Dr. Patterson from the University of Texas Health Science Center at San Antonio
reviewed the difficulties in diagnosing and treating refractory invasive
aspergillosis (IA).
Dr. Patterson began by presenting data showing the increase in mortality from
Aspergillus
infections
since the 1980s. This increase is reported in a recent review by Lin and
colleagues,
1 who reviewed 1,941 patients from 50 studies. The
overall mortality rate was 58% in patients with IA. In BMT patients, however,
mortality was greater than 90%, a result of severe immunosuppression and
underlying disease according to Dr. Patterson. These data suggest that dramatic
changes are needed in the approach to treating IA, especially in severely
immunocompromised patients.
Dr. Patterson stressed that one of
the reasons IA is so difficult to manage is that diagnosis still remains
extremely difficult to establish. He emphasized the importance of CT scans in
identifying hallmark clinical signs and symptoms of pulmonary IA. CT scans potentially improve the
ability to diagnose these infections, and earlier diagnosis may improve
outcomes. A study by Caillot and colleagues reported that the early use of CT
scans led to improved outcomes in febrile neutropenic patients with IA.
2 Another study by Yeghen and colleagues
found that patients who underwent surgical lung resection of suspected lesions
had improved responses compared to patients who had a diagnosis established by
a positive respiratory sample.
3 In addition, non-culture based
methods such as serial galactomannan and polymerase chain reaction (PCR)
screening may be useful in establishing earlier diagnosis and may result in
improved outcomes. None of these methods are approved for clinical use in the
United States.
Dr. Patterson then reviewed the
antifungal agents currently used to treat IA. The efficacy of amphotericin B
deoxycholate is hampered by toxicity; response rates are about 30%. New options are available with the
lipid formulations of amphotericin B, the extended spectrum triazoles, and the
echinocandins, a new class of antifungals. Specifically, Dr. Patterson pointed
out that higher doses of the lipid formulations of amphotericin B may be
efficacious in high-risk patients with documented refractory IA. Recent
clinical data suggest that very high doses of liposomal amphotericin B (7.5 to
15 mg/kg/day) were well tolerated and provided effective therapy for IA and
other filamentous fungal infections in a highly immunosuppressed patient
population.
4
Dr. Patterson mentioned that the
newer triazoles such as voriconazole may have a role in treating patients with
IA, and presented results of a study that showed encouraging response rates in
patients with advanced disease treated with voriconazole as primary therapy.
5
The Global Comparative Aspergillosis Study, which compared voriconazole to
amphotericin B deoxycholate followed by other licensed antifungal therapies
(OLAT), found that responses in allogeneic BMT recipients treated with
voriconazole were about 30%,
6 a substantial improvement compared
with earlier outcomes. An interesting point in this study raised by Dr.
Patterson was that patients who received OLAT following amphotericin B therapy
did not fare very well, suggesting that the standard approach of initiating
antifungal therapy with amphotericin B deoxycholate and switching patients to
OLAT produces suboptimal outcomes.
Dr. Patterson also explored the
potential role of the echinocandins in treating IA, and presented results of a
study that reported a response rate of 41% in 56 patients treated with
caspofungin.
7 The
potential role of these agents in combination therapy with amphotericin B and
the azoles is currently being studied in animal models, and ongoing-clinical
studies are aimed at establishing the optimal dose of these preparations.
References:
1. Lin
S, et al. Aspergillosis case fatality rate: systematic review of the
literature. Clin Infect Dis 2001;32:358–66.
2. Caillot D, et al. Improved management of invasive pulmonary
aspergillosis in neutropenic patients using early thoracic computed tomographic
scan and surgery. J Clin Oncol 1997;15:139–147.
3. Yeghen T, et al. Management of invasive pulmonary
aspergillosis in hematology patients: a review of 87 consecutive cases at a
single institution. Clin Infect Dis 2000;31:859–68.
4. Walsh TJ, et al. Safety, tolerance, and pharmacokinetics of
high-dose liposomal amphotericin B (AmBisome) in patients with Aspergillus
species and other filamentous fungi: Maximum tolerated dose study. Antimicrob
Agents Chemother 2001;45:3487–96.
5. Denning DW, et al. Efficacy and safety of voriconazole in
the treatment of acute invasive aspergillosis. Clin Infect Dis
2002;34:563–71.
6. Herbrecht R, et al. Open, randomised comparison of
voriconazole (VRC) and amphotericin B (AmB) followed by other licensed
antifungal therapy (OLAT) for primary therapy of invasive aspergillosis (IA).
Proceedings of the 41st ICAAC 2001;[abstract J-680].
7. Maertens J, et al. Efficacy of caspofungin as salvage
therapy in invasive aspergillosis as compared to standard therapy in a
historical cohort ECCMID 2001;[abstract O-248].
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