Single-agent chemotherapy is usually effective in HIV-associated multicentric Castleman's disease (MCD). However, in most patients, chemotherapy cannot be discontinued.
To evaluate the efficacy of ...four weekly rituximab infusions (375 mg/m(2)) after discontinuation of chemotherapy in HIV-associated MCD, 24 patients were enrolled onto a prospective open-label trial.
At study entry, the median time from MCD diagnosis was 21 months. All patients had stable disease on chemotherapy and were dependent on chemotherapy for a median time of 13 months. The median CD4 cell count was 270 x 10(6)/L, and the plasma HIV RNA was less than 50 copies/mL in 18 patients. One patient died with progressive disease at day 15, and 23 patients completed the four cycles of rituximab. Sustained remission (SR) off treatment at day 60 (primary end point) was achieved in 22 patients (92%). From day 60 to day 365, one patient died with acute respiratory failure of undetermined origin, and four patients experienced relapse. Seventeen patients (71%) were alive in SR at day 365 without specific treatment, and the overall survival rate was 92% (95% CI, 71% to 98%). Rituximab was well tolerated, and the majority of adverse events were mild to moderate infections. Mild exacerbation of Kaposi's sarcoma (KS) lesions was observed in eight of 12 patients with previous KS.
Rituximab was both effective and safe in HIV-infected patients with chemotherapy-dependent MCD.
Preemptive rituximab (R) treatment decreases the incidence of Epstein-Barr virus (EBV) posttransplantation lymphoproliferative disease, but the extent of immune deficiency related to R in patients ...who received allogeneic hematopoietic stem-cell transplantation is unclear. The aim of our study was to evaluate the incidence of late infections and immune reconstitution after preemptive R treatment of EBV infection.
Seventy-eight patients receiving preemptive R between January 2005 and January 2010 were studied. Fifty-two of them could be matched with controls (not receiving R) according to administration of antithymoglobulin, stem-cell source and donor type, age and grade of acute graft-versus-host disease.
Among the 78 patients with EBV reactivation treated with R, the 36-month cumulative incidence of bacterial, viral, and fungal infections was 64%, 59%, and 23%, respectively. When compared with controls, bacterial infection incidence was significantly higher in R patients (55% vs. 35%), and a slower reconstitution of B cells was observed. R patients had modest but not significantly higher nonrelapse mortality (35% vs. 15%) than controls.
R has dramatically decreased risks of posttransplantation lymphoproliferative disease but is followed by a prolonged and profound B-cell deficiency associated with an excess risk of bacterial infection and higher mortality. R should be given with caution, and immunoglobulin replacement should be provided to limit these excess risks.
The ZEBRA protein (encoded by the BZLF1 gene), is the major transcription factor of EBV, expressed upon EBV lytic cycle activation. Several studies highlighted the critical role of EBV lytic ...infection as a risk factor for lymphoproliferative disorders like post-transplant lymphoproliferative disease (PTLD). Here, we use an antigen-capture ELISA assay specifically designed to detecting the circulating soluble ZEBRA (sZEBRA) in serum samples (threshold value determined at 40ng/mL). We retrospectively investigated a population of 66 transplanted patients comprising 35 PTLD. All the samples from a control population (30 EBV-seronegative subjects and 25 immunocompetent individuals with EBV serological reactivation), classified as sZEBRA < 40ng/mL were assigned as negative. At PTLD diagnosis, EBV genome (quantified by qPCR with EBV DNA>200 copies/mL) and sZEBRA were detectable in 51% and 60% of cases, respectively. In the patients who developed a pathologically-confirmed PTLD, the mean sZEBRA value in cases, was 399 ng/mL +/- 141 versus 53ng/mL +/- 7 in patients who did not (p < 0,001). This is the first report relating to the detection of the circulating ZEBRA in serum specimens, as well as the first analysis dealing with the lytic cycle of EBV in PTLD patients with this new biomarker.
Background. In patients with human immunodeficiency virus (HIV) infection, genital herpetic lesions may be extensive and tend to persist for longer periods; in addition, atypical hypertrophic, ...ulcerative, or pseudotumor forms have been reported, frequently showing resistance to acyclovir (ACV) treatment. Methods. Between 2003 and 2011, 10 HIV-1–infected patients presenting with chronic pseudotumoral anogenital herpes simplex type 2 (HSV-2) infections were studied. Results. All patients developed chronic, hypertrophic HSV-2 anogenital lesions with multilesional presentation in 7 cases and involvement of 2 anatomical sites in 6 of them. At the time of diagnosis, the median CD3 + CD4 + absolute blood count was 480.5 cells/μL (range, 165–632 cells/μL), whereas the plasma HIV load was undetectable in all cases. Histopathologic analysis of lesion biopsies showed a moderately dense dermal polytypic plasma cell infiltrate. Detection of HSV-2 by culture and/or polymerase chain reaction was positive for all patients, with evidence for ACV-resistant strains in 6 of 8 cases. In addition, viral resistance to ACV was found only in HSV-2 isolated from ulcerative lesions, whereas purely pseudotumoral ones harbored sensitive strains. Durable control was observed with HSV DNA polymerase inhibitors in only 2 cases, and the immunomodulators imiquimod and thalidomide allowed 5 patients to reach sustained complete response. Conclusions. HSV-2–related pseudolymphoma in HIV-infected patients is characterized by a predominant polyclonal lymphoplasmacytic infiltration, and is frequently refractory to antiherpetic drugs. Immunomodulatory therapeutic strategies using thalidomide showed consistent efficacy, and should be considered early during the course of disease.
Organ transplant recipients have a higher risk of Kaposi sarcoma (KS). A quantitative real-time polymerase chain reaction assay was developed to evaluate KS-associated herpesvirus (KSHV) as a ...prognostic tool in transplant recipients with KS. Forty-three patients who developed KS after transplantation were included in a cross-sectional study to correlate virus load with transplantation or KS parameters. Seventeen patients (40%) had KSHV viremia (>100 copies/μg of DNA; median, 6067 copies/μg of DNA). Factors associated with these levels of viremia by univariate analysis were progression of KS (P=.00002), time from KS diagnosis (P=.0007), actual stage of KS (P=.006), initial stage of KS (P=.22), graft loss (P=.013), and time from transplantation (P=.0246). Disease progression remained associated with KSHV viremia in a multivariate analysis (P=.01). Thus, quantification of KSHV load in peripheral blood mononuclear cells could represent a useful tool for monitoring transplant recipients with KS
Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of human ...immunodeficiency virus (HIV) infection, MCD is associated with human herpesvirus 8 (HHV8) infection. In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma human IL-6 and IL-10 levels. Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.
Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin 6 (IL-6) dysregulation. In the context of human ...immunodeficiency virus (HIV) infection, MCD is associated with Kaposi sarcoma–associated herpesvirus, also called human herpesvirus type 8 (KSHV/HHV8). Within a prospective cohort study on 60 HIV-infected patients with MCD, and a median follow-up period of 20 months, 14 patients developed KSHV/HHV8-associated non-Hodgkin lymphoma (NHL): 3 “classic” KSHV/HHV8+ Epstein-Barr virus–positive (EBV+) primary effusion lymphoma (PEL), 5 KSHV/HHV8+ EBV− visceral large cell NHL with a PEL-like phenotype, and 6 plasmablastic lymphoma/leukemia (3/3 KSHV/HHV8+ EBV−). The NHL incidence observed in this cohort study (101/1000 patient-years) is about 15-fold what is expected in the general HIV+ population. MCD-associated KSHV/HHV8+ NHL fell into 2 groups, suggesting different pathogenesis. The plasmablastic NHL likely represents the expansion of plasmablastic microlymphoma from the MCD lesion and progression toward aggressive NHL. In contrast, the PEL and PEL-like NHL may implicate a different original infected cell whose growth is promoted by the cytokine-rich environment of the MCD lesions.
We repo rt a case of primary Epstein-Barr virus infection with lung involvement occurring 1 month after bone marrow transplantation. The transplant recipient had serological test results that were ...negative for Epstein-Barr virus before transplantation. The virus must have been transmitted by the donor's bone marrow, which was positive for Epstein-Barr virus. The patient recovered after rituximab and corticosteroid therapy.
HIV-associated multicentric Castleman disease (MCD) is associated with a high risk of developing nonHodgkin lymphoma (NHL). Rituximab is effective in HIV-MCD, but its impact on NHL incidence remains ...unknown. From a single-center prospective cohort, 113 patients were identified with a diagnosis of HIV-MCD for the present study. To compare the incidence of NHL between patients who had received a rituximab-based treatment (R+ group) and those who had not (R− group), data were analyzed before and after matching on propensity scores and after multiple imputation. The mean follow-up was 4.2 years. In the R− group (n = 65), 17 patients developed NHL (incidence, 69.6 of 1000 person years). In the R+ group (n = 48), only 1 patient developed NHL (incidence, 4.2 of 1000 person years). Based on the propensity score-matching method, a significant decrease in the incidence of NHL was observed in patients who had been treated with rituximab (hazard ratio, 0.09; 95% confidence interval, 0.01-0.70). Ten Kaposi sarcoma (KS) exacerbations and 1 newly diagnosed KS were observed in 9 patients after rituximab therapy. Rituximab was associated with an 11-fold lower risk of developing lymphoma. KS exacerbation was the most challenging adverse event after rituximab therapy.
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