis of ALF causes.     

肝移植患者人类微小病毒B19感染与相关贫血的临床特点分析

目的：探讨肝移植术后人类微小病毒B19（human parvovirus B19, HPV B19）感染致纯红细胞再生障碍性贫血（pure red cell aplasia, PRCA）的诊断和治疗方法。方法：描述和分析19例肝移植术后HPV B19感染引起的PRCA病例的临床特点、诊断、治疗及预后。结果：19例肝移植受者术后2个月内出现贫血,排除导致贫血的其他原因,经实时定量聚合酶链反应（quantitative real-time polymerase chain reaction, qRT-PCR）检测HPV B19 DNA诊断为HPV B19感染致PRCA。所有患者给予静脉注射用免疫球蛋白（intravenous immunoglobulins, IVIG）等治疗后,贫血症状得到改善。结论：对于肝移植术后早期不明原因的PRCA患者,排除其他病因后可考虑HPV B19感染可能。PCR检测HPV B19 DNA是诊断PRCA的主要依据。早期应用IVIG治疗对于治疗肝移植后HPV B19感染相关的PRCA效果良好。     

应用PCR法对临床血标本中人微小病毒B19的检测分析

目的探讨PCR法检测临床血标本中人微小病毒B19(HPV B19)的应用价值。方法根据序列比对结果,在HPV B19核苷酸相对保守区设计引物进行PCR扩增。应用双脱氧链末端终止法对HPV B19阳性PCR产物进行克隆测序。结果应用该法最终检出HPV B19的血清稀释度为10^3。序列比较表明,用本法检出的1株HPV B19阳性标本与标准株(Au株)核苷酸序列同源性为92％。检测肝癌和肝硬化患者血清标本各14例,结果HPV B19阳性分别为8例和5例。结论本法可用于HPV B19的临床诊断和流行病学调查。     

Laboratory diagnosis of parvovirus B19 infection.

The sensitivity and application of the polymerase chain reaction (PCR) for the diagnosis of parvovirus B19 (B19) infection was investigated by simultaneously assaying a collection of 279 consecutively received samples for presence of anti-B19 IgM and IgG antibodies by Western blot and for B19 DNA by PCR and dot-blot hybridization (dot-blot); samples were sera from patients with suspected B19 infection. PCR and dot-blot detected B19 DNA in 9% (16/179) and 1% (2/179), respectively of Ab-positive samples (IgM+/IgG-, IgM+IgG+, IgM-IgG+), and in 28% (15/54) and 2% (1/54), respectively, of IgM+ samples. PCR also detected B19 DNA in 2% (2/100) of IgM-/IgG- samples, both of which had normal total IgG and IgM levels. PCR is of unique value because it permits diagnosis of B19 infection even in the absence of specific acute phase (IgM) and in the presence or absence of convalescent-phase (IgG) Ab.     

Immune reconstitution to parvovirus B19 and resolution of anemia in a patient treated with highly active antiretroviral therapy

Immune reconstitution inflammatory syndrome (IRIS) is an unsolved problem in the treatment of human immunodeficiency virus (HIV)-1 infection. Despite the high seroprevalence of parvovirus B19 (PVB19) among HIV-1-positive patients, reports on PVB19-induced anemia, especially that associated with PVB19-related IRIS, in these patients are limited. We present the case of a man with acquired immunodeficiency syndrome who developed severe transfusion-dependent anemia and was seropositive and borderline positive for immunoglobulin-M and IgG antibodies against PVB19, respectively. PVB19-DNA was also detected in his serum. The patient was diagnosed with pure red cell anemia (PRCA) caused by a primary PVB19 infection and was treated with periodical blood transfusions. However, he subsequently tested negative for IgG antibodies and developed chronic severe anemia with high levels of PVB19 viremia. This indicated a transition from primary to persistent infection. After initiation of highly active antiretroviral therapy, the patient showed an inflammatory reaction with rapid deterioration of anemia and seroconversion of the IgG antibody to PVB19. Subsequently, PRCA was completely resolved, but the patient’s serum still contained low levels of PVB19-DNA. Thus, this was a case of IRIS associated with PVB19 infection. Our report highlights the significance of seroconversion to PVB19 in the diagnosis of IRIS and re-emphasizes the finding that persistently high levels of PVB19 viremia after primary infection are probably because of the lack of protective antibodies.     

佛山地区无偿献血人群人细小病毒B19感染情况分析

目的了解佛山地区无偿献血人群人细小病毒(HPV)B19感染现状。方法采用ELISA检测血液中的HPV B19IgG和IgM抗体,并用PCR检测抗体阳性标本HPV B19DNA。结果 368例无偿献血者标本中检出HPV B19IgG阳性92例,阳性率为25.00%;检出HPV B19IgM阳性2例,阳性率为0.54%,两者比较差异有统计学意义(P0.01)。94例抗体阳性标本中,检测HPV B19DNA阳性4例,阳性率为4.26%。结论佛山地区无偿献血人群存在较高的HPV B19既往感染率,急、慢性感染率较低,慢性感染者HPV B19病毒载量较低。     

61例不完全性川崎病与微小病毒B19感染

目的 探讨不完全性川崎病与微小病毒B19(HPVB19)感染相关性.方法 应用巢式PCR法对166例典型川崎病(KD)(观察组)及61例不完全性川崎病(对照组)进行B19-DNA检测.对观察组与对照组HPVB19-DNA检测阳性的与阴性的两组中应用心脏彩超检测冠状动脉内径值进行比较.结果 观察组(典型川崎病)B19-DNA阳性检出率为27.4%(45/166),对照组(不完全性川崎病)B19-DNA阳性检出率检为47.5%(29/61),两组比较有显著差别(P＜0.01).观察组(典型川崎病)与对照组(不完全性川崎病)HPVB19-DNA检测阳性的两组中,心脏彩超冠状动脉内径值比较有显著差异(P＜0.01).结论 微小病毒B19 与不完全性川崎病(KD) 相关,并且微小病毒B19感染造成冠状动脉病变比较严重.     

Intrauterine infection with parvovirus B19 and CMV: implications in early and late gestation fetal demise

In utero viral infections have been associated with an adverse pregnancy outcome and may have a causative role in the unexplained fetal death file. Parvovirus B19 and cytomegalovirus are among the most common pathogens implicated in fetal loss cases. Parvovirus B19 has been reported to account for cases of spontaneous abortions, intrauterine fetal death and nonimmune hydrops fetalis, whereas cytomegalovirus accounts for nonimmune hydrops fetalis, intrauterine growth retardation and congenital anomalies. This review aims to summarize the current literature in an attempt to underline the need for routine screening, close follow-up and prevention. A better understanding of the pathogenetic mechanisms of viral infections during the crucial time of organogenesis, along with early detection, may contribute to the reduction in stillbirth rate.     

Prevention of parvovirus B19-induced repetitive acute kidney failure by subcutaneous immunoglobulins

Human parvovirus B19 has been associated with various cases of kidney injuries with different glomerular phenotypes. In immunocompromised individuals, insufficient production of neutralizing antibodies can lead to chronic PVB19 carriage and manifestations. However, PVB19 DNA has been detected in bone marrow and peripheral blood for months or years in seemingly immunocompetent individuals, despite the presence of neutralizing antibodies. We report here PVB19-induced recurrent anuric acute kidney failures in a 57-year-old man over a 7-year period with persistent PVB19 infection and then PVB19-associated cryoglobulinemia. Acute renal failures were preceded by influenza-like syndrome associated with arthralgia, skin rash, and low-grade fever. Serum, bone marrow, renal, and digestive PVB19 replication was found in the different episodes. Endocapillary proliferative glomerulonephritis evolved into membranoproliferative glomerulonephritis. Complete renal recovery occurred after each bout. Off-label subcutaneous immunoglobulin therapy resulted in disappearance of blood and bone marrow PVB19 viral load and stopped the glomerulonephritis recurrence. Subcutaneous immunoglobulin therapy withdrawal resulted in renal relapse with cryoglobulin-associated manifestations.     

Human parvovirus B19-associated early postoperative acquired pure red cell aplasia in simultaneous pancreas-kidney transplantation: A case report

BACKGROUNDAcquired pure red cell aplasia (aPRCA) related to human parvovirus B19 (HPV B19) is rarely reported in simultaneous pancreas-kidney transplantation (SPKT) recipients; there has yet to be a case report of early postoperative infection. In this current study, we report the case of a Chinese patient who experienced the disease in the early postoperative period.CASE SUMMARYA 63-year-old man, with type 2 diabetes and end-stage renal disease, received a brain dead donor-derived SPKT. Immunosuppression treatment consisted of tacrolimus, prednisone, enteric-coated mycophenolate sodium (EC-MPS), and thymoglobulin combined with methylprednisolone as induction. The hemoglobin (Hb) level declined due to melena at postoperative day (POD) 3, erythropoietin-resistant anemia persisted, and reticulocytopenia was diagnosed at POD 20. The bone marrow aspirate showed decreased erythropoiesis and the presence of giant pronormoblasts at POD 43. Metagenomic next-generation sequencing (mNGS) of a blood sample identified HPV B19 infection at POD 66. EC-MPS was withdrawn; three cycles of intravenous immunoglobulin (IVIG) infusion therapy were administered; and tacrolimus was switched to cyclosporine. The HPV B19-associated aPRCA resolved completely and did not relapse within the 1-year follow-up period. The diminution in mNGS reads was correlated with Hb and reticulocyte count improvements. CONCLUSIONHPV B19-associated aPRCA can occur at an early period after SPKT. An effective therapy regimen includes IVIG infusion and adjustment of the immuno-suppressive regimen. Moreover, mNGS can be used for the diagnosis and to reflect disease progression.     

Pure red cell aplasia caused by parvovirus B19 in two patients without chronic hemolysis

Infection with human parvovirus B19 (PVB19) induces acquired pure red cell aplasia (PRCA). Chronic hemolytic anemia is well known as an underlying condition. However, additional factors have been recognized to accompany parvoviral PRCA; however, there are only limited reports on iron-deficiency anemia (IDA) and rituximab-induced B-cell dysfunction. We report two patients with PVB19-associated PRCA confirmed by positivity of viral DNA. Although they had no chronic hemolysis, patient 1 had IDA, and patient 2 had remitted small-lymphocytic lymphoma treated with rituximab-containing chemotherapy. Absence of reticulocytes in peripheral blood and marked depletion of erythroid precursors in bone marrow were observed both. Whereas patient 1 received only symptomatic therapy because anemia was not severe, patient 2 was treated with steroids, as PRCA etiology was at first uncertain, and immunological PRCA was not excluded. Both showed rapid increase of reticulocyte counts and recovery from anemia. Although immunoglobulin is considered effective for parvoviral PRCA, notable adverse reactions have been reported. When anemic symptom is not severe, reticulocyte observation only is recommended. The effects of steroids should also be re-evaluated. Optimal treatment according to disease severity remains to be established.     

中国人细小病毒B19系统发育关系研究

目的探讨在中国分布的人细小病毒B19的系统发育。方法对B19病毒阳性的23份来自中国献血者和5份B19/HIV共感染者标本,采用病毒基因组NS1-VP1-u区测序后,与Genbank下载的参考序列比对,用软件MRBAYES 3.1.2作贝叶斯推断,用在线软件RaxML作最大似然法运算,绘制进化树并分析。结果 28份来自中国的标本均属于B19-1A亚型,且呈现复系,其中来自新疆乌鲁木齐来自四川的各1例标本与非中国序列聚在一起,其他中国26份标本与来自美国的病毒株Au聚在一枝并有着很好的支持率,来自西安的2条参考序列出现在B19-1A亚型的基部。结论中国的B19病毒是多起源的,其在中国中西部地区进化速率较慢;应该积极开展不同地区B19病毒多样性的研究。     

Up-regulation of adhesion molecule expression and induction of TNF-alpha on vascular endothelial cells by antibody against human parvovirus B19 VP1 unique region protein

BACKGROUND: Human parvovirus B19 infection has been frequently described as a cause or trigger of various autoimmune diseases. In previous studies, we have postulated the association among human parvovirus B19 (B19)-VP1 unique region (VP1u), production of anti-beta2-glycoprotein I (anti-beta2GPI) antibody and anti-phospholipid syndrome (APS)-like autoimmunity. However, the precise role of B19-VP1u in induction of APS is still obscure. METHODS: To further elucidate the pathogenic roles of VP1u in B19 infection and autoimmunity, we examined the effect of anti-B19-VP1u IgG antibodies on endothelial cells that is recognized to play crucial roles in APS. Human vascular endothelial cells, ECV-304, were incubated with various preparations of purified human or rabbit IgG. The activation of endothelial cells and production of cytokines were assessed by flow cytometry and ELISA, respectively. RESULTS: Purified IgG from rabbits immunized with recombinant B19-VP1u proteins can up-regulate ICAM-1 (CD54), VCAM-1 (CD106), E-selectin (CD62E), MHC class II (HLA-DR, DP, DQ) molecule expression, and TNF-alpha production in endothelial cells as compared to those endothelial cells cultured with control IgG. Additionally, significantly increased phosphorylated-P38 mitogen-activated protein kinase (P38 MAPK) and iNOS were observed in both human anti-beta2GPI IgG and rabbit anti-B19-VP1u IgG treated-ECV-304 cells, respectively. CONCLUSIONS: These experimental results imply that antibodies against B19-VP1u play important roles in the immunopathological processes as well as human anti-beta2GPI IgG that leads to development of APS by involving p38 phosphorylation and iNOS activation. It could provide a clue in understanding the role of anti-B19-VP1u antibodies in APS manifestations.