Infections Post Transplant

A nationwide survey of deep fungal infections and fungal prophylaxis after hematopoietic stem cell transplantation in Japan

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Summary:

We conducted a nationwide survey to define incidence of deep fungal infections and fungal prophylaxis practices after HSCT. In all, 63 institutions responded. Total number of in-patient transplantations was 935: 367 autologous, 414 allogeneic myeloablative, and 154 allogeneic reduced-intensity (RIST) (n=154). Number of patients who were cared for in a clean room at transplant was 261 (71%) in autologous, 409 (99%) in conventional and 93 (66%) in RIST, respectively. All patients received prophylactic antifungal agents; 89% fluconazole. Number of patients who received the dosage recommended in the CDC guidelines (400 mg/day) was 135 (42%) in conventional transplant and 34 (30%) in RIST (P=0.037). Number of patients who received fluconazole until engraftment and beyond day 75 in conventional transplant vs RIST was, respectively, 324 (100%) vs 109 (97%), and 39 (12%) vs 18 (16%), with no significant difference between the two groups. A total of 37 patients (4.0%) were diagnosed with deep fungal infections; autologous transplantation (0.03%), conventional transplantation (6.0%) and RIST (7.1%). Wide variations in antifungal prophylaxis practice according to the type of transplant and the institutions, and deep fungal infection remain significant problems in RIST.

Main

Fungal infection is a common complication after hematopoietic stem cell transplantation (HSCT), and the primary causative organisms are Candida and Aspergillus, with significant mortalities even if properly treated with antifungal agents.1 Therefore, antifungal prophylaxis has been emphasized following HSCT.2 In 2000, the Centers for Disease Control and Prevention (CDC) in the United States issued guidelines for the prevention of fungal infections in the setting of allogeneic HSCT and some cases of autologous transplantation,3 and these are considered a gold standard in many countries throughout the world, including Japan. To prevent Candida infections, the CDC guidelines recommend the use of fluconazole (400 mg/day) until engraftment,3 based on the results of two randomized controlled studies published in 1992 and 1995.4,5 However, since then, the circumstances surrounding HSCT have been changing rapidly. The use of fluconazole has been questioned, since it is ineffective against Aspergillus species. Moreover, the rationale for selecting the recommended dose of 400 mg/day fluconazole and the optimal duration of prophylaxis need to be clarified.6 A major concern regarding emerging fluconazole-resistant Candida species needs to be critically evaluated.7,8

Aspergillus is the most common pathogen in fungal infections in the course of transplantation or treatment for leukemia.9 The importance of hospital environment control has been emphasized for effective prevention. The outbreak of nosocomial infections due to the renovation of transplant buildings10,11 and via the water system in transplant wards has been reported.12 The CDC guidelines recommend the use of air conditioning systems/tools.3 However, the guidelines may have become outdated due to changing circumstances. First, the timing of the development of aspergillosis has changed. Most Aspergillus infections occur late beyond 100 days after transplantation.13 This trend may be enhanced by the wider application of reduced-intensity stem cell transplantation (RIST) on an outpatient basis.14 Second, newly developed antifungal agents have been shown to be effective in the prevention of Aspergillus infection.15,16 Moreover, a recent drastic change is that RIST has been extended to unrelated transplantation,17 umbilical cord blood transplantation18 and elderly patients.19 RIST has the advantage of a shorter period of neutropenia, and it is likely that the incidence of Candida infection is reduced. On the other hand, the incidence of steroid-therapy requiring GVHD remains the same as in conventional transplantations, and the intensity of immune suppression is similar.20 It is expected that late-occurring fungal infections by Aspergillus, etc may become a significant problem after RIST.21,22,23

Thus, a re-evaluation and update of the guidelines appears to be necessary, particularly in the area of RIST. There have been only a few studies on fungal infections after RIST.21,22,23 The objective of this study was to survey antifungal prophylaxis in Japanese transplantation practice, and to compare the findings in RIST, conventional allogeneic transplantation (CST), and autologous transplantation.

Patients and methods

Data collection

Of the 418 Japanese medical institutions in which HSCT is performed, 122 institutions agreed to participate in this survey. Each of these institutions received a questionnaire that included the following items: the number of transplantations performed in 2001, the type of the patient's disease and the type of transplantation, use of a clean room or designated room for transplantation, practice regarding prophylactic use of antifungal agents, and occurrence of systemic fungal infections. For cases that developed deep fungal infections, age, sex, date of onset, diagnostic approaches, infected organs, pathogens, neutrophil count at onset, coexistence of GVHD, use of immunosuppressants, prophylactic use of antifungal agents, and patient outcome were also recorded.

We used the EORTC/NIH-MSG criteria for the diagnosis of deep fungal infections.24 We defined both proven and probable infectious cases as deep fungal infection.

Antifungal prophylaxis measures

We defined the nine measures listed below as measures for preventing fungal infection. All of the methods were evaluated as A or B based on the evidence level in the CDC guidelines, as previously reported.25 The guidelines use a combination of category (A–D) and the recommendation (I–III). We used two recommendation levels, A and B, which indicated strong or moderate evidence supported by well-established clinical trials (I or II) or respected authorities (III).

  • (a) Yeast infection following allogeneic HSCT

  • (a1) Medical staff in contact with HSCT recipients should follow appropriate hand-washing practices to safeguard patients from exposure (Evidence level A III).

  • (a2) Fluconazole (400 mg/day, orally or intravenously) should be administered from the day of transplant until engraftment (Evidence level A II).

  • (b) Mold infections following allo-SCT

  • (b3) HSCT recipients who remain immunocompromised should avoid hospital construction or renovation areas (Evidence level A III).

  • (b4) Use of high efficiency particulate air (HEPA) filtration (Evidence level B III).

  • (b5) Air should flow from patient rooms to corridors (Evidence level B III).

  • (b6) Correctly sealed rooms, including correctly sealed windows and electrical outlets (Evidence level B III).

  • (b7) High rates of room air exchange (ie, >12 air changes/h) (Evidence level B III).

  • (b8) Barriers between patient care areas and renovation or construction areas to prevent dust from entering patient care areas. The barriers must be impermeable to Aspergillus species.

  • (c) Autologous HSCT

  • (c9) Autologous HSCT recipients generally are at lower risk of invasive fungal infection than allogeneic HSCT recipients. Autologous HSCT recipients do not require routine intense anti-yeast prophylaxis. Nevertheless, some researchers recommend the use of an anti-yeast prophylaxis in patients who have underlying hematologic malignancies, and who have or will have prolonged neutropenia and mucosal damage from intense conditioning regimens or graft manipulation, or who have recently received purine analogues (Evidence level B III). Regarding mold infections, no guideline has been reported for autologous HSCT.

Prophylaxis for deep fungal infections in Japan

In Japan, the antifungal agents approved for the treatment of deep fungal infections in 2001 included amphotericin B, fluconazole, itraconazole, miconazole and terbinafine. With the exception of itraconazole, they can be administered either orally or intravenously. The only available formula of itraconazole was a capsule, and in this form, absorption through the gastrointestinal tract is inconsistent.26 Itraconazole oral solution, voriconazole, liposomal amphotericin B and echinocandin have not yet been approved.

Governmental approval has not yet been granted for the prophylactic use of any antifungal agents, although this is widely applied as a practice in most medical institutions.27 Fluconazole, up to 400 mg, is approved only for the treatment of fungal infection.

Use of a clean room within a transplant ward is reimbursed by insurance. We considered that prophylactic measures (b3)–(b8) were satisfied if HSCT was performed in a clean room. A clean room was defined as an isolated room equipped with HEPA filtration and air flow toward an exit of the room with sealed windows.

End points and statistical methods

The objective of this study was to conduct a survey of antifungal prophylaxis in HSCT. The levels of compliance with the established prophylactic measures in RIST and CST were compared. The second objective was to compare the CST, RIST and auto-SCT groups with respect to the incidence and characteristics of fungal infections.

We examined (a2) and (b3)–(b8) of the nine items listed above. Item (a1) was excluded from the survey because of inconsistency of proper evaluation in a retrospective survey. We considered that items (b3)–(b8) were satisfied when a clean room was used. We aimed to evaluate differences in fungal prophylaxis between conventional and reduced-intensity transplants. We did not collect detailed information on transplantation procedures such as stem cell sources and drugs used in the preparative regimens. A univariate analysis using Fisher's exact test and the Mann–Whitney U test was performed to compare the differences in prophylactic measures between RIST and CST. Values of P<0.05 were considered significant.

Results

Patients background

We received questionnaires from 63 medical institutions, representing 935 transplantations. In Japan, a total of 1964 transplantations were performed in 2001,28 and approximately half of the patients were surveyed in this study. The median number of transplantations per institute/year was 10 (range, 1–108). The types of transplantation were autologous HSCT (367, 40%), CST (414, 45%), and RIST (154, 15%). All of the RIST recipients received purine-analog-based preparative regimens with or without low-dose TBI.

Patients’ diseases included malignant lymphoma (191 cases, 21%), acute myelocytic leukemia (147, 16%), acute lymphocytic leukemia (107, 11%), multiple myeloma (80, 9%), chronic myelocytic leukemia (74, 8%), myelodysplastic syndrome (51, 5%), solid tumors (50, 5%), aplastic anemia (16, 2%), and others (219, 23%).

All patients were hospitalized during transplantation. The number of autologous HSCT, CST and RIST recipients who were in a clean room at the time of transplantation was 261/367 (71%), 409/414 (99%) and 93/154 (66%), respectively.

Prophylactic use of antifungal agents

All patients including autologous HSCT cases received an antifungal agent as a prophylaxis, and azole antifungal agents were administered in 742 patients (79%). The most commonly used azole antifungal agent was fluconazole (89%). Figure 1 shows the types of agents used in CST, RIST and autologous HSCT.

Figure 1
figure1

Types of prophylactic antifungal agents used in each type of HSCT Azole agents were the most-administered drugs for prophylactic use in HSCT patients.

Fluconazole was administered to 324 (78%) CST and 112 (73%) RIST recipients. The numbers of patients who received fluconazole 400, 200 and 100 mg/day were 135 (42%), 169 (52%) and 20 (6%), respectively. Those patients who were given fluconazole 400, 200 and 100 mg/day were 34 (30%), 70 (63%) and 8 (7%), respectively. Significantly larger doses of fluconazole were used in CST than in RIST (P=0.037).

The numbers of patients who received fluconazole until engraftment and beyond day 75 in the CST and RIST groups were, respectively, 324 (100%) and 39 (12%), and 109 (97%) and 18 (16%). Duration of fluconazole use was not significantly different between CST and RIST.

Incidence and clinical characteristics of deep fungal infections

Of the 935 transplant cases, 37 (4.0%) were diagnosed with deep fungal infections (13 proven and 24 probable cases); 0.03% (1/367) of autologous HSCT, 6.0% (25/414) of CST, and 7.1% (11/154) of RIST. The causative organisms included Candida (n=9), Aspergillus (n=16), Mucor (n=1), Fusarium (n=1) and unknown (n=10). The median onset date from the time of transplant was 85 days (range, 1–392 days): 92 days in CST and 117 days in RIST, with nine cases developing within 30 days of transplant (one case in autologous HSCT, seven in CST and one in RIST). Three cases of 37 deep fungal infections had a previous history of fungal infection. All of them received fluconazole and AMPH-B intravenously as a prophylaxis.

The causative organisms for the nine cases of candidiasis included C. albicans (n=4), C. glabrata (n=2), C. tropicalis (n=1), C. inconspicua (n=1), and a combination of C. lusitaniae and C. guilliermondii (n=1). The infected organs included blood (fungemia, six cases), the respiratory system (n=2) and the liver and spleen (n=1). Among four patients who were infected with C. albicans, two had not received any antifungal agents including fluconazole as a prophylaxis, while the remaining two cases had been on fluconazole prophylaxis and were considered to be prophylaxis failure. Among these four patients, three started or continued to receive fluconazole following infection, and three patients subsequently died.

The causative organisms for the 16 cases of aspergillosis included Aspergillus spp. (n=14), A. fumigatus (n=1) and A. terreus (n=1). Six and 10 of these patients received RIST and CST, respectively. In all, 14 and two patients had received prophylactic fluconazole and itraconazole, respectively. GVHD requiring corticosteroid therapy was documented at the onset of the disease in 13 of the 16 cases. The initially infected organ was the respiratory system in all cases, with a median onset of invasive aspergillosis of 85 days (range, 9–392). Four of the 16 patients were neutropenic at the diagnosis of aspergillosis. Treatment for invasive aspergillosis included intravenous AMPH-B (13 cases), oral itraconazole (two cases), and fluconazole (one case). Eight patients subsequently died without resolution of invasive aspergillosis.

Comparison of CST and RIST recipients

Table 1 shows the characteristics of fungal infections developed in CST and RIST recipients. There was no significant difference between the two groups with respect to the incidence, date of onset or death rate.

Table 1 Comparison on clinical features of deep fungal infection between CST and RIST

Discussion

This study highlights the current problems in antifungal prophylaxis. In Japan, a total of 1964 transplantations were performed in 2001,28 and about half of these were surveyed in this study. We believe that sufficient data were collected to characterize prophylaxis practice and fungal infection in this country, while it is limited by bias as a retrospective design, and we should be careful in interpreting the results of this study.

With improvements in prophylactic measures, the incidence of early mold infections has decreased,14,29,30 and most infections occur late in association with GVHD.13 The need for a HEPA filter or laminar air flow (LAF) may be questioned in RIST. All transplant wards in Japan, but not all nontransplant wards, are equipped with these systems. Although 99% of CST was performed in transplant wards, this percentage decreased to 71% in autografts and 66% in RIST. The potential economic benefits of RIST may be related to an increase in RIST performed in nontransplant wards without expensive air filtration systems.

In autologous HSCT, the prophylactic use of antifungal agents is recommended only for high-risk patients3 based on several clinical studies.4,31 However, this study demonstrates that all of the Japanese autologous HSCT recipients received some prophylactic antifungal agents. This is an overuse of antifungal agents because the overall risk of fungal infection in autologous transplants is lower than allogeneic transplant. There are several possible explanations for this overuse. Since the definition of ‘low-risk patients’ in the CDC guidelines is unclear, physicians take a more conservative way to reduce the risk of fungal infection. It has been suggested that long-term use of azole antifungal agents may cause resistance.32 Additionally, azole antifungal agents are expensive, and long-term use is not economical.33 On the other hand, for the prophylactic use of antifungal agents in allogeneic transplant, the CDC recommends prophylactic fluconazole 400 mg/day during the neutropenic period following transplantation. However, the rationale for the selection of fluconazole from among many other available antifungal agents, its dose setting and prophylaxis period remain unclear. Its usefulness in RIST recipients has not been established.

After the CDC issued its guidelines in 2000, various drugs, including voriconazole, itraconazole (oral solution and intravenous formulation), and echinocandin, have been developed and are now commercially available. Moreover, Aspergillus is not susceptible to fluconazole, and recent comparative studies suggest that itraconazole is more effective than fluconazole in the prevention of Aspergillus infection.15,34 Hence, the recommendation of fluconazole over any other agent may no longer be defensible. Nevertheless, this study clearly documented that fluconazole was used in 75% of allogeneic transplant in Japan. This bias is likely due to the CDC recommendation and to the fact that an alternative antifungal agent is not commercially available in Japan. As of June 2003, the only available itraconazole formula in Japan is a capsule, which carries an obvious risk of inadequate absorption of the drug. Voriconazole and caspofungin have not yet been approved, and micafungin was approved only recently. Regarding Aspergillus infections, it is difficult to conclude that the CDC's recommendation for the prophylactic administration of fluconazole is useful. With the present availability of all of these alternative agents, a comparative study to identify a suitable procedure will be required.

While all of the patients received prophylactic fluconazole at least until engraftment, only 44% received the recommended dose of 400 mg/day. Moreover, only 20% of both the CST and RIST recipients received fluconazole beyond 75 days following transplantation, as recommended in a previous study.6 It has been reported that C. albicans can be controlled at a lower dose of 200 mg/day.35,36 Many physicians believe that 400 mg of fluconazole is not required for prophylactic use, and optimal duration of fluconazole prophylaxis remains to be established. Since fluconazole is expensive and costs about 100 000 yen ($850) when used at 400 mg/day to cover from the commencement of pre-transplant treatment and engraftment, validation of the adequate dose and the duration for prophylactic use is important.

With an increasing number of patients undergoing transplant, establishment of fungal management is important in RIST. The practice for the prevention and treatment of fungal infection varies among institutions. Mortality of invasive aspergillosis was 50% in this survey, which were far lower than reported previously.1 The differences might be attributable to diagnostic approaches. In Japan, diagnostic measures using computed tomography and blood tests such as beta-D-glucan assay or an enzyme-linked immunosorbent test detecting galactomannan antigen are widely used.37,38,39 These tests might have contributed to make an early diagnosis of aspergillosis, improving its prognosis. These situations are similar to antifungal prophylaxis. The guidelines for antifungal prophylaxis, which were prepared based on previous clinical studies, should be updated, since the circumstances surrounding transplantation have been changing. However, there are little data to make new recommendations for guidelines of antifungal prophylaxis, and more information is needed regarding fungal infections following RIST. Further investigation is needed to determine what measures are effective to accommodate the changes in transplant practices.

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Acknowledgements

This study was supported by a Grant-in-Aid for scientific research from the Ministry of Health, Labor and Welfare.

Author information

Correspondence to M Kami.

Appendix

Appendix

This study was conducted at the following institutions under the auspices of the following investigators in Japan:

Masaya Mukai (Sapporo City General Hospital, Hokkaido), Aoyagi Yumei (Dokkyo University School of Medicine, Tochigi), Kazuaki Yakushiji (Kurume University School of Medicine, Fukuoka), Hisashi Tsurumi (Gifu University School of Medicine, Gifu), Yukiyoshi Moriuchi (Sasebo City General Hospital, Nagasaki), Shin Imamura (Fukui Medical University, Fukui), Hiroatu Ago (Shimane Prefectural Central Hospital, Shimane), Sachiko Suzuki (Hakodate Central General Hospital, Hokkaido), Akira Yokota (Chiba Aoba Municipal Hospital, Chiba), Hideki Mitsui (Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka), Yuichi Ishikawa (Chukyo Hospital, Aichi), Yasushi Takamatsu (Fukuoka University School of Medicine, Fukuoka), Kazutaka Sunami (National Okayama Medical Center, Okayama), Nobuo Masauzi (Hakodate Manucipal Hospital, Hokkaido), Tsunehiko Komatsu (Tsukuba Memorial Hospital, Ibaraki), Tadao Ishida (Sapporo Medical University School of Medicine, Hokkaido), Hideo Hyodo (Hiroshima University Research Institute for Radiation Biology and Medicine, Hiroshima), Hiroto Kaneko (Aiseikai-Yamashina Hospital, Kyoto), Hidetaka Takimoto (Kochi Municipal Central Hospital, Kochi), Tadasu Tobita (Yakizu City Hospital, Shiga), Tsutomu Kato (Toyama Medical and Pharmaceutical University, Toyama), Eiichi Ohtsuka (Oita Medical University, Oita), Hideo Kimura (Kita-Fukushima Medical Center, Fukushima), Kimiharu Uozumi (Kagoshima University, Faculty of Medicine, Kagoshima), Toshiro Ito (Shinshu University, The Department of Medicine, Nagano), Masami Inoue (Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka), Yoshinao Yamamoto (Kishiwada City Hospital, Osaka), Shoichi Doi (Kyoto-Katsura Hospital, Kyoto), Yasuhiko Miyazaki (Kansai Medical University, Osaka), Jyunichi Yamagami (Saitama Prefectural Children Medical Center, Saitama), Toshiharu Tamaki (Rinku General Medical Center, Osaka), Yujiro Yamano (Kyushu Kosei-Nenkin Hospital, Fukuoka), Makoto Hirokawa (Akita University School of Medicine, Akita), Shuji Ozaki (Tokushima University Hospital, Tokushima), Koichiro Muta (Kyushu University Graduate School of Medical Science, Fukuoka), Shuichi Hanada (National Kyushu Cardiovascular Center, Fukuoka), Nobuhiko Uoshima (Matsushita Memorial Hospital, Osaka), Hiroyuki Tsuda (Kumamoto City Hospital, Kumamoto), Chihiro Shimazaki (Kyoto Prefectural University of Medicine, Kyoto), Atsushi Wakita (Nagoya City University Graduate School of Medical Sciences, Aichi), Tetsuya E Tanimoto (Kyushu University Faculty of Medicine, Fukuoka), Masaki Ri (Shizuoka Saiseikai General Hospital, Shizuoka), Eisaburo Sueoka (Saga Medical School, Saga), Jyunichi Tsukada (University of Occupational and Environmental Health School of Medicine, Fukuoka), Akihiro Ihara (National Hospital Kure Medical Center, Hiroshima).

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Imataki, O., Kami, M., Kim, S. et al. A nationwide survey of deep fungal infections and fungal prophylaxis after hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant 33, 1173–1179 (2004) doi:10.1038/sj.bmt.1704526

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Keywords

  • hematopoietic stem cell transplantation (HSCT)
  • fungal infection
  • antifungal prophylaxis
  • reduced-intensity stem cell transplantation (RIST)

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