acyclovir and Lymphoproliferative-Disorders

Twenty-six cases of B cell lymphoproliferative disorder (BLPD) were identified among 2395 patients following hematopoietic stem cell transplants (HSCT) for which an overall incidence of BLPD was 1.2%. The true incidence was probably higher, since 9/26 of the diagnoses were made at autopsy. No BLPD was observed following autologous HSCT, so risk factor analyses were confined to the 1542 allogeneic HSCT. Factors assessed were HLA-mismatching (> or = 1 antigen), T cell depletion (TCD), presence of acute GvHD (grades II-IV), donor type (related vs unrelated), age of recipient and donor, and underlying disease. Factors found to be statistically significant included patients transplanted for immune deficiency and CML, donor age > or = 18 years, TCD, and HLA-mismatching, with recipients of combined TCD and HLA-mismatched grafts having the highest incidence. Factors found to be statistically significant in a multiple regression analysis were TCD, donor age and immune deficiency, although 7/8 of the patients with immunodeficiencies and BLPD received a TCD graft from a haploidentical parent. The overall mortality was 92% (24/26). One patient had a spontaneous remission, but subsequently died >1 year later of chronic GVHD. Thirteen patients received therapy for BLPD. Three patients received lymphocyte infusions without response. The only patients with responses and longterm survival received alpha interferon (alphaIFN). Of seven patients treated with alphaIFN there were four responses (one partial and three complete). These data demonstrate that alphaIFN can be an effective agent against BLPD following HSCT, if a timely diagnosis is made.

Topics: Acyclovir; Adjuvants, Immunologic; Adolescent; Adult; Antiviral Agents; B-Lymphocytes; Blood Donors; Child; Epstein-Barr Virus Infections; Female; Genetic Diseases, Inborn; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Histocompatibility; Humans; Immunocompromised Host; Immunoglobulins, Intravenous; Immunophenotyping; Immunosuppression Therapy; Incidence; Infant; Interferon-alpha; Leukemia; Life Tables; Lymphoproliferative Disorders; Male; Middle Aged; Nuclear Family; Parents; Remission, Spontaneous; Retrospective Studies; Risk Factors; Severe Combined Immunodeficiency; T-Lymphocytes, Cytotoxic; Transplantation, Homologous; Treatment Outcome

Thanks to a simplification of surgical techniques, single or double lung transplants have expanded significantly in latter years. Infection remains an important cause for morbidity and mortality, more so in early rather than late stages. Bacterial infections cause approximately fifty per cent of all infections. They can be prevented in part by prophylaxis. Infections to CMV have become less frequent thanks to adequate prophylaxis with ganciclovir. Herpetic infections are prevented by acyclovir or ganciclovir. A better control of immunosuppression seems to be associated with fewer lymphoproliferative disorders secondary to the Epstein-Barr virus. Respiratory viruses remain a serious threat for these patients, although infections due to respiratory syncitial virus may be attenuated by ribavirine. Fungal infections are dangerous but prophylactic prescription of azole derivatives have reduced the incidence and severity. Prophylaxis of infections to Pneumocystis carinii is essential, the use of sulfamethoxazole trimethoprim is efficacious against this as well as nocardiosis. Infections to Mycobacterium tuberculosis are often atypical and should be looked for and anticipated whenever possible.

Topics: Acyclovir; Antibiotic Prophylaxis; Antifungal Agents; Antiviral Agents; Bacterial Infections; Chemoprevention; Cytomegalovirus Infections; Ganciclovir; Graft Survival; Heart-Lung Transplantation; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Lung Transplantation; Lymphoproliferative Disorders; Mycobacterium Infections, Nontuberculous; Nocardia Infections; Pneumonia, Pneumocystis; Respiratory Syncytial Virus Infections; Ribavirin; Survival Rate; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Pulmonary; Tumor Virus Infections; Virus Diseases

The introduction of new protocols of immune suppression and especially the use of cyclosporine have led to a marked reduction of infective pathology in children receiving transplants. Nevertheless, infections still represent a major factor of morbidity and mortality in these patients. The above study lists the main viral infections, according to apparatus involved, that may arise, also with reference to the time elapsed since transplantation. The most up-to-date diagnostic possibilities for each infection are reviewed together with some indications on therapy which may subsequently be examined in greater detail.

Topics: Acyclovir; Age Factors; Child; Child, Preschool; Gastrointestinal Diseases; Heart Transplantation; Humans; Immunoglobulins; Immunosuppressive Agents; Infant; Infant, Newborn; Kidney Transplantation; Lymphoproliferative Disorders; Pneumonia, Viral; Skin Diseases, Infectious; Urinary Tract Infections; Virus Diseases

Both oral and intravenous acyclovir administration for seven days in the early stages of infectious mononucleosis caused an inhibition of oropharyngeal Epstein-Barr virus (EBV) replication. Minimal effect on clinical symptoms was observed. Development of normal cellular and humoral EBV-specific immunity was seen in all patients. The combination of intravenous acyclovir and prednisolone treatment for 10 days in 11 patients with fulminant mononucleosis caused transient cessation of virus shedding in all patients. A dramatic clinical effect on pharyngeal symptoms and on fever was seen in nine of 11 patients within 72 hours. Treatment with chemotherapy or irradiation is recommended in EBV-associated B cell lymphomas seen in immunosuppressed, transplanted, and human immunodeficiency virus-I seropositive patients. No effect of acyclovir has been reported, but such therapy may be considered in the early stage when EBV induces a polyclonal B cell activation. Acyclovir treatment is effective in the EBV-genome positive hairy leukoplakia in human immunodeficiency virus-seropositive patients. No effect of antiviral therapy has been reported in the X-linked lymphoproliferative syndrome. Prophylactic use of immunoglobulin or acyclovir has been suggested in susceptible children.

Topics: Acquired Immunodeficiency Syndrome; Acyclovir; Burkitt Lymphoma; Clinical Trials as Topic; Female; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immune Tolerance; Infectious Mononucleosis; Lymphoproliferative Disorders; Male; Prednisolone

In a randomized, placebo-controlled, double-blind trial of intravenous acyclovir in the treatment of varicella zoster virus (VZV) infections, 8 of 20 immunocompromised children with varicella received acyclovir (500 mg/m2/dose three times daily for 7 days). There was no significant difference in skin healing between the acyclovir and placebo groups although there was a significant reduction in the incidence of development of pulmonary involvement during acyclovir treatment. Nineteen out of 34 patients received vidarabine (10 mg/kg/day for 5 days). Vidarabine significantly shortened the duration of new vesicle formation. Both drugs significantly reduced the incidence of visceral varicella, the most serious complication of VZV infection. An open trial also concluded that early treatment of varicella in these patients is essential. Of the 94 patients with zoster infection, 52 received acyclovir (500 mg/m2/dose infused over one hour three times daily for 7 days). Acyclovir recipients healed more rapidly, had fewer days of pain and shorter duration of viral shedding compared with placebo patients. The most important finding was that acyclovir significantly protected against progression of zoster as defined by development or progression of cutaneous dissemination and development of visceral zoster. Vidarabine seemed to be equally effective in this respect. The likelihood of cutaneous dissemination is related to the nature of the underlying condition. The in vitro sensitivity of VZV isolates from patients with second episode VZV infection during the trial did not change appreciably which suggests that VZV does not become resistant to acyclovir during therapy.

Topics: Acyclovir; Adolescent; Adult; Aged; Bone Marrow Transplantation; Chickenpox; Child; Clinical Trials as Topic; Double-Blind Method; Drug Resistance, Microbial; Female; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunosuppression Therapy; Injections, Intravenous; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Neoplasms; Random Allocation; Vidarabine

Several interventions can cure posttransplant lymphoproliferative disease (PTLD); a sequential approach is usual, starting with reduction in immunosuppressives (RI). The efficacy of RI remains poorly defined, particularly in adults. We assessed an algorithm starting with a defined course of RI in all patients, escalating to interferon (IFN) alpha2b, and finally to chemotherapy, in a prospective multicenter phase II study of adult solid organ transplant recipients. The design predated rituximab.. Reduction in immunosuppressives: cyclosporine or tacrolimus reduction by 50% for 2 weeks; a further 50% reduction for 1 week if not in complete remission (CR). Intravenous acyclovir was given for the duration of all RI. Patients with less than CR, or any rejection, resumed immunosuppressives and proceeded to IFN 3 MIU/m(2)/day for up to 3 months; if less than CR, ProMACE-CytaBOM chemotherapy.. Twenty patients were registered over 60 months; 16 patients with biopsy-proven PTLD were eligible (13 heart, 3 kidney recipients). Median age was 47 (24-75) years. Reduction in immunosuppressives resulted in only 1 of 16 partial responses (12.5%), no CR. Progressive disease occurred in 8 of 16 (50%) and 6 of 16 (38%) experienced rejection. Only 1 of 13 (7%) patients achieved durable CR with IFN. Seven eligible patients received ProMACE-CytaBOM chemotherapy, five of seven (67%) achieving CR, four of five durable beyond 2 years.. Reduction in immunosuppressives produced no CR, progressive disease and rejection were frequent; response to IFN was rare. A strong case can be made for adding rituximab to RI as initial therapy. Chemotherapy resulted in 57% durable CR, data that are relevant for the up to two thirds of PTLD patients who are refractory to rituximab.

Topics: Acyclovir; Adult; Aged; Antineoplastic Agents; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Postoperative Complications; Recombinant Proteins; Remission Induction; Tacrolimus

In this prospective single-center study, we evaluated the efficacy and safety of valaciclovir (VACV) in the prevention of cytomegalovirus (CMV) infection after allogeneic bone marrow transplantation (BMT). The study population consisted of 12 patients who underwent allogeneic BMT from an unrelated donor. Patients received acyclovir (ACV) intravenously until they became able to take VACV orally. VACV was administered at a daily dose of 3000 mg and continued until day 100. CMV infection was monitored by CMV antigenemia assay and real-time polymerase chain reaction analysis of plasma. Thirty-five patients who did not receive any form of CMV chemoprophylaxis served as control subjects. CMV infection was detected in 4 (33.3%) of the 12 patients and in 24 (68.6%) of the 35 control subjects (P < .05). The onset of CMV infection was significantly delayed in the VACV group (median, day 43) compared with the control group (median, day 28.5; P < .01). Gastrointestinal symptoms as an adverse event due to VACV administration were observed in 2 patients. The plasma levels of ACV after VACV administration were measured in 8 patients and were similar to those in the healthy subjects. In conclusion, VACV shows normal absorption, even in the early posttransplantation period, and may prevent or delay CMV infection effectively and safely in allogeneic BMT recipients.

Topics: Acyclovir; Adolescent; Adult; Antiviral Agents; Bone Marrow Transplantation; Cytomegalovirus Infections; DNA, Viral; Female; Humans; Lymphoproliferative Disorders; Male; Middle Aged; Prospective Studies; Transplantation, Homologous; Valacyclovir; Valine

Given its association with Epstein-Barr virus (EBV), there is considerable interest in assessing the impact of prophylactic anti-viral therapy on post-transplant lymphoproliferative disorder (PTLD). A recently completed multi center case-control study assessed the impact of immunosuppressive therapy on PTLD risk among renal transplant patients and collected information on the use of anti-viral therapy. Biopsy-confirmed PTLD cases (n = 100) were matched to 375 controls by center, date of transplant, and age. Data were collected on immunosuppression and rejection therapies, demographics, pre-transplant viral status, number of rejections, and anti-viral use. With adjustment for known risk factors, prophylactic anti-viral use was associated with up to 83% reduction in the risk of PTLD, depending on the anti-viral agent. These results were stronger for the first year post-transplant. For every 30 days of ganciclovir treatment, risk of PTLD during the first year was lower by 38% (Odds Ratio [OR]= 0.62; 95% confidence interval [CI]= 0.38-1.0); acyclovir effects were less striking (OR = 0.83; 95% CI = 0.59-1.16). Anti-viral therapy appears to play a role in reducing the risk of PTLD in renal transplant patients. Ganciclovir may be more potent than acyclovir.

Topics: Acyclovir; Adolescent; Adult; Antiviral Agents; Case-Control Studies; Ganciclovir; Humans; Kidney Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Risk Factors

A widely held view is that any increase in the potency of an immunosuppressive agent will lead to an increase in infection and malignancy, such as life-threatening Epstein-Barr virus (EBV) induced posttransplant lymphoproliferative disorders (PTLD). We tested this paradigm by studying the effect of adding mofetil to a steroid-free protocol under cover of high-dose aciclovir prophylaxis on the number of acute rejections, EBV infections and PTLDs after kidney transplantation.. EBV serology was performed in 267 consecutive renal transplantations (1990-1997). All were treated with cyclosporine with an initial 10-day antilymphocyte globulin course, supplemented from September 1995 with MMF. In 208 consecutive transplantations after June 1992 aciclovir 3200 mg/day was given for 3 months posttransplantation.. After an observation period of up to 7 years we found that: (1) primary or reactivated EBV infection (PREBV) was correlated to acute rejection (treated with OKT3; P<0.00005) and to the incidence of PTLD (P=0.03; P=0.01, if Hodgkin's disease is included); (2) aciclovir protected against PREBV (P<0.00005) and (3) adding mofetil to the immunosuppressive protocol reduced PREBV further (P=0.0001), (4) in 78 transplantations treated with cyclosporine/antilymphocyte globulin/mofetil we observed only 10 acute rejections (P=0.0001), 10 PREBVs (P<0.00005), and no PTLDs compared with the cyclosporine/antilymphocyte globulin group (P=0.04).. Supplemental immunosuppression with mofetil protects against acute rejection. In combination with aciclovir, there is also a reduction in the number of PREBVs, apparently as a result of both direct viral prophylaxis and better rejection control, and in the incidence of EBV-induced PTLD.

Topics: Acute Disease; Acyclovir; Adolescent; Adult; Antilymphocyte Serum; Antiviral Agents; Child; Female; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Prospective Studies; Retrospective Studies

Both oral and intravenous acyclovir administration for seven days in the early stages of infectious mononucleosis caused an inhibition of oropharyngeal Epstein-Barr virus (EBV) replication. Minimal effect on clinical symptoms was observed. Development of normal cellular and humoral EBV-specific immunity was seen in all patients. The combination of intravenous acyclovir and prednisolone treatment for 10 days in 11 patients with fulminant mononucleosis caused transient cessation of virus shedding in all patients. A dramatic clinical effect on pharyngeal symptoms and on fever was seen in nine of 11 patients within 72 hours. Treatment with chemotherapy or irradiation is recommended in EBV-associated B cell lymphomas seen in immunosuppressed, transplanted, and human immunodeficiency virus-I seropositive patients. No effect of acyclovir has been reported, but such therapy may be considered in the early stage when EBV induces a polyclonal B cell activation. Acyclovir treatment is effective in the EBV-genome positive hairy leukoplakia in human immunodeficiency virus-seropositive patients. No effect of antiviral therapy has been reported in the X-linked lymphoproliferative syndrome. Prophylactic use of immunoglobulin or acyclovir has been suggested in susceptible children.

Topics: Acquired Immunodeficiency Syndrome; Acyclovir; Burkitt Lymphoma; Clinical Trials as Topic; Female; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immune Tolerance; Infectious Mononucleosis; Lymphoproliferative Disorders; Male; Prednisolone

Topical acyclovir favorably influences the healing of localized herpes zoster in immunocompromised patients. This therapy, or placebo, was applied to forty-three patients in a random access, double-blind trial, four times daily for 10 days, beginning within 72 hours after the onset of skin lesions. The mean time to pustulation is decreased from 12.4 to 6.7 days and the mean time to crusting is decreased from 16.0 to 11.4 days (p = 0.038 and 0.086, respectively) by topical treatment. The mean time to 50% healing is decreased from 24.5 to 15.2 days and the mean time to 100% healing is decreased from 34.9 to 25.8 days (p = 0.023 and 0.033, respectively). Favorable effects in treated patients are not associated with a more rapid decline in lesion virus titer, but do accrue without any toxicity.

Topics: Acyclovir; Administration, Topical; Adult; Clinical Trials as Topic; Double-Blind Method; Female; Herpes Zoster; Humans; Immunologic Deficiency Syndromes; Lymphoproliferative Disorders; Male; Middle Aged; Random Allocation; Time Factors

In a randomized, placebo-controlled, double-blind trial of intravenous acyclovir in the treatment of varicella zoster virus (VZV) infections, 8 of 20 immunocompromised children with varicella received acyclovir (500 mg/m2/dose three times daily for 7 days). There was no significant difference in skin healing between the acyclovir and placebo groups although there was a significant reduction in the incidence of development of pulmonary involvement during acyclovir treatment. Nineteen out of 34 patients received vidarabine (10 mg/kg/day for 5 days). Vidarabine significantly shortened the duration of new vesicle formation. Both drugs significantly reduced the incidence of visceral varicella, the most serious complication of VZV infection. An open trial also concluded that early treatment of varicella in these patients is essential. Of the 94 patients with zoster infection, 52 received acyclovir (500 mg/m2/dose infused over one hour three times daily for 7 days). Acyclovir recipients healed more rapidly, had fewer days of pain and shorter duration of viral shedding compared with placebo patients. The most important finding was that acyclovir significantly protected against progression of zoster as defined by development or progression of cutaneous dissemination and development of visceral zoster. Vidarabine seemed to be equally effective in this respect. The likelihood of cutaneous dissemination is related to the nature of the underlying condition. The in vitro sensitivity of VZV isolates from patients with second episode VZV infection during the trial did not change appreciably which suggests that VZV does not become resistant to acyclovir during therapy.

Topics: Acyclovir; Adolescent; Adult; Aged; Bone Marrow Transplantation; Chickenpox; Child; Clinical Trials as Topic; Double-Blind Method; Drug Resistance, Microbial; Female; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunosuppression Therapy; Injections, Intravenous; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Neoplasms; Random Allocation; Vidarabine

X-linked lymphoproliferative disorder typically presents as an Epstein-Barr virus-specific immune defect with a poor prognosis. Herein we present the clinical and pathologic findings for the first known case of X-linked lymphoproliferative disorder with visual symptoms at initial presentation.. Retrospective chart review, clinicopathologic correlation (brain biopsy and postmortem brain and eye tissue), and literature review.. An 18-year-old boy had a unique presentation of X-linked lymphoproliferative disorder with visual symptoms and retinal findings. He subsequently developed central nervous system vasculitis. He never had evidence of Epstein-Barr virus infection during his clinical course, but in situ hybridization was positive in scattered cells in the brain postmortem. Eye pathologic examination at autopsy showed ischemic changes, but no inflammation.. When a young patient presents with cotton wool spots, a thorough workup must be done, and immunologic disorders should be considered in the differential diagnosis. X-linked lymphoproliferative disorder-associated eye findings may not always be associated with Epstein-Barr virus infection and, as demonstrated by this case, can be indicative of an underlying vasculitic process.

Topics: Acyclovir; Adolescent; Antiviral Agents; Diagnosis, Differential; Epstein-Barr Virus Infections; Fatal Outcome; Herpesvirus 4, Human; Humans; In Situ Hybridization; Ischemia; Lymphoproliferative Disorders; Male; Meningococcal Vaccines; Real-Time Polymerase Chain Reaction; Retinal Diseases; Retinal Vessels; Retrospective Studies; Skin Diseases, Viral; Vasculitis, Central Nervous System

The case of a 14-year-old girl who developed Epstein-Barr virus-related lymphoproliferative disorder, cytomegalovirus reactivation, and Varicella zoster virus encephalitis during treatment for medulloblastoma is described. The patient was diagnosed with a cerebral medulloblastoma and treated with systemic chemotherapy, intrathecal chemotherapy, and radiotherapy. Six months later, she developed persistent low-grade fever, abdominal pain, and vomiting. Several mucosal or ulcerated lesions of the stomach and colon were found on fiberscopy. The infiltrating cells were positive for CD20 and EBER1, and the diagnosis of lymphoproliferative disorder was made. CMV antigen was found in the peripheral lymphocytes at that time. At the same time, it was noted that the patient's language was inappropriate for her age, and a facial and abdominal rash, as well as a right facial palsy, had developed. She was then diagnosed as having VZV encephalitis, because VZV was detected in the CSF. She was treated subsequently with acyclovir and oral steroid, and the VZV encephalitis resolved. The lymphoproliferative disorder improved gradually with rituximab, ganciclovir, and total nutritional support. At the time of the development of the lymphoproliferative disorder and VZV encephalitis, the patient had severe lymphopenia and this may have caused these rare phenomena in a non-transplant setting.

Topics: Acyclovir; Adolescent; Antibodies, Monoclonal, Murine-Derived; Antiviral Agents; Brain Neoplasms; Combined Modality Therapy; Cytomegalovirus Infections; Encephalitis, Varicella Zoster; Epstein-Barr Virus Infections; Female; Ganciclovir; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppression Therapy; Lymphopenia; Lymphoproliferative Disorders; Medulloblastoma; Rituximab; Virus Activation

A 75-year-old woman with rheumatoid arthritis (RA) who was receiving methotrexate (MTX) therapy developed Epstein-Barr virus (EBV)-associated CD8(+) T-cell lymphoproliferative disorder (LPD) and meningoencephalitis. She was successfully treated with acyclovir and corticosteroids plus MTX cessation. T-cell LPD is relatively rare in RA patients receiving MTX. To our knowledge, this is the first report of CD8(+) T-cell LPD with EBV genome occurring during MTX therapy for RA. EBV infection should be carefully monitored to assess severe EBV-associated complications.

Topics: Acyclovir; Aged; Antirheumatic Agents; Antiviral Agents; Arthritis, Rheumatoid; CD8-Positive T-Lymphocytes; Epstein-Barr Virus Infections; Female; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunophenotyping; Lymph Nodes; Lymphoproliferative Disorders; Meningoencephalitis; Methotrexate; Methylprednisolone

EBV-associated post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication following solid organ transplantation and hematopoietic stem cell transplantation (HSCT) using bone marrow or peripheral blood as stem cell sources, but rarely reported in umbilical cord blood transplantation (UCBT). We report two cases in unrelated UCBT setting and added the following new information to the literature: (i) EBV-related PTLD can be presented late in recipients of unrelated UCBT; (ii) in contrast to reported literatures that PTLD is a serious complication with unfavorable outcome, especially in monomorphic form, our cases showed that the clinical course may be relatively benign if treatment is initiated promptly.

Topics: Acyclovir; Adrenoleukodystrophy; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antiviral Agents; Child; Child, Preschool; Combined Modality Therapy; Cord Blood Stem Cell Transplantation; Cyclosporine; Epstein-Barr Virus Infections; Graft vs Host Disease; Herpesvirus 4, Human; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Postoperative Complications; Prednisolone; Remission Induction; Rituximab; Tumor Virus Infections; Virus Activation

Varicella zoster virus (VZV) infection is one of the frequent opportunistic infections after allogeneic bone marrow transplantation, with a high incidence of 30-50%. However, no data have been reported on VZV infection after allogeneic peripheral blood stem cell transplantation (PBSCT).. We report a retrospective analysis of VZV infection in 192 allogeneic PBSCT recipients. Twenty-seven patients (14%) received long-term prophylaxis of low-dose acyclovir (200 mg twice daily orally > or =3 months) for recurrent oral (n=21) or genital herpes simplex virus infection (n=5) or for a previous history of recurrent VZV infection (n=1).. Forty-two patients (22%) developed VZV infections: localized (n=37) and disseminated infection (n=5). The incidence of VZV infection at 1 and 3 years was 19.3+/-3.3% and 36.8+/-5.2%, respectively. Complications included post-herpetic neuralgia (n=18, 43%), secondary bacterial infections (n=3), and intracranial hemorrhage (n=1) with 2 deaths. A higher risk factor for VZV infection was pre-transplant diagnosis of a lymphoproliferative disorder (LPD): chronic lymphocytic leukemia, Hodgkin's disease, or non-Hodgkin's lymphoma (P=0.021, 52.5% in LPD vs. 32.6% in non-LPD group). The use of low-dose acyclovir prophylaxis (P=0.043, 14.7% in acyclovir vs. 41.6% in nonacyclovir group) was found to be protective. Although no VZV infection episodes were noted during the period of acyclovir prophylaxis, 3 episodes of VZV infection were noted after acyclovir cessation.. The incidence of VZV infection after PBSCT was high at 36.8%, with patients transplanted for LPDs at higher risk. The long-term use of low-dose acyclovir may be protective for VZV infection, although it does not completely prevent rebound of late VZV infection.

Topics: Acyclovir; Adolescent; Adult; Aged; Antibiotic Prophylaxis; Antiviral Agents; Female; Herpes Simplex; Herpes Zoster; Humans; Lymphoproliferative Disorders; Male; Middle Aged; Multivariate Analysis; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Risk Factors

Post-transplant lymphoproliferative disorder complicates approximately 1% of all renal transplants. The usual site of occurrence is within the abdomen, thorax, allograft, or head and neck. Central nervous system involvement is uncommon but, when present, occurs in isolation, sparing other organ systems. Few articles in the radiology literature have focused on the acute and follow-up central nervous system findings of the disease, especially in children. Because the clinical and imaging characteristics of central nervous system post-transplant lymphoproliferative disorder overlap those of infection and primary central nervous system lymphoma and the fact that untreated posttransplant lymphoproliferative disorder has a poor prognosis, it is important to maintain a high index of suspicion for this disorder so that appropriate treatment can be instituted.

Topics: Acyclovir; Antiviral Agents; Brain; Child; Diagnosis, Differential; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Magnetic Resonance Imaging; Viral Matrix Proteins

We report a 12-year-old girl suffering from end-stage renal disease due to focal-segmental sclerosis and retardation of statomotoric and mental development of unknown origin. Renal transplantation (TX) was performed 7 months after initiation of peritoneal dialysis at the age of 11 years. Immunosuppressive therapy included cyclosporine A, mycophenolate mofetil and methylprednisolone. The patient developed spiking fever up to 40 degrees C without signs of infection 10 months after TX. Kidney function remained stable but ultrasound examination and CT-scan showed hypodense masses within both liver and spleen. Epstein-Barr virus (EBV) polymerase chain reaction (PCR) results with a high number of copies (20 x 10(6) copies/ml blood) against the background of a previous EBV infection (IgG positive, IgM negative) made the diagnosis of EBV-reactivation likely. Splenectomy was performed. Examination of the spleen showed EBV-associated polymorphic posttransplant lymphoproliferative disease (PTLD) with predominant B cell proliferation and monoclonal VH3-rearrangement of the IgG heavy chain locus. Therapy with acyclovir was introduced and immunosuppression was reduced. No rejection episode occurred. Body temperature normalized and the patient recovered over a 3-month period. EBV-PCR in plasma was negative (0.02 x 10(6) copies/ml blood) 12 weeks after reduction of immunosuppression. The liver masses completely resolved after 27 months. After a total follow-up of 36 months the child remains in good health.

Topics: Acyclovir; Antiviral Agents; Child; Epstein-Barr Virus Infections; Female; Humans; Immunosuppression Therapy; Kidney Transplantation; Lymphoproliferative Disorders; Tomography, X-Ray Computed

Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after solid organ transplantation. Primary Epstein-Barr virus (EBV) infection is the major risk factor for PTLD after lung transplantation, with 30% to 50% of EBV-naive patients who seroconvert and are diagnosed with PTLD.. In this study, we analyzed the incidence of PTLD in lung and heart-lung transplant recipients before 1996 (historic group) and then compared the impact of long-term anti-viral prophylaxis on the development of PTLD in EBV-seronegative recipients from January 1996 to December 2000 (post-1996 group). Routine induction therapy was not given after 1995. Patients not surviving 30 days, 25 of 341 (7.3%), were excluded.. Historic group: PTLD developed in 7 of 167 (4.2%) patients, at a mean of 394 +/- 278 (95-885) days. The mortality was 87.5% at a mean follow-up of 186 +/- 207 (17-520) days after diagnosis. Post-1996 group: Eighteen of 149 (12.3%) patients were EBV seronegative at the time of transplantation, and of these 15 (83%) began receiving continuous anti-viral prophylaxis: acyclovir or valacyclovir or ganciclovir from January 1996. None of the EBV-seronegative recipients receiving continuous anti-viral prophylaxis were diagnosed with PTLD; however, 1 of 3 (33%) of the EBV-seronegative recipients who did not receive anti-viral prophylaxis were diagnosed with PTLD. In the EBV-seronegative recipients, no deaths had been caused by PTLD at a mean follow-up of 806 +/- 534 (39-1,084) days. In the post-1996 group, PTLD developed in 1 of 131 (0.76%) EBV-seropositive recipients.. Continuous, specific anti-viral prophylaxis in high-risk EBV-seronegative recipients significantly reduces the incidence of PTLD after lung transplantation in the absence of induction therapy.

Topics: Acyclovir; Adult; Antibodies, Viral; Antiviral Agents; Female; Herpesvirus 4, Human; Humans; Lung Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Premedication; Valacyclovir; Valine

The treatment of posttransplant lymphoproliferative disorder (PTLD) remains empirical. We review our treatment of seven cases of PTLD consisting of five interventions: 1) reduction of immunosuppression; 2) antiviral drugs; 3) interferon-alpha; 4) gamma-globulins; and 5) anti-CD19 monoclonal antibodies. METHODS AND RESULTS; Seven consecutive patients who had undergone a simultaneous pancreas-kidney, liver, heart, or kidney transplantation were treated. One patient acquired a primary EBV infection with an oligoclonal immunoblastic lymphoma early after pancreas-kidney transplantation; all others developed a monoclonal polymorphic or immunoblastic lymphoma 2 to 123 months after transplantation. In all patients extranodal sites were involved, in three the graft was also involved. Five patients received the full quintuple approach and all rapidly obtained a complete remission (CR) with a median follow-up of 31 months (7-74 months). Of the two patients who did not receive interferon-alpha for fear of graft rejection one responded slowly with a CR after 7 months, and the other obtained a rapid CR followed by a relapse at 4 months. All three patients with a liver or heart transplant could keep their graft. All patients are still alive with a median follow-up of 31 months (7-74 months).. This combined approach resulted in a favorable outcome in patients with high risk monoclonal PTLD after solid organ transplantation.

Topics: Acyclovir; Antibodies, Monoclonal; Antiviral Agents; Humans; Immunoglobulins, Intravenous; Interferon-alpha; Lymphoproliferative Disorders; Organ Transplantation; Prognosis; Remission Induction; Treatment Outcome

Polymorphic lymphoproliferative disorder is a recognised cause of upper airway obstruction in children [N. Sculerati, M. Arriga, Ann. Otol. Rhinol. Laryngol 99 (1990) 445-450]. It is associated with long-term immunosuppression therapy and frequently with Epstein-Barr virus (EBV) infection [D.W. Hanto, Annu. Rev. Med. 46 (1995) 381-394; B.D. Fletcher, H.E. Heslop, H.C. Kaste, S. Bodner, Upper airway obstruction and pulmonary abnormalities due to lymphoproliferative disease following bone marrow transplantation in children, Pediatr. Radiol. 28 (1998) 492-496]. The prevalence in reported series ranges from 4 to 13% among post-transplant children [M. Ho, R. Jaffe, G. Miller, Transplantation 45 (1988) 719-727; G.B. Hammer, S. Cao, M.G. Boltz, A. Messner, Anesthesiology 89 (1998) 263-265; B.V. Lattyak, P. Rosenthal, Post-transplant lymphoproliferative disorder presenting in the head and neck, Laryngoscope 108 (1998) 1195-1198]. This condition may present in the transplanted allograft, the gastrointestinal tract, the head and neck, and in particular in the upper airway. Previously reported cases of upper airway obstruction have been in the supraglottis, Waldeyer's ring, the glottis, and one case of an intra tracheal mass [M. Ho, R. Jaffe, G. Miller, Transplantation 45 (1988) 719-727; G.B. Hammer, S. Cao, M.G. Boltz, A. Messner, Anesthesiology 89 (1998) 263-265]. We report a case of post-transplant lymphoproliferative disorder in the sub-glottis causing acute upper airway obstruction with negative (EBV) serology.

Topics: Acyclovir; Airway Obstruction; Child; Humans; Infectious Mononucleosis; Laryngoscopy; Liver Transplantation; Lymphoproliferative Disorders; Male; Prognosis; Respiratory Sounds; Steroids; Tracheostomy; Transplantation Immunology; Treatment Outcome

In the period 1973-1998, among 2139 allograft recipients treated with standard immunosuppression, posttransplant lymphoproliferative disorders (PTLD) developed in 19 patients (0.9%): one plasmacytic hyperplasia, two polymorphic PTLD, one myeloma, and 15 lymphomas. PTLD developed 1 year after transplantation (tx) in 14 patients. Five patients were diagnosed at autopsy, 2 were lost to follow up, 3 died before therapy could be instituted, and 1 patient has just started chemotherapy. Of the 8 evaluable patients, 2 received acyclovir and are alive in complete remission (CR) and 6 received chemotherapy +/- surgery. Of these 6, 4 died of lymphoma and/or infection, 1 died of unrelated causes in CR, and 1 is alive in CR. PTLD is a severe complication of tx, usually running an aggressive course which may preclude prompt diagnosis and treatment. Nevertheless, therapy is feasible and must be tailored on the histologic subtype. Seventy-four percent of patients were diagnosed with late-onset PTLD stressing the need for long-term follow up.

Topics: Acyclovir; Adult; Aged; Antiviral Agents; Bone Marrow Transplantation; Drug Therapy, Combination; Humans; Immunophenotyping; Immunosuppressive Agents; Incidence; Italy; Kidney Transplantation; Lymphoproliferative Disorders; Middle Aged; Organ Transplantation; Postoperative Complications; Retrospective Studies; Time Factors; Transplantation, Homologous

Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of transplantation, which comprises a morphologically and clinically heterogeneous spectrum of B-lymphocyte diseases. Risk factors include primary or reactivated Epstein-Barr virus (EBV) infection, and the type and duration of immunosuppression. Interleukin-10 (IL-10) is a pleiotropic cytokine, produced primarily by T-helper 2 (Th2) lymphocytes in the later stages of T-cell activation, suggested to play a role in EBV-associated PTLD. We recently reported preliminary findings on IL-10 in relation to the development of PTLD in three kidney transplanted patients. The study now includes nine patients that could be followed before and/or after the occurrence of lymphoma.. Nine patients with lymphomas (eight PTLDs and one Hodgkin's disease) were diagnosed among 268 consecutive renal transplantations (1990-1997). All were treated with cyclosporine with an initial 10-day course of antilymphocyte globulin, supplemented from 1995 with mycophenolate mofetil. Serum antibodies against EBV were detected using recombinant antigens. A double sandwich enzyme-linked immunosorbent assay using rabbit antibodies to purified human recombinant IL-10 was employed; the assay is specific for human natural and viral IL-10.. Three patients experienced primary EBV infection, five reactivated EBV infections, and one did not change EBV status. Three patients had a fulminant course and died with EBV-associated PTLD confirmed post mortem. The other six are alive and are apparently cured. Treatment was immediate discontinuation of immunosuppression (in all PTLDs) and long-term high-dose aciclovir in all but one. Two patients have maintained excellent graft function for 3 and 2 years, respectively, without immunosuppression and are now in a state of operational tolerance. In three of four cases with initial lymphoma, EBV infection (primary or reactivation) preceded the increase in IL-10. In all four cases, the IL-10 increase preceded the PTLD diagnosis. In six cases, IL-10 could be followed after treatment showing either immediate zero or a decrease to zero.. IL-10 seems to play a role in EBV-associated PTLD. Moreover, IL-10 may have an important role in transplant tolerance by inducing long-lasting anergy to donor- and host-specific alloantigens, perhaps caused by down-regulation of Th1 cytokines in the graft. If substantiated, this may provide new insight into the pathogenesis of PTLD introducing new strategies for prevention and therapy of PTLD, and for the induction of tolerance in transplanted patients.

Topics: Acyclovir; Adult; Animals; Child; Female; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Interleukin-10; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Rabbits; Tumor Virus Infections

Topics: Acyclovir; Aged; Antiviral Agents; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Kidney Transplantation; Lung; Lymphoproliferative Disorders; Male

B cell lymphoproliferative disorders (LPD) and liver rejection are major lethal complications after hepatic transplantation. Reduction in immunosuppression is the treatment for the former, but is a risk factor for the latter.. Here, we report three consecutive children with monoclonal LPD complicating orthotopic liver transplantation. All of them were treated with brief (<4 months) but intensive chemotherapy.. These three patients have remained in complete remission for LPD for 18 months to more than 3 years. Aggressive antimicrobial prophylaxis was successful in preventing life-threatening infections. The patient who received the highest cumulative doses of chemotherapy may have also developed relative immune tolerance to the allograft.. High-dose-intensity chemotherapy may be effective in the treatment of monoclonal LPD, as well as in the induction of immune tolerance for the prevention of allograft rejection and LPD recurrence.

Topics: Acyclovir; Antiviral Agents; Female; Graft Rejection; Humans; Immune Tolerance; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Male; Remission Induction; Tacrolimus; Time Factors

Between September 1994 and October 1995, we diagnosed and treated four cases of early onset posttransplantation lymphoproliferative disorder (PTLD) occurring within 62 days of pancreas transplantation. The development of PTLD was associated with both a significantly higher total muromonab-CD3 (OKT3) dose and a lack of ganciclovir/acyclovir prophylaxis, but it was not associated with the total dose of antithymocyte globulin or cytomegalovirus serostatus. All four patients were treated aggressively and survived without evidence of recurrent PTLD more than 1.5 years later. We conclude that the use of a high total dose of OKT3 puts pancreas transplant recipients at increased risk for early onset PTLD, while ganciclovir/acyclovir prophylaxis may help to prevent this disorder; however, if early onset PTLD does occur in these patients, aggressive therapy can lead to a favorable outcome.

Topics: Acyclovir; Adult; Antiviral Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Ganciclovir; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Muromonab-CD3; Pancreas Transplantation; Treatment Outcome

We describe a 1-year-old female who underwent living-related liver transplantation for biliary atresia and developed Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder. This disorder was resolved after withdrawal of immunosuppression therapy and administration of a high dose of acyclovir.. To quantify the extent of EBV activation and EBV load in peripheral blood, we measured the levels of EBV-infected peripheral lymphocytes by in situ hybridization (ISH) of EBV-encoded small mRNA 1 (EBER1).. The decline in the number of EBER1-positive lymphocytes (from 362/50,000 mononuclear cells to 0/50,000) after treatment was in accord with the patient's clinical improvement.. This finding showed that quantitative analysis of EBV-infected peripheral lymphocytes by ISH of EBER1 is very useful for monitoring the EBV load and response to treatment of patients with EBV-related disorders. Furthermore, ISH may become an important tool for the early diagnosis and prevention of life-threatening posttransplant lymphoproliferative disorder in posttransplant patients.

Topics: Acyclovir; Antiviral Agents; Female; Herpesviridae Infections; Herpesvirus 4, Human; Humans; In Situ Hybridization; Infant; Liver Transplantation; Lymphocytes; Lymphoproliferative Disorders; RNA, Viral; T-Lymphocytes, Cytotoxic; Transplantation, Homologous; Viral Load; Virus Activation

Posttransplant lymphoproliferative disorder (PTLD) has been observed with increasing frequency consequent to the availability of more effective and potent immunosuppression. Prior work suggested that a peripheral blood monitoring strategy detecting peripheral B lymphoproliferation was effective in the early diagnosis of PTLD among 7 of 179 (3.9%) consecutive transplant recipients. Each of those seven patients received at least one course of antithymocyte globulin, Minnesota antilymphocyte globulin, or OKT3 before developing PTLD.. To determine whether antiviral prophylaxis might reduce the incidence of PTLD, a subsequent group of 198 consecutive recipients received either ganciclovir or acyclovir during antilymphocyte antibody administration. When the donor or recipient were cytomegalovirus-seropositive, ganciclovir was given; acyclovir was used when both were cytomegalovirus-seronegative. Baseline and protocol posttransplant cell surface profiles were obtained using immunofluorescence and flow cytometry to detect T cells, lymphocyte activation markers, and the CD19 B cell antigen.. Demographic factors, including the incidence of recipients more than 50 years of age, non-Caucasians, previous transplantation, and diabetes mellitus, were similar in both groups. Additionally, the number of patients receiving antilymphocyte preparations was similar. However, only one patient (0.5%) from the latter group who received preemptive antiviral therapy developed PTLD. Although elevations in CD19+ B cells preceded clinical PTLD among each of the seven earlier patients, evidence of peripheral B cell proliferation was not demonstrated for the sole patient from the latter group, which suggests a possible effect of antiviral therapy.. Prophylactic antiviral therapy may reduce the sensitivity of peripheral monitoring for B lymphoproliferation, but the dramatic reduction in PTLD incidence strongly supports its use among transplant recipients at risk.

Topics: Acyclovir; Adolescent; Adult; Antigens, CD; Antigens, CD19; Antilymphocyte Serum; Antiviral Agents; Ganciclovir; Herpesvirus 4, Human; Humans; Immunophenotyping; Immunosuppressive Agents; Incidence; Kidney Transplantation; Liver Transplantation; Lymphoproliferative Disorders; Middle Aged; Muromonab-CD3; Pancreas Transplantation; Postoperative Complications; Retrospective Studies

A 5-year-old girl with a kidney transplant developed post-transplant Epstein-Barr virus-induced lymphoproliferative disease. She was treated with acyclovir, alpha-interferon, and gamma globulin. A transplant nephrectomy was performed on day 4 due to acute rejection and she was started on hemodialysis. The acyclovir dose was decreased at this time. However, 6 days following the start of acyclovir she developed progressively worsening neurological symptoms resulting in a coma on day 8. Fourteen days after acyclovir was begun pre- and post-dose serum concentrations were 7.02 microM and 182.5 microM, respectively. Acyclovir was then discontinued and 2 days later the child's neurological status began to improve. We conclude that acyclovir in children with end-stage renal failure may lead to severe and reversible neurotoxicity, despite acyclovir dosage adjustment based on renal impairment.

Topics: Acyclovir; Antiviral Agents; Child, Preschool; Female; Humans; Kidney Transplantation; Lymphoproliferative Disorders; Nervous System Diseases; Postoperative Complications; Renal Dialysis

A frequently fatal complication of organ transplantation, post-transplant lymphoproliferative disorder (PTLD) develops in 2%-6% of cardiac recipients. Treatment remains poorly defined. Reduction in immunosuppression is effective in a proportion of cases, but mortality in the order of 80% is reported for patients requiring chemotherapy. The reason for such poor outcomes is unclear, but may be partly due to the concomitant use of immunosuppressives. An update report is provided on nineteen consecutive cardiac recipients with PTLD, studied retrospectively in terms of clinical features and outcome. Patients were managed according to a uniform treatment approach. Initial therapy was a trial of reduced immunosuppression with concomitant acyclovir followed, if unsuccessful, by aggressive combination chemotherapy. The regimen used was predominantly ProMACE-CytaBOM. Six patients with phenotypically polyclonal PTLD presented <6 months after transplantation (median 6 weeks). Only 1/4 (25%) treated patients responded to reduced immunosuppression; the remainder died of multiorgan failure. Thirteen patients presented with phenotypically monoclonal disease > or =6 months after transplantation. In 8/12 (75%) treated patients initial therapy was reduction in immunosuppression. None achieved CR; 2 experienced fatal rejection. Two patients achieved durable surgical CR. The remaining 8 patients received chemotherapy; 2/8 (25%) died during treatment, 6/8 (75%) achieved CR. None have relapsed, at a median duration of follow-up of 64 months. Neutropenic sepsis, and subclinical doxorubicin cardiotoxicity at a mean cumulative dose of 63 mg/m2 were the principal toxicities. Our data indicate that aggressive chemotherapy is feasible and can produce very durable remissions in phenotypically monoclonal PTLD refractory to reduced immunosuppression. ProMACE-CytaBOM is well suited to cardiac recipients, minimizing doxorubicin exposure and obviating the need for concurrent immunosuppressives.

Topics: Acyclovir; Adult; Antimetabolites; Antineoplastic Combined Chemotherapy Protocols; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Injections, Intravenous; Lymphoproliferative Disorders; Male; Middle Aged; Remission Induction; Retrospective Studies; Transplantation, Homologous; Treatment Outcome

Patients with primary or secondary immunodeficiency are at high risk for B cell lymphoproliferative syndromes (LPS) that are generally Epstein-Barr virus (EBV)-associated. We established a cell line, termed JuWa, from an immunoblastic lymphoma that developed in a child with severe combined immunodeficiency. JuWa cells were representative of the original lymph node as shown by a similar IgH gene rearrangement pattern. The cell line exhibited the typical features of a lymphoblastoid cell line (LCL): (1) growth pattern in large clumps, (2) lack of structural chromosome abnormalities, (3) type III latency with expression of EBV-associated EBNA2 and LMP, as well as B cell activation markers CD23 and CD30, thereby showing characteristics of an EBV producer cell line, i.e. a latent infection with a small subpopulation of cells spontaneously entering the lytic cycle, (4) inducibility of the lytic cycle by IdU and TPA, leading to an increase of early antigen and viral capsid antigen-positive cells from 1 to 15-20%, and (5) elimination of the linear viral genomes by treatment with acyclovir (ACV), without affecting the circular episomal genomes. After withdrawal of ACV, viral replication resumed within 7 days. Thus, JuWa cells support the concept of the LCL-like features of LPS and lymphomas occurring in the setting of immunodeficiency. In our in vitro model, ACV treatment could effectively suppress the viral replication but not cure EBV infection of B cells.

Topics: Acyclovir; Antigens, Viral; Antiviral Agents; Cells, Cultured; DNA, Viral; Female; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunophenotyping; In Situ Hybridization; Infant; Lymph Nodes; Lymphocytes; Lymphoproliferative Disorders; Severe Combined Immunodeficiency; Syndrome

Forty-six days after renal transplantation for inborn tubulointerstitial nephropathy, an 18-year-old man was rehospitalized for renal failure with creatinine at 200 mumol/l. There was no sign of infection and ciclosporin level was within therapeutic range. Transplant biopsy showed minor interstitial infiltration with mononucleated cells. Methylprednisolone by 10 mg/kg/d bolus did not improve renal function and OKT3 5 mg/d was substituted for ciclosporin but had to be stopped on day 8 because of a severe infectious syndrome. The patient developed fever (39 degrees C), erythemato-pultaceous pharyngitis followed by major multiple lymph node and spleen enlargement. The diagnosis of primary Epstein-Barr infection was confirmed serologically. Histology of a submaxillary lymph node reported monomorphic immunoblastic lymphoproliferation. Immunologic phenotyping showed CD19, CD20 and CD22 surface antigens characteristic of B cells and in situ Epstein-Barr hybridization was positive in 100% of the cells. Southern Blot showed an oligoclonal pattern. Ciclosporin and azathioprin were stopped and the patient was treated with corticosteroids (15 mg/d) and aciclovir given orally (3.2 g/d) for 3 months. Outcome at six months was favorable with normalization of the renal function and complete regression of the infectious syndrome. This case demonstrated the importance of molecular biology techniques for virologic and genotypic assessment of lymphomatous proliferation allowing positive aetiologic diagnosis.

Topics: Acyclovir; Adolescent; Blotting, Southern; Herpesviridae Infections; Herpesvirus 4, Human; Humans; In Situ Hybridization; Kidney Transplantation; Lymphoproliferative Disorders; Male; Nephritis, Interstitial; Postoperative Complications; Tumor Virus Infections

Epstein Barr virus (EBV) infection has been associated with the post-transplant lymphoproliferative disorder (PTLD) in up to 8% of transplant recipients. Primary EBV infection and the use of antilymphocyte preparations appear to increase the incidence of PTLD. Experimental evidence suggests that the antiviral prophylaxis used by many transplant programs may influence the development of this post-transplant complication. In order to investigate the influence of antiviral prophylaxis (intravenous ganciclovir followed by high-dose oral acyclovir) on the development of PTLD in kidney-pancreas and liver allograft recipients from the University of Washington Medical Center, records were reviewed for pretransplant EBV status, antilymphocyte preparation use and for histologic documentation of PTLD. Two of 83 kidney-pancreas recipients (1 EBV-seronegative, 1 EBV-seropositive) and 1 of 123 liver recipients (EBV-seropositive) has developed PTLD. Six of 83 kidney-pancreas patients were EBV-seronegative prior to transplantation and 4 of these patients received at least two courses of an antilymphocyte preparation. Thirty-eight (49%) of the 77 EBV-seropositive kidney-pancreas recipients received at least two courses of an antilymphocyte globulin without the development of PTLD. Both the EBV-seronegative kidney-pancreas and the liver recipient who developed PTLD had received multiple courses of antilymphocyte globulins. One EBV-seropositive kidney-pancreas recipient had only received one course of OKT3 1 year prior to the development of PTLD. The incidence of PTLD reported here in patients receiving intravenous ganciclovir followed by high-dose oral acyclovir antiviral prophylaxis is lower than previously recorded when consideration is given for patient's EBV status and the use of antilymphocyte preparations.

Topics: Acyclovir; Antilymphocyte Serum; Ganciclovir; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Liver Transplantation; Lymphoproliferative Disorders; Pancreas Transplantation; Postoperative Complications; Time Factors; Tumor Virus Infections

Topics: Acyclovir; Adult; Ganciclovir; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Opportunistic Infections; Treatment Failure

Topics: Acyclovir; Adult; Child; Female; Humans; Immunosuppression Therapy; Liver Transplantation; Lymphoproliferative Disorders; Male; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Acyclovir; Adult; Antiviral Agents; Female; Ganciclovir; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Pancreas Transplantation; Postoperative Complications

Epstein-Barr virus (EBV) is associated with lymphomas and lymphoproliferative diseases that occur mainly in immunocompromised patients, but the role EBV plays in their pathogenesis is unclear. The evidence linking EBV etiologically to these disorders includes the presence of EBV DNA and nuclear antigens in the lesions and serologic evidence that some patients with these lesions are experiencing primary or reactivated EBV infections. These syndromes may represent proliferation of cells latently infected with EBV, but the possibility of viral replication has not been rigorously studied. DNA extracted from biopsies of 35 lymphoproliferative diseases was probed with regions of the EBV genome capable of distinguishing circular, episomal DNA found in latency from linear, replicating EBV DNA. All samples contained restriction fragments characteristic of fused termini, indicative of circular, latent genomes. Thirteen samples contained additional restriction fragments diagnostic of linear EBV DNA. Therefore, replicating EBV DNA is found in approximately 40% of EBV-associated lymphoproliferative disorders.

Topics: Acyclovir; Adolescent; Adult; Blotting, Southern; Burkitt Lymphoma; Cell Line; Child; Child, Preschool; Deoxyribonuclease BamHI; DNA Probes; DNA Replication; DNA, Viral; Female; Herpesvirus 4, Human; Humans; Immune Tolerance; Lymphoma; Lymphoproliferative Disorders; Male; Middle Aged; Nucleic Acid Hybridization; Restriction Mapping; Tumor Cells, Cultured; Virus Replication

We review 15 cases of secondary B-cell lymphoproliferative disorders that occurred among 2,475 patients who received allogeneic bone marrow transplants (BMTs) at the Fred Hutchinson Cancer Research Center (Seattle) between 1969 and 1987. The histopathologic findings in 14 of the 15 patients spanned a wide spectrum of lymphoproliferative lesions. One patient had features characteristic of angioimmunoblastic lymphadenopathy. Epstein-Barr virus (EBV) genomic sequences were identified by Southern blot analysis in each of the 13 patients evaluated. Ten of the 12 lesions evaluated originated in donor cells. In two patients, who had mixed chimerism after transplantation, the lesions originated in host cells. The combined evidence from immunoglobulin light chain staining and the analysis of immunoglobulin heavy chain gene rearrangement indicated that the lesions in most patients represented polyclonal proliferations that gave rise to clonal subpopulations. The results indicate an overall actuarial incidence of 0.6% for this complication in BMT recipients. Anti-CD3 monoclonal antibody (MoAb) treatment of acute graft-v-host disease (GVHD) and T cell depletion of the donor marrow were statistically significant risk factors, and GVHD appeared to play a contributing role, particularly in the setting of human leukocyte antigen (HLA) disparity. Two patients had no identifiable risk factors. Prophylaxis or treatment with acyclovir had no detectable effect in the patients; all but two died with uncontrolled lymphoproliferation.

Topics: Acyclovir; Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Genes, Immunoglobulin; Graft vs Host Disease; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Lymph Nodes; Lymphoproliferative Disorders; Risk Factors

Prevention of EBV-associated lymphoproliferative diseases in immune deficient individuals is preferred; however, standard therapy for the B cell lymphomas has been successful. Chemotherapy must be given cautiously lest further immune compromise result in opportunistic infections. Recently, Acyclovir has decreased morbidity of patients with acute infectious mononucleosis in immune competent persons. In contrast, immunodeficient patients with X-linked lymphoproliferative (XLP) syndrome do not seem to respond favorably. Hence, a prospective study is underway using prophylactic immunoglobulin containing (EBV)-specific antibodies. The mortality rate is 85% following EBV infection in XLP due to fatal infectious mononucleosis associated with fulminant hepatitis and virus-associated hemophagocytic syndrome, acquired hypogammaglobulinemia or malignant B cell lymphoma. We can detect XLP by noting failure of switching from IgM to IgG antibody production on secondary challenge with bacteriophage phi X174. Also, linkage studies with the XLP locus using restriction fragment length polymorphisms are being done to detect affected males pre-EBV infection. Our rationale for prevention of phenotypes of XLP is based on observations that infants in tropical Africa and males with XLP do not develop EBV-induced diseases while neutralizing maternal antibodies are present. An EBV vaccine will be used, when available, in seronegative males with XLP. Prevention of acquired immune deficiency by screening blood for human immune deficiency virus, encouraging prudent life styles, development of specific immunosuppressive agents, development of new antiviral agents (i.e., DHPG), and identification of high risk seronegative patients offer possibilities for preventing life-threatening EBV-induced diseases.

Topics: Acyclovir; Genetic Counseling; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Immunotherapy; Interferons; Lymphoma; Lymphoproliferative Disorders; Male; Prospective Studies; Viral Vaccines; X Chromosome

Topics: Acyclovir; Humans; Lymphoproliferative Disorders; Mycosis Fungoides; Skin Diseases

In order to reveal the activity of polymorphonuclear neutrophil leukocytes (PMNL) representing the first step of defence against infections, measurements of chemiluminescence (CL) were performed in patients suffering from acquired immune deficiency syndrome (AIDS), lymphadenopathy, or hemophilia. In comparison with healthy controls, AIDS patients revealed significant reduction (about 50 per cent) of phagocytic, i.e. CL activity of neutrophils, which had been induced by Zymosan. Only part of the patients suffering from lymphadenopathy answered with decreased granulocyte activity on the application of Zymosan. If concanavalin A was used as stimulant of metabolic activity of PMNL-independently of phagocytosis-again AIDS and some of the lymphadenopathy patients showed a markedly reduced neutrophil response. In conclusion it should be stated that there is some evidence for at least two defects of cellular immunity associated with AIDS and to some extent, with AIDS-endangered homosexuals suffering from lymphadenopathy: first the defect of PMNL to answer to concanavalin A with increased metabolic activity, and secondly the defect of PMNL to start phagocytosis induced by Zymosan with a subsequent release of oxygen radicals which are measurable as chemiluminescence. The appraisal of granulocyte activity by means of measurements of chemiluminescence might become an additional criterion for AIDS diagnostics.

Topics: Acquired Immunodeficiency Syndrome; Acyclovir; Anti-Infective Agents, Urinary; Concanavalin A; Drug Combinations; Hemophilia A; Humans; Immunoglobulins; Luminescent Measurements; Luminol; Lymphoproliferative Disorders; Male; Neutrophils; Phagocytosis; Sulfamethoxazole; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Zymosan

Topics: Acyclovir; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Lymphoproliferative Disorders

The clinical, immunopathologic, and virologic features of the lymphoproliferative diseases occurring after renal transplantation have been characterized. Clinically, patients may present with an infectious mononucleosis-like illness or with localized solid tumor masses. These lymphoproliferative diseases have unique histologic features that can be classified as polymorphic diffuse B-cell hyperplasia (PDBH) or polymorphic B-cell lymphoma (PBL). Immunologic cell-typing studies have shown that the majority are polyclonal B-cell proliferations, but monoclonal B-cell tumors have also been documented. These B-cell proliferations may, however, evolve from a benign polyclonal B-cell hyperplasia to a monoclonal malignant lymphoma. The Epstein-Barr virus (EBV) has been implicated as the cause of these disorders. Serologic studies frequently demonstrate evidence of a primary or reactivation infection, touch imprints from involved tissue may stain for the presence of EBNA (Epstein-Barr nuclear antigen), and EBV DNA hybridization studies demonstrate the presence of EBV-specific DNA sequences within tumor cells. Since EBV induces a polyclonal B-cell proliferation in vitro and in vivo, the polyclonality of these diseases also implicates EBV. Acyclovir, a new synthetic antiviral agent that inhibits EBV DNA replication may be effective in some patients during the polyclonal growth phase but is ineffective once the tumor evolves into a monoclonal lymphoma. We have identified several factors that may be useful in predicting responsiveness to acyclovir therapy.

Topics: Acyclovir; Adult; Antigens, Viral, Tumor; B-Lymphocytes; Cell Transformation, Neoplastic; DNA; Herpesvirus 4, Human; Humans; Hyperplasia; Kidney Transplantation; Lymphoma; Lymphoproliferative Disorders; Nucleic Acid Hybridization; Transplantation Immunology

Topics: Acyclovir; Bone Marrow Transplantation; Humans; Immunosuppression Therapy; Lymphoma; Lymphoproliferative Disorders; Postoperative Complications; Premedication

Topics: Acyclovir; Adult; Antibodies, Viral; Child; DNA, Viral; Electrophoresis, Agar Gel; Female; Genes, Viral; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Lymphoproliferative Disorders; Male; Nucleic Acid Hybridization; Virus Replication

Nineteen immunocompromised children with varicella were given intravenous acyclovir in dosages of 1000-1500 mg/m2 per day every 8 h for 5-10 days. The effect of treatment was compared with data from a group of patients previously treated with arabinoside cytosine (ara-c). The median times to cessation of new lesion formation, lesion crusting and lesion healing were shorter in the acyclovir-treated group than for ara-c. The time-to-event probability curves for cessation of new lesion formation, lesion crusting and lesion healing were significantly different for the acyclovir and ara-c group. Patients receiving acyclovir experienced no major adverse effects. Anticancer therapy did not require modification in most cases treated with acyclovir. Acyclovir was highly effective and nontoxic when used in the treatment of varicella-zoster infections in children with hematological malignancies being given anticancer treatment in comparison with ara-c therapy.

Topics: Acyclovir; Adolescent; Chickenpox; Child; Child, Preschool; Cytarabine; Female; Humans; Infant; Lymphoproliferative Disorders; Male

Two pediatric patients with life-threatening Epstein-Barr virus infections were studied immunologically and treated with acyclovir [9-(2-hydroxyethoxymethyl) guanine]. The patient with chronic active Epstein-Barr virus infection who experienced massive hepatosplenomegaly, pancytopenia, and failure to thrive demonstrated abnormalities of T and B lymphocytes. A second patient, with the X-linked lymphoproliferative syndrome, experienced a rapidly fatal course of acute Epstein-Barr virus infection which typifies this yet undefined immunodeficiency to Epstein-Barr virus. In each case, objective evidence for clinical improvement or antiviral effect of acyclovir treatment was not apparent. Abnormally productive Epstein-Barr virus infections did not appear to play a major role in the clinical syndromes observed. Current studies are focused on treatment of immunologically normal patients with early complicated Epstein-Barr virus infection.

Topics: Acyclovir; Antiviral Agents; B-Lymphocytes; Child, Preschool; Drug Evaluation; Female; Guanine; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Infant; Lymphoproliferative Disorders; Male; T-Lymphocytes