Despite antimicrobial prophylaxis, growth factors, and new antimicrobial agents, infections are a major cause of morbidity and mortality in patients with hematologic malignancies who are receiving chemotherapy and subsequent bone marrow or stem-cell transplant. The article by Wilkin and Feinberg is timely because formal recommendations on preventing infections in stem-cell transplant recipientsfrom the Centers for Disease Control and Prevention (CDC), Infectious Diseases Society of America (IDSA), and the American Society of Blood and Marrow Transplantation (ASBMT)were presented at the 38th IDSA annual meeting in September 2000 in New Orleans.
Appropriately, these guidelines, which were subsequently published in Morbidity and Mortality Weekly Report, do not contain lengthy discussion that might obscure concrete recommendations, but instead focus on recommendations with appropriate grading of the referenced evidence base. The guidelines are much more comprehensive than the review by Wilkin and Feinberg, which focuses on Candida and Aspergillus organisms and cytomegalovirus (CMV) and features much discussion on most of the studies referenced in the guidelines.
Preventing Fungal Infections
The incidence of systemic fungal infections and the diversity of involved organisms are increasing. Almost 10% of non-Candida fungal infections in transplant recipients are due to Fusarium species. In their well-written review of the clinical studies, Wilkin and Feinberg fail to discuss methods for preventing disease by limiting exposure and using growth factors. Also, most of the cited studies are older, and little attention is given to the more recent antifungal drug trials.
Although there are limited data that prove a benefit from avoiding environmental exposures, most clinicians advise their patients to avoid areas with high concentrations of dust (eg, construction sites), areas of high fungal burden (eg, caves, chicken coops), and foods that contain molds. To prevent fungal spore exposure, most transplant centers limit or prohibit bringing in fresh food and natural and artificial plants.
Other recommendations to minimize fungal contamination (especially during renovation) include (1) high-efficiency particulate air filtration; (2) positive air pressure in patient rooms; (3) correctly sealed rooms, including windows and electrical outlets; (4) high rates of room air exchange; and (5) barriers between patient care and construction areas. As the authors point out, various topical agents can diminish colonization, but this does not appear to reduce the incidence of invasive disease. (Of note, contrary to the authors’ report, amphotericin B(Drug information on amphotericin b) oral solution is still commercially available.) Health-care workers should consistently follow handwashing recommendations to prevent Candida species transmission to patients.
Shortening the Duration of Neutropenia
Wilkin and Feinberg appropriately emphasize the alteration of host risk factors for fungal infection, including the long duration of neutropenia, corticosteroid use, broad-spectrum antibiotics, and indwelling intravascular devices. Broad-spectrum antibiotic coverage should be narrowed and indwelling catheters should be removed as soon as possible. Although growth factors, such as granulocyte colony-stimulating factor (G-CSF [Neupogen]) and granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]), diminish the duration of neutropenia, evidence is inconclusive that they reduce the incidence of invasive disease.
In bone marrow transplantation patients receiving fluconazole(Drug information on fluconazole) (Diflucan), Marr and colleagues recently reported that several "traditional" risk factors, including prolonged neutropenia, were less significant predictors of candidemia than were bacteremia, CMV disease, and the administration of quinolones. Although these findings require confirmation, there is a noteworthy trend toward increasing invasive fungal disease, despite antifungal prophylaxis and the use of growth factors to shorten the duration of neutropenia.
The authors note two of three clinical trials that have shown that fluconazole, 400 mg/d, decreases the incidence of candidiasis. However, the optimal duration of fluconazole prophylaxis is unknown.[4-6] Marr and colleagues recently reported that in allogeneic bone marrow transplant recipients, fluconazole, 400 mg/d for 75 days after bone marrow transplant, was associated with less gut graft-vs-host disease (GVHD), persistent protection against disseminated candidiasis and related death, and an overall survival benefit.
As Wilkin and Feinberg note, the data on regimens for the prevention of aspergillosis are inconclusive. In a randomized, controlled trial in patients with hematologic malignancies receiving chemotherapy or bone marrow transplant, Morgenstern and colleagues reported that patients receiving fluconazole suspension, 100 mg/d, experienced a greater incidence of parenteral amphotericin B use, mucosal candidal infections, and aspergillosis than those receiving itraconazole(Drug information on itraconazole) (Sporanox) solution, 5 mg/kg/d. However, the fluconazole dose was significantly less than that which is usually prescribed for prophylaxis.
In a double-blind, placebo-controlled trial of patients with prolonged neutropenia, Nucci and colleagues reported a decrease in the use of amphotericin B and frequency of systemic fungal disease in patients receiving itraconazole, 100 mg twice daily, vs those receiving placebo. Wolff and colleagues conducted a randomized trial comparing fluconazole with low-dose amphotericin B and reported no significant difference between the two groups. Schwartz and colleagues reported no benefit of aerosolized amphotericin B over placebo in an unblinded, randomized trial; however, the overall incidence of invasive aspergillosis was low. Although liposomal amphotericin B is as effective as conventional amphotericin B in patients with neutropenic fever, the data supporting liposomal amphoterin B for prophylaxis are insufficient.
In summary, fluconazole, 400 mg/d, has been effective in reducing Candida infection. At this time, however, there are no proven strategies for reducing the incidence of aspergillosis or other mold infections. Future studies with voriconazole(Drug information on voriconazole), caspofungin(Drug information on caspofungin), and interferon gamma(Drug information on interferon gamma) may lead to improved results.
Disease resulting from CMV infection continues to be one of the most common and dreaded complications following bone marrow transplantation. Attributable mortality remains high after the establishment of end-organ disease in this population, primarily from the development of CMV pneumonitisdespite the availability of agents that are active against this virus. Much effort has therefore been focused on the prevention of CMV infection and disease development. In this issue of Oncology, Wilkin and Feinberg provide a thorough review of the literature on this topic and outline current strategies to limit the impact of CMV infection on bone marrow transplant recipients.
The decision of whether to use prophylactic or preemptive anti-CMV therapy in allogeneic bone marrow transplant recipients at risk for disease (ie, all recipients who are CMV-seropositive or whose donor is seropositive) depends on several factors and must be individualized to each institution. An important variable in this evaluation includes the capabilities of the affiliated virology laboratory to perform sensitive and specific tests for CMV, such as pp65 antigenemia assays or polymerase chain reaction (PCR).
Most authorities agree, however, that one of the two preventive strategies should be adopted for at-risk allogeneic bone marrow transplant recipientsat least between the time of engraftment and 3 to 4 months following transplantation. Beyond 100 days, prophylactic therapy has not been shown to be beneficial, although continued surveillance for CMV may be warranted, especially if chronic GVHD is present. Because of the low incidence of CMV disease in autologous bone marrow transplant recipients, prophylaxis is not recommended in these patients, whereas a preemptive strategy may be appropriate in more immunosuppressed subpopulations.
As discussed by the authors, prophylactic therapy has primarily been evaluated for acyclovir and ganciclovir(Drug information on ganciclovir) (Cytovene). Despite its favorable toxicity profile, the modest activity of acyclovir against CMV makes it a suboptimal agent for the purpose of preventing CMV disease. Ganciclovir is the drug of choice for both prophylactic and preemptive therapy; however, its myelosuppressive toxicity often complicates its use in this population.
As outlined by the authors, many different dosing regimens have been studied in an attempt to find the proper balance between efficacy and toxicity, but a consensus does not currently exist. Preemptive strategies are now favored in most transplant centers because of the increased risk of bacterial and fungal infections associated with ganciclovir-related prolongation of neutropenia. In addition, the advent of more sensitive CMV detection methods has improved the ability to detect infection before the onset of end-organ disease. Although Goodrich and colleagues showed improved overall survival of allogeneic recipients who received ganciclovir preemptive therapy triggered by a positive CMV culture (from weekly blood, urine, or throat specimens), CMV infection went unrecognized before the onset of disease in 12% of patients.
The complexity of deciding on a preventive strategy for CMV is well described by Wilkin and Feinberg, and most likely because of this, they offer no specific guidelines. While recognizing the need for more studies, the CDC, IDSA, and ASBMT currently recommend a preemptive approach, using either the CMV pp65 antigenemia assay on leukocytes or PCR assays to initiate ganciclovir therapy. Future studies evaluating the use of valganciclovir are in development.