Concomitant Epstein-Barr Virus Research Articles

Acute Clinical Syndrome of HLH in Patients with Hematologic Malignancy and EBV Infection

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by dysregulation of the reticuloendothelial system, overactivation of macrophages and lymphocytes, hemophagocytosis, and cytokine storm collectively causing systemic inflammation and organ damage. Malignancy-associated HLH (M-HLH) is associated with poor prognosis and survival of 1-2 months (Daver N, et.al., Cancer. 2017). Viral infections such as Epstein-Barr Virus (EBV) can independently contribute to development of lymphoproliferative neoplasms and non-malignancy associated HLH. While both malignancy and EBV are recognized as independent risk factors for HLH, a syndrome of overlapping M-HLH and EBV-HLH remains underreported. The optimal long-term treatment strategy for M-HLH in EBV positive patients is unknown, with combinations of HLH and malignancy directed therapy reported in the literature without significant improvement in survival (Zhao A, et.al., Front Immunol. 2022). We report a case series of patients with EBV infection and newly diagnosed hematologic malignancies complicated by HLH demonstrating poor prognosis despite initial control of disease. Methods: Between July 2020 and July 2021, 8 patients >18 years of age hospitalized at Montefiore Medical Center were identified meeting diagnostic criteria of HLH with associated primary hematologic malignancy, and concomitant EBV infection. Data on demographics and clinical characteristics, laboratory studies, malignancy diagnosis, treatments received, and disease course were collected. HLH-04, H-Score were recorded for all patients. Data were analyzed using descriptive statistics. Results: The median age was 53.6 years old (range 29-75). Five out of 8 patients met systemic inflammatory response syndrome (SIRS) criteria on presentation. The median H-Score was 217.1 (range 183-247). All but one patient exceeded CD25 and ferritin parameters of optimized HLH inflammatory (OHI) index suggestive of high mortality risk. Classical Hodgkin Lymphoma (cHL) was seen in 4/8 patients; other diagnoses included large B cell lymphoma, angioimmunoblastic T cell lymphoma, intravascular large B cell lymphoma, and anaplastic large cell lymphoma. Dexamethasone was the backbone of treatment and the initial HLH directed therapy in all patients, starting on average 9 days after presentation (range 2-17) and preceding treatment with other HLH directed therapies by median of 7.2 days (range 0-33). Four out of 8 patients received dexamethasone, etoposide, and rituximab; 2 patients received dexamethasone with etoposide and 2 received dexamethasone alone. The administration schedule and cumulative doses of both rituximab and etoposide varied significantly between the patients. Initiation of malignancy directed chemotherapy lagged the initiation of dexamethasone by median of 16.5 days (range 0-53). Delays were due to patients' clinical condition, organ function, and pending diagnosis of malignancy. Median overall survival from the initial presentation was 102.5 days (range 33-219). Two out of 8 patients in our case series survived. One received dexamethasone and etoposide, followed by 6 cycles of malignancy-directed chemotherapy and autologous stem cell transplant. The second patient was treated with dexamethasone, rituximab, etoposide with addition of anakinra, followed by malignancy directed therapy without rituximab or etoposide. At the time of death, 4 out of 6 patients had active HLH and 3 out of 6 patients were treated for an overwhelming polymicrobial infection. Conclusion: HLH is the setting of EBV-positive malignancy results in a syndrome with an aggressive clinical course and high early mortality rate. Here we demonstrate that HLH-directed therapy prior to or incorporated into malignancy-directed therapy extended patients' survival to median 3 months, as compared to 1-2 months reported in the literature. Nevertheless, most patients suffered HLH relapse and succumbed to infectious complications of prolonged hospitalization and immunosuppression. Long term HLH therapy with immunomodulatory agents and EBV-directed therapies is needed to achieve sustained control of systemic inflammation. Patients who survive initial HLH episode need to be closely monitored for recurrence. Preemptive strategies such as autologous stem cell transplant should be considered in eligible patients to further reduce the risk of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S2150 Triangle of Lymphocytic Colitis, Epstein-Barr Virus, and Lymphoma: Is There Any Association?

Introduction: Epstein–Barr virus (EBV), is linked to range of lymphoproliferative lesions and malignant lymphomas of B-, T- and NK-cell origin. EBV-positive diffuse large B cell lymphoma (DLBCL) not otherwise specified is a variant of DLBCL seen in patients without known immunodeficiency or prior lymphoma. In few reports EBV infection was more commonly detected in colonic mucosa of patients with Microscopic Colitis (MC), but it remains unclear if this translates to higher incidence of lymphoma in this subgroup of people. Here, we describe a case of DLBCL in patient with MC associated with EBV infection in context of recent findings. Case Description/Methods: 77-year-old female with history of COPD, diabetes underwent colonoscopy for chronic diarrhea of 4-month duration. She suffered from 3-4 loose stools/day, and had normal celiac panel, fecal elastase, and infectious workup. Colonoscopy was unremarkable except for 4 mm Paris Is polyp in sigmoid colon removed with cold snare. On pathology, the random colon biopsies were positive for lymphocytic colitis along and polyp showed DLBCL (non-germinal center phenotype) along with positive EBV infection (Figure). Discussion: It is widely believed that overall risk of malignancy is not increased in MC. However, theoretically MC should increase risk of lymphoma as it is more likely to be associated with oncogenic EBV than Ulcerative colitis or irritable bowel syndrome (90 % vs 66 % vs 0 % respectively). EBV increases the risk of lymphoma due to protein expression in transformed infected lymphocytes that results in immune evasion and suppression of apoptosis. Earlier studies have shown no evidence of higher risk of lymphoma in MC, however recently Bergman et al. (2021) analyzed data from Sweden´s pathology departments and from the Swedish Cancer Register and included 11758 patients with incident MC and found an increased risk of lymphoma (adjusted HR 1.43 [1.06–1.92]). Studies are needed to explore risk of lymphoma in subgroup of MC patients with EBV infection as inflammation cause by MC and concomitant EBV infection enhance the overall malignant potential. In conclusion, MC may not be as benign entity as it was once thought to be as it is more likely to harbor oncogenic EBV virus. Even diminutive polyps in MC can potentially harbor lymphoma and should be removed and submitted for analysis rather than being discarded.Figure 1.: Colonoscopy image showing small polyp (left) and schematic (right) of triangle between CMV, microscopic colitis and lymphoma error.

Hemophagocytic lymphohistiocytosis in advanced melanoma treated with dabrafenib and trametinib combination: two cases.

Hemophagocytic lymphohistiocytosis (HLH) has been only rarely reported in patients with BRAF-mutated advanced melanoma treated with targeted therapies and never with first-line dabrafenib/trametinib combination thus far. Two patients treated with first-line dabrafenib and trametinib combination therapy for metastatic melanoma presented with sudden occurrence of fever, cytopenia, rhabdomyolysis, hepatic cytolysis, hypertriglyceridemia and very high ferritin levels after few weeks of treatment, associated with concomitant epstein-barr virus (EBV) reactivation in one patient. In both cases, drug-induced HLH was primarily considered owing to a high H-score and the absence of other etiology. Patients rapidly improved after treatment discontinuation associated with oral steroids in one patient and did not relapse after subsequent treatment resumption with a concurrent anti-BRAF/anti-MEK combination. In metastatic melanoma HLH may occur either spontaneously in the absence of any treatment as a paraneoplastic condition, related to an intercurrent infection or drug-induced mainly with various immunotherapy or with dabrafenib and trametinib following immunotherapy. However, such observations are scarce and these are the first cases of HLH occurring during first-line treatment with dabrafenib and trametinib in advanced melanoma to our knowledge. Pathomechanisms remain to be elucidated since triggering factors may encompass the treatment itself but also other significant actors including viral reactivation along with the underlying disease. The liability of treatment should be considered in cases of HLH occurring in patients with advanced melanoma successfully treated with a combined targeted therapy. A rechallenge with a concurrent anti-BRAF/anti-MEK can be proposed in this setting.

Primary toxoplasmosis complicated by possible IRIS 15 years after renal transplantation

Abstract Background Acute toxoplasmosis in the transplant recipient can be a serious infection and usually represents reactivation of latent infection. Primary toxoplasmosis after transplantation is much rarer and is associated with greater morbidity and mortality. We report a case of primary toxoplasmosis 15 years after kidney transplantation with concomitant Epstein–Barr virus (EBV) reactivation as well as an IRIS-like reaction to anti-toxoplasma treatment. Case report A 26-year-old man, who received a living donor kidney transplant 15 years previously, presented with a 1-week history of fevers, headache, photophobia and dry cough. Immunosuppression was maintained with prednisolone 5 mg daily, mycophenolate mofetil (MMF) 500 mg twice daily and tacrolimus 5 mg twice daily. He was treated empirically for meningitis, although initial investigations were unremarkable. Due to worsening of symptoms, he was transferred to the transplant centre where he was also investigated for suspected post-transplant lymphoproliferative disorder owing to rising titres of EBV DNA. Retrospective serology and PCR supported a diagnosis of primary toxoplasmosis and he started treatment with sulfadiazine and pyrimethamine. After 72 h, he presented with recrudescence of fever and worsening lymphadenopathy. Sulfadiazine was switched to clindamycin with good effect and his symptoms resolved. Unfortunately, his kidney transplant later failed and he re-commenced haemodialysis. Conclusions Primary toxoplasmosis after kidney transplantation is rare, with existing literature limited to case-series and case reports. Since 1966, there have been 20 well described cases. Early presentation post-transplant is associated with worse outcomes. Acute toxoplasmosis may have resulted in concomitant EBV reactivation due to impaired immunosurveillance and specific cell-mediated immunity. There is a lack of consensus regarding toxoplasma screening and chemoprophylaxis in transplant recipients. A high index of suspicion is required to ensure that cases are not missed and transplant recipients should receive counselling to prevent infection.

Identification of genomic alterations in nasopharyngeal carcinoma and nasopharyngeal carcinoma-derived Epstein-Barr virus by whole-genome sequencing.

Nasopharyngeal carcinoma (NPC) is a common tumor in southern China with marked ethnic and geographic distributions and concomitant Epstein-Barr virus (EBV) infection. However, the molecular basis of NPC remains largely unknown, and the role of EBV genomic variations in the pathogenesis of NPC is unclear. Whole-genome sequencing of a collection of 12 EBV-positive paired NPC tumor/peripheral blood samples from Hunan Province was performed, and the FBXO11 gene was subjected to further functional analyses. We identified 69 missense mutations in signaling pathways typically altered in cancer, including NF-κB and Wnt/Hedgehog/Notch. Additionally, 122 variations were identified in non-coding regions. Among these, a subset of genes was confirmed as dysregulated in NPC by mining the NPC cDNA microarray database. The randomly selected gene, FBXO11, could promote the malignant progression of NPC in vitro. Full-length EBV genomes from 8 of the 12 patients with NPC were also successfully assembled, and latent EBV infection is a primary cause of NPC. The various subtypes of EBV detected exhibited clear correlations with its geographical distribution. This study has explored novel biological markers and tumorigenic pathways with substantial potential to enhance therapeutic strategies for NPC.

Infection by Epstein-Barr virus in Fes (Morocco). Prevalence and predictors of positivity in nasopharyngeal cancer.

To determine the prevalence and genotypic distribution of Epstein-Barr virus (EBV) in a sample of patients of Hassan II University Hospital (Morocco) due to nasopharyngeal pathologies and requiring a biopsy. We identified factors associated to the EBV infection. 112 patients were recruited (January 2012-October 2014). Biopsies were conducted for the molecular diagnosis of EBV. The data collected included sociodemographic characteristics, smoking and drug abuse, medical background and histologic diagnosis. The EBV diagnosis was performed via the Polymerase Chain Reaction. 50% of patients were infected by EBV (98.2% with EBV type A compared to 1.8% type B). Most infected patients were ≥40years(65.5%), male (59.6%) and in unfavorable socioeconomic circumstances. 83.3% of patients with lymphoma and 69.8% of patients with nasopharyngeal carcinoma presented concomitant EBV infections. 88.9% of patients who took drugs were infected by EBV compared to 47.7% of those who did not. In the multivariate analysis, age (OR 1.03; IC95% 1.02-1.06), smoking (OR 4.28; IC95%1.24-14.78) and having a malignant process (OR 6.96; IC95% 2.26-21.44) were significantly associated with EBV. Infection by EBV is related to several factors, such as advanced age, smoking, and suffering a malignant process. In subjects with malignant pathologies, positivity to EBV seems to be inferior to that found in other countries.

Simultaneous pancreas/kidney transplant recipients are predisposed to tissue-invasive cytomegalovirus disease and concomitant infectious complications.

Infections have increased in simultaneous pancreas/kidney transplant recipients (SPKTRs) with cytomegalovirus (CMV) infection being the most important viral infection with adverse impact on patient and allograft outcomes. We studied all primary SPKTRs and deceased-donor kidney transplant recipients (KTRs) between 2008 and 2015 for the development of CMV infection. A total of 21/62 SPKTRs (33.9%) and 90/335 KTRs (26.9%) were diagnosed with CMV infection. A control group of 41 SPKTRs without CMV infection was used for comparison. SPKTRs showed an increased incidence of CMV infection compared with KTRs. SPKTRs were more likely to develop CMV disease, CMV pneumonia, recurrent CMV infection, higher initial and peak CMV loads, and more need for intravenous antiviral therapy compared with KTRs (P<.05). High-risk CMV serostatus (D+R-) and 2 HLA-B/-DR mismatches increased the risk of CMV infection in SPKTRs (P<.05). No differences were observed for patient and allograft outcomes (P>.05). SPKTRs with CMV infection were more likely to show concomitant Epstein-Barr virus (EBV) viremia compared with SPKTRs without CMV infection (P<.05). SPKTRs with CMV infection showed higher incidences of concomitant BK polyomavirus-associated nephropathy, EBV viremia, and sepsis compared with KTRs with CMV infection (P<.05). Our results suggest a higher incidence and more severe course of CMV infection in SPKTRs compared with KTRs. The increased incidence of concomitant infectious complications among SPKTRs with CMV infection suggests an overall impaired immunity, and calls for more intense screening.

Concomitant Classic Hodgkin Lymphoma of Lymph Node and cMYC-Positive Burkitt Leukemia/Lymphoma of the Bone Marrow Presented Concurrently at the Time of Presentation: A Rare Combination of Discordant Lymphomas

Discordant lymphoma is rare condition in which different types of malignant lymphomas occurring in different anatomic sites. The two diseases may present clinically as concurrent or sequential disease (10). Herein we are reporting a Pakistani female in her 60s, a carrier of hepatitis B virus with multiple comorbidities presented with cervical lymphadenopathy, diagnosed as Hodgkin’s lymphoma, mixed cellularity. During the staging workup, the patient was discovered to have extensive bone marrow (BM) involvement by Burkitt leukaemia/lymphoma (BL). Cytogenetic analysis revealed positivity for t(8;14)(q24;q32) confirmed by Fluorescence In Situ Hybridization (FISH) for IGH/MYC. Epstein-Barr virus (EBV) was demonstrated heavily in our case, with (EBV) DNA of 24,295,560 copies/ml by PCR at time of presentation, in addition, the neoplastic cells in both diagnostic tissues (cervical lymph node and BM) demonstrated positivity for EBV. A diagnosis of concomitant EBV related discordant lymphoma (classical Hodgkin lymphoma (cHL) and Burkitt lymphoma (BL) in leukemic phase was made. Among all reported cases, this case is highly exceptional because it is the first case of discordant/composite lymphoma, with this combination and concomitant presentation. Since we are dealing with a case with an exceptionally rare combination, we found it significant to elaborate more on its clinical features, contributing factors including EBV role, response to treatment, complications, and prognosis.

Invasive Fusobacterium necrophorum infections and Lemièrre's syndrome: the role of thrombophilia and EBV.

The purpose of this investigation was to describe the clinical spectrum of invasive Fusobacterium necrophorum infections and Lemièrre's syndrome, to examine the role of underlying thrombophilia and concomitant mononucleosis in Lemièrre's syndrome, and to describe thromboembolic complications. Patients with invasive F. necrophorum infections were identified either prospectively or retrospectively through the regional database of clinical microbiology from 2000 to 2015. Patient records were reviewed and blood samples from patients with Lemièrre's syndrome were collected for Epstein-Barr virus (EBV) serology and screening for thrombophilia. Of the 65 patients included, 33 had Lemièrre's syndrome. Of the remaining 32 patients, other infections of the respiratory tract and abdominal or urogenital infections were most common. Patients with Lemièrre's syndrome or other tonsillar infections were younger than patients from the other groups. For Lemièrre's syndrome, the 26 patients with severe sepsis on admittance had longer duration of symptoms. Three of five patients who developed distant manifestations had more than 14days of symptoms. Jugular vein thrombosis was verified in 14 patients, two of whom developed serious complications. Three of 26 patients tested had factor V Leiden mutation, corresponding to the background prevalence. One of 22 patients tested had a concomitant EBV infection. This study confirms earlier studies of the clinical spectrum caused by F. necrophorum. For Lemièrre's syndrome, the study adds to the knowledge on thromboembolic outcome, demonstrating that jugular vein thrombosis may cause severe complications. The time to treatment seems to be important for the risk of severe disease. In this study, concomitant EBV infection or underlying thrombophilia was uncommon.

A Young Man Presenting with Pleuritic Chest Pain and Fever after Electrophysiological Study and Implantable Cardioverter-Defibrillator Placement: Diagnostic Difficulties and Value of Bedside Thoracic Sonography.

We describe the case of a 23-year-old man presenting with recurrent pleuritic chest pain and prolonged fever after electrophysiology testing and placement of an implantable cardioverter-defibrillator because of a suspected arrhythmogenic right ventricular dysplasia. The clinical suspicion was initially directed toward pneumonia with pleural effusion and later toward an infection of the cardiac device complicated by septic pulmonary embolism. The definitive diagnosis of pulmonary embolism and infarction was suggested by a point-of-care thoracic sonography, performed at the bedside by a clinician caring for the patient, and then confirmed by contrast enhanced computed tomography, which also showed thrombosis of the left iliofemoral vein, site of percutaneous puncture for cardiac catheterization. Prolonged fever was attributable to a concomitant Epstein-Barr virus primary infection that acted as confounding factor. The present report confirms the value of bedside thoracic sonography in the diagnostic evaluation of patients with nonspecific respiratory symptoms.

Clinical features, genetics, and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in Korea: report of a nationwide survey from Korea Histiocytosis Working Party.

BackgroundWe analyzed a nationwide registry of pediatric patients with hemophagocytic lymphohistiocytosis (HLH) in Korea to assess the clinical and genetic features and treatment outcomes in pediatric HLH.MethodsThe Korea Histiocytosis Working Party retrospectively analyzed data on 251 pediatric patients diagnosed with HLH between 1996 and 2011.ResultsIn the study cohort, 25 cases were categorized with familial HLH, 64 with presumed secondary HLH, and 162 with unspecified HLH. Of 217 evaluable patients, 91 (42%) had concomitant Epstein–Barr virus infection. Of 238 evaluable patients, central nervous system (CNS) involvement, which was more frequent in the familial group, was evident in 81 cases (34%). Genetic tests revealed a predominant UNC13D mutation with a high incidence of two recurrent splicing mutations (c.118‐308C>T and c.754‐1G>C). The 5‐yr overall survival rate was 68% (38% in the familial group and 81% in the presumed secondary group). The 5‐yr overall survival rate among 32 patients who underwent allogeneic hematopoietic stem cell transplantation was 64%. In multivariate analysis, a younger age at diagnosis, severe transaminasemia, and a coagulation abnormality were independent prognostic factors for survival. Responses during initial treatments were also significant indicators of outcome.ConclusionOur study showed the unique predominance of a UNC13D mutation and vulnerability to Epstein–Barr virus infection in Korean children with HLH and emphasizes the prognostic significance of age, liver dysfunction, and treatment responses in this disease. A multicenter prospective trial that builds on the present results is warranted to identify subgroups of patients with a poor prognosis and identify optimal treatments.

Coinfection with Parvovirus B19 and Epstein Barr Virus in An Adolescent with Sickle Cell Disease Manifesting As Septic Shock

Abstract 4854Patients with Sickle Cell Disease (SCD) are at an increased risk of serious and life-threatening infections. Epstein Barr Virus (EBV) and Human Parvovirus B19 (HPV-B19) are common viral infections that are usually asymptomatic or self-limiting in healthy children. However, SCD patients can have significant morbidity and mortality caused by these infections. In patients with SCD, EBV can cause splenic rupture, thrombocytopenia, agranulocytosis, hemolytic anemia and hemophagocytic lymphocytosis while HPV-B19 can cause severe aplastic crisis, stroke, nephrotic syndrome, myocardial infarction and splenic sequestration. Coinfection with EBV and HPV-B19 has not been reported in SCD patients and there are no reports of EBV or HPV B19 causing septic shock.A 15 year old male with SCD presented with a one day history of fever, oliguria, and hypotension caused by simultaneous viremia with EBV and HPV-B19. He had been discharged 2 days previously after an admission for a vaso-occlusive crisis. He did not have pharyngitis, rash hepatosplenomegaly (spleen likely autoinfarcted) or lymphadenopathy. Peripheral smear did not show lymphocytosis, atypical lymphocytes or features of microangiopathic hemolytic anemia. Fluid resuscitation with normal saline and then with red cell transfusion was done and he was transferred to pediatric intensive care unit. He received supportive therapy for septic shock with fluids, antibiotics and red cell transfusions. Blood and urine bacterial cultures were negative and blood quantitative DNA PCR was positive for EBV (3300 copies/ml) and HPV-B19 (2.3×107 copies/ml). His EBV titers were positive for viral capsid antigen (VCA)-IgM and IgG and Epstein Barr nuclear antigen (EBNA)-IgG. He had EBV titers done 2 years previously which were positive for VCA-IgG and EBNA-IgG documenting previous primary EBV infection. The patient gradually improved with supportive therapy and was discharged on Day 8. The patient returned to Pediatric Hematology clinic on Day 19 and had resolution of signs and symptoms. Table 1 shows an overview of his blood counts and transfusion requirements. [Display omitted] Coinfection with EBV and HPV-B19 in healthy adults has rarely been reported. Severe aplastic anemia caused by EBV and HPV-B19 infections was reported in a previously healthy 22-year-old male. He was treated with immunosuppressive therapy followed by allogeneic bone marrow transplant (Kaptan K et al, Am J Hematol 2001). Acute HPV-B19 infection and concomitant EBV reactivation causing moderate hemophagocytic syndrome was reported in a previously healthy 37-year-old-male (Larroche C et al, Eur J Clin Microbiol Infect Dis 2002). HPV-B19 infection with EBV reactivation has not been reported in children.Sepsis from viremia is not common with either EBV or HPV-B19, however together this co-infection can be life-threatening as seen in our patient. HPV-B19 infection has been reported to produce false positive EBV VCA-IgM serology assay. Our patient had a true coinfection because he had viremia documented by EBV DNA PCR.This is the first report of viremia and septic shock associated with an acute HPV-B19 infection and EBV reactivation in a patient with SCD.WBC- White Blood Cell Count, ANC- Absolute Neutrophil Count, ALC- Absolute Lymphocyte Count, Plt- Platelet Count, Hgb- Hemoglobin, HCT- Hematocrit, Retic: Corrected Reticulocyte Count, U- Units, PRBC- Packed red blood cells, ER- Emergency room Disclosures:No relevant conflicts of interest to declare.

Intestinal perforation associated with rituximab therapy for post-transplant lymphoproliferative disorder after liver transplantation

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after organ transplantation with a cumulative incidence of 1.1% at 18 months and 4.7% at 15 years. It has been reported in patients with or without concomitant Epstein-Barr virus infection. Therapy ranges from a reduction of immunosuppression to administration of conventional cytotoxic chemotherapy. Rituximab, a recombinant chimeric anti-CD20 monoclonal antibody has been used for the treatment of PTLD with promising results and a reduction in treatment-associated mortality. However, the use of rituximab has been associated with spontaneous gastrointestinal perforation. We describe a case of recurrent intestinal perforations after a single dose of rituximab.

Distinct Subsets of Primary Effusion Lymphoma Can Be Identified Based on Their Cellular Gene Expression Profile and Viral Association

Primary effusion lymphomas (PELs) are specifically associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection and most frequently occur in human immunodeficiency virus (HIV)-positive individuals as lymphomatous effusions in the serous cavities without a detectable solid tumor mass. Most PELs have concomitant Epstein-Barr virus (EBV) infection, suggesting that EBV is an important pathogenetic cofactor, although other as yet unidentified cofactors, such as cellular genetic alterations, are also likely to play a role. Lymphomatous effusions that lack KSHV also occur; these are frequently EBV associated in the setting of HIV infection. Here we used gene expression profile analysis to determine the viral impact on cellular gene expression and the pathogenesis of these lymphomatous effusions. Our results show that many genes, including cell cycle and signal transduction regulators, are differentially expressed between KSHV-positive PELs and KSHV-negative lymphomatous effusions and also between KSHV-positive, EBV-positive and KSHV-positive, EBV-negative PELs. Our results confirm that KSHV plays an important role in the pathogenesis of PELs, as its presence selects for a very distinct cellular gene expression category and a clearly different lymphoma type. Within the KSHV-positive PELs, the effect of EBV is more subtle but nevertheless clear.

The value of prospective monitoring of Epstein-Barr virus DNA in blood samples of pediatric liver transplant recipients.

Post-transplant lymphoproliferative disease (PTLD) is one of the major causes of morbidity and mortality in transplantation patients. A primary Epstein-Barr virus (EBV) infection is a major risk factor for developing PTLD. The aim of this study was to determine circulating EBV DNA after liver transplantation in pediatric patients in relation to primary EBV infection and development of PTLD. EBV serology was performed before transplantation. Every 4 weeks after transplantation a competitive quantitative polymerase chain reaction (PCR) assay for EBV nuclear antigen-1 was performed in 13 patients. Patients were followed for development of a PTLD. Before transplantation four patients were EBV seropositive and nine patients were EBV seronegative. In one of the four patients who were EBV seropositive before transplantation, EBV DNA became detectable after transplantation, with a peak load of 3600 copies/mL. None of these four patients developed a PTLD. Eight of the nine patients who were EBV seronegative before transplantation developed positive EBV DNA samples. EBV DNA was first detected at a mean of 64 days after transplantation (range 38-89). The mean peak EBV DNA load was 79,700 copies/mL (3600-446,000). Two of these patients developed PTLD, but they could not be identified based on prior or concomitant EBV PCR results. In pediatric liver transplantation EBV DNA load is higher in patients with a primary infection than in patients who were EBV seropositive before transplantation. The EBV PCR cannot be used to identify individual patients who develop PTLD. However, elevated EBV DNA load can be used to detect a group of patients at increased risk for PTLD.

Concurrent infectious mononucleosis and measles: a potentially life-threatening association sharing underlying immunodeficiency

We report lethal interstitial pneumonia in an 18-year-old young man with measles infection following recent infectious mononucleosis. We speculate that the documented T cell immune impairment caused by the concurrent Epstein-Barr and measles viral infections (as expressed by a proportionately low CD4+ lymphocyte count) was responsible for the complicated clinical course and unfavorable outcome.