acyclovir and Graft-vs-Host-Disease

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation. Significant progress has been made in the prevention of CMV disease over the past decade, but prevention of late CMV disease continues to be a challenge in selected high-risk populations. The pretransplantation CMV serostatus of the donor and/or recipient remains an important risk factor for posttransplantation outcome despite the use of antiviral prophylaxis and preemptive therapy; CMV-seropositive recipients of T cell-depleted grafts in particular continue to have a survival disadvantage compared with seronegative recipients with seronegative donors. The risk of developing antiviral drug resistance remains low in most patients; however, in a setting of intense immunosuppression (eg, after transplantation from a haploidentical donor), the incidence may be as high as 8%. Primary CMV infection via blood transfusion can be reduced by the provision of seronegative or leukocyte-depleted blood products; however, a small risk of 1% to 2% of CMV disease remains. Surveillance and preemptive therapy are effective in preventing the sequelae of transfusion-related CMV infection. Indirect immunomodulatory effects of CMV are increasingly recognized in hematopoietic stem cell transplant recipients. Strategies currently being investigated include long-term suppression of CMV with valganciclovir for the prevention of late CMV infection and disease, adoptive transfer of CMV-specific T cells, and donor and recipient vaccination strategies.

Topics: Acyclovir; Antigens, CD34; Antiviral Agents; Cidofovir; Cytomegalovirus Infections; Cytosine; Foscarnet; Ganciclovir; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunotherapy; Lymphocyte Depletion; Organophosphonates; Organophosphorus Compounds; Transplantation Conditioning

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

Allogeneic bone marrow transplantation has been used for over two decades as a therapy to treat patients with malignant disease [Thomas et al., 1977; Geller et al., 1989; Clift et al., 1987; Gratwohl et al., 1990; Goldman et al., 1986; Thomas et al., 1986]. High doses of chemotherapy are administered either alone or in combination with total body irradiation in an attempt to eradicate malignant cells. The treatment may be lethal to normal bone marrow function, but this toxicity is overcome by providing bone marrow from an external source. In allogeneic bone marrow transplantation, bone marrow is obtained from an HLA identical family member or unrelated donor. In recent years the use of less well-matched donors has increased, thus expanding the use of this strategy to a larger patient population. The success rate of allogeneic bone marrow transplantation has been greatest in the treatment of haematopoietic malignancies. Patients with acute or chronic leukaemia have a 30-80 percent likelihood of being free of disease at 5 years following transplantation. The success rate depends on the stage of disease at the time of transplantation. Certain nonmalignant diseases have also been treated successfully with allogeneic bone marrow transplantation. These include severe aplastic anaemia, inborn errors of metabolism, and other genetically determined diseases [Storb et al., 1986a, 1991; Lucarelli et al., 1990; Kirkpatrick et al., 1991]. With the availability of effective antiviral therapy, treatment and prophylaxis are available for HSV, CMV, and VZV. Acyclovir has been shown to be effective in treating established infections with HSV and VZV, and in the prophylaxis against HSV, severe CMV infections, and VZV.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acyclovir; Bone Marrow Transplantation; Graft vs Host Disease; Herpesviridae Infections; Humans

Virus infections account for considerable morbidity in bone marrow transplant (BMT) recipients. In all ages, members of the herpes virus group are the predominant pathogens. Of these, cytomegalovirus is pre-eminent in being the most frequent cause of death due to infection associated with the transplant procedure. Considerable effort is being invested in the development of preventative and therapeutic strategies to control this virus. Other potentially life-threatening virus infections may be acquired on the transplant unit as a result of cross-infection and can be caused by enteroviruses, rotaviruses and adenoviruses. Prevention of these infections is best achieved by implementation of strict infection-control measures.

Topics: Acyclovir; Adult; Bone Marrow Transplantation; Child; Cytomegalovirus Infections; Ganciclovir; Graft vs Host Disease; Herpes Simplex; Humans; Neutropenia; Respiratory Syncytial Viruses; Respiratory Tract Infections; Respirovirus Infections; Tissue Donors; Virus Diseases

Topics: Acyclovir; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Antiprotozoal Agents; Blood Transfusion; Bone Marrow Transplantation; Cytomegalovirus Infections; Drug Therapy, Combination; Graft vs Host Disease; Granulocytes; Herpes Simplex; Humans; Immunosuppressive Agents; Infection Control; Infections; Interferons; Intestines; Patient Isolation; Penicillins; Pneumonia; Vaccination; Viral Vaccines; Whole-Body Irradiation

In a double-blind controlled study, oral acyclovir has been compared to a placebo in a series of 39 consecutive patients undergoing bone marrow transplantation. A dose of 200 mg was given every 6 h from day 8 to day 35 after transplantation. Pharmacokinetic studies have shown the good absorption of the drug despite intestinal damage related to chemoradiotherapy or gut graft-versus-host disease (GVHD); there was no sign of toxicity. The protection against herpes simplex virus (HSV) infection was complete in the treated group when compared to the control group even in patients with high anti-HSV antibody titres. The same protection was observed against cytomegalovirus (CMV) infection. The incidence of HSV and CMV was the same in both groups after treatment ended. This study confirms the efficacy of acyclovir against HSV infection and possibly against CMV infection when it is given prophylactically after bone marrow transplantation.

Topics: Acyclovir; Administration, Oral; Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Child; Child, Preschool; Clinical Trials as Topic; Cytomegalovirus Infections; Double-Blind Method; Drug Administration Schedule; Graft vs Host Disease; Herpes Simplex; Humans; Immunosuppression Therapy; Intestinal Absorption; Leukemia; Random Allocation; Recurrence

Varicella-zoster virus (VZV) disease occurs in 30% of allogeneic hematopoietic cell transplant recipients who had a history of VZV infection. A safe and effective prevention strategy has not been established. In a double-blind controlled trial, 77 hematopoietic cell transplant recipients at risk for VZV reactivation were randomized to acyclovir 800 mg twice daily or placebo given from 1 to 2 months until 1 year after transplantation. VZV disease at 1 year was the primary end point; VZV disease after discontinuation of prophylaxis, VZV-specific T-cell immunity, herpes simplex virus (HSV) infection, cytomegalovirus (CMV) disease, survival, and safety were secondary end points. Acyclovir significantly reduced VZV infections at 1 year after transplantation (HR, 0.16; 95% CI, 0.035-0.74; P = .006). In the post-intervention observation period, this difference was not statistically significant (2 years: HR, 0.52; 95% CI, 0.21-1.3; 5 years: HR, 0.76; 95% CI, 0.36-1.6). There was no statistically significant difference in reconstitution of VZV-specific T-helper cell responses, HSV infections, CMV disease, chronic graft-versus-host disease, and overall survival between the groups. Acyclovir was well tolerated. Post-study VZV disease predominantly occurred in patients with continued need for systemic immunosuppression. In conclusion, acyclovir effectively and safely prevents VZV disease during the first year after hematopoietic cell transplantation. Periods of prophylaxis longer than 12 months may be beneficial for those hematopoietic cell transplant recipients on continued immune suppression.

Topics: Acyclovir; Adolescent; Adult; Aged; Child; Chronic Disease; Cytomegalovirus; Cytomegalovirus Infections; Double-Blind Method; Female; Follow-Up Studies; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Herpes Zoster; Humans; Male; Middle Aged; Simplexvirus; T-Lymphocytes, Helper-Inducer; Transplantation, Homologous; Virus Activation

Reactivation of varicella zoster virus (VZV) is a common event in patients undergoing allogeneic bone marrow transplantation (BMT) and may lead to life-threatening complications. We retrospectively analyzed the incidence, clinical outcome, and risk factors for VZV infections occurring within the first 5 years of transplantation in 100 consecutive adults undergoing allogeneic BMT between 1992 and 1997. Forty-one patients (41%) developed VZV reactivation a median of 227 days (range 45-346 days) post-transplantation. Twelve percent of VZV reactivation occurred in the first 100 days and 88% within the first 24 months. Among those who survived for 2 or more years after transplantation (n = 47), 59% developed VZV infection. Forty percent of patients with VZV reactivation required admission with a mean hospital stay of 7.2 days. Two patients developed encephalitis, and 1 died despite antiviral therapy. The most frequent complications were post-herpetic neuralgia and peripheral neuropathy (68%). Thoracic dermatomal zoster represented 41% of the infections; disseminated cutaneous involvement was observed in 17% of patients. No clinical or epidemiologic risk factors were associated with recurrence. Administration of ganciclovir for prevention of cytomegalovirus infection delayed the onset of VZV infection beyond 4 months (P = .06). In a further subset analysis, patients with a limited chronic graft-versus-host disease (GVHD) had a lower estimated incidence of VZV reactivation compared with those with extensive chronic GVHD (P = .11). We conclude that complications from reactivation of VZV infection are common and associated with considerable morbidity and mortality in patients undergoing allogeneic BMT.

Topics: 2-Aminopurine; Acyclovir; Adolescent; Adult; Antiviral Agents; Bone Marrow Transplantation; Chickenpox; Cytomegalovirus Infections; Famciclovir; Female; Graft vs Host Disease; Herpes Zoster; Herpesvirus 3, Human; Humans; Incidence; Male; Middle Aged; Pain; Retrospective Studies; Risk Factors; Skin Diseases; Transplantation, Homologous; Treatment Outcome; Virus Activation

We examined the incidence of herpes varicella-zoster virus (VZV) infection in 151 patients undergoing allogeneic BMT between August 1990 and September 1997 and who survived at least 3 months. Median follow-up was 17 (range 3.3-80.7) months. Herpes simplex virus antibody positive (HSV+) patients received aciclovir 1200 mg p.o. daily or 750 mg i.v. daily, in divided doses from day 0 to engraftment. Ganciclovir (5 mg/kg i.v. three times per week) was given in CMV+ patients (or if the donor was CMV+) from engraftment to day 84. Ganciclovir was continued or recommenced if a dose of greater than 20 mg of prednisone was used for the treatment of GVHD otherwise aciclovir was recommenced. In HSV+ patients not receiving ganciclovir, aciclovir 600 mg p.o. daily in divided doses was given until at least 6 months after BMT. Thirty-two patients developed VZV infection from 4.1 to 28 months after transplant. The estimated cumulative incidence of VZV was 13% (95% confidence interval 6-19%) at 12 months, 32% (22-42%) at 24 months and 38% (27-50%) at 28 months, with no further cases beyond that time. No patient developed VZV whilst receiving aciclovir or ganciclovir (P < 0.0001). However, there was a rapid onset of VZV following cessation of antiviral therapy (33% (20-46%) at 1 year post cessation). The presence of GVHD and the prior duration of antiviral prophylaxis were significant and independent risk factors for the development of VZV. Age, underlying disease, conditioning therapy or donor type were not. We conclude that 3-6 months of low-dose aciclovir and ganciclovir are effective at delaying the onset of VZV after allogeneic BMT, but may not affect the overall incidence of infection. Prolonged prophylaxis may be warranted in patients at high risk of infection, for example those patients with GVHD.

Topics: 2-Aminopurine; Acyclovir; Adolescent; Adult; Age of Onset; Aged; Analysis of Variance; Antiviral Agents; Bone Marrow Transplantation; Chickenpox; Dose-Response Relationship, Drug; Enzyme Activation; Famciclovir; Female; Ganciclovir; Graft vs Host Disease; Herpes Zoster; Herpesvirus 3, Human; Humans; Incidence; Male; Middle Aged; Prodrugs; Retrospective Studies; Risk Factors; Skin Diseases; Transplantation, Homologous; Valacyclovir; Valine

The occurrence of HSV infection and the effect of prophylaxis with oral acyclovir were evaluated prospectively in 34 consecutive patients undergoing bone marrow transplantation (BMT). All allogeneic BMT procedures involved T-lymphocyte depletion for prevention of graft-vs.-host disease (GVHD). Five HSV-seronegative patients did not receive acyclovir, and they did not develop HSV infection. Oral acyclovir was administered to 15 HSV-seropositive BMT recipients; 14 untreated HSV-seropositive BMT recipients served as a control group. The adult dose of acyclovir was 400 mg three times a day on Days -6 to +14 and 200 mg three times a day on Days +15 to +90. Children received 500 mg/m2 per day divided into three equal doses on Days -6 to +14 and 250 mg/m2 per day again divided into three on Days +15 to +90. In the group on prophylaxis, only one developed HSV infection during the time prior to engraftment. In the reference group, 12 of 14 (85.7%) developed oral HSV infection within 0 to 16 days (median 11 days) after the transplantation. Time for engraftment (duration of neutropenia) was shorter in patients receiving acyclovir. After engraftment, HSV infection was not observed during administration or following discontinuation of acyclovir on Day 90, but occurred in three patients in whom acyclovir was discontinued on Days 25, 35 and 40 after BMT. In the untreated group, two patients had recurrence of HSV infection on Days 40 to 60, and one had two infectious episodes. GVHD occurred in only two recipients, neither of whom had HSV infection. We conclude that the incidence of HSV infection during the period until engraftment in recipients of T-lymphocyte-depleted BMT is high, similar to that reported by others in recipients of whole BMT. Relatively low-dose oral acyclovir administered for 90 days can effectively prevent HSV infections in previously HSV-seropositive BMT recipients and may also shorten the period until engraftment.

Topics: Acyclovir; Administration, Oral; Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Child; Child, Preschool; Clinical Trials as Topic; Drug Administration Schedule; Female; Graft vs Host Disease; Herpes Simplex; Histocompatibility Testing; HLA Antigens; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphocyte Depletion; Male; Middle Aged; Stomatitis, Herpetic; T-Lymphocytes; Transplantation, Homologous

In this randomized double-blind and placebo controlled trial of 6 months' prophylaxis with acyclovir (ACV) in 42 bone marrow transplant (BMT) recipients, patients receiving ACV had fewer herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections during the prophylaxis compared to the placebo treated patients (P less than 0.05). During the first 6 months after the prophylaxis had been discontinued the frequency of clinical HSV reactivations was low both in the ACV (1/13) and in the placebo (1/13) treated patient groups. Altogether the ACV treated patients had significantly fewer HSV reactivations during the first year after BMT (P less than 0.05). The HSV-specific lymphocyte proliferation response was also lower in the ACV treated group at 3, 6 and 12 months after BMT (P less than 0.05). VZV infections recurred rather frequently, however, after discontinuation of ACV prophylaxis. Therefore no difference was found in the number of VZV infections during the first year after BMT. The VZV-specific lymphocyte proliferation response was significantly lower in the ACV treated group only at 6 months (P less than 0.05). ACV prophylaxis had no effect on the frequency of CMV infections; CMV-specific lymphocyte proliferative responses were not decreased.

Topics: Actuarial Analysis; Acyclovir; Antigens, Viral; Bone Marrow Transplantation; Cell Transformation, Viral; Child; Child, Preschool; Clinical Trials as Topic; Double-Blind Method; Graft vs Host Disease; Herpes Simplex; Humans; Lymphocyte Activation; Random Allocation; Simplexvirus

The frequencies of reactivated disease due to varicella-zoster virus (VZV) in immunocompromised patients were determined by enzyme-linked immunosorbent assay for antibody and also by the lymphocyte proliferation response to VZV antigen. Subclinical reactivations were as common as classical herpes zoster in all patient groups. Among bone marrow transplant (BMT) recipients, 36% developed herpes zoster and 26%, a subclinical reactivation. The corresponding frequencies for patients with leukemia during induction therapy were 5% and 10%; in renal transplant recipients, 0% and 26%; and in patients with seminoma, 0% and 6%, respectively. Subclinical reactivation of VZV thus appears to be a common finding in severely immunocompromised patients. A regained lymphocyte proliferation response to VZV antigen is a sensitive indicator of subclinical reactivation of VZV in BMT recipients. None of 19 BMT recipients with subclinical disease due to VZV later developed clinical reactivation of VZV. Acyclovir given as prophylaxis against infection with herpes simplex virus reduced the number of clinical and subclinical reactivations of VZV during treatment in BMT recipients, but not thereafter.

Topics: Acyclovir; Antibodies, Viral; Antigens, Viral; Bone Marrow Transplantation; Chickenpox; Dysgerminoma; Graft vs Host Disease; Herpes Zoster; Herpesvirus 3, Human; Humans; Immune Tolerance; Immunoglobulin G; Kidney Transplantation; Leukemia; Lymphocyte Activation; Male; Recurrence; Testicular Neoplasms

Forty-two patients undergoing bone marrow transplantation were included in a randomised, double-blind and placebo controlled trial of prolonged acyclovir prophylaxis against infections with viruses of the herpes group. Twenty patients were allocated to receive acyclovir and 22 to receive placebo. Acyclovir or placebo was administered i.v. at a dose of 250 mg/m2 twice daily, starting 5 days before transplantation. At 5 weeks after transplantation, administration was changed to tablets, 400 mg three times daily (children less than 6 years, 200 mg three times daily) and continued until 6 months after transplantation. In the placebo group, 10 acute herpes simplex virus (HSV) infections occurred in 7 patients (5 HSV-1 and 2 HSV-2), and another patient repeatedly shed HSV in throat washings. Five patients developed herpes zoster. Among patients receiving acyclovir only one episode of HSV infection occurred and no herpes zoster. The difference in the number of infection episodes and the number of infected patients was strongly significant (p = 0.0002 and 0.0017, respectively). The only acyclovir patient who reactivated HSV was terminally ill, and it is highly likely that she did not absorb a sufficient amount of the orally administered drug to control infection. All HSV and varicella zoster virus (VZV) infections were reactivations, and 9 of 10 patients who developed HSV infections or shed virus had a pre-transplantation HSV IgG titer of greater than 10 000 (ELISA). Acyclovir had no effect on cytomegalovirus (CMV), time of engraftment, or graft versus host disease (GVHD). Apart from a possible allergic reaction (skin rash) to acyclovir tablets, no adverse reactions were seen during this long prophylaxis with acyclovir.

Topics: Acyclovir; Bone Marrow Transplantation; Clinical Trials as Topic; Double-Blind Method; Female; Graft vs Host Disease; Herpesviridae Infections; Humans; Male; Postoperative Complications; Premedication; Prospective Studies; Random Allocation; Virus Activation

In a double-blind controlled study, oral acyclovir has been compared to a placebo in a series of 39 consecutive patients undergoing bone marrow transplantation. A dose of 200 mg was given every 6 h from day 8 to day 35 after transplantation. Pharmacokinetic studies have shown the good absorption of the drug despite intestinal damage related to chemoradiotherapy or gut graft-versus-host disease (GVHD); there was no sign of toxicity. The protection against herpes simplex virus (HSV) infection was complete in the treated group when compared to the control group even in patients with high anti-HSV antibody titres. The same protection was observed against cytomegalovirus (CMV) infection. The incidence of HSV and CMV was the same in both groups after treatment ended. This study confirms the efficacy of acyclovir against HSV infection and possibly against CMV infection when it is given prophylactically after bone marrow transplantation.

Topics: Acyclovir; Administration, Oral; Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Child; Child, Preschool; Clinical Trials as Topic; Cytomegalovirus Infections; Double-Blind Method; Drug Administration Schedule; Graft vs Host Disease; Herpes Simplex; Humans; Immunosuppression Therapy; Intestinal Absorption; Leukemia; Random Allocation; Recurrence

Acyclovir is commonly used to prevent and treat herpes simplex virus (HSV) reactivation after hematopoietic cell transplant (HCT), and only few reports have been published on acyclovir-resistant HSV in HCT recipients. We reviewed the medical records of patients with a microbiologic diagnosis of acyclovir-resistant HSV by plaque reduction test who received an HCT from 2002 through 2014. A total of 4 028 HCTs were performed during the study period, and 18 of the recipients met the diagnostic criteria for acyclovir-resistant HSV. All cases had undergone allogeneic HCTs. Most patients were in the pre-engraftment period or on systemic corticosteroid therapy for graft-versus-host disease (GVHD). The median time between diagnosis and susceptibility testing was 15 days, and antiviral therapy was changed at a median of 27 days. Patients required prolonged therapy (~80 days), and many had serious complications including renal failure and hospitalization. In conclusion, acyclovir-resistant HSV infection is more likely during the period of profound deficit in T-cell-mediated immunity and is associated with significant morbidities. Higher doses of acyclovir prophylaxis might be needed for patients with history of HSV during pre-engraftment or GVHD treatment. In patients who do not respond or progress after 1 week of acyclovir therapy, testing for drug-resistant HSV, and early switch to an alternative antiviral should be considered.

Topics: Acyclovir; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Antiviral Agents; Drug Resistance, Viral; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans; Male; Middle Aged; Retrospective Studies; Stem Cell Transplantation; Transplantation, Homologous; Treatment Outcome; Young Adult

Herpes simplex virus (HSV)-1/2 can still be reactivated after allogeneic haematopoietic stem cell transplantation (allo-HSCT) even when the prophylactic acyclovir is used. However, the risk factors for HSV-1/2 viremia and the clinical outcomes following unmanipulated haploidentical HSCT remain unknown.. Nineteen patients with HSV-1/2 viremia and fifty-seven patients without HSV-1/2 viremia which were selected using the case-pair method after undergoing haploidentical HSCT were enrolled. We analysed the risk factors for HSV-1/2 viremia and compared the clinical outcomes between the two groups.. The risk factors for HSV-1/2 viremia included HLA disparity ≥2 loci (p=0.049) and cytomegalovirus (CMV) reactivation (p=0.028). The incidences of platelet engraftment, oral mucositis and severe haemorrhagic cystitis (HC) in patients with and without HSV-1/2 viremia were 77% and 94% (p=0.003), 78% and 13% (p=0.000), and 25% and 6% (p=0.04), respectively. Moreover, the median time to platelet engraftment in patients with and without HSV-1/2 viremia was +25days (range, +11-+80) and +17days (range, +8-+67) (p=0.004), respectively. According to the multivariate analyses, HSV-1/2 viremia was associated with delayed platelet engraftment (p=0.038), a higher incidence of oral mucositis (p=0.000) and severe HC (p=0.038). However, HSV-1/2 viremia was not associated with non-relapse mortality (34.0% vs. 31.5%, p=0.26), leukaemia-free survival (60.9% vs. 57.9%, p=0.46) and overall survival (61.2% vs. 60.7%, p=0.37).. Based on our study results, we recommend that HSV-1/2 PCR should be performed upon clinical suspicion of HSV-1/2 infection.

Topics: Acyclovir; Adolescent; Adult; Child; Child, Preschool; Cystitis; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Incidence; Male; Middle Aged; Real-Time Polymerase Chain Reaction; Retrospective Studies; Risk Factors; Transplantation, Haploidentical; Viremia; Young Adult

Infections of the central nervous system (CNS) with varicella zoster virus (VZV) is a rare occurrence after allogeneic hematopoietic stem cell transplantation. We herein report a case of VZV meningitis, radiculitis and myelitis that developed 8 months after cord blood transplantation, shortly after the cessation of cyclosporine and low-dose acyclovir. Although treatment with acyclovir did not achieve a satisfactory response, the patient was successfully treated with foscarnet. Our report indicates that VZV infection should be considered in allo-hematopoietic stem cell transplantation (HSCT) patients with CNS symptoms and that foscarnet may be effective for the treatment of acyclovir-resistant VZV infections of the CNS. The development of optimal prophylactic strategies and vaccination schedules may eradicate post-transplant VZV disease.

Topics: Acyclovir; Antiviral Agents; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpes Zoster; Herpesvirus 3, Human; Humans; Meningitis, Viral; Transplantation, Homologous

Alternaria species have been reported as a rare cause of fungal infection in organ and stem cell transplant recipients, but to date, no reports have been published of infection in humans caused by Alternaria rosae. Here, we report cutaneous A. rosae infection in a 66-year-old farmer with a history of primary myelofibrosis who had undergone allogeneic unrelated donor hematopoietic stem cell transplantation. Forty-nine days post transplant, he presented with a nodule on the thumb with no findings suggestive of disseminated infection. Pathology, culture, and molecular speciation showed the nodule was caused by cutaneous A. rosae. He had been on voriconazole as antifungal prophylaxis, but was found to have a subtherapeutic voriconazole level. He was switched to posaconazole based on published in vitro data showing its superior efficacy in Alternaria treatment. Susceptibility testing showed that the A. rosae isolate was indeed susceptible to posaconazole. His cutaneous lesion remained stable, but he died from respiratory failure secondary to lobar pneumonia. At lung autopsy, A. rosae was not identified in the lungs. We believe this to be the first published report, to our knowledge, of A. rosae infection in humans.

Topics: Acute Kidney Injury; Acyclovir; Aged; Alternaria; Alternariosis; Antibiotic Prophylaxis; Antifungal Agents; Drug Therapy, Combination; Fatal Outcome; Graft vs Host Disease; Hand; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Levofloxacin; Magnetic Resonance Imaging; Male; Microbial Sensitivity Tests; Paranasal Sinuses; Phaeohyphomycosis; Pneumonia; Prednisone; Primary Myelofibrosis; Respiratory Insufficiency; Spores, Fungal; Transplantation, Homologous; Triazoles; Voriconazole

We present the case of a patient, with history of myelodysplastic syndrome and recent bone marrow transplant, who developed fulminant liver failure secondary to herpes simplex virus (HSV) hepatitis. His presentation was unique, as findings of liver microabscesses on computed tomography scan have not been described previously in this patient population. Despite initial treatment with acyclovir, he continued to deteriorate, and later sensitivities found the HSV strain to be resistant to acyclovir. HSV hepatitis with secondary liver failure is rare and, without appropriate treatment, its mortality is >80%. Early suspicion and immediate therapy are the keys to improve patient survival.

Topics: Acyclovir; Adrenal Cortex Hormones; Antiviral Agents; Bone Marrow Transplantation; Drug Resistance, Viral; Fatal Outcome; Foscarnet; Graft vs Host Disease; Hepatitis, Viral, Human; Humans; Liver; Liver Failure, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Patient Comfort; Polymerase Chain Reaction; Simplexvirus; Transaminases; Transplantation, Homologous; Valacyclovir; Valine

Brincidofovir (BCV) is a broad-spectrum antiviral agent active in vitro against double-stranded DNA viruses including herpesviruses, adenoviruses, polyomaviruses, and poxviruses. We report successful BCV use in management of disseminated acyclovir- and cidofovir-resistant varicella zoster virus in an immunocompromised hematopoietic stem cell transplant patient with chronic graft-versus-host disease who was intolerant to foscarnet.

Topics: Acyclovir; Adult; Antibiotic Prophylaxis; Antineoplastic Agents; Antiviral Agents; Cytosine; Drug Resistance, Viral; Drugs, Investigational; Female; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunocompromised Host; Investigational New Drug Application; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Organophosphonates; Transplantation, Homologous; Valacyclovir; Valine

Topics: Acyclovir; Adult; Aged; Antiviral Agents; Case-Control Studies; Drug Resistance, Viral; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans; Immunocompromised Host; Male; Middle Aged; Risk Factors; Simplexvirus; Treatment Outcome

Varicella zoster virus (VZV) disease is one of the major infectious complications that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Many reports have shown visceral VZV infection, a special type of VZV disease, to be rare. However, few studies so far have included a large number of patients.. Visceral VZV infection was found in 20 (0.8%) of 2411 patients who underwent allo-HSCT at our hospitals. Seventeen (85%) patients were taking immunosuppressive agents at the time of presentation with zoster. The presenting symptom was abdominal pain in 16 patients (80%), unconsciousness in 3 patients (15%), and no symptoms in 1 patient. The mean time interval from allo-HSCT to symptomatic visceral VZV infection was 273 days (103-800 days). The eruptions appeared within 3 days (0-13) after the first symptoms. Treatment with intravenous acyclovir was initiated before the appearance of eruptions in 3 of 18 patients (all 3 survived) with vesicular eruptions, the same day in 12 patients (11 survived, 1 died), and after the appearance in 3 patients (1 survived, 2 died). The overall mortality was 20%.. In conclusion, these data confirm that the incidence of visceral VZV infection is infrequent, but this disease is serious. When patients being treated with immunosuppressive agents demonstrate abdominal pain or unconsciousness, the possibility of visceral VZV infection should be considered as well as earlier therapeutic intervention.

Topics: Abdominal Pain; Acyclovir; Adult; Antiviral Agents; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpes Zoster; Herpesvirus 3, Human; Humans; Incidence; Male; Middle Aged; Transplantation, Homologous; Unconsciousness; Virus Activation; Viscera; Young Adult

This study was performed in order to evaluate the incidence and characteristics of cytomegalovirus (CMV) infection in children with acute leukemia according to donor source and graft type.. We retrospectively identified children with acute leukemia who had received allogeneic hematopoietic cell transplantation at Samsung Medical Center in Korea from October 1998 to December 2009.. In total, 134 recipients were identified. The patients were classified into the following three groups: unrelated cord blood (CB, n=36), related bone marrow or peripheral blood stem cells (RD, n=41), and unrelated bone marrow or peripheral blood stem cells (UD, n=57). The 365-day cumulative incidence of CMV antigenemia was not significantly different among the three groups (CB 67% vs. RD 49% vs. UD 65%, p=0.17). However, CB recipients had the highest median value of peak antigenemia (CB 160/2×10⁵ leukocytes vs. RD 7/2×10⁵ leukocytes vs. UD 19/2×10⁵ leukocytes, p<0.01) and the longest duration of CMV antigenemia than the other stem cell source recipients (CB 87 days vs. RD 17 days vs. UD 28 days, p<0.01). In addition, the 730-day cumulative incidence of CMV disease was the highest in the CB recipients (CB 36% vs. RD 2% vs. UD 5%, p<0.01). Thirteen CB recipients developed CMV disease, in which five of them had more than one organ involvement. Two patients, who were CB recipients, died of CMV pneumonia.. This study suggests that CB recipients had both longer and higher cumulative incidences of CMV infection. Therefore, a more aggressive and effective strategy of CMV management should be considered in CB recipients.

Topics: Acyclovir; Adolescent; Antiviral Agents; Child; Child, Preschool; Cyclosporine; Cytomegalovirus Infections; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Leukemia; Male; Retrospective Studies; Young Adult

Topics: Acyclovir; Adult; Antiviral Agents; Fatal Outcome; Ganciclovir; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpes Zoster Ophthalmicus; Herpesvirus 3, Human; Humans; Immunosuppression Therapy; Leukemia, Myeloid, Acute; Male; Polymerase Chain Reaction; Recurrence; Retinal Necrosis Syndrome, Acute; Tomography, Optical Coherence; Vision Disorders; Visual Acuity

Meningitis or encephalitis by varicella-zoster virus (VZV) after hematopoietic stem cell transplantation (HSCT) is rarely reported. We encountered a case of meningoencephalitis with VZV re-activation 18 months after related bone marrow transplantation for recurrent acute lymphoblastic leukemia. The patient had been administered steroid and cyclosporine for chronic graft-versus-host disease. A high DNA copy number of VZV, 4.9×10(7) copies was detected in the cerebrospinal fluid. VZV also caused severe pneumonia and acute renal failure soon after the onset of meningoencephalitis. The patient was successfully treated with acyclovir, although he was left with persistent neurological sequelae. Both prompt diagnosis and early treatment of VZV reactivation are important to avoid a fatal outcome.

Topics: Acute Kidney Injury; Acyclovir; Adult; Antiviral Agents; Bone Marrow Transplantation; Chronic Disease; Cyclosporine; Encephalitis, Varicella Zoster; Graft vs Host Disease; Herpesvirus 3, Human; Humans; Immunosuppressive Agents; Male; Pneumonia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Recurrence; Time Factors; Virus Activation

Topics: Acyclovir; Antiviral Agents; Epstein-Barr Virus Infections; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Middle Aged; Tongue Diseases; Treatment Outcome; Valacyclovir; Valine

We retrospectively reviewed our 10-year experience with living donor liver transplantation (LDLT) in 30 consecutive patients with end-stage primary sclerosing cholangitis (PSC) to determine long-term patient and graft survival and risk factors for recurrence of PSC. For strict diagnosis of recurrence, patients with hepatic artery thrombosis (n = 2), ABO blood type incompatible transplantation (n = 3), and postoperative survival shorter than 1 year (n = 5) were excluded from the study, leaving 20 patients for analysis. Recurrence was diagnosed in 11 patients 26-71 months after transplantation. Multivariate analysis showed that cytomegalovirus diseases within 3 months after transplantation and related donors were independent risk factors for recurrence. When the effects on recurrence were compared among donor-recipient relationships, there were significant differences, especially between nonrelated donors and parents. Multivariate analysis showed that age was an independent risk factor for time to graft loss. Cytomegalovirus prophylaxis and avoidance of related donors are important in reducing PSC recurrence, although this is a preliminary report with limitations due to the small number of patients. LDLT for young patients with PSC using grafts from their parents might have to be avoided where deceased donor liver transplantation is available.

Topics: Acyclovir; Adolescent; Adult; Antiviral Agents; Child; Child, Preschool; Cholangitis, Sclerosing; Cytomegalovirus Infections; Female; Graft vs Host Disease; Humans; Liver Transplantation; Male; Middle Aged; Recurrence; Retrospective Studies; Risk Factors; Young Adult

Two adolescents, on immunosuppressive therapy for graft-versus-host disease, developed hemophagocytic lymphohistiocytosis (HLH) after varicella zoster virus (VZV) reactivation. In the absence of dermatome restricted characteristic skin lesions, VZV reactivation was not immediately recognized and treatment with acyclovir was delayed. The first patient developed optical neuritis and died 2 months after the VZV episode due to massive intracranial hemorrhage. The second patient presented with severe abdominal pain and pancreatitis, followed by atypical skin eruptions, which prompted a faster diagnosis. Both patients recovered from their HLH, the first patient being successfully treated with immunosuppressive agents and the second with VZV treatment only. These two cases demonstrate the difficulties in recognizing VZV reactivation, and in order to start adequate and timely treatment, the need to consider VZV as a possible cause of HLH in severely immunocompromised patients.

Topics: Acyclovir; Adolescent; Antiviral Agents; Graft vs Host Disease; Herpes Zoster; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Lymphohistiocytosis, Hemophagocytic; Male

Topics: Acyclovir; Adolescent; Adult; Antibodies, Viral; Antigens, Viral; Antiviral Agents; Child; Child, Preschool; Cytomegalovirus; Cytomegalovirus Infections; Disease-Free Survival; Ethnicity; Female; Foscarnet; Ganciclovir; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Living Donors; Male; Middle Aged; Myeloablative Agonists; Postoperative Complications; Premedication; Proportional Hazards Models; Recurrence; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Virus Activation; Young Adult

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

Fatal problems encountered in allogeneic stem cell transplantation include EBV reactivation and post transplant lymphoproliferative disorders (PTLDs) with high mortality rates. We performed a retrospective analysis in all consecutive adult and pediatric EBV reactivations and PTLD during a period of 8.5 years. There were 26 patients with EBV reactivation/PTLD out of a total of 854 transplantations giving an overall incidence of 3.0%. Specifically, the incidence of EBV-PTLD was 1.3%, whereas that of EBV reactivation was 1.8%. Median age was 46.0 and 11.0 years in the adult and pediatric patients, respectively. There were high rates (54%) of concomitant bacterial, viral, fungal and parasitic infections at the time of EBV manifestation. Variable treatment regimens were applied including in most cases an anti-CD20 regimen often in combination with virustatic compounds, polychemotherapy or donor lymphocytes. The mortality rates were 9 of 11 (82%) in patients with EBV-PTLD and 10 of 15 (67%) in patients with reactivation. Only 7 of 26 patients (27%) are alive after a median follow-up of 758 days (range 24-2751). The high mortality rates of EBV reactivation and of EBV-PTLD irrespective of multimodal treatment approaches emphasize standardization and optimization of post transplant surveillance and treatment strategies to improve control of these often fatal complications.

Topics: Acyclovir; Antiviral Agents; Bacterial Infections; Child; Epstein-Barr Virus Infections; Graft vs Host Disease; Herpesvirus 4, Human; Histocompatibility Testing; Humans; Immunosuppression Therapy; Middle Aged; Mycoses; Parasitic Diseases; Stem Cell Transplantation; Tissue Donors; Virus Activation

Reactivation of latent varicella zoster virus is one infectious complication associated with the extensive immunosuppression necessary for hematopoietic stem cell transplant. Most cases are limited to skin and mortality is low. Isolated visceral zoster is rare, presenting with ileus/abdominal pain, hepatitis, and/or hyponatremia. We present 2 cases of visceral varicella zoster virus in adolescents with chronic graft-versus-host disease after hematopoietic stem cell transplant. Both presented with elevated liver enzymes, severe abdominal pain, and hyponatremia but lacked cutaneous involvement. Both received high-dose acyclovir and showed improvement, but eventually expired from hepatic failure. The diagnosis of visceral zoster can be difficult especially without cutaneous manifestations. Vigilance is necessary in patients with chronic graft-versus-host disease, abdominal pain, and/or hepatitis and antiviral therapy should be initiated promptly.

Topics: Acyclovir; Antiviral Agents; Chronic Disease; Fatal Outcome; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpes Zoster; Herpesvirus 3, Human; Humans; Leukemia, Myeloid, Acute; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Homologous; Virus Activation; Viscera; Young Adult

Varicella-zoster virus (VZV) infection of the central nervous system (CNS) is rare after hematopoietic stem cell transplantation (SCT). Here, we describe the first patient who developed VZV encephalitis after cord blood transplantation (CBT). A 35-year-old man with myelodysplastic syndrome-overt leukemia underwent CBT. On day +23, a neutrophil count consistently greater than 0.5 x 10(9)/L was achieved. On day +42, 1 mg/kg per day of prednisolone therapy was initiated for grade III acute graft-versus-host disease (GVHD). Then, the dose of prednisolone was slowly reduced. For exacerbation of chronic GVHD, the dose of prednisolone was again increased to 1 mg/kg per day on day +231. On day +265, localized cutaneous zoster in the left thoracic region occurred, but soon resolved after acyclovir therapy. On day +309, he suddenly developed diplopia. Subsequently, right facial palsy and hearing impairment occurred. No skin rash was observed. Magnetic resonance imaging (MRI) scans revealed multifocal abnormal high-signal intensity in the CNS. A high level of VZV DNA was detected in a cerebrospinal fluid specimen. He was diagnosed with VZV encephalitis. Acyclovir was given intravenously for 40 days. Four months after the onset, the neurologic symptoms had incompletely resolved. MRI scans showed substantial resolution but with mild residual lesions. The present report indicates that VZV should be considered as a possible causative agent in patients who develop multifocal neurologic symptoms of the CNS after SCT.

Topics: Acyclovir; Adult; Anti-Inflammatory Agents; Antiviral Agents; Cord Blood Stem Cell Transplantation; DNA, Viral; Encephalitis, Varicella Zoster; Graft vs Host Disease; Herpes Zoster; Herpesvirus 3, Human; Humans; Leukemia; Male; Myelodysplastic Syndromes; Prednisolone; Radiography; Remission Induction; Skin Diseases, Viral

Human herpesvirus 7 (HHV-7) is the least studied beta-herpesvirus in transplant settings. This prospective study examined the activity of HHV-7 during the first 12 weeks post-stem cell transplant in 59 paediatric patients. The presence of HHV-7, human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) in blood was monitored weekly by a multiplex nested polymerase chain reaction. Overall, 33 (55.9%) patients had one or more surveillance blood sample(s) positive for HHV-7. In contrast to HCMV and HHV-6, no obvious peak time of reactivation was observed for HHV-7. The occurrence of HHV-7 DNAaemia showed a significant negative association with HHV-6 (P=0.022), but with no association with HCMV. A significant higher positive rate for HHV-7 was found in autologous versus allogeneic (P=0.002), and in peripheral blood versus umbilical cord/marrow (P<0.001) transplant. Acyclovir had no effect, whereas ganciclovir was associated with a lower rate of HHV-7 reactivation (P=0.009). One patient died of HHV-7 associated brain stem encephalitis. The administration of colony stimulating factor, occurrence of acute graft versus host disease, time to neutrophil and platelet engraftment showed no significant association with the occurrence of HHV-7 DNAaemia.

Topics: Acyclovir; Antiviral Agents; Child; Child, Preschool; Colony-Stimulating Factors; Cord Blood Stem Cell Transplantation; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Female; Ganciclovir; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesviridae Infections; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Male; Polymerase Chain Reaction; Prospective Studies; Risk Factors; Roseolovirus Infections; Viremia

Cytomegalovirus (CMV) disease remains an important cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). We evaluated high-dose acyclovir (HDACV) and pre-emptive ganciclovir to prevent CMV disease in 76 children who underwent peripheral blood stem cell transplantation (PBSCT) and were at risk for CMV reactivation and disease (both recipient and donor seropositive) from May 1998 to April 2003. All received HDACV from day -9 to 6 months post transplant in conjunction with weekly CMV pp65 antigenemia monitoring. The incidence of antigenemia in this cohort was 19.7%, at a median of 22 days post-PBSCT. The frequencies were 26.4 and 4.4% in allogeneic and autologous groups, respectively (P=0.03). Patients with nonmalignant disease had higher CMV antigenemia than those with malignant disease (30.8 vs 8.1%, P=0.02). Age at PBSCT, sex, graft-versus-host disease (GVHD) prophylaxis regimen and presence of acute GVHD did not affect the risk of CMV antigenemia. None of the patients who had positive pp65 antigenemia developed CMV disease during the study period. We conclude that pp65 antigenemia-guided HDACV and pre-emptive ganciclovir may prevent CMV disease in children undergoing PBSCT.

Topics: Acyclovir; Adolescent; Antiviral Agents; Child; Child, Preschool; Cohort Studies; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Ganciclovir; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Neoplasms; Phosphoproteins; Risk Factors; Time Factors; Treatment Outcome; Viral Matrix Proteins

Varicella-zoster virus (VZV) infection was studied in 40 adult patients who underwent cord blood transplantation (CBT) from unrelated donors. Twenty-five patients developed VZV reactivation at a median of 5 months after CBT (range 1.7-26 months). The cumulative incidence of VZV reactivation after CBT was 80% at 30 months. Twenty-two patients developed localized herpes zoster. The remaining three patients developed atypical non-localized herpes zoster, which was associated with visceral dissemination in one patient. All the patients responded well to antiviral therapy. Unexpectedly, the absence of grade II-IV acute graft-versus-host disease (GVHD) was associated with a higher rate of VZV reactivation after CBT (100% versus 55%, P=0.01). These results suggest that recovery of VZV-specific immune responses after CBT is delayed even in patients without severe acute GVHD.

Topics: Acute Disease; Acyclovir; Adult; Antiviral Agents; Cord Blood Stem Cell Transplantation; Female; Follow-Up Studies; Graft vs Host Disease; Hematologic Diseases; Herpes Zoster; Herpesvirus 3, Human; Humans; Incidence; Male; Middle Aged; Proportional Hazards Models; Risk Factors; Time Factors; Transplantation Conditioning; Virus Activation

Visceral disseminated varicella-zoster virus (VZV) infection occurred with acute graft-versus-host disease in a 33-year-old Japanese male with non-Hodgkin lymphoma who had undergone allogeneic stem cell transplantation from an HLA-identical sibling after reduced intensity conditioning chemotherapy. Although ganciclovir and acyclovir treatment was effective temporarily, the number of VZV-DNA copies in the blood remained at a high level, and the hepatitis was prolonged. The patient was treated with foscarnet, which led to improvement of the VZV viremia and the hepatic dysfunction. Foscarnet therapy should be considered for acyclovir-resistant VZV infection in the setting of allogeneic hematopoietic stem cell transplantation.

Topics: Acyclovir; Adult; Antiviral Agents; Central Nervous System Neoplasms; Drug Resistance, Viral; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpes Zoster; Humans; Lymphoma, Non-Hodgkin; Male; Recurrence; Transplantation, Homologous

Retroviral transfer of Herpes simplex virus thymidine kinase to T cells has been used to confer sensitivity to the antiviral agent ganciclovir. This has allowed therapeutic approaches to be developed in which T cells mediating graft-versus-host disease after bone marrow transplantation can be selectively eliminated by the administration of ganciclovir. Although the strategy has been shown to be generally successful in early clinical trials, there are concerns about possible resistance to ganciclovir and the risk of myelosuppressive side-effects at the doses required to induce T cell suicide. We have incorporated the enhanced mutant HSV-TKSR39 into retroviral vectors tailored to exhibit high levels of expression in T cells and have used protocols optimized for the transduction and selection of primary lymphocytes. We demonstrate that leukemic and primary T cells can be efficiently transduced and highly enriched under conditions that should be readily adaptable for clinical use. T cells carrying HSV-TKSR39 were inhibited by exposure to ganciclovir at concentrations an order of magnitude below those required for wild-type HSV-TK. The less toxic agent aciclovir also eliminated T cells transduced with HSV-TKSR39 (but not HSV-TK), underlining the increased therapeutic potential of the mutant suicide gene system in the bone marrow transplantation setting.

Topics: Acyclovir; Antiviral Agents; Bone Marrow Transplantation; Cell Line; Cells, Cultured; Ganciclovir; Genetic Therapy; Genetic Vectors; Graft vs Host Disease; Humans; Leukemia, T-Cell; Mutation; Retroviridae; Simplexvirus; T-Lymphocytes; Thymidine Kinase; Transduction, Genetic

This study was conducted to compare the survival rates of bone marrow transplantation (BMT) patients who were affected with the survival rates of those who were not affected by oral recrudescent human herpes virus-1 infection (HHV-1) after transplantation.. Fifty-two consecutive patients who underwent BMT were included in the study. The time of death after BMT was displayed, by means of the Kaplan-Meier method, for the following parameters: age and gender of the patient, donor gender, primary disease, stem cells, conditioning regimen, platelet number after day 100, acute and chronic graft-versus-host disease, oral recurrent HHV-1 infection post-BMT, oral lichenoid lesions of graft-versus-host disease, graft-versus-host disease at the salivary glands, parenteral nutrition, and oral mucositis. The data were initially analyzed by means of the log-rank test and then included in the Cox proportional hazards model.. The multivariate analysis demonstrated a significance of 5% for only the platelet numbers and oral recurrent HHV-1 infection.. The present study provides evidence that platelet numbers below 100,000 cells/mm(3) after day 100 and oral recurrent HHV-1 infection are independent negative prognostic variables in BMT patients' 24-month survival rates.

Topics: Acute Disease; Acyclovir; Adolescent; Adult; Age Factors; Anemia, Aplastic; Antiviral Agents; Bone Marrow Transplantation; Chronic Disease; Female; Graft vs Host Disease; Humans; Leukemia; Linear Models; Lymphoma; Male; Middle Aged; Multivariate Analysis; Platelet Count; Prognosis; Proportional Hazards Models; Recurrence; Salivary Gland Diseases; Sex Factors; Stomatitis; Stomatitis, Herpetic; Survival Rate; Tissue Donors; Transplantation Conditioning

Over an eight-month period from October 1997 to May 1998, four patients who had received bone marrow transplant (BMT) from unrelated donor presented with severe mucosal cutaneous infections involving acyclovir resistant herpes simplex virus 1 (HSV-1). The four isolates were acyclovir (ACV) resistant, three of which were also foscarnet resistant as determined by the dye uptake method. The sequencing of the thymidine kinase (TK) gene did not permit to establish a relation between mutations and resistance to ACV. Three patients were considered as clinically cured of their HSV infection by replacement of ACV or foscarnet with either valacyclovir (one case) or cidofovir (two cases) but eventually two of them died of graft vs host disease. One patient died of extensive HSV infection despite administration of cidofovir. This study emphasizes the importance of monitoring the herpes virus resistance to antiviral drugs in bone marrow transplant recipients and the usefulness of the evaluation of novel antiviral drug for treatment of infections due to strains of HSV resistant to ACV and foscarnet that occur in about 5% of immunocompromised patients.

Topics: Acute Disease; Acyclovir; Adolescent; Amino Acid Substitution; Antiviral Agents; Bone Marrow Transplantation; Child; Cidofovir; Codon; Cytosine; DNA Mutational Analysis; Drug Resistance, Viral; Female; Foscarnet; Graft vs Host Disease; Herpes Simplex; Humans; Immunocompromised Host; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Male; Mutation, Missense; Organophosphonates; Organophosphorus Compounds; Point Mutation; Salvage Therapy; Simplexvirus; Thymidine Kinase; Transplantation, Homologous; Valacyclovir; Valine; Viral Proteins; Virus Activation

A 45-year-old matched unrelated BMT recipient had sequential mucocutaneous herpes simplex virus (HSV) type 2 infections. Five months after BMT, a penile lesion occurred and was cured using acyclovir, as expected from in vitro susceptibility results. The same lesion recurred 1 month later but worsened with acyclovir. The HSV isolate was resistant to acyclovir (IC(50) = 105 microM), and a nucleotide (G) was added to the thymidine kinase gene leading to a premature stop codon. The lesion improved markedly with foscarnet. During this treatment a second HSV infection occurred on the buttocks 2 weeks after the first one and healed completely with acyclovir. This course correlated with in vitro results of the buttock HSV isolate which was foscarnet-resistant (IC(50) = 300 microg/ml) and acyclovir-sensitive. Surprisingly, no mutation gene of the foscarnet-resistant isolate was detected in the DNA polymerase gene. This case shows that an HSV acyclovir-resistant infection may be followed by an acyclovir-sensitive one. Determination of antiviral susceptibility is needed to monitor the treatment of various HSV infections in immunocompromised BMT recipients.

Topics: Acyclovir; Antineoplastic Agents, Alkylating; Antiviral Agents; Bone Marrow Transplantation; Cidofovir; Combined Modality Therapy; Cyclosporine; Cytarabine; Cytomegalovirus Infections; Cytosine; Drug Resistance, Viral; Fatal Outcome; Foscarnet; Graft vs Host Disease; Herpes Genitalis; Herpes Simplex; Humans; Hydroxyurea; Immunocompromised Host; Immunosuppressive Agents; Interferons; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Methotrexate; Middle Aged; Organophosphonates; Organophosphorus Compounds; Simplexvirus; Transplantation Conditioning; Whole-Body Irradiation

Herpes simplex virus (HSV) infections in 75 allogeneic stem cell transplant recipients were analyzed. Sixteen patients developed HSV disease following transplantation. The risk factors were age, sex (females), unrelated donor graft, and graft-versus-host disease (GVHD) grade >/=2. Seven patients did not respond to acyclovir, and 3 patients failed to respond to foscarnet. Isolates from 4 patients developed resistance to acyclovir/penciclovir, and 3 patients had foscarnet-resistant isolates. The remaining 3 patients failed to respond to acyclovir, despite having sensitive isolates. All the isolates were sensitive to cidofovir, for which the IC(50) values correlated inversely with those for acyclovir (P=.01). The risk factors for clinical resistance to antiviral drugs were a GVHD grade >/=2 (P=.001) and the lack of ganciclovir prophylaxis (P=.01), with a higher nonrelapse mortality in the latter group (P<.0001). Clinical as well as in vitro resistance to antiviral drugs is common in patients with severe GVHD and is associated with a poor outcome.

Topics: Acyclovir; Adolescent; Adult; Antiviral Agents; Drug Resistance; Female; Ganciclovir; Graft vs Host Disease; Guanine; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans; Male; Middle Aged; Prognosis; Risk Factors; Transplantation, Homologous

Cutaneous lesions arising in herpes zoster (HZ) scars are rare. We report a 34-year-old woman with acute lymphoblastic leukemia underwent allogenic bone marrow transplant (BMT). Ten days after the BMT, she developed clusters of vesicles over the right neck, scapula, shoulder and chest. She was treated with intravenous acyclovir and foscarnet. One month after the vesiculous episode of HZ she showed 5 mm to 2 cm clustered flat violaceous lichenoid papules and confluent plaques within the HZ scars. Histopathologic examination revealed a inflammatory infiltrate present in the papillary dermis with granulomatous aggregated formed by histiocytes, multinucleated giant cells and lymphocytes. She was treated with topic steroids with significant improvement. Pathologic findings are similar to those of an unusual lichenoid reaction named "giant cell lichenoid dermatitis". We present the first reported case of giant cell lichenoid dermatitis at the sites of HZ scars.

Topics: Acyclovir; Adult; Antiviral Agents; Bone Marrow Transplantation; Cicatrix; Dermatitis; Female; Foscarnet; Giant Cells; Glucocorticoids; Graft vs Host Disease; Herpes Zoster; Humans; Lichenoid Eruptions; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The aim of this study was to correlate human herpesvirus (HHV)-6 viral load with clinical symptoms in allogeneic stem cell transplant (SCT) patients. Seventy-four patients were monitored during the first 3 months after SCT using a qualitative polymerase chain reaction (PCR) for HHV-6 DNA. HHV-6 was detected in 181 out of 494 samples (36%) from 58 (78%) patients. These 181 samples were analysed using a quantitative competitive PCR. DNA could be quantified from 146 out of 181 samples (80.6%). The HHV-6 viral load was highest at 4 weeks compared with 8 weeks (P < 0.001) and 12 weeks (P = 0.01) after SCT. Three patients had HHV-6 encephalitis and one patient had hepatitis. The HHV-6 DNA levels were higher in patients with HHV-6 than in those without HHV-6 (P = 0.01). Patients who received grafts from unrelated or HLA-mismatched family donors had significantly higher HHV-6 DNA levels than patients who received grafts from matched sibling donors (P < 0.001). In a multiple regression model, unrelated donor grafts (P < 0.001) and use of intravenous immunoglobulin prophylaxis (P = 0.04) influenced HHV-6 DNA levels. HHV-6 viral load was significantly correlated with delayed platelet engraftment in both univariate (P < 0.01) and multivariate analysis, and to the number of platelet transfusions.

Topics: Acyclovir; Adolescent; Adult; Antiviral Agents; Blood Platelets; Bone Marrow Transplantation; Central Nervous System Diseases; Child; Child, Preschool; Cytomegalovirus; DNA, Viral; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatitis; Herpesviridae Infections; Herpesvirus 6, Human; Histocompatibility Testing; Humans; Immunoglobulins, Intravenous; Leukocytes; Male; Middle Aged; Multivariate Analysis; Platelet Transfusion; Polymerase Chain Reaction; Postoperative Period; Prospective Studies; Transplantation, Homologous; Viral Load

Topics: Acyclovir; Adolescent; Adult; Antiviral Agents; Bone Marrow Transplantation; Child; Drug Resistance, Microbial; Female; Graft vs Host Disease; Herpes Simplex; Humans; Leukemia; Male; Mouth Diseases; Opportunistic Infections

Quantitative competitive PCR was used to monitor the quantity of cytomegalovirus (HCMV) in 1647 blood samples from 110 BMT recipients. DNAemia was detected in 49/110 (45%) of the patients, of whom 15/49 experienced HCMV disease. Peak virus load during surveillance was elevated in symptomatic (median 4.5 log10 genomes/ml) vs asymptomatic patients (median 3.6 log10 genomes/ml, P=0.002) and was also significantly elevated in HCMV seropositive recipients of seronegative marrow, (R+D-, median 5.0 log10), compared to those in the R-D- and R+D+ groups (P < 0.01 and <0.005). Odds ratios for disease per 0.25 log10 increase in viral load, recipient seropositivity and aGVHD were 1.43 (P=0.004), 6.60 (P=0.05) and 3.17 (P=0.08), respectively. In multivariate logistic regression analysis only elevated viral load remained a significant risk factor for HCMV disease. The computed disease probability viral load curve showed a rapid increase in disease risk at viral loads between 3.8 and 5.5 log10 genomes/ml in blood, and odds ratios for disease were determined for different threshold viral loads. These data demonstrate the central role of viral load in the pathogenesis of HCMV in BMT recipients and provide an additional marker for targeting and monitoring therapy.

Topics: Acyclovir; Antiviral Agents; Bone Marrow Transplantation; Cytomegalovirus Infections; Ganciclovir; Graft vs Host Disease; Hematologic Neoplasms; Humans; Longitudinal Studies; Polymerase Chain Reaction; Tissue Donors; Viral Load

Several preventive strategies against cytomegalovirus (CMV) disease have been developed during the last decade. These have frequently been used in combination, and it has been difficult to identify each strategy's contribution.. Risk factors for CMV disease, death in CMV disease and transplant-related mortality were analyzed in 584 patients, who underwent a total of 594 allogeneic bone marrow transplants.. The overall probability of CMV disease was 8.9%. No seronegative patient who had a seronegative marrow donor developed CMV disease. The corresponding probabilities for seronegative patients with seropositive donors, seropositive patients with seronegative donors, and seropositive patients with seropositive donors were 5.4%, 13.7%, and 11.7%, respectively. In multivariate Cox models, the use of preemptive antiviral therapy and being CMV-seronegative reduced the risk for CMV disease, CMV-associated death, and transplant-related mortality (TRM). Patients who received unrelated or mismatched family donor transplants had increased risks for CMV disease, CMV-associated death, and TRM. Older age was a significant risk factor for CMV disease and TRM. A total of 258 patients who were monitored by polymerase chain reaction for CMV DNA were analyzed separately to assess whether addition of another CMV preventive strategy could give benefit. Patients who received mismatched or unrelated donor transplants had increased risk for CMV disease, death in CMV disease, and TRM. High-dose acyclovir prophylaxis or addition of intravenous immune globulin had no influence.. Preemptive therapy based on polymerase chain reaction for CMV DNA was associated with reduced risks for CMV disease, CMV-associated death, and TRM, whereas other prophylactic modalities did not give additional benefit.

Topics: Acyclovir; Adolescent; Adult; Antiviral Agents; Bone Marrow; Bone Marrow Transplantation; Child; Child, Preschool; Cytomegalovirus Infections; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Middle Aged; Multivariate Analysis; Tissue Donors

Human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6), and human herpesvirus-7 (HHV-7) DNA in peripheral blood leukocytes (PBL) of 61 bone marrow transplant recipients was monitored weekly during the first 12 weeks post-transplantation by a nested polymerase chain reaction (PCR). Thirty-seven (61%), 17 (28%), and 32 (53%) of patients had one or more PBL specimens positive for HCMV, HHV-6 or HHV-7 DNA, respectively. HHV-7 DNA in PBL during the early post-transplant period was associated with a longer time to neutrophil engraftment (mean 28.8 days vs 19.8 days; P = 0.01). In two patients who failed to engraft, HHV-6 DNA and HHV-7 DNA was detected in plasma and PBL, respectively, early in their post-transplant period. Patients with HCMV disease were more likely to have concurrent HHV-7 DNA in PBL prior to onset of disease than were patients with asymptomatic HCMV infection, suggesting that HHV-7 may be a cofactor in the progression from HCMV infection to HCMV disease. In the 17 patients (179 specimens) in whom viral DNA in plasma was studied (in addition to PBL), a positive result was found only in 3. In each, viral DNA in plasma appeared to correlate with clinically significant disease. HHV-7 DNA in plasma was associated with encephalitis in an allograft recipient.

Topics: Acyclovir; Adolescent; Adult; Antiviral Agents; Bone Marrow Transplantation; Child; Child, Preschool; Cytomegalovirus; DNA, Viral; Female; Graft vs Host Disease; Herpesviridae Infections; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Leukocytes, Mononuclear; Longitudinal Studies; Male; Middle Aged; Polymerase Chain Reaction

This is a report on 60 consecutive patients with chronic myeloid leukemia (CML) who received an allogeneic bone marrow transplant (BMT) in this Unit. Donors were HLA-identical siblings (SIB) (n = 36) or unrelated donors (MUD) (n = 24) matched by serology for HLA A and B and by molecular biology for HLA DR. All patients were prepared with cyclophosphamide 120 mg/kg and fractionated total body irradiation 10-12 Gy. GVHD prophylaxis consisted of cyclosporin A (CsA) starting on day -7 and short-course methotrexate. Bone marrow was unmanipulated in all cases. Cytomegalovirus prophylaxis consisted of acyclovir for SIBs and foscarnet for MUDs. When compared to SIB transplants, MUD patients were younger (29 vs 36 years; P = 0.002), had younger donors (31 vs 39; P = 0.001), had a longer interval between diagnosis and BMT (1459 vs 263 days; P < 0.001) and received a smaller number of nucleated cells at transplant (3.3 vs 4.4 x 10(8)/kg; P = 0.003). More MUDs had advanced disease (50 vs 17%, P = 0.005). The median day to 0.5 x 10(9)/l neutrophils was similar in both groups (18 days for SIBs vs 17 days for MUDs; P = 0.06); the median platelet count on days +30, +50, +100 was significantly (P < 0.01) higher in SIB than in MUD patients (122 vs 38, 113 vs 50 and 97 vs 45 x 10(9)/l, respectively). Acute GVHD was scored as absent-mild, moderate, or severe, in 36, 58 and 6% of SIBs vs 25, 42 and 33% in MUD patients (P = 0.01). Chronic GVHD was comparable (P = 0.1). The actuarial risk of CMV antigenemia at 1 year was 60% in both groups. There were six deaths in SIB patients (two leukemia, two infections, one GVHD, one pneumonitis) and four deaths in MUD patients (three acute GVHD and one infection). Fifty patients survive with a median follow-up of 656 days for SIBs and 485 for MUDs. The actuarial 3-year transplant-related mortality is 12% in SIBs and 17% in MUDs (P = 0.5); the actuarial relapse is 18% in SIBs vs 6% in MUDs (P = 0.4) and 3-year survival 78% in SIBs vs 82% in MUDs (P = 0.7). This study suggests that survival of CML patients after marrow transplantation from unrelated or sibling donors is currently similar, provided the former are well matched. The increased incidence of GVHD in MUD patients is possibly compensated by a lower risk of relapse.

Topics: Acyclovir; Adolescent; Adult; Antigens, Viral; Antiviral Agents; Bone Marrow Transplantation; Cause of Death; Cytomegalovirus; Cytomegalovirus Infections; Disease-Free Survival; Female; Foscarnet; Graft vs Host Disease; Histocompatibility Testing; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Life Tables; Male; Middle Aged; Neutrophils; Nuclear Family; Premedication; Prospective Studies; Recurrence; Risk; Tissue Donors; Transplantation, Homologous; Viremia

A 17-year-old girl had linear and dermatomal lichenoid chronic graft-versus-host disease (GVHD) 18 months after receiving an allogeneic bone marrow transplantation for aplastic anemia. The cutaneous GVHD lesions appeared on previously normal skin.

Topics: Acyclovir; Adolescent; Anemia, Aplastic; Bone Marrow Transplantation; Female; Graft vs Host Disease; Herpes Zoster; Humans; Lichenoid Eruptions; Skin Diseases

Few longitudinal studies have investigated the onset, duration, and resolution of ulcerative mucositis in bone marrow transplant recipients. This study prospectively followed a group of such patients on a daily basis to obtain data on the incidence of ulcerative mucositis, location and duration of lesions, severity with different conditioning regimens, and the relationship of such mucositis to the absolute neutrophil count.. Fifty-nine bone marrow transplant recipients on prophylactic acyclovir were examined daily for 26 days after marrow infusion, and all oral ulcerative lesions were recorded.. Oral ulcers occurred in 76.3% of patients, began at a mean of 5 days after marrow infusion (day + 5), and lasted for a median of 6 days. More than 90% of patients showed complete resolution of ulcers on or before day + 15, and all showed resolution when the absolute neutrophil count was > 500 cells/ml. Persistence of ulcers was noticed in patients who had oral graft-versus-host disease and in some patients who initially developed more severe ulcerations. Ninety-six percent of ulcers were located on nonkeratinized mucosa.. Ulcerative mucositis occurs in about 75% of bone marrow transplant recipients in the absence of herpes simplex virus infection. Most lesions occur on nonkeratinized mucosae which are vulnerable to trauma, especially if such mucosae are rendered atrophic by conditioning regimens. Oral ulcers may persist beyond day + 15 and after recovery of the neutrophil count in patients who initially develop more severe ulcerations or in patients who develop graft-versus-host disease.

Topics: Acyclovir; Adolescent; Adult; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Candidiasis, Oral; Child; Cohort Studies; Diagnosis, Differential; Female; Graft vs Host Disease; Humans; Incidence; Longitudinal Studies; Male; Middle Aged; Mouth Diseases; Prospective Studies; Stomatitis; Time Factors; Ulcer

Three marrow transplant patients developed pneumonia due to acyclovir-resistant thymidine-kinase-deficient herpes simplex virus (HSV) type 1. In all three, pneumonia was evident at autopsy by both standard and immunohistology, and virus was recovered from culture of lung tissue. Two patients also had other pulmonary infections at death; one had only HSV pneumonia. All had received prophylaxis and repeated treatment courses with acyclovir, and all initially had acyclovir-sensitive virus. The acyclovir-resistant HSV strains were sensitive to foscarnet, and in at least one case to vidarabine, but as expected were resistant to ganciclovir. These cases represent potentially severe visceral infection in which acyclovir-resistant virus strains were primary or important copathogens. Although acyclovir-resistant HSV is generally considered less virulent, these cases illustrate the potential importance of infection due to acyclovir-resistant HSV in severely immunocompromised patients. They also highlight the need to test HSV strains for antiviral sensitivity and to consider alternative therapies to acyclovir in appropriate clinical situations.

Topics: Acyclovir; Adult; Animals; Antiviral Agents; Bone Marrow Transplantation; Cells, Cultured; Drug Resistance, Microbial; Female; Foscarnet; Ganciclovir; Graft vs Host Disease; Herpes Simplex; Humans; Male; Middle Aged; Phosphonoacetic Acid; Pneumonia, Viral; Simplexvirus; Thymidine Kinase; Vero Cells; Vidarabine

Over three years 81 consecutive bone marrow transplant recipients (32 allogeneic and 49 autologous) who received prophylaxis with acyclovir, were studied for symptomatic virus infection. Thirty nine infections were documented in a total of 28 patients. Thirty two infections were mild, five were moderately severe, and two were severe. Cytomegalovirus infection occurred in only six allogeneic recipients. Herpes simplex virus and varicella zoster virus infections occurred infrequently. Seven patients who were considered at the time of death to have died due to an infectious cause were studied virologically at necropsy. In only one patient was a virus infection thought to have been the cause of death. Prophylaxis with acyclovir may have influenced the rate and clinical prominence of herpes virus infections. In this study viruses were considered to have had a relatively minor role in causing morbidity and mortality.

Topics: Acyclovir; Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Graft vs Host Disease; Humans; Middle Aged; Postoperative Complications; Prospective Studies; Virus Diseases

Patients undergoing allogeneic bone marrow transplantation who are seropositive for cytomegalovirus are vulnerable to serious cytomegalovirus infection, presumably because of reactivation of latent endogenous virus and severe immunosuppression. We administered intravenous acyclovir from 5 days before to 30 days after allogeneic marrow transplantation for hematologic neoplasms in an effort to prevent cytomegalovirus infection and disease in patients seropositive for cytomegalovirus before transplantation. Eighty-six patients seropositive for both cytomegalovirus and herpes simplex virus before transplantation received acyclovir, whereas 65 patients seropositive only for cytomegalovirus served as controls (acyclovir is the standard prophylactic agent against herpes simplex virus in this setting). The probability that cytomegalovirus infection would develop within the first 100 days after transplantation was 0.70 among acyclovir recipients and 0.87 among control patients at medians of 62 and 40 days after transplantation, respectively (P = 0.0001 by log-rank test). Invasive cytomegalovirus disease developed in 19 acyclovir recipients (22 percent) and 25 control patients (38 percent) (P = 0.008). Survival within the first 100 days after transplantation was better among acyclovir recipients (P = 0.002). Acyclovir prophylaxis was associated with a relative risk of 0.5 or less for the development of cytomegalovirus infection or disease or for death within the first 100 days after transplantation (P less than or equal to 0.04), in proportional-hazards regression analysis. We conclude that prophylaxis with intravenous acyclovir significantly reduced the risk of both cytomegalovirus infection and cytomegalovirus disease in seropositive patients after allogeneic bone marrow transplantation and that it was also associated with significantly improved survival.

Topics: Acyclovir; Adolescent; Adult; Analysis of Variance; Antibodies, Viral; Bone Marrow Transplantation; Child; Child, Preschool; Cytomegalovirus; Cytomegalovirus Infections; Drug Evaluation; Female; Graft vs Host Disease; Herpes Simplex; Humans; Injections, Intravenous; Leukemia; Male; Middle Aged; Postoperative Complications; Pulmonary Fibrosis; Risk Factors

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

Topics: Acyclovir; Adult; Biopsy; Bone Marrow Transplantation; Graft vs Host Disease; Herpes Simplex; Humans; Lung; Male; Pulmonary Fibrosis

Bone marrow from HLA-identical siblings was transplanted in 14 patients with chronic myeloid leukaemia (CML), including one patient in acceleration phase and one in chronic phase following 2 blast crises. Restoration of the bone-marrow occurred in all cases and Philadelphia chromosome could not be detected in any of the patients after the transplantation. Two patients died due to lung complications. Twelve patients who received antiviral prophylaxis (aciclovir per os, anti-CMV-hyperimmunoglobulin) after the transplantation are in very good condition with 140 to 790 days complete clinical and cytogenetic remission. Bone-marrow transplantation, as a curative measure for patients with CML up to the age of 45 (50), should be included in therapy schemes when an HLA-identical sibling is available.

Topics: Acyclovir; Adolescent; Adult; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cyclosporins; Cytomegalovirus; Graft vs Host Disease; Histocompatibility Testing; HLA Antigens; Humans; Hydroxyurea; Immunization, Passive; Immunoglobulins; Immunoglobulins, Intravenous; Leukemia, Myeloid; Middle Aged; Philadelphia Chromosome; Tissue Donors; Vindesine

Bone marrow transplantation was performed between IV/82 and X/85 in 64 patients with acute leukemia (n = 36), chronic myelogenous leukemia (CML; n = 13), severe aplastic anemia (n = 12), and neuroblastoma stage IV (n = 3). Of these patients 57 received allogeneic marrow from HLA-ABCDR identical, MLC-negative sibling donors. Six transplants were performed with syngenic marrow and one with autologous marrow. Of the 64 patients 48 survived 40-1,250 days after transplantation, resulting in a survival rate (SR) of 75% and a survival probability (SP) of 71%. Of the 36 patients suffering from acute leukemia (SR = 64%, SP = 51%), patients with acute myelogenous leukemia (AML) in first complete remission (n = 11; SR = 81%, SP = 76%), as well as patients with acute lymphatic leukemia (ALL) in 1st to 4th complete remission at the time of transplantation (n = 14; SR = 81%, SP = 76%) show a favorable prognosis. A poor survival rate was seen for patients with AML when transplanted in second or partial remission (1/5; SR = 20%), as well as for patients suffering from ALL and transplanted during relapse or partial remission (1/6; SR = 16%). Of 13 patients suffering from CML 12 survived the transplantation free of relapse (SR = 93%, SP = 92%), and one patient died from varicella zoster pneumonia. Of the transplanted patients with severe aplastic anemia, 12 of 13 are surviving with complete hematologic reconstitution; one patient, however, died on day 10 from a sepsis. In our patient group, the SR as well as the SP has been improved through changes in the irradiation protocol concomitant with prophylactic application of anti-CMV hypergammaglobulin, as well as through additional oral medication of Azyklovir. The 41 patients (BMT No. 7-47) with total body irradiation at one time show an SR of 44% and an SP of 41%. The following 46 patients (BMT No. 48-93) have reached an SR of 83% and an SP of 74% under the regimen of fractionated total body irradiation, plus prophylaxis with anti-CMV hypergammaglobulin and Azyklovir. Within this group, no fatal CMV pneumonia was encountered as opposed to six patients lost from CMV pneumonia in the first group.

Topics: Acyclovir; Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Cytomegalovirus Infections; Graft vs Host Disease; Humans; Immunization, Passive; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Middle Aged; Neoplasm Staging; Neuroblastoma; Pneumonia, Viral; Postoperative Complications

Topics: Acyclovir; Administration, Oral; Bone Marrow Transplantation; Coxsackievirus Infections; Enterovirus Infections; Graft vs Host Disease; Herpes Simplex; Humans; Immunoglobulins; Transplantation, Homologous

Ten children between the ages of five and fifteen years old with leukemia (two with acute nonlymphocytic leukemia in first remission, four with acute lymphocytic leukemia in first or second remission, one with acute lymphocytic leukemia in relapse, and one with chronic myelocytic leukemia in chronic phase), malignant lymphoma (one) or severe aplastic anemia (one) were given transplants from HLA-matched or mismatched family members between March, 1982 and April, 1984. Two patients died of leukemia relapses on days 107 and 257 following transplantation. One patient died of cardiac failure on day 157. One patient who received HLA-mismatched marrow from his father died of pulmonary edema and acute graft versus host disease on day 32. Six are alive 268-843 days post transplantation. None of the ten patients developed interstitial pneumonia due to cytomegalovirus which is one of the major causes of death reported in other published studies.

Topics: Acute Disease; Acyclovir; Adolescent; Anemia, Aplastic; Bone Marrow Transplantation; Child; Child, Preschool; Cyclophosphamide; Female; Graft vs Host Disease; Herpesviridae Infections; Humans; Immunologic Deficiency Syndromes; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma; Male; Methotrexate; Transplantation, Homologous

Allogeneic bone marrow transplantations were carried out between March 1983 and July 1985 in 31 patients aged 7 to 45 years (median 18 years). Acute lymphoblastic leukaemia in 1st to 5th remission was present in 8 patients, acute myeloblastic leukaemia in 1st and 2nd remission in 4 patients, chronic myeloid leukaemia, with various remission status, in 6 patients, 3 patients had severe aplastic anaemia and there were single cases of myelodysplasia and immature cell megakaryocytic myelosis. Transplantation was carried out during relapse in 8 patients with either acute myeloid or lymphoblastic leukaemia. Phenotypic HLA-identical mothers (n = 2) as well as genotypic HLA-identical siblings (n = 27), and in two cases HLA-non-identical mothers, served as bone marrow donors. In leukaemia patients the conditioning treatment consisted of fractionated total body irradiation and high dose cyclophosphamide or etoposide. Patients with severe aplastic anaemia received cyclophosphamide (4 X 50 mg/kg) and fractionated total nodal irradiation (total dose 8 Gy). 19 patients (61%) survived 14 to 605 days after bone marrow transplantation. 15 patients (48%) continue to remain in complete remission with Karnofsky indices of greater than or equal to 90%. Causes for death were infection (n = 3), interstitial pneumonia (n = 3), relapse (n = 3) as well as single cases involving acute graft-versus-host-disease, non-engraftment of donor marrow and veno-occlusive disease of the liver.

Topics: Acyclovir; Adolescent; Adult; Amphotericin B; Anemia, Aplastic; Bone Marrow Transplantation; Child; Cyclophosphamide; Etoposide; Female; Graft Survival; Graft vs Host Disease; Herpes Genitalis; HLA Antigens; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Methotrexate; Middle Aged; Nystatin; Prednisolone; Tissue Donors; Whole-Body Irradiation