8 research outputs found
Epstein-Barr Virus Lymphoproliferative Disease Following Allogeneic Hematopoietic Stem Cell Transplantation: Prediction and Early Intervention
Epstein-Barr virus (EBV) has been associated with a variety of both infectious and malignant human diseases. These viruses are characterized by (B-cell) lymphotropism, their ability to establish latent infection in host cells and to induce proliferation of these latently infected cells. Approximately 90% of humans will become infected with EBV, generally without clinical evidence of disease. Primary infection usually occurs asymptomatically in childhood and results in a lifetime carrier state with periodic release of infectious virus into saliva which may cause infection of naive individuals. E.g. during adolescence, the latter type of infection may be referred to as kissing disease or Pfeiffer’s disease. EBV causes various benign syndromes, such as infectious mononucleosis, chronic active EBV infection, X-linked lymphoproliferative disease and oral hairy leukoplakia. EBV has also been associated with malignant diseases including nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, and post-transplant lymphoproliferative disease (PTLD). PTLD refer to a range of hyperplastic to neoplastic lymphoid proliferations which occur after solid organ- or bone marrow transplantation, they mostly are of B-cell origin, and commonly (90%) contain EBV.
The lack of early and accurate markers of EBV reactivation and disease has long hampered a timely diagnosis of post-transplant EBV lymphoproliferative disease. The introduction of polymerase chain reaction (PCR)-based assays, however, has allowed for sensitive and quantitative monitoring of viral DNA in peripheral blood samples. This thesis has addressed the question whether molecular monitoring of EBV-DNA would accurately predict for EBV-LPD and whether preventive and therapeutic strategies could be developed based on viral load monitoring
Development of a real-time quantitative assay for detection of Epstein-Barr virus
With the use of real-time PCR, we developed and evaluated a rapid,
sensitive, specific, and reproducible method for the detection of
Epstein-Barr virus (EBV) DNA in plasma samples. This method allowed us to
screen plasma and serum samples over a range between 100 and 10(7) copies
of DNA per ml using two sample preparation methods based on absorption. A
precision study yielded an average coefficient of variation for both
methods of less than 12%, with a coefficient of regression for the
standard curve of a minimum of 0. 98. We detected EBV DNA in 19.2% of
plasma samples from immunosuppressed solid-organ transplant patients
without symptoms of EBV infections with a mean load of 440 copies per ml.
EBV DNA could be detected in all transplant patients diagnosed with
posttransplant lymphoproliferative disorder, with a mean load of 544,570
copies per ml. No EBV DNA could be detected in healthy individuals in
nonimmunosuppressed control groups and a mean of 6,400 copies per ml could
be detected in patients with infectious mononucleosis. Further studies
revealed that the inhibitory effect of heparinized plasma could be
efficiently removed by use of an extraction method with Celite as the
absorbent
Tetramer-based quantification of cytomegalovirus (CMV)-specific CD8+ T lymphocytes in T-cell-depleted stem cell grafts and after transplantation may identify patients at risk for progressive CMV infection
Recovery of cytomegalovirus (CMV)-specific T-cell-mediated immunity after
allogeneic hematopoietic stem cell transplantation (SCT) is critical for
protection against CMV disease. The study used fluorochrome-conjugated
tetrameric complexes of HLA-A2 molecules loaded with the immunodominant
NLVPMVATV (NLV) peptide derived from the CMV protein pp65 to quantify
A2-NLV-specific CD8+ T cells in partially T-cell-depleted grafts
administered to 27 HLA-A*0201+ patients and to monitor recovery of these T
cells during the first 12 months after SCT. None of the 9 CMV-seronegative
patients became infected with CMV, whereas 14 of 18 CMV-seropositive
patients developed CMV antigenemia after SCT. CMV-seropositive recipients
of grafts from CMV-seronegative donors required more preemptive treatment
with ganciclovir (GCV) than those of grafts from CMV-seropositive donors
(3 [1-6] versus 1 [0-3] courses, respectively; P =.009). The number of
A2-NLV-specific CD8+ T cells in the grafts correlated inversely with the
number of preemptive GCV courses administered (r = -0.61; P =.01). None of
the 9 CMV-seronegative patients mounted a CMV-specific immune response as
measured by monitoring A2-NLV-specific CD8+ T cells after SCT. Thirteen of
14 CMV-seropositive patients without CMV disease recovered these T cells.
In spite of preemptive GCV treatment, CMV disease developed in 4 patients,
who all failed to recover A2-NLV-specific CD8+ T cells after SCT (P
=.002). Thus, enumeration of HLA-restricted, CMV-specific CD8+ T cells in
the grafts and monitoring of these T cells after SCT may constitute a
rapid and sensitive tool to identify SCT recipients at risk for developing
CMV disease
Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation
Recipients of a partially T-cell-depleted (TCD) allogeneic stem cell transplantation (allo-SCT) developing reactivation of Epstein-Barr virus (EBV) with quantified viral DNA levels exceeding 1000 genome equivalents/milliliter (geq/mL) are at high risk for EBV-lymphoproliferative disease (EBV-LPD). We studied whether preemptive therapy with rituximab prevents EBV-LPD, LPD-mo
A patient with autoimmune pancreatitis type 1 with previously known lymphadenopathy, both in the context of igG4-related disease
Objective: Unusual clinical course Background: Autoimmune pancreatitis (AIP) is an important clinical pathologic concept of IgG-4-related disease. AIP is a rare cause of chronic pancreati
Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation
We evaluated the efficacy, toxicity, and outcome of preemptive ganciclovir
(GCV) therapy in 80 cytomegalovirus (CMV)-seropositive patients
allografted between 1991 and 1996 and compared their outcome to 35
seronegative patients allografted during the same period. Both cohorts
were comparable with respect to diagnosis and distribution of high- versus
standard-risk patients. All patients received a stem cell graft from an
HLA-identical sibling donor, and grafts were partially depleted of T cells
in 109 patients. Patients were monitored for CMV antigenemia by leukocyte
expression of the CMV-pp65 antigen. Fifty-two periods of CMV reactivation
occurring in 30 patients were treated preemptively with GCV. A favorable
response was observed in 48 of 50 periods, and only 2 patients developed
CMV disease: 1 with esophagitis and 1 with pneumonia. Ten of 30 treated
patients developed GCV-related neutropenia (less than 0.5 x 10(9)/L),
which was associated with a high bilirubin at the start of GCV therapy.
Overall survival at 5 years was 64% in the CMV-seronegative cohort and 40%
in the CMV-seropositive cohort (P =.01). Increased treatment-related
mortality accounted for inferior survival. CMV seropositivity proved an
independent risk factor for developing acute graft-versus-host disease,
and acute graft-versus-host disease predicted for higher treatment-related
mortality and worse overall survival in a time-dependent analysis. We
conclude that, although CMV disease can effectively be prevented by
preemptive GCV therapy, CMV seropositivity remains a strong adverse risk
factor for survival following partial T-cell-depleted allogeneic stem cell
transplantation
Large and medium-sized pulmonary artery obstruction does not play a role of primary importance in the etiology of sickle-cell disease-associated pulmonary hypertension
Background: Pulmonary hypertension (PHT) occurs in approximately 30% of adult patients with sickle-cell disease (SCD) and is a risk factor for early death. The potential role of pulmonary artery obstruction, whether due to emboli or in situ thrombosis, in the etiology of SCD-related PHT is unknown. Methods: Consecutive SCD patients were screened for PHT (defined as a tricuspid regurgitant jet flow velocity ≥ 2.5 m/s) employing echocardiography and were evaluated for pulmonary artery obstruction with ventilation-perfusion (VQ) scintigraphy. Results: Fifty-three HbSS, 6 HbSβ0-thalassemia, 20 HbSC, and 6 HbSβ+-thalassemia patients were included. The overall prevalence of PHT was 41% in HbSS/HbSβ0-thalassemia patients and 13% in HbSC/HbSβ+-thalassemia patients. High-probability VQ defects (Prospective Investigation of Pulmonary Embolism Diagnosis criteria) were detected in two patients, one of whom had PHT. In HbSS/HbSβ0-thalassemia patients with PHT, 19 patients (86%), 2 patients (9%), and 1 patient (5%) had low-, intermediate-, or high-probability scan results as compared to 30 patients (97%), 1 patient (3%), and 0 patients (0%) in HbSS/HbSβ0-thalassemia patients without PHT (p = 0.31). In HbSC/HbSβ+-thalassemia patients with PHT, 3 patients (100%), 0 patients (0%), and 0 patients (0%) had low-, intermediate-, and a high-probability scan as compared to 19 patients (90%), 1 patient (5%), and 1 patient (5%) in HbSC/HbSβ+-thalassemia patients without PHT (p = 0.86). There were no statistical differences in irregular distribution of the radiopharmaceutical or nonspecific signs associated with PHT between patients with and without PHT. Conclusions: Although small pulmonary artery obstruction cannot be excluded, large to medium-sized pulmonary artery obstruction is an unlikely primary causative factor in SCD-related PHT
Impaired recovery of Epstein-Barr virus (EBV)--specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease
Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes are considered
pivotal to prevent lymphoproliferative disease (LPD) in allogeneic stem
cell transplantation (SCT) recipients. We evaluated the recovery of
EBV-specific CD8+ T cells after partially T-cell-depleted SCT and studied
the interaction between EBV-specific CD8+ T cells, EBV reactivation, and
EBV-LPD. EBV-specific CD8+ T cells were enumerated using 12 class I HLA
tetramers presenting peptides derived from 7 EBV proteins. Blood samples
were taken at regular intervals after SCT in 61 patients, and EBV DNA
levels were assessed by real-time polymerase chain reaction. Forty-five
patients showed EBV reactivation, including 25 with high-leve