Prophylaxis Against Fungal Infections and Cytomegalovirus Disease After Bone Marrow Transplantation

Despite antimicrobial prophylaxis, growthfactors, and new antimicrobial agents, infections are a major cause of morbidityand mortality in patients with hematologic malignancies who are receivingchemotherapy and subsequent bone marrow or stem-cell transplant. The article byWilkin and Feinberg is timely because formal recommendations on preventinginfections in stem-cell transplant recipients—from the Centers for DiseaseControl and Prevention (CDC), Infectious Diseases Society of America (IDSA), andthe American Society of Blood and Marrow Transplantation (ASBMT)—werepresented at the 38th IDSA annual meeting in September 2000 in New Orleans.

Appropriately, these guidelines, which were subsequentlypublished in Morbidity and Mortality Weekly Report,[1] do not containlengthy discussion that might obscure concrete recommendations, but insteadfocus on recommendations with appropriate grading of the referenced evidencebase. The guidelines are much more comprehensive than the review by Wilkin andFeinberg, which focuses on Candida and Aspergillus organisms andcytomegalovirus (CMV) and features much discussion on most of the studiesreferenced in the guidelines.

Preventing Fungal Infections

The incidence of systemic fungal infections and the diversity ofinvolved organisms are increasing. Almost 10% of non-Candida fungalinfections in transplant recipients are due to Fusarium species. In theirwell-written review of the clinical studies, Wilkin and Feinberg fail to discussmethods for preventing disease by limiting exposure and using growth factors.Also, most of the cited studies are older, and little attention is given to themore recent antifungal drug trials.

Although there are limited data that prove a benefit fromavoiding environmental exposures, most clinicians advise their patients to avoidareas with high concentrations of dust (eg, construction sites), areas of highfungal burden (eg, caves, chicken coops), and foods that contain molds. Toprevent fungal spore exposure, most transplant centers limit or prohibitbringing in fresh food and natural and artificial plants.

Other recommendations to minimize fungal contamination(especially during renovation) include (1) high-efficiency particulate airfiltration; (2) positive air pressure in patient rooms; (3) correctlysealed rooms, including windows and electrical outlets; (4) high rates of roomair exchange; and (5) barriers between patient care and construction areas. Asthe authors point out, various topical agents can diminish colonization, butthis does not appear to reduce the incidence of invasive disease. (Of note,contrary to the authors’ report, amphotericin B oral solution is stillcommercially available.) Health-care workers should consistently followhandwashing recommendations to prevent Candida species transmission topatients.

Shortening the Duration of Neutropenia

Wilkin and Feinberg appropriately emphasize the alteration ofhost risk factors for fungal infection, including the long duration ofneutropenia, corticosteroid use, broad-spectrum antibiotics, and indwellingintravascular devices. Broad-spectrum antibiotic coverage should be narrowed andindwelling catheters should be removed as soon as possible. Although growthfactors, such as granulocyte colony-stimulating factor (G-CSF [Neupogen]) andgranulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]), diminishthe duration of neutropenia, evidence is inconclusive that they reduce theincidence of invasive disease.[2]

In bone marrow transplantation patients receiving fluconazole(Diflucan), Marr and colleagues recently reported that several"traditional" risk factors, including prolonged neutropenia, were lesssignificant predictors of candidemia than were bacteremia, CMV disease, and theadministration of quinolones.[3] Although these findings require confirmation,there is a noteworthy trend toward increasing invasive fungal disease, despiteantifungal prophylaxis and the use of growth factors to shorten the duration ofneutropenia.

Fluconazole

The authors note two of three clinical trials that have shownthat fluconazole, 400 mg/d, decreases the incidence of candidiasis. However, theoptimal duration of fluconazole prophylaxis is unknown.[4-6] Marr and colleaguesrecently reported that in allogeneic bone marrow transplant recipients,fluconazole, 400 mg/d for 75 days after bone marrow transplant, was associatedwith less gut graft-vs-host disease (GVHD), persistent protection againstdisseminated candidiasis and related death, and an overall survival benefit.[7]

As Wilkin and Feinberg note, the data on regimens for theprevention of aspergillosis are inconclusive. In a randomized, controlled trialin patients with hematologic malignancies receiving chemotherapy or bone marrowtransplant, Morgenstern and colleagues reported that patients receivingfluconazole suspension, 100 mg/d, experienced a greater incidence of parenteralamphotericin B use, mucosal candidal infections, and aspergillosis than thosereceiving itraconazole (Sporanox) solution, 5 mg/kg/d. However, the fluconazoledose was significantly less than that which is usually prescribed forprophylaxis.[8]

In a double-blind, placebo-controlled trial of patients withprolonged neutropenia, Nucci and colleagues reported a decrease in the use ofamphotericin B and frequency of systemic fungal disease in patients receivingitraconazole, 100 mg twice daily, vs those receiving placebo.[9] Wolff andcolleagues conducted a randomized trial comparing fluconazole with low-doseamphotericin B and reported no significant difference between the twogroups.[10] Schwartz and colleagues reported no benefit of aerosolizedamphotericin B over placebo in an unblinded, randomized trial; however, theoverall incidence of invasive aspergillosis was low.[11] Although liposomalamphotericin B is as effective as conventional amphotericin B in patients withneutropenic fever,[12] the data supporting liposomal amphoterin B forprophylaxis are insufficient.

In summary, fluconazole, 400 mg/d, has been effective inreducing Candida infection. At this time, however, there are no provenstrategies for reducing the incidence of aspergillosis or other mold infections.Future studies with voriconazole, caspofungin, and interferon gamma may lead toimproved results.

Cytomegalovirus

Disease resulting from CMV infection continues to be one of themost common and dreaded complications following bone marrow transplantation.Attributable mortality remains high after the establishment of end-organ diseasein this population, primarily from the development of CMV pneumonitis—despitethe availability of agents that are active against this virus. Much effort hastherefore been focused on the prevention of CMV infection and diseasedevelopment. In this issue of Oncology, Wilkin and Feinberg provide athorough review of the literature on this topic and outline current strategiesto limit the impact of CMV infection on bone marrow transplant recipients.

The decision of whether to use prophylactic or preemptiveanti-CMV therapy in allogeneic bone marrow transplant recipients at risk fordisease (ie, all recipients who are CMV-seropositive or whose donor isseropositive) depends on several factors and must be individualized to eachinstitution. An important variable in this evaluation includes the capabilitiesof the affiliated virology laboratory to perform sensitive and specific testsfor CMV, such as pp65 antigenemia assays or polymerase chain reaction (PCR).

Most authorities agree, however, that one of the two preventivestrategies should be adopted for at-risk allogeneic bone marrow transplantrecipients—at least between the time of engraftment and 3 to 4 monthsfollowing transplantation.[1] Beyond 100 days, prophylactic therapy has not beenshown to be beneficial, although continued surveillance for CMV may bewarranted, especially if chronic GVHD is present. Because of the low incidenceof CMV disease in autologous bone marrow transplant recipients, prophylaxis isnot recommended in these patients, whereas a preemptive strategy may beappropriate in more immunosuppressed subpopulations.

As discussed by the authors, prophylactic therapy has primarilybeen evaluated for acyclovir and ganciclovir (Cytovene). Despite its favorabletoxicity profile, the modest activity of acyclovir against CMV makes it asuboptimal agent for the purpose of preventing CMV disease. Ganciclovir is thedrug of choice for both prophylactic and preemptive therapy; however, itsmyelosuppressive toxicity often complicates its use in this population.

As outlined by the authors, many different dosing regimens havebeen studied in an attempt to find the proper balance between efficacy andtoxicity, but a consensus does not currently exist. Preemptive strategies arenow favored in most transplant centers because of the increased risk ofbacterial and fungal infections associated with ganciclovir-related prolongationof neutropenia. In addition, the advent of more sensitive CMV detection methodshas improved the ability to detect infection before the onset of end-organdisease. Although Goodrich and colleagues[13] showed improved overall survivalof allogeneic recipients who received ganciclovir preemptive therapy triggeredby a positive CMV culture (from weekly blood, urine, or throat specimens), CMVinfection went unrecognized before the onset of disease in 12% of patients.

The complexity of deciding on a preventive strategy for CMV iswell described by Wilkin and Feinberg, and most likely because of this, theyoffer no specific guidelines. While recognizing the need for more studies, theCDC, IDSA, and ASBMT currently recommend a preemptive approach, using either theCMV pp65 antigenemia assay on leukocytes or PCR assays to initiate ganciclovirtherapy.[1] Future studies evaluating the use of valganciclovir are indevelopment.

References:

1. Centers for Disease Control and Prevention: Guidelines forpreventing opportunistic infections among hematopoietic stem cell transplantrecipients: recommendations of CDC, the Infectious Disease Society of America,and the American Society of Blood and Marrow Transplantation. MMWR49(RR-10):1-125, 2000.

2. Gavira JM, van Burik JH, Dale DC, et al: Comparison ofinterferon-l, granulocyte colony-stimulating factor, and granulocyte-macrophagecolony-stimulating factor for priming leukocyte-mediated hyphal damage ofopportunistic fungal pathogens. J Infect Dis 179:1038-1041, 1999.

3. Marr KA, Seidel K, White TC, et al: Candidemia in allogeneicblood and marrow transplant recipients: Evolution of risk factors after adoptionof prophylactic fluconazole. J Infect Dis 181:309-316, 2000.

4. Goodman JL, Winston DJ, Greenfield RA, et al: A controlledtrial of fluconazole to prevent fungal infections in patients undergoing bonemarrow transplantation. N Engl J Med 326:845-851, 1992.

5. Slavin MA, Osborne B, Adams R, et al: Efficacy and safety offluconazole prophylaxis for fungal infections after marrow transplantation—aprospective, randomized, double-blind study. J Infect Dis 171:1545-1552, 1995.

6. Rotstein C, Bow EJ, Laverdiere M, et al: Randomized,placebo-controlled trial of fluconazole prophylaxis for neutropenic cancerpatients: Benefit based on purpose and intensity of cytotoxic therapy. TheCanadian Fluconazole Prophylaxis Study Group. Clin Infect Dis 28:331-340, 1999.

7. Marr KA, Seidel K, Slavin MA, et al: Prolonged fluconazoleprophylaxis is associated with persistent protection against candidiasis-relateddeath in allogeneic marrow transplant recipients; long-term follow-up of arandomized, placebo-controlled trial. Blood 96:2055-2061, 2000.

8. Morgenstern GR, Prentice AG, Prentice HG, et al: Arandomized, controlled trial of itraconazole versus fluconazole for theprevention of fungal infections in patients with haematoloical malignancies: UKMulticentre Antifungal Prophylaxis Study Group. Br J Haematol 105:901-911, 1999.

9. Nucci M, Biasoli I, Akiti T, et al: A double-blind,randomized, placebo-controlled trial of itraconazole capsules as antifungalprophylaxis for neutropenic patients. Clin Infect Dis 30:300-305, 2000.

10. Wolff SN, Fay J, Stevens D, et al: Fluconazole vs low-doseamphotericin B for the prevention of fungal infections in patients undergoingbone marrow transplantation: A Study of the North American Marrow TransplantGroup. Bone Marrow Transplant 25:853-859, 2000.

11. Schwartz S, Behre G, Heinemann V, et al: Aerosolizedamphotericin B inhalations as prophylaxis of invasive Aspergillus infectionsduring prolonged neutropenia; results of a prospective randomized multicentertrial. Blood 93:3654-3661, 1999.

12. Walsh TJ, Finberg RW, Arndt C, et al: Liposomal amphotericinB for empiric therapy in patients with persistent fever and neutropenia.National Institute of Allergy and Infectious Diseases Mycoses Study Group. NEngl J Med 340:764-771, 1999.

13. Goodrich JM, Mori M, Gleaves CA, et al: Early treatment withganciclovir to prevent cytomegalovirus disease after allogeneic bone marrowtransplant. N Engl J Med 325(23):1601-1607, 1991.