The importance of neutropenia in the risk of serious infection in patients with cancer who are receiving cytotoxic chemotherapy was first recognized nearly 30 years ago1. Since then, considerable progress has been made in the management of fever and neutropenia in both adults and children, resulting in improved survival rates not only for these patients but also for other immunosuppressed patients, including those undergoing organ or bone marrow transplantation and those with bone marrow failure or human immunodeficiency virus (HIV) infection2,3. Some of the current principles for the management of fever in patients with neutropenia are outlined . . .

Management of fever in patients with cancer and treatment-induced neutropenia.

Objective: To study the efficacy and toxicity of ganciclovir prophylaxis given at engraftment to cytomegalovirus (CMV)-seropositive, allogeneic bone marrow transplant recipients. Design: A double-b...

Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant

Solid-organ transplantation is a therapeutic option for many human diseases. Infections are a major complication of solid-organ transplantation. All candidates should undergo a thorough infectious-disease screening prior to transplantation. There are three time frames, influenced by surgical factors, the level of immunosuppression, and environmental exposures, during which infections of specific types most frequently occur posttransplantation. Most infections during the first month are related to surgical complications. Opportunistic infections typically occur from the second to the sixth month. During the late posttransplant period (beyond 6 months), transplantation recipients suffer from the same infections seen in the general community. Opportunistic bacterial infections seen in transplant recipients include those caused by Legionella spp., Nocardia spp., Salmonella spp., and Listeria monocytogenes. Cytomegalovirus is the most common cause of viral infections. Herpes simplex virus, varicella-zoster virus, Epstein-Barr virus and others are also significant pathogens. Fungal infections, caused by both yeasts and mycelial fungi, are associated with the highest mortality rates. Mycobacterial, pneumocystis, and parasitic diseases may also occur.

Infections in solid-organ transplant recipients.

Background. Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir for the early treatment of CMV infection in asymptomatic recipients of bone marrow transplants whose surveillance cultures for CMV became positive. Methods. Bone marrow—allograft recipients who were seropositive for CMV antibodies or who received seropositive marrow were screened for CMV excretion by culture of throat swabs, blood, urine, or bronchoalveolar-lavage fluid. In this double-blind trial, 72 patients who had marrow engraftment and were excreting virus were randomly assigned to receive either placebo or ganciclovir (5 mg per kilogram of body weight twice a day for one week, followed by 5 mg per kilogram per day) for the first 100 days after transplantation. Patients were followed for the development of biopsy-confirmed CMV disease, ganciclovir-related toxicity, and survival. Results. Between assignment to the ...

https://www.nejm.org/doi/pdf/10.1056/NEJM199112053252303

Early Treatment with Ganciclovir to Prevent Cytomegalovirus Disease after Allogeneic Bone Marrow Transplantation

Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis.

Background. Because of the immunosuppression required, heart-transplant recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, esophagitis, gastritis, and a syndrome of fever, hepatitis, and leukopenia. We undertook a controlled trial to evaluate the prophylactic administration of ganciclovir to prevent CMV-induced disease after heart transplantation. Methods. This randomized, double-blind, placebo-controlled trial was conducted at four centers. Before randomization, the patients were stratified into two groups: those who were seropositive for CMV before transplantation and those who were seronegative but who received hearts from seropositive donors. Ganciclovir was given intravenously at a dose of 5 mg per kilogram of body weight every 12 hours from postoperative day 1 through day 14, then at a dose of 6 mg per kilogram each day for 5 days per week until day 28. Results. Among the seropositive patients, CMV illness occurred during the first 120 days after ...

https://www.nejm.org/doi/pdf/10.1056/NEJM199204303261803

A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation.

Cell surface receptors for the 86-kDa glycoprotein (gp86) of human cytomegalovirus (HCMV) were identified by using two monoclonal anti-idiotype antibodies that bear the internal image of gp86. These antibodies bound to cells permissive for HCMV infection by both ELISA and immunofluorescence assay and inhibited HCMV plaque formation in human embryonic lung (HEL) cells. Immunoblot analysis showed specific binding of both internal image anti-idiotype antibodies as well as gp86 to an HEL cell membrane protein with an approximate molecular mass of 92.5 kDa. In addition, immunoprecipitation of radiolabeled membrane and cell surface proteins from human foreskin tissue, human foreskin fibroblasts, or HEL cells showed specific binding of anti-idiotype antibody predominantly to the 92.5-kDa protein.

https://www.pnas.org/content/pnas/86/24/10100.full.pdf

Identification of cell surface receptors for the 86-kilodalton glycoprotein of human cytomegalovirus.

We conducted a randomized, double-blind, placebo-controlled trial of two forms of topical interferon therapy for condyloma acuminata in women. Gel containing 10(6) IU of leukocyte interferon/g, with or without nonoxynol-9, was compared with treatment with gel base alone. Eighty-nine patients applied the gel three times a day for four weeks and were studied for at least 16 w. Side effects were generally mild and limited to the site of application for all three drugs. Although a transient, statistically significant therapeutic effect was noted early in the course of treatment with both interferon gels as compared with placebo, this effect was lost by the end of the follow-up period, possibly because of a generally high response rate in patients receiving placebo. Hence, there was no overall difference in the number of patients with a partial or complete response to any of the agents by the end of therapy or by the end of the study.

Topical interferon for treating condyloma acuminata in women.

Experience with ganciclovir treatment of life- or sight-threatening cytomegalovirus (CMV) infections in 22 heart and heart-lung transplant recipients at six medical centers was reviewed. All six heart-lung recipients and six of 16 heart recipients had CMV pneumonitis; five heart recipients had CMV gastrointestinal disease, three had retinitis, and two had infections in more than one organ system. Of the 18 patients (82%) surviving initial ganciclovir therapy, 16 improved, one stabilized, and one showed no change in clinical status. All cultures positive for CMV before treatment became negative during therapy. Six patients (33% of survivors) had recurrent episodes and received additional therapy. Four patients (18%) died during initial therapy; death was believed to be related to CMV infection in only two cases and to ganciclovir treatment in no case. Adverse reactions possibly attributable to ganciclovir included neutropenia (four patients), impaired renal function (one), thrombocytopenia (one), decreased blood pressure (one), and seizure (one). Ganciclovir appears to be well tolerated and to alter favorably the outcome of serious CMV infection in this patient population.

Ganciclovir treatment of serious cytomegalovirus infection in heart and heart-lung transplant recipients.

Two glycoproteins have been identified on human CMV that induce neutralizing antibody; an 86,000-Da glycoprotein and a 130,000-, 92,000-, and 50,000-Da glycoprotein coimmunoprecipitating complex that appears to be the gB homologue of HSV. We have produced syngeneic monoclonal anti-Id antibodies (mAb2) of the IgM isotype to a CMV-neutralizing monoclonal antibody (mAb1) that is known to bind to the 86,000-Da glycoprotein on the virion envelope. These mAb2 bear the internal image of the original viral antigen as shown by their ability to 1) recognize an interspecies idiotype in CMV-positive human antisera, 2) block mAb1 binding to CMV antigen, and 3) block CMV neutralization by mAb1 in vitro. Immunization of mice with both of these affinity chromatography-purified mAb2 stimulated the production of anti-anti-Id monoclonal antibodies (which we termed mAb3), which bound to the mAb2 by ELISA and neutralized CMV infectivity.

Susan Keay

Papers

A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation.

Identification of cell surface receptors for the 86-kilodalton glycoprotein of human cytomegalovirus.

Topical interferon for treating condyloma acuminata in women.

Ganciclovir treatment of serious cytomegalovirus infection in heart and heart-lung transplant recipients.

Syngeneic monoclonal anti-idiotype antibodies that bear the internal image of a human cytomegalovirus neutralization epitope.