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Prophylaxis Against Fungal Infections and Cytomegalovirus Disease After Bone Marrow Transplantation

Prophylaxis Against Fungal Infections and Cytomegalovirus Disease After Bone Marrow Transplantation

During the last decade, there has been much debate concerning the utility of strategies for primary and secondary prophylaxis of common infections in immunocompromised hosts—namely those caused by cytomegalovirus (CMV) and fungi. In this issue of Oncology, Drs. Wilkin and Feinberg present a review of studies performed to address prevention of infection. The two major advances of the late 1980s and 1990s were the introduction of fluconazole (Diflucan) for prevention of Candida infection and ganciclovir for prevention of CMV infection and disease. Although a number of randomized trials of these agents have been performed, controversy persists regarding their optimal use. Recent information on the importance of host risk factors and pathogen pathogenesis should allow us to use these drugs in a cost-effective manner.

Candidiasis Prevention

One area of controversy is the use of fluconazole for the prevention of infection with C albicans and C tropicalis. Points of controversy include the optimal dose and duration of treatment as well as the patient population that might benefit. Because risks for Candida and Aspergillus infections are not limited to the neutropenic period, any conclusions from trials have been qualified by the inclusion of patients with different risk factors. This is especially true in the case of allogeneic hematopoietic stem cell transpant (HSCT) recipients, who continue to be at risk for candidiasis and aspergillosis during acute graft-vs-host disease.[1,2] Subtle differences in risks have not always been appreciated, leading to conflicting results.

A good example comes from two large studies performed in the early 1990s that randomized HSCT recipients to fluconazole vs placebo and produced disparate results.[3,4] One trial enrolled a 50:50 ratio of autologous and allogeneic HSCT recipients and administered the drug only during neutropenia[4]; the other enrolled predominantly allograft recipients (88%) and administered the drug during graft-vs-host disease.[3] Only the study that enrolled the high-risk patients found a survival benefit.

Follow-up studies have documented that prophylactic therapy in high-risk populations can have a significant impact on survival, especially if the drug is given during the period of risk. This was recently confirmed in a long-term follow-up study of the Slavin trial, which documented a 17% survival benefit after 8 years in allograft recipients who received fluconazole.[5] This study demonstrates the difference between risks in autologous and allogeneic transplant patients. Other recent randomized studies have shown that specific risks dictate the benefit of prophylaxis in patients with chemotherapy-induced neutropenia.[6] Historically, lumping these patients together has resulted in a dilution of survival benefits, and sample sizes have not been large enough to enable legitimate stratification of high- vs low-risk populations.

The importance of host risk factors is supported further by large retrospective studies, which have also demonstrated the survival advantage attributable to prophylactic therapy. One such study documented in a multivariable model that fluconazole prophylaxis is an independent predictor of survival in patients who receive an unrelated-donor HSCT for underlying chronic myelogenous leukemia.[7] Collectively, these data suggest that anti-C albicans prophylaxis is effective and indicated for high-risk patients. Anti-Aspergillus prophylaxis is a different issue, given the differences among the pathogens.

One concern with fluconazole prophylaxis arises from the emergence of drug resistance in non-albicans Candida species. While it is true that infection with C glabrata and C krusei infections have increased during the "azole era," there is some indication that infection caused by these organisms is associated with a lower incidence of sepsis, peripheral manifestations, and mortality. One study noted a decrease in mortality associated with C glabrata and C krusei infections in HSCT recipients compared to infections caused predominantly by C albicans and C tropicalis.[1] Another review of outcomes did not show such an effect, as people with C glabrata infections had the worst survival.[8]

While the issue of outcome is obviously mired in factors associated with both underlying disease and therapy, it must be appreciated that Candida species differ not only with regard to antifungal susceptibilities, but pathogenic potential as well. Thus, continued surveillance is necessary to determine the overall impact of the emergence of more resistant but less virulent organisms.

Aspergillosis Prevention

Fluconazole has no activity against Aspergillus species, and prophylaxis against these pathogens may present different challenges, given the toxicities associated with effective therapies. Prophylaxis strategies may be challenged further by the exogenous pulmonary acquisition of the organism and the fact that the primary risk period now extends beyond engraftment in allogeneic transplant recipients with graft-vs-host disease or on steroid therapy.[2] Drs. Wilkin and Feinberg discuss several studies that utilize amphotericin B formulations and itraconazole (Sporanox). Other more recent studies are worthy of mention.

One was a German trial that compared the use of nebulized amphotericin B with standard strategies.[9] Although this trial failed to show a statistical difference in aspergillosis, it did demonstrate a trend toward decreased infection, despite a low rate of invasive infection in the prophylactic arm (7% vs 4%). Also, the results of more recent European studies using the better-absorbed liquid formulation of itraconazole suggest that this drug may effectively prevent Aspergillus infections.[10] Definitive conclusions await trials performed in more high-risk patients.

Finally, it must be mentioned that although low doses of amphotericin B result in decreased levels of nephrotoxicity, they also result in low—perhaps ineffective—tissue concentrations. The future of Aspergillus prevention will more likely be affected by the introduction of new mold-active azoles and tests to detect circulating Aspergillus, such as galactomannan antigen or polymerase chain reaction.[11]

Cytomegalovirus Prevention

Early CMV disease has been reduced dramatically with the use of ganciclovir prophylaxis or preemptive therapy. Progress in CMV diagnostics resulted in widespread use of preemptive therapy, which is now guided primarily by detection of pp65 antigenemia or CMV DNA.[12] However, preemptive therapy continues to fail in about 3% to 6% of CMV seropositive allogeneic recipients.[13,14] The reasons for failure include lack of detection of CMV prior to the onset of CMV disease, progression to CMV disease while on preemptive therapy, and early rebound disease immediately after discontinuation of preemptive therapy.

Recent insight into the viral dynamics of CMV replication in vivo can be used to optimize preemptive strategies. The in vivo doubling time of CMV in HSCT recipients is only 1 day, compared to the replication time in fibroblast cell lines, where CMV replicates very slowly and both the initial viral load and the slope of increase of the CMV load are risk factors for CMV disease.[15,16] Also, our recent data have found that up to 40% of HSCT recipients have increases in the CMV load during ganciclovir therapy—depending on the cumulative dose of corticosteroids.[17]

Given the short doubling time of CMV in vivo and its apparent correlation with the underlying immunosuppression, twice-daily induction doses of anti-CMV treatment should be continued until the CMV load starts declining. Conversely, in patients who show an immediate decline in viral load, 1 week of induction dosing seems to be sufficient. If viral load increases occur during the receipt of maintenance doses of ganciclovir, reinduction should be performed. If increases in viral load occur after prolonged exposure to antiviral therapy (> 4 weeks), antiviral resistance should also be considered.

Both short-term and long-term courses of ganciclovir have been used for preemptive therapy. Short courses are usually administered until the virologic marker is negative, although repeated courses may be required. Advantages of short-term treatment include lower cost, a lower risk for side effects, and an improved CMV-specific immune reconstitution, which may be associated with a lower risk for late CMV disease.[18]

The paradigm of using host immune status to stratify prophylaxis by risk also applies to CMV prevention strategies. As discussed in the review, low-dose intermittent maintenance dosing is not effective in recipients of T-cell-depleted or unrelated-donor transplants,[19] probably due to shorter replication time of CMV in these patients. Also, a recent study suggests that CD34 selection of the stem cell product dramatically increases the risk of CMV in high-risk autologous transplant recipients.[20] Thus, prevention strategies can be designed that take into account host immune status using quantitative measurements of viral dynamics.

Conclusions

The review by Drs. Wilkin and Feinberg discusses the results of prophylaxis studies that were performed in the early 1990s, and concludes that the most important factor is to define risk factors to guide CMV and antifungal prophylaxis. We would go one step further and state that more recent data have definitely documented the benefits of both anti-C albicans and anti-CMV strategies in high-risk patients. In fact, it is possible that the debate continues only because successful prevention of early death due to these organisms enables infection with new pathogens, such as non-albicans Candida species and Aspergillus.

References

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

2. Wald A, Leisenring W, van Burik J, et al: Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 175:1459-1466, 1997.

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

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

5. Marr K, Seidel K, Slavin M, et al: Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: Long-term follow-up of a randomized, placebo-controlled trial. Blood 96:2055-2061, 2000.

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

7. Hansen JA, Gooley TA, Martin PJ, et al: Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338:962-928, 1998.

8. Viscoli C, Girmenia C, Marinus A, et al: Candidemia in cancer patients: A prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis 28:1071-1079, 1999.

9. Schwartz S, Behre G, Heinemann V, et al: Aerosolized amphotericin B inhalations as prophylaxis of invasive Aspergillus infections during prolonged neutropenia: Results of a prospective randomized multicenter trial. Blood 93:3654-3661, 1999.

10. Morgenstern G, Prentice A, Prentice H, et al: A randomized controlled trial of itraconazole vs fluconazole for the prevention of fungal infections in patients with hematological malignancies. Br J Haematol 105:901-911, 1999.

11. Maertens J, Verhaegen J, Demuynck H, et al: Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for hematological patients at risk for invasive Aspergillosis. J Clin Microbiol 37(10):3223-3228, 1999.

12. Boeckh M, Boivin G: Quantitation of cytomegalovirus: Methodologic aspects and clinical applications. Clin Microbiol Rev 11:533-554, 1998.

13. Boeckh M, Gooley TA, Myerson D, et al: Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir vs ganciclovir at engraftment after allogeneic marrow transplantation: A randomized double-blind study. Blood 88:4063-4071, 1996.

14. Einsele H, Ehninger G, Hebart H, et al: Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation. Blood 86:2815-2820, 1995.

15. Emery VC, Cope AV, Bowen EF, et al: The dynamics of human cytomegalovirus replication in vivo. J Exp Med 190:177-182, 1999.

16. Emery VC, Sabin CA, Cope AV, et al: Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 355:2032-2036, 2000.

17. Nichols WG, Corey L, Gooley T, et al: Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: Risk factors, correlation with DNA load, and outcomes. blood (in press, 2001).

18. Boeckh M, Riddell SR, Cunningham T, et al: Increased incidence of late CMV disease in allogeneic marrow transplant recipients after ganciclovir prophylaxis is due to a lack of CMV-specific T cell responses. Blood 88(suppl 1):302a, 1996.

19. Atkinson K, Arthur C, Bradstock K, et al: Prophylactic ganciclovir is more effective in HLA-identical family member marrow transplant recipients than in more heavily immune-suppressed HLA-identical unrelated donor marrow transplant recipients. Australasian Bone Marrow Transplant Study Group. Bone Marrow Transplant 16:401-405, 1995.

20. Holmberg L, Boeckh M, Hooper H, et al: Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation. Blood 94:4029-4035, 1999.

 
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