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Objective: To assess the prevalence of TT virus (TMV) infection in a series of patients with chronic hepatitis C virus (HCV) infection, with or without benign (mixed cryoglobulinemia) or malignant (B-cell non-Hodgkin lymphoma (B-NHL)) lymphoproliferative disease., Methods: Sixty-six HCV patients were studied, including patients with mixed cryoglobulinemia (n=30), B-NHL (n=15), and no mixed cryoglobulinemia or B-NHL (n=21). All HCV patients had increased transaminase levels and were HCV RNA positive. Patients were considered to have mixed cryoglobulinemia if two successive determinations of their serum cryoglobulin level were above 0.05 g/L. Mixed cryoglobulinemia-negative patients never had mixed cryoglobulins in their serum on multiple determinations. Subjects without HCV infection included 79 patients with histologically proven B-NHL, and 50 healthy blood donors. Serum samples were analyzed for TTV DNA by nested polymerase chain reaction, with two couples of primers in different regions of the genome, in two independent laboratories., Results: In the group of HCV-positive patients, TTV DNA was found in one of 15 (6.7%) patients with B-NHL, and in nine of 51 (17.6%, P = 0.43) of those without B-NHL. Among HCV-positive patients without B-NHL, TTV DNA was more frequently found in those with type II mixed cryoglobulinemia vasculitis than in those without it (six of 16 (37.5%) versus two of 21 (9.5%), P = 0.05). In subjects without HCV infection, TTV DNA was present in 10 of 79 (12.7%) patients with B-NHL and in seven of 50 (14.0%, P = 0.82) blood donors., Conclusion: In patients chronically infected with HCV, TTV co-infection: (1) is not associated with the presence of B-NHL; and (2) is more frequently found in patients presenting a type II mixed cryoglobulinemia vasculitis.

Cryoglobulins are immunoglobulins that persist in the serum, precipitate with cold temperature and resolubilize when rewarmed. Types II and III are mixed cryoglobulins (MC), composed of different immunoglobulins, with a monoclonal component in type II and only polyclonal immunoglobulins in type III. Mixed cryoglobulins are associated with connective-tissue disease, malignant hematological disorder (type B lymphoproliferation) or obvious infectious process. Mixed cryoglobulinemia syndrome is characterized by the clinical triad of purpura, arthralgia and asthenia associated with type II or type III MC. The disorder is the consequence of an immune-complex-type vasculitis as supported by clinical features, analysis of the cryoglobulins, the usually depressed level of complement during the active phase of the disease, and the deposition of immunoglobulins and complement in the lesions. Such cryoglobulinemia vasculitis may involve numerous organs, particularly the peripheral nervous system and the kidneys. MC is frequently associated with clinical and biological evidence of liver disease. There has been some controversy about which comes first, MC or chronic liver disease, but it seems fairly clear that MC is often a manifestation of underlying chronic active or persistent hepatitis. In MC patients, the hepatotropic antigen(s) capable of triggering production of antibodies which can later form immune complexes has been sought for many years. In the last ten years, numerous studies have demonstrated that infection with hepatitis C virus is involved in the pathogenesis of most mixed cryoglobulinemia. This review analyzes the main published data on hepatitis C virus-mixed cryoglobulinemia, the role of liver alterations, the predictive factors associated with MC production in HCV patients and its symptomatic nature or not, and the different types of vasculitis associated with HCV chronic infection.

We report 4 cases of peripheral neuropathy induced by type II IgM kappa mixed cryoglobulinemia associated with hepatitis C virus infection. Worsening of peripheral neuropathy was observed 2 to 13 weeks after the initiation of interferon. The evolution of the hepatic and neurological diseases did not coincide, as all patients decreased or normalized transaminases with interferon. After stopping interferon, peripheral neuropathy worsened (1 case), stabilized (1 case), improved (2 cases). Low doses of interferon alpha may cause worsening of peripheral neuropathy in patients with hepatitis C virus infection associated with mixed cryoglobulinemia.

The aim of this study was to investigate the peripheral blood lymphocyte (PBL) phenotypes and T cell repertoire in patients with HCV infection, with or without mixed cryoglobulinaemia (MC). The patients were: Group 1, 23 patients with HCV infection and MC; Group 2, 14 patients with HCV infection but without MC; Group 3, 10 patients with symptomatic essential MC. Twenty healthy blood donors were used as controls. Blood lymphocyte counts were determined, and flow cytometry was used to measure proportions of B cells (CD19+), natural killer (NK) cells (CD16+CD56+), T cells (CD3+), CD4+ T cell subsets (memory CD4+CD45RO+; naive CD4+CD45RO-; Th0/Th2CD4+CD7-; activated CD4+CD25+), and CD8+ T cell subsets (immunoregulatory CD8+CD57+; cytotoxic CD8+S6F1+, activated CD8+CD25+). Bias in the usage of T cell receptor (TCR) Vbeta chains was studied in a subgroup of 10 representative patients of Group 1 using a polymerase chain reaction (PCR) analysis of the Vbeta segments with a series of 20 oligonucleotides specific for the Vbeta families. The three groups were comparable for blood lymphocyte counts, and we observed no abnormal repartition of the following PBL subsets: T cells (CD3+), CD4+ and CD8+ subpopulations, B cells (CD19+), and the NK cells (CD16+56+). In none of the groups could we observe lymphocyte ex vivo activation as assessed by the normal expression of the activation cell markers: CD25 on CD4+ or CD8+ T cells, or CD5 on B cells. The repartition of naive and memory (CD45RO-/RO+) CD4+ T cells was normal and we did not observe any amplification of the CD4+CD7- T cell subset differentiated in vivo in Th0/Th2 cells. There was no significant amplification of cytotoxic (SF6+) and immunoregulatory (CD57+) CD8+ T cells in HCV patients with or without MC. Finally, the usage of Vbeta families in the TCR repertoire was normal in the patients tested. In patients with chronic HCV infection, with or without MC, we did not find any significant expansion or abnormal activation of T, B and NK cell subsets, dysbalance of the naive/memory subsets, or expansion of the Th0/Th2 subpopulation. These findings differ from the profound immune alterations that are observed in other chronic infections such as HIV or Epstein-Barr virus. Although this study was restricted to the peripheral blood, it suggests that in chronic HCV infection, MC is not the consequence of a chronic activation or dysregulation of the peripheral blood immune cells.

Background: Infection with human parvovirus B19 (B19) has been reported in a few patients with various vasculitis syndromes. Mixed cryoglobulinaemia (MC), a model of small vessel size vasculitis, may result from numerous infectious diseases, particularly hepatitis C virus (HCV) infection., Aim: To assess the prevalence of seric B19 infection markers in a large series of patients with MC, with or without HCV infection., Patients and Methods: Sixty-four patients were studied: essential MC (EMC, n = 19), MC associated with non-infectious diseases (non-essential MC, n = 9), and patients with HCV infection with (HCV-MC, n = 18) or without MC (HCV-no-MC, n = 18). Patients were considered to have MC if two successive determinations of their serum cryoglobulin concentration were above 0.05 g/l. Serum samples were analysed for specific IgG and IgM antibodies to B19 by enzyme immunoassay. B19 DNA detection was performed by polymerase chain reaction using a set of primers located in the VP1 gene, separately in serum and in cryoprecipitates to investigate a possible capture of B19 DNA in cryoprecipitate. The study also looked for a possible enrichment for of IgG antibodies to B19 in MC., Results: The presence of specific IgG antibodies to B19 was found in 68% EMC, 56% non-essential MC, 78% HCV-MC, and 78% HCV-no-MC. No patient of either group had specific IgM antibodies to B19, or B19 DNA in serum or in cryoprecipitate. Overall, IgG antibodies to B19 were found in 46 of 64 (72%) serum samples, a prevalence quite similar to the prevalence in general adult population (> 60%). A specific enrichment of IgG antibodies to B19 in the MC was not found., Conclusion: These results suggest that B19 infection is neither an aetiological factor of EMC, nor a cofactor that may lead to MC production in patients with chronic HCV infection.

Few well-documented cases of central nervous system involvement in patients with hepatitis C virus infection have been reported. We describe three patients (two men and one woman) with cerebral involvement (ischemia and/or hemorrhage). Hepatitis C virus infection was confirmed in all patients by polymerase chain reaction detection of hepatitis C virus RNA. These three cases document the occurrence of central nervous system involvement in patients with hepatitis C virus infection and mixed cryoglobulinemia. Cerebral involvement may be the initial manifestation of hepatitis C virus infection.

summary. Chronic hepatitis C virus (HCV) infection is frequently associated with type II mixed cryoglobulinaemia (MC), a benign lymphoproliferative disease (LPD). More recently, HCV has been implicated as a possible aetiologic factor of B-cell non-Hodgkin lymphoma (B-NHL). CD81, a B-cell surface receptor, has been proposed as a receptor for HCV binding and entry in circulating B cells. The stimulation of CD81 complex enables B cells to respond to lower concentrations of antigen and finally induces B-cell proliferation. We studied the phenotypic expression of CD81, CD19 and CD5 on circulating B cells in HCV patients LPD-positive or LPD-negative. Sixty-two patients were anti-HCV antibody positive. Among HCV positive patients, 44 were HCV RNA positive with an histologically proven chronic active hepatitis of whom 10 had a B-NHL, 14 an MC and 24 no extrahepatic manifestation. Eighteen patients were HCV RNA negative with evidence of resolved infection. A control group included 40 healthy subjects. Peripheral blood mononuclear cells (PBMC) were stained for surface expression of CD81, CD19 and CD5 using monoclonal antibodies, and were analyzed by flow cytometry. The percentage of PBMC expressing CD81, CD19 and CD5 receptors were compared between the groups by univariate analysis. Logistic regression model variables were then evaluated to correlate the presence of an LPD with HCV infection characteristics (i.e. age, gender, genotype, duration of infection, HCV RNA positivity, liver histological lesions), or phenotypic expression of CD81, CD19 and CD5 receptors on PBMC. HCV antibody-positive compared with HCV-negative subjects had a higher expression of CD19 receptor (23 ± 13 vs 13 ± 1%, P = 0.003). Among HCV RNA positive-patients, LPD+ compared with LPD– patients had a lower expression of CD81 (58 ± 28 vs 82 ± 18%, P = 0.001) and CD5 receptor (66 ± 16 vs 74 ± 13%, P = 0.04). In multivariate analysis, the expression of CD81 receptor... [ABSTRACT FROM AUTHOR]