In a recent Blood article, Schwartz et al reported on the largest cohort of patients with central nervous system (CNS) aspergillosis published to date.1  In this study, complete and partial responses were recorded in 35% of patients, which is much better than previous reports, when mortality rates were close to 100%.2  The authors concluded that voriconazole treatment together with neurosurgical management, whenever feasible, is currently the best approach to treat patients with CNS aspergillosis.1 

We fully agree that voriconazole represents an outstanding progress for the treatment of invasive aspergillosis, and probably even more among patients with CNS involvement because of voriconazole pharmacokinetic properties.3,4  Likewise, progress in neurosurgical procedures may allow more effective management of CNS aspergillosis complications in selected cases.2,5  However, our ability to more easily reduce or reverse the underlying immunosuppression in these patients is another factor that may have played a significant role in the improved outcome of CNS aspergillosis during recent years. Long-term survivors in Schwartz et al's series were mostly patients with low or chronic underlying immunosuppression, and patients with hematopoietic stem cell transplantation had an inferior outcome compared with all other patients.1  Experimental studies as well as case series strongly suggest that underlying immunosuppression is one of the most powerful predictive factors in invasive aspergillosis.2,6  According to the Infectious Diseases Society of America (IDSA) guidelines, the ultimate response of invasive aspergillosis to antifungal therapy is largely related to host factors, such as the resolution of neutropenia and the return of neutrophil function, lessening immunosuppression and the return of graft function from a bone marrow or organ transplant.5  The emerging repertoire of novel immunosuppressive agents allows more specific tailoring on the immune system,7  while the growing use of adjuvant therapies such as growth factors in neutropenic patients can augment antifungal therapy.2 

Attempts to reverse underlying factors and particularly to reduce the level of immunosuppression is a key component in the treatment of patients with invasive aspergillosis. This aspect should not be forgotten, even in the era of new antifungal agents and improved neurosurgical procedures.

Improved outcome in CNS aspergillosis, using voriconazole

We appreciate the comments made by Tattevin and Le Tulzo and fully agree that the type and degree of immunosuppression is likely a prognostic factor in patients with invasive aspergillosis. This is also reflected by the varying response and survival rates in patient subgroups with different causes and severities of immunosuppression in our recent analysis of central nervous system (CNS) aspergillosis.1  However, there is no clear evidence that a low burden of immunosuppression is associated with less than 90% to 100% mortality in patients treated with antifungal drugs other than voriconazole for CNS aspergillosis. It is noteworthy that the response rate of patients with hematologic malignancies was comparable with that of patients with chronic immunosuppression or other underlying conditions. However, 7 (54%) of 13 patients with hematologic malignancies eventually died due to causes unrelated to CNS aspergillosis.1 

It is well established that various types of immunosuppression (eg, neutropenia, corticosteroid therapy, and graft-versus-host disease after hematopoietic stem cell transplantation) increase the risk for invasive fungal infections.2-4  However, it is less clear that modulation of immunosuppression always impacts positively on the outcome. Clinicopathologic data clearly indicate that the use of higher corticosteroid doses and OKT3 is associated with a higher mortality rate in nonneutropenic patients with filamentous fungal infections after allogeneic hematopoietic stem cell transplantation.5  Interestingly, the predominant histopathologic finding in these patients was acellular necrosis, suggesting that corticosteroids severely impair leukocyte trafficking. Although regaining neutrophil function is commonly regarded as an important factor for a successful outcome, recovery from neutropenia was not associated with an improved survival in a recent study evaluating 87 patients with invasive aspergillosis.6  Furthermore, fatal pulmonary complications in patients with mold infections have been reported repeatedly upon recovery from neutropenia.7,8  This is supported by experimental data demonstrating that the neutrophil response is a major cause of tissue damage.9  The current dilemma, especially in patients who have had allogeneic hematopoietic stem cell transplantation and invasive aspergillosis, is to reduce the burden of immunosuppression while maintaining a low risk of graft-versus-host disease. Optimal patient management after restoration of the immune function clearly needs further study.

Correspondence: Stefan Schwartz, Medizinische Klinik III, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; e-mail: stefan.schwartz@charite.de.

1
Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in central nervous system aspergillosis, using voriconazole treatment.
Blood
.
2005
;
106
:
2641
-2645.
2
Patterson TF. Advances and challenges in management of invasive mycoses.
Lancet
.
2005
;
366
:
1013
-1025.
3
Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections.
Lancet
.
2003
;
362
:
1828
-1838.
4
Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors.
Blood
.
2002
;
100
:
4358
-4366.
5
Shaukat A, Bakri F, Young P, et al. Invasive filamentous fungal infections in allogeneic hematopoietic stem cell transplant recipients after recovery from neutropenia: clinical, radiologic, and pathologic characteristics.
Mycopathologia
.
2005
;
159
:
181
-188.
6
Ellis M, Spence D, de Pauw B, et al. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages of liposomal amphotericin B for treatment of invasive aspergillosis.
Clin Infect Dis
.
1998
;
27
:
1406
-1412.
7
Pagano L, Ricci P, Nosari A, et al. Fatal haemoptysis in pulmonary filamentous mycosis: an underevaluated cause of death in patients with acute leukaemia in haematological complete remission: a retrospective study and review of the literature.
Br J Haematol
.
1995
;
89
:
500
-505.
8
Todeschini G, Murari C, Bonesi R, et al. Invasive aspergillosis in neutropenic patients: rapid neutrophil recovery is a risk factor for severe pulmonary complications.
Eur J Clin Invest
.
1999
;
29
:
453
-457.
9
Stephens-Romero SD, Mednick AJ, Feldmesser M. The pathogenesis of fatal outcome in murine pulmonary aspergillosis depends on the neutrophil depletion strategy.
Infect Immun
.
2005
;
73
:
114
-125.
1
Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in central nervous system aspergillosis, using voriconazole treatment.
Blood
.
2005
;
106
:
2641
-2645.
2
Patterson TF. Aspergillus species. In: Mandell GL, Bennett JE, Dolin R, eds.
Principles and Practice of Infectious Diseases. Sixth ed.
Philadelphia, PA: Churchill Livingstone,
2005
:
2958
-2972.
3
Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.
N Engl J Med
.
2002
;
347
:
408
-415.
4
Lutsar I, Roffey S, Troke P. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients.
Clin Infect Dis
.
2003
;
37
:
728
-732.
5
Stevens DA, Kan VL, Judson MA, et al. Practice guidelines for diseases caused by Aspergillus: Infectious Diseases Society of America.
Clin Infect Dis
.
2000
;
30
:
696
-709.
6
Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature.
Clin Infect Dis
.
2001
;
32
:
358
-366.
7
Ingelfinger JR, Schwartz RS. Immunosuppression—the promise of specificity.
N Engl J Med
.
2005
;
353
:
836
-839.