Antifungal and Surgical Treatment Aspergilo JSTOR

Antifungal and Surgical Treatment of Invasive Aspergillosis: Review of 2,121 Published
Cases
Author(s): David W. Denning and David A. Stevens
Source: Reviews of Infectious Diseases, Vol. 12, No. 6 (Nov. - Dec., 1990), pp. 1147-1201
Published by: Oxford University Press
Stable URL: https://www.jstor.org/stable/4455714
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REVIEWS OF INFECTIOUS DISEASES * VOL. 12, NUMBER 6 * NOVEMBER-DECEMBER 1990
i) 1990 by The University of Chicago. All rights reserved. 0162-0886/90/1206-0015$02.00
Antifungal and Surgical TReatment of Invasive Aspergillosis:

Review of 2,121 Published Cases
David W. Denning and David A. Stevens From the Division of Infectious Diseases, Department of
Medicine, Santa Clara Valley Medical Center, and the
California Institute for Medical Research, San Jose; and the
Division of Infectious Diseases, Department of Medicine,
Stanford University School of Medicine, Stanford, California
No controlled trials of therapy for invasive aspergillosis have been done. This review ap-
praises 2,121 cases reported in 497 articles in the literature and analyzes 440 courses of
treatment of infection at various body sites in 379 patients. The exclusion of early failures
of therapy skews the results toward a favorable outcome. The rate of response to am-
photericin B is 55%. Mortality from pulmonary aspergillosis in bone marrow transplant
recipients exceeds 94% regardless of therapy, as does that from cerebral aspergillosis in
all hosts. Amphotericin B (1 mg/[kg.dJ) with flucytosine lowers mortality in neutropenic
patients with pulmonary aspergillosis who did not receive a bone marrow transplant; re-
lapse is common. Surgical debridement of aspergillus maxillary sinusitis is usually cura-
tive in nonimmunocompromised patients, whereas it increases mortality among neutro-
penic patients. Valve replacement is essential for aspergillus endocarditis. Both vitrectomy
and intravitreal amphotericin B treatment are essential for aspergillus endophthalmitis.
Flucytosine is somewhat useful clinically. Itraconazole shows efficacy in the treatment
of pulmonary, skeletal, and pericardial aspergillosis. Although liposomal amphotericin
B is less toxic than standard preparations of the drug, relevant data are limited. The pro-
posed potentiation of amphotericin B by rifampin is unsupported by clinical data. De-
spite "conventional" therapy, mortality from invasive aspergillosis remains high; new ap-
proaches must be investigated.
The increasing use of cytotoxic therapy and trans- though the condition of three patients stabilized tem-
plantation procedures has been associated with a porarily with AmB therapy, the rest of these indi-
viduals (including one patient who also had cerebral
manyfold increase in the frequency of invasive asper-
gillosis. Unfortunately, therapy for this often-fatal aspergillosis) failed to respond. A later report (1977)
condition can be described as mediocre at best. This [2] described nine cases of pulmonary aspergillosis
article critically appraises the treatment of the diagnosed in patients with leukemia and lymphoma;
numerous forms of invasive aspergillosis. seven (78%) of these patients died, six despite AmB
The review by Young et al. in 1970 eloquently treatment. Another report in the same year [3] indi-
stated the problem posed by invasive aspergillosis l1].cated that earlier diagnosis by aggressive means could
These authors noted that only 14 of 98 cases of in- lower mortality. Among six patients with pulmonary
vasive aspergillosis complicating malignant hemato- aspergillosis diagnosed early, the mortality was 83%;
logic diseases (most often leukemia and lymphoma) among those whose cases were diagnosed late, mor-
were diagnosed antemortem. All of the 14 patients, tality was l000o.
who were treated with amphotericin B (AmB), died. In CNS aspergillosis, few instances of survival have
Thirteen of the 14 cases were pulmonary, and al- been recorded. Diagnosis is difficult and requires in-
vasive techniques. In a group of nine renal transplant
recipients, mortality was 1000/ despite the adminis-
Received for publication 10 September 1989 and in revised formtration of AmB in four cases [4]. Among 182 cardiac
13 April 1990. transplant recipients seen at Stanford University up
The authors are indebted to Maureen Cervelli, who graciously to 1980, 10 developed cerebral aspergillosis and all
typed the manuscript and its multiple revisions.
10 died [5]. Four of these patients received at least
Please address requests for reprints to Dr. David W. Denning,
Division of Infectious Diseases, Department of Medicine, Santa
14 days of AmB therapy. Even in nontransplant pa-
Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, tients, successful therapy is rare. The outlook for pa-
California 95128. tients with aspergillus endocarditis is also dismal.
1147
1148 Denning and Stevens
The mainstay of
patients who died early in the course thera
of therapy have
been excluded from our analysis. We have not in-
losis is presently AmB. No thorough or prospective
studies have been done relating dosage to outcome, cluded cases of superficial and noninvasive disease
and recommendations as to dosage are based mainly (such as otomycosis, keratitis, allergic bronchopul-
on the ability of the patient to tolerate the drug. In monary aspergillosis or aspergilloma, and other
one study of patients with leukemia, lymphoma, and noninvasive pulmonary disease) unless they led to
other types of cancer treated in the early 1970s [6], invasive disease. We hope that this undertaking will
the duration of AmB therapy was not significantly allow more intensive study of individual cases and
longer, nor was the dose greater, in the 10 survivors will spawn some prospective randomized trials of
of pulmonary aspergillosis than in the 19 patients chemotherapy for aspergillosis. The need to exclude
who died. This result suggests that AmB does not such a large number of cases because of insufficient
greatly influence the course of aspergillosis in leuke- detail prompts us to make suggestions in the final
mia and that outcome is related much more to discussion as to the minimal essential information
granulocytopenia and underlying disease processes. that future authors of case reports of invasive asper-
A recent survey of AmB use in eight patients with gillosis should provide.
aspergillosis indicated failure in four cases and an The data from each case included are presented
indeterminate outcome in four [7]. Other papers have in two sets of tables, with each pair of tables for a
emphasized the importance of early diagnosis, a different site of aspergillosis. The underlying disease
point that is acknowledged by most clinicians car- is the main category used to classify each case. The
ing for these patients. Recent reports of early em- tables in the text are summary tables, while those
piric therapy in neutropenic patients, with later con- in the appendix are detailed tables with each case
firmation of the diagnosis, have described better referenced. The top part of each appendix table
results [8, 9]. shows data for the patients who responded to treat-
Some authors have recommended the use of ment (with relapse, if recorded, marked by a foot-
5-fluorocytosine (flucytosine) alone or in combina- note), and the bottom part shows data for non-
tion with AmB for treatment. Some have recom- responders. The data in each table are discussed in
mended rifampin in addition to AmB. In neutrope- the text. Short sections on rare manifestations of
nia or chronic granulomatous disease (CGD), other aspergillosis (for example, aspergillus meningitis) are
investigators have recommended granulocyte trans- not tabulated if the amount of information avail-
fusions. No prospective or randomized studies of able does not warrant it. The animal model data and
these adjunctive modes of therapy have been done. the pharmacokinetics of the relevant antifungal
The role of surgery in some forms of aspergillosis, agents are given in earlier separate sections. This re-
particularly bony and cerebral disease, epidural ab- view does not attempt to cover in depth the phar-
scess, and endocarditis, has not been evaluated. For macology and toxicity of antifungal agents but in-
the most part these deficiencies in the literature re- stead focuses on those aspects of each drug as they
late to the rarity of the disease and the individual pertain to in vivo data or specific treatment issues.
problems that each patient presents. The roles of granulocyte transfusions, adjunctive ri-
On the other hand, hundreds of case reports in fampin or flucytosine therapy, itraconazole, and
the literature offer advice on management that is L-AmB are discussed in separate sections. Surgical
based on one or at most a handful of cases. An at- management is assessed in each organ system and
tempt to synthesize these data is needed, particularly summarized in the final discussion. Recommenda-
as promising new antifungal agents such as itracona- tions for in vitro susceptibility testing also are made
zole and liposomal AmB (L-AmB) become available. in the final discussion.
We have collected data from cases of invasive asper-
gillosis in the literature in which treatment was well
documented and was given for >14 days: a total of Methods
379 cases out of 2,121 surveyed. The analysis there-
Literature Search
fore is concerned with the mycologic efficacy of a
given therapeutic regimen. Because we have not used The articles reviewed included those in our own files.
an intention-to-treat analysis, which would entail Reference lists from these articles, and in particular
study of all patients designated for treatment, many the reviews, were carefully scrutinized for additional
Treatment of Aspergillosis 1149
articles. This information was supplemented by a they required more than one course of therapy. As
literature search on MEDLINE with a combination an example, if a CGD patient with bony aspergillo-
of key words (e.g., Aspergillus, aspergillosis, and sis received AmB and did not respond, then received
transplant) and text word searching. Only reports AmB with surgical debridement and did respond,
available on MEDLINE as of 1 January 1990 are relapsed 5 months later, then failed to respond to
included. AmB and flucytosine, and finally died, three entries
would be made: one response with relapse and two
failures. Likewise, different sites of disease for which
Case Findings and Criteria for Inclusion
details were included were evaluated separately. If
The following information was required for each case response was noted generally but was documented
included in our detailed summaries. in only one site, then only that site was included.
(1) Definitive diagnosis. The diagnosis was AmB doses were classified as low, medium, and
high. These categories corresponded to <0.5 mg/
preferably made on histologic grounds but occasion-
ally was based on, for example, occurrence in (kgd),
an ap-0.5-0.95 mg/(kg.d), and >1 mg/(kg.d). In
propriate host, characteristic roentgenographic more recent articles doses were cited in these terms,
find-
ings, lack of response to antibacterial agents, and but the older literature tended to focus on total dose
sputum or bronchoalveolar lavage culture for Asper- and duration. Authors rarely recorded patients'
gillus. Serology was used in fewer than 10 cases, and weights; therefore, assumptions were made about
only in combination with other supporting data, as weight when the dose of AmB was calculated. It was
evidence of disease. assumed that women weigh 50 kg and men 70 kg
(2) Details of underlying disease. A detailed ac- and that children fall on the 50th percentile for age.
count of the patient's underlying condition, includ- As broad ranges of AmB doses were grouped, these
ing immunosuppressive therapy and leukocyte assumptions should not have produced large errors.
counts, was required. For our purposes neutropenia Several studies of the susceptibility of Aspergillus
was defined as <5 x 108 neutrophils/L. species to many antifungal agents have been done,
(3)Adequate details of treatment. Cases in which and susceptibility data are given for some isolates
the total dose of AmB was stated but no time period in case reports included here. However, we have omit-
was specified were excluded, even if the reason for ted reference to these data in almost all cases because
cessation of therapy was death of the patient. Cases of a lack of standardization from laboratory to lab-
in which treatment was given for <14 days were also oratory and of in vitro-in vivo correlation. We have
excluded arbitrarily because an adequate trial of prepared a separate article on this topic. Neverthe-
therapy could not be assumed. Because this criterionless, comments about in vitro testing are offered in
would tend to exclude some instances of therapy fail-the discussion to guide clinicians in the use of these
ure, the data are probably slanted in favor of suc- tests.
cessful therapy. The greater inclination of authors Of 497 articles concerned with clinical aspects of
to report success rather than failure may also bias aspergillosis, 287 were excluded because of insuffi-
the data. Details on the dosage of flucytosine, rifam- cient data pertaining to treatment. Many of these
pin, itraconazole, or L-AmB or the number of gran- were pathology reports of infections not diagnosed
ulocytes transfused were not required for inclusion, in life. A total of 1,152 cases were excluded for this
although this information was frequently given. reason. Reviews that contributed no new clinical data
(4) Details of response. The clinical and radio- were also excluded. From the 210 articles selected,
440 courses of treatment of disease at various sites
logic details of the patient's response (if any) to treat-
ment were given in all cases analyzed. Few reports in 379 patients were included and an additional 590
presented data on the response of cultures to therapy. cases were excluded. We therefore surveyed 2,121
(S) Follow-up data. Details on immediate relapse cases and selected 18% of them for evaluation. For
rates were required for inclusion in virtually all in- some disease entities (e.g., renal aspergillosis), the
stances. Data obtained during long-term follow-up majority of cases reported were included; for others
(>3 months) were not required as they were only oc- (e.g., pulmonary aspergillosis), only a small minority
casionally given and our primary concern was with were included. Disseminated aspergillosis was con-
response rates rather than cure rates. sidered not as a separate entity but in terms of each
Individual cases were included more than once if organ system involved.
Results immediately after infection [13]. In an earlier set of

experiments by the same investigator (and col-
Animal Model and Pharmacologic Data
leagues) in the same model, lower doses of AmB
Each section reviews the animal model data and the (K0.1 mg/kg), with more frequent administration in
serum and tissue concentrations of a given agent. the first 3 days and no subsequent therapy, yielded
Complete reviews of the pharmacology and toxicity a mortality of 30%-70% [14].
of these agents are available in the literature and are Another group of researchers gave 106 conidia per
not reiterated here. Agents not currently available mouse and then administered four alternate-day
in the United States for systemic therapy and those doses of AmB (either 0.1 mg/kg or 1 mg/kg) start-
with no activity are omitted; those with limited ac- ing 24 hours after infection [101. Ninety percent of
tivity are discussed briefly. the untreated control group died within 8 days,
AmR AmB has been used in various experimen- whereas mortality at 8 days was 50% in the group
tal models of invasive aspergillosis. For our purposes given 0.1 mg/kg and 30% in the group given 1
we shall divide these models into two groups: im- mg/kg. However, survival at 14 days was identical
munosuppressed and nonimmunosuppressed (most in the two treatment groups. These investigators also
of the former being neutropenic models). In addi- tried delaying the start of AmB therapy (1 mg/kg)
tion, a model of aspergillus endocarditis has been for 5 days; 30% of treated animals and no controls
described. All of the models described have used var- survived. Intravenous AmB in doses of 0.2-1.0
ious isolates of Aspergillusfumigatus as the test or- mg/kg daily or on alternate days had little or no ef-
ganism. fect on mortality [10].
The nonimmunocompromised murine model is In one study in nonimmunocompromised guinea
the most frequently used. The route of infection is pigs, treatment was started on the day of infection
iv in all cases if AmB is the agent used for treatment. or the day after infection [15]. All control animals
This model is one of disseminated disease with high died within 7 days of infection. A range of AmB
counts in brain and kidney and virtually no pulmo- doses was used (0.63-5 mg/[kg.d]). Survival varied
nary infection. Variables in the model include age, with dose and time of initiation of AmB treatment.
weight, and strain of the mice used; inoculum size All animals given 0.63 mg/kg died, whereas 67% and
(with viability not always stated); route of AmB ad- 42% of animals given 5 mg/kg starting on day 0 and
ministration (early high serum concentrations are on day 1, respectively, survived.
achieved by ip injection, with less immediate toxic- In immunocompromised models researchers have
ity than is associated with rapid iv injections [10]); used steroids and/or cyclophosphamide (or, in one
dose of AmB; frequency of dosing; time after infec- case, nitrogen mustard). In the guinea pig model just
tion when treatment is started; and duration of ther- mentioned, AmB at a dose of 2.5 or 5 mg/(kg-d)
apy. In all instances AmB has shown some activity- appeared to have slightly better activity in immuno-
in some cases marked, in others marginal. In one suppressed animals than in nonimmunosuppressed
model AmB given three times a week for 18 days re- animals: these two doses resulted in respective sur-
duced mortality from 1000/o at 14 days to 33% at vival rates of 50% and 83% when treatment was
20 days [111. On day 7 the number of colony-forming started on the same day as infection. TWo neutro-
units in the kidneys of treated animals was lower than penic rabbit models using AmB are described, one
that in the kidneys of untreated controls, but counts of respiratory infection [161 and the other of dissem-
in the liver were unaffected. In another experiment inated infection [17]. In the first, 10 days of daily
inoculum doses of 1 x 106, 2 x 106, and 5.5 x 106 treatment with iv AmB (1 mg/kg) reduced mortal-
conidia resulted in mortality of 50%, 90%, and ity from 90% to 36% and also reduced the pulmo-
1000o, respectively [12]. At an inoculum of 2 x 106,nary fungal burden [16]. In the second, rabbits were
AmB (0.5 mg/kg three times weekly, starting 48 immunosuppressed with steroids (triamcinolone)
hours after infection) reduced mortality from 90% and cyclophosphamide at doses that did not lead to
to 70% [12]. neutropenia. Among control animals mortality was
In an experiment with larger inocula (4 x 106 to 1000/ [17]. AmB given iv at a dose of 1.5 mg/(kg.d)
8 x 106), 1007o of control mice died within 5 days; starting 24 or 48 hours aftet infection reduced
only 70% of animals died when a 21-day period of mortality at day 9 to 35 % in both groups. When neu-
sc treatment with 0.5 mg of AmB/(kg.d) was started tropenia was induced with additional doses of cy-
Teatment of Aspergillosis 1151
clophosphamide, mortality was reduced even fur- Likewise, measurement of the serum fungistatic con-
ther - from 100% to 0- at day 9, and the kidneys centration is not thought to be helpful in manage-
and livers were sterilized by AmB. ment but has not been systematically studied.
In the only neutropenic murine model (which in- In nonhuman primates the highest concentrations
cluded a single dose of cortisone) two isolates were of AmB 24 hours after iv administration were found
tested [181. The LDso and LD1o were reduced by \.'3 (in descending order) in kidney, liver, spleen, adre-
logs and 2.5 logs, respectively, from those for nonim- nal glands, lung, thyroid, heart, skeletal muscle, pan-
munocompromised mice. On days 2-8 after chal- creas, brain, and bone. In a study of eight patients
lenge, AmB (2 mg/[kg.d]) was given by iv injection who received AmB antemortem, high levels were
in two daily doses 60-90 minutes apart to reduce found in liver, spleen, kidney, and lung (usually far
acute toxicity. If the start of therapy was delayed until
exceeding the MIC for the organism isolated from
12-24 hours after infection, survival fell from 100% the same tissues), with lesser concentrations in heart,
to 85%; if it was delayed until 48 hours, survival esophagus, muscle, and fat [24]. Penetration into
dropped further to 66%. bronchial secretions, endocardial vegetations [25],
Endocarditis due to A. fumigatus has been in- and aqueous and vitreous humor [26] is poor. Pro-
duced in two published models. In both a catheter tein binding in serum is high: 91%-95%, mainly to
was surgically implanted in a carotid artery so that J-lipoproteins. This property may account in part
it passed through the aortic valve. An iv inoculum for the poor tissue penetration of AmB in some sites.
of conidia given later almost invariably led to en- L-AmR Although liposomes were first formu-
docarditis, with 10007 of cases fatal in 7 days or in lated in the 1960s, it was not until recently that al-
a mean of 7 days [19, 20]. AmB alone was ineffec- ternative delivery systems for AmB involving lipids
tive in both models, but both infections were very began to generate considerable interest. The prin-
acute indeed. cipal systems studied have been liposomes or vari-
The pharmacology of AmB in humans has been ous complexes of lipid with the drug. Liposomes are
studied in some detail. After iv administration of generally concentric bilayers (multilamellar) of lipid
AmB in doses of 5-50 mg, peak serum levels were material with aqueous-phase material between; how-
0.14-2.39 gg/mL [21]. Doses of >50 mg did not in- ever, unilamellar vesicles are also encompassed by
crease serum levels of AmB proportionally. Serum this term [27]. Although most data obtained have
levels fell by half after 18 hours and by half again related to liposomes, statements made about lipo-
after 42 hours. Higher peak levels were attained bysomes are likely to apply to other AmB-lipid com-
more rapid administration of AmB: 2.02 gg/mL af- plexes as well. The interest in L-AmB relates to the
ter a 45-minute infusion and 1.18 gg/mL after a 5- findings that it is less toxic than AmB for mam-
hour infusion of the same dose (50 mg). Mean se- malian cells but retains the activity of AmB against
rum concentrations were the same after the two fungi [28, 29]. However, some lipid formulations
methods of infusion. The volume of distribution of have been found to be less efficacious in vitro than
AmB in humans is r4 L/kg [22]. A three- conventional AmB complexed with desoxycholate
compartment model is postulated to explain the ki- (so-called free AmB). Also of note is that L-AmB
netics: a central compartment and two peripheral preparations are less toxic than conventional AmB
compartments, one fast and one slow. The volumes in vivo; although there is not a good correlation be-
of these compartments are estimated to be 0.44, 0.35, tween in vitro and in vivo toxicology testing [30].
and 3.20 L/kg, respectively [22]. The central com- Moreover, many of the in vivo experimental toxico-
partment is probably blood volume, but the iden- logic studies have been based an acute AmB cardi-
tity of the other compartments is not clear. otoxicity, and it is unclear how the findings will re-
It is also unclear what the optimal serum concen- late to the usual AmB toxicities noted in humans.
tration of AmB is. Although one paper in 1968 [23] The toxicology and pharmacokinetics of the lipid
suggested that a concentration of twice the MIC for preparations reflect the types of lipid used, the size
the organism 1 hour after infusion was a desirable of the delivery vehicle, and the surface charge
goal (very infrequently achieved for aspergilli), other [30-32]. With most lipid preparations the phar-
authors 10 years later questioned the value of the macokinetic properties of AmB are markedly al-
serum concentration, as it is unclear which phar- tered, particularly in organ distribution. In general,
macokinetic compartment is most important [22]. more AmB is delivered to the liver and spleen, less
to the kidney and serum, and a varied amount to may be mimicked more closely by ip than by iv ad-
the lung. This distribution profile may be profoundlyministration to animals, the latter necessarily being
important for the treatment of some presentations given as a rapid iv pulse). Definite demonstration
of aspergillosis. The lower serum concentrations per of the superiority of L-AmB thus has generally re-
dose administered with the lipid formulations may quired an effective dose greater than that which can
be compensated for by an ability to give more of the be given as free Amp B. These observations appear
drug systemically by the latter method. The lower to apply to the few studies that have been done with
kidney concentrations could result in lower AmB experimental aspergillosis.
nephrotoxicity. With respect to the enhanced AmB Flucytosine. The activity of flucytosine in ani-
concentrations distributed to various organs, it is of mal models has generally been slight. In one study
concern that liposomes (and their AmB content) may mice were infected iv with any of three isolates of
not traverse capillaries [27]. This inability may ex- A. fumigatus. Virtually no activity was seen with one
plain drug accumulation in the liver, where there are isolate, but with another mortality decreased from
gaps between capillary cells. It is possible that lipo-
100!7o to 80%'o when large doses of flucytosine were
somes cross capillaries inside macrophages as a re- given sc for the first 3 days of the 21-day experiment
sult of phagocytosis by these cells and that they cross
[14]. In the same model but with a different regimen
capillaries damaged by local disease. That brain con- (10 daily doses, starting the day of infection), flucyto-
centrations of L-AmB materials are higher than those sine had definite but slight activity against all four
of free AmB may reflect passage through capillaries isolates tested [13]. In another murine model 5 mg
with damaged endothelium [27]. However, it is not of flucytosine daily was as effective as a combina-
clear that the increased AmB concentrations detect- tion of 10 ug of AmB and 1.25 mg of flucytosine:
able in some organs after extraction with lipophilic mortality was 100070 for controls and 60%o for the
solvents are truly available to act against local in- group given flucytosine alone or in combination with
fection in those organs. Because toxicity after in- AmB [12]. The activity of flucytosine in another iv
travitreal administration is markedly reduced, four murine model was slight [34]. In aspergillus en-
times as much L-AmB as AmB can be given [33]. docarditis flucytosine sterilized vegetations of one
A likely mechanism for the decreased toxicity of of 10 rabbits but had no appreciable effect on mor-
L-AmB is the binding of AmB to the lipids and a tality or survival time [19]. In another endocarditis
delay in transfer of AmB to the sites of its toxic ac- model colony counts in vegetations were reduced by
tions [30]. It is also possible that lipid complexing "-2 logs from control values in flucytosine-treated
of the AmB affects dispersion and orientation of the animals [20].
AmB molecules and thus their relative affinity for The pharmacology of flucytosine in humans has
fungal ergosterol vs. mammalian cholesterol. A pos- been well delineated. Flucytosine is highly water solu-
sible mechanism for its antifungal activity in vivo ble and can be given iv or orally. On the basis of tox-
is the penetration of L-AmB material into phago- icity and susceptibility studies, doses are adjusted
cytes and the fusion of lysosomes containing in humans to produce serum levels between 20 and
degraded lipid material (with AmB) with parasitized 100 pg/mL [35, 36]. Excretion is almost exclusively
phagosomes [27]. renal, and dosing needs to be altered in patients with
L-AmB has been compared with AmB in a vari- impaired renal function [35]. With concurrent AmB
ety of animal models. Almost without exception use, therefore, serum flucytosine concentrations may
these studies have shown that free AmB is more ef- rise later in therapy. The half-life of flucytosine is
fective on a milligram-per-kilogram basis (though "-4.5 hours in healthy individuals and increases to
the difference appears to be less marked after chronic 4.2 times the serum creatinine concentration in
administration) but that more L-AmB can be given. mg/dL in those with impaired renal function [35].
Some studies have therefore concluded that a high Hematologic toxicity has not generally been observed
dose of L-AmB is more effective than a lower dose in patients with persistent therapeutic serum concen-
of free Amp B, but many such investigations have trations.
not shown that the AmB doses used are the most One of the major virtues of flucytosine is its high
that can be given. (Moreover, most studies have com- penetration of many organs and fluids - CSF, joint
pared iv L-AmB with iv free AmB, whereas AmB fluid, peritoneal fluid, and ocular aqueous fluid in
pharmacokinetics after iv administration to humans particular. CSF concentrations are "-75% of those
Theatment of Aspergillosis 1153
in serum [35], and concentrations in the aqueous hu- survival after LD1. challenge, with 14 long-term sur-
mor range from 20% to 30% of those in serum [37, vivors out of 50 animals treated [44]. At autopsy,
38]. infection was found to have been eradicated in eight
Miconazole. The activity of miconazole in the of these animals. In a subsequent study with four
one animal model studied was slight [39]. Details of different isolates and LD1o, challenges, 5-day courses
the use of miconazole and of its pharmacokinetics, of itraconazole were associated with 0 to 600/ sur-
toxicity, and efficacy have been reviewed [40]. vival [45]. At autopsy, all residual infection had been
Ketoconazole. Ketoconazole has little effect on eradicated in 25%-500o of survivors. In a rabbit
invasive aspergillosis in animal models. In an im- model of A. fumigatus endocarditis, itraconazole (5
munosuppressed murine model, ketoconazole was mg/[kg.dJ ip for 14 days) was superior to AmB,
ineffective: 15 of 16 animals treated with ketocona- flucytosine, or a combination of the latter drugs [19].
zole died, whereas none of 15 receiving AmB died This was a rigorous test of drug efficacy in that ther-
[18]. In an another iv murine model (nonim- apy was initiated 3 days after the infection was es-
munocompromised), ketoconazole therapy resulted tablished. The vegetations were sterilized by itracona-
in 70% mortality (vs. 95 % among controls) [14]. On zole. However, the relevance to humans of the doses
a weight basis, ketoconazole had less activity than of all drugs used in this study is not known because
flucytosine in this model [14]. In a rabbit model of the blood concentrations achieved were not studied.
aspergillus keratitis, ketoconazole was ineffective, Itraconazole (5 mg/[kg d] for 14 days) was effective
given topically and/or orally, but did slightly aug- in 5001o-8007o and 70%-92%, respectively, of neu-
ment the activity of the polyene natamycin [41]. tropenic and nonneutropenic guinea pigs inoculated
Ketoconazole is well absorbed after oral use [21], iv with one LD,. of a resistant A. fumigatus isolate
although reduction in serum concentrations by (MIC of itraconazole, 10 gg/mL) [15]. The efficacy
differing degrees has been reported if the drug is of itraconazole was superior to that of AmB at the
taken after food, antacids, and H2 blockers or by same doses, but dosage was not pressed to toxicity.
AIDS patients. Fasting serum peak concentrations Itraconazole is formulated only for oral use at
after 400 mg of ketoconazole daily range from 3.4 present, although an iv formulation may soon be-
to 6.5 mg/L. Allogeneic bone marrow transplant come available. Pharmacokinetic studies in volun-
(BMT) recipients show a steady decline in serum teers have indicated slow absorption (peaking at
ketoconazole levels after 2 weeks of treatment, pre- 2.8-3.4 hours) and wide intersubject variations in
sumably as a result of intestinal damage. Tissue con- peak serum concentrations [46]. A wide person-to-
centrations vary from 0.4 mg/L in bone and muscle person variation was also seen [47, 481 in serum con-
(with a dosage of 200 mg/d) to 10.7 mg/L in skin centrations measured by bioassay (<1-26 ,g/mL).
[42]. CSF concentrations vary from 0.2 to 2.9 mg/L Elimination half-lives varied from 25 to 42 hours af-
in patients receiving high doses (800-2,000 mg/d) ter the administration of 200 mg of itraconazole ev-
[43]. ery 12 hours [46]. Steady-state serum concentrations
Itraconazole. Several animal model systems have were obtained by 13 days [46]. We measured serum
demonstrated the activity of itraconazole in vitro itraconazole concentrations during and after a load-
against aspergilli. This activity is especially notewor- ing regimen of 200 mg every 8 hours for 4 days and
thy with oral therapy. In a mouse model of iv chal- found steady state to be reached in patients on day
lenge, 17-day courses of itraconazole and AmB were 6 or 7 of administration. We also observed increases
approximately equal in their effect on survival and in serum concentrations - often by as much as
on the extent of renal infection [11]. Neither drug 100% - over months of continued therapy, but this
affected the extent of liver infection. However, com- change was not seen in all patients (authors' unpub-
parisons are difficult since only one set dose of the lished data). Itraconazole is highly protein bound
two drugs was compared. Together the two drugs in blood (99.8%) [49]. After single 200-mg doses,
showed no interaction (enhancement or decrease of concentrations of the drug in lung, liver, bone, stom-
efficacy) in vivo. Intranasal challenge was more le- ach, spleen, and muscle were two to three times
thal; itraconazole was ineffective in a 4-day course, higher than corresponding serum concentrations,
and AmB was not studied. Other workers, using a and levels in adipose tissue were 20 times those in
mouse model of iv infection with A. fumigatus, serum [49]. Brain or meningeal concentrations have
found that 3-day courses of itraconazole prolonged not been determined in humans: in dogs, however,
levels of drug at
Table 1. In vivo combinations these
of antifungal agents against
concentrations Aspergillus species. during
Concentrations of itraconazole in vaginal fluid, Combination* Effectt [reference(s)]
bronchial exudate, and pus were high, but those in
AmB + 5FC S [12, 14, 19]
ocular fluid, CSF, and urine were very low. Modifi-
I [14, 19, 20]
cation of dose is not required in patients undergo- AmB + Rif S [12]
ing hemodialysis. The relatively minor toxic effects AmB + Ket A [13, 14, 18]
of itraconazole have been described [481 and include I [15]
AmB + Itr S [15]
nausea, vomiting, rash, changes in liver function
I [11, 13]
tests, hypokalemia, ankle edema, gynecomastia, and A [13]
possibly hypertriglyceridemia and pancreatitis. In ex-5FC + Ket I [13, 14]
tremely few patients does toxicity require interrup- 5FC Itr S [13]t
tion of therapy. I [13]?
5FC + Flu I [13]t
Fluconazole. In humans, fluconazole is remark-
able among the new azoles in reaching very high CSF * 5FC = flucytosine;
concentrations relative to serum levels (750o-85%o) = itraconazole; and Flu = fluconazole.
t S = synergistic/additive; I = indifferent; and A = antagonistic.
[50], reaching high urine levels in an active form
t Organism susceptible to 5FC in vitro.
(53 %-86% in 96 hours), and showing excellent ? Organism resistant to 5FC in vitro.
penetration into the eye [51], saliva, skin, sputum,
kidney, and brain. These properties may relate at least
in part to the drug's low protein binding (11 7%).
Fluconazole can be given orally or iv, with half-lives
of 22-25 hours and 29-30 hours, respectively. The with other drugs, including corticosteroids, cyclospo-
few adverse effects noted (160%7 incidence at 200-400 rin, ketoconazole, and itraconazole, are often pro-
mg/d) have consisted mostly of nausea, headache, found.
skin rash, vomiting, abdominal pain, and diarrhea. Combination therapy. The results of combina-
Severe hepatic and skin reactions seen during tion therapy for experimental aspergillus infection
fluconazole treatment may have been related to other are shown in table 1. A total of 16 isolates of A.
medications. fumigatus have been studied; no other species have
In two reports of the efficacy of fluconazole in been used experimentally in treatment models. Defi-
animal models of aspergillosis, the activity of this nitions of synergy (including an "additive" effect),
agent was inferior to that of AmB, although flucona- indifference, and antagonism are problematic. We
zole was much better tolerated [16, 52]. In one ex- have used the same terms used by the original inves-
periment fluconazole was directly compared with tigators.
ketoconazole and was found to be five- to 20-fold AmB and flucytosine have been observed to be
more active [52]. synergistic [12, 14, 19] or indifferent [14, 19, 20] in
To our knowledge, no reports of human aspergillus several models but have never been found to be an-
infections treated with fluconazole have been pub- tagonistic. AmB and rifampin were synergistic in a
lished. In view of this lack of data and the lack of single model [12]. AmB and ketoconazole were usu-
significant activity in two animal model systems, ally antagonistic [13, 14, 18] or indifferent [15]. AmB
fluconazole will not be considered further here. and itraconazole were reported to be synergistic [15],
Rifampin. Rifampin is not active alone against indifferent [11, 13], or antagonistic [13]. Combina-
aspergilli. However, in vitro studies, animal model tions of flucytosine and ketoconazole were indiffer-
work, and anecdotal clinical experience suggest that ent [13, 14]. Itraconazole and flucytosine together
it may be a valuable adjunct to therapy with AmB. were indifferent [13] if the organism was resistant to
The pharmacokinetics of rifampin are unique: ex- flucytosine in vitro and synergistic [13] if the organ-
tensive, saturable first-pass metabolism by the liver, ism was susceptible to flucytosine in vitro: the en-
considerable enterohepatic circulation, and rapid au- hancement of activity in this instance was relatively
toinduction of hepatic metabolism. Rifampin is well minor. The combination of fluconazole and flucyto-
absorbed orally and reaches serum levels of >10 sine in vivo was indifferent against a flucytosine-
Ztg/mL after an oral dose of 600 mg. Interactions susceptible strain [13].
7featment of Aspergillosis 1155
Clinical Data only those with a definitive diagnosis and those in

which no reasonable doubt remains as to the diag-
Infection caused by Aspergillus has been noted in nosis have been included.
almost every organ and system of the human body. (1) Neutropenic patients. For many reasons, mor-
When multiple-organ involvement is seen, the term tality from IPA is not truly known. Figures vary from
disseminated aspergillosis is used. As this term is 13% [8] to 100% [1]. Among patients with leuke-
most frequently used after death (with specific or- mia, mortality in various reports published since
gan involvement the usual focus before death), we 1980 ranges from 13% [8, 9, 53] to 40% [54], 50!70
have not reviewed disseminated aspergillosis as a sin- [55], 60% [56], and 100% [57].
gle entity. Instead, we have dealt with each site of The risk of development of IPA increases progres-
involvement on an individual basis. sively with the number of granulocytopenic days,
As has already been mentioned, data are presented reaching a plateau of 700/o among patients granu-
in two sets of tables. The first set consists of sum- locytopenic for >34 days [58]. In one institution, al-
mary tables for all disease sites (not patients) evalu- though mortality among patients with hematologic
ated. The second set is archival in nature and is in- recovery was 40%0 [54], that among those without
cluded in the appendix preceding the references at hematologic recovery was 100%. The degree and du-
the end of the article. Each disease site is referenced, ration of granulocytopenia are probably the most
and complete footnotes allow detailed comparisons. important factors determining outcome, but several
Pulmonary aspergillosis. Pulmonary aspergillo- other important factors are likely to be operative in
sis occurs as three major discrete disease entities: in- any given patient. These include whether the under-
vasive pulmonary aspergillosis (IPA), aspergilloma lying disease is in remission; whether the patient is
in a preexisting cavity, and allergic bronchopulmo- receiving corticosteroids as part of the chemother-
nary aspergillosis. These are all to be distinguished apy regimen, for graft-vs.-host disease, or for some
from simple colonization of the bronchial tree, which other reason; the virulence of the particular Asper-
is relatively common and entirely benign. Other over- gillus isolate; its susceptibility to the administered
lapping syndromes have been described but here are antifungal agent; and the ease with which any an-
included under the broad umbrella of IPA if tissue tifungal agent can be given.
invasion was demonstrated. We have therefore attempted to estimate the du-
IPA occurs primarily in the immunocompromised ration of granulocytopenia as a variable in the suc-
host and is usually insidious in onset. All too often cess of treatment of IPA. A lack of complete data
this diagnosis is not suspected early in the course in most reports prevents a -direct comparison, but
except by those experienced in managing neutropenic there is a clear trend toward more favorable responses
to therapy in patients granulocytopenic for shorter
patients or transplant recipients. Definitive diagno-
sis depends on histologic demonstration of typical periods. For example, in one report on patients
hyphae in tissue. Confirmation of the fungus in- receiving high-dose AmB and flucytosine and hav-
volved (to avoid possible confusion with, for exam- ing a mortality of only 13% [8], the mean interval
ple, Pseudallescheria boydii, which may resemble between diagnosis of IPA and granulocyte recovery
Aspergillus histologically) is possible with a concom- was 12 days; in contrast, for 12 patients (with data
itant positive culture. However, a positive culture of culled from many reports) in whom therapy with
a percutaneous aspirate taken from a lesion radio- medium-dose AmB failed, the mean neutropenic
logically consistent with aspergillosis in an im- period after the diagnosis of IPA was 28 days long
munocompromised febrile host may also be regarded (range, 0-67 days). Efforts to shorten the period of
as definitive. Lesser degrees of confidence accom- granulocytopenia with recombinant colony-stimu-
pany diagnoses made by sputum culture, bronchial lating factors may influence the outcome of IPA.
washing culture or cytology, or serology, even if Among patients with acute myeloid leukemia
results are positive in the typical setting. Unfortu- (AML), 31 were successfully treated and 15 unsuc-
nately, neutropenic patients usually are also throm- cessfully treated with AmB (table 2, appendix table
bocytopenic, and this situation often precludes a tis- IA). Estimated for weight as accurately as possible,
sue diagnosis. Empiric treatment is frequently given. the mean daily dose of AmB was 46.3 mg for
For this reason the vast majority of cases of IPA responders and 43.6 mg for nonresponders. The
reported in the literature cannot be included here; results suggest that there is no advantage to the
Table 2. Summary table of treatment results for pulmonary aspergillosis.
No. of infection sites with

indicated type(s)
of treatment No. of infection sites with indicated medical treatment* Total no.
Medical AmB only (mg/d) AmB (mg/d) and 5FC of sites

Host factor, Surgical Medical and treated
group only only surgical <30 31-59 >60 <30 31-59 >60 L-AmB Itr (%)
Neutropeniat
Responders 4 46 1 8 15 5 2 2 5 1 7 51 (68)
Nonresponders 0 24 0 1 14 2 1 1 4 1 0 24 (32)
BMT
Responders 0 0 0 0 0 0 0 0 0 0 0 0
Nonresponders 0 15 0 2 9 1 0 2 0 0 0 15 (100)
R/HT
Responders 0 23 3 6 6 1 4 6 0 1 2 26 (76)
Nonresponders 0 8 0 2 2 1 0 2 0 0 1 8 (24)
CGD
Responders 0 10 0 1 6 3 0 0 0 0 0 10 (83)
Nonresponders 0 2 0 0 1 1 0 0 0 0 0 2 (17)
Other
Responders 2 15 1 2 3 0 4 1 0 0 2 18 (86)
Nonresponders 0 3 0 0 0 0 0 1 0 0 1 3 (14)
NOTE. Full details are given in appendix table IA.

* 5FC = flucytosine; Itr = itraconazole; R/HT = renal/heart treatment.
t The neutropenia group includes all patients in whom neutropenia had been documented; however, this condition was no
present at the time of diagnosis of aspergillosis.
higher dose. However, in the study quoted earlier as teau with doses of >50 mg. A possible explanation
yielding a mortality of only 13% [8], 11 of 14 pa- is that serum binding sites become saturated and
tients developed IPA during therapy with AmB at more AmB remains free, with much more rapid
a dose of 0.5 mg/(kg.d), which was given for a mean penetration of diseased tissue sites. It is not known
of 17.6 days (median, 11 days) before IPA was diag- whether AmB concentrations in either the slow or
nosed. There were two groups of patients: those with the fast peripheral pharmacokinetic compartments
IPA and those with necrotic chest wall lesions. Af- are correlated with efficacy, but in either instance
ter the diagnosis of IPA, they were all given high- rapid filling may allow greater AmB activity locally.
dose AmB (1.0-1.5 mg/[kg*d]) and recovered. The It is our view that a high dose of AmB is appro-
only exceptions were two patients whose bone mar- priate for the treatment of IPA in neutropenic pa-
row failed to recover. The mean interval to recovery tients. This view is based in part on the apparent suc-
of peripheral granulocyte counts was 12 days, a re- cess of this regimen in recent studies from a small
sult implying that high-dose AmB prevented death number of institutions in the United States, despite
within this period. One patient of four with necrotic the figures given in table 2. A notable lack of suc-
chest wall lesions developed IPA after 17 days of cess with lower doses prompted the recent higher-
high-dose AmB. The addition of flucytosine to AmB dose regimens. In addition, the knowledge that high
in this group of 14 patients- and overall in those withlevels are not attained experimentally in bronchial
granulocytopenia-did not appear to offer any ad- secretions or lung tissue and that many isolates show
ditional advantage. only borderline susceptibility or even resistance to
The failure of low-dose AmB followed by the suc- AmB in vitro supports this view. We currently recom-
cess of high-dose AmB in the same patient [8] may mend rapid (e.g., within 42 days) escalation of the
best be viewed within the context of a three- daily dose to 1 mg/kg after a test dose. Higher doses,
compartment pharmacokinetic model. The serum such as 1.25 mg/(kg.d), can be used if the drug is
concentration of AmB after iv infusion reaches a pla-
tolerated well and no initial response is noted. If we
7Teatment of Aspergillosis 1157
opt for alternate-day therapy for the sake of conve- may be responsible for this entity, which is not seen
nience after the initial intensive phase, we double the with most other fungal pulmonary infections. In the
dose given on alternate days to a maximum of 1.5 articles cited here, there were 22 cases of massive pul-
mg/kg; this decision is supported by pharmacoki- monary hemorrhage [3, 54, 55, 64-72], with 15
netic studies [591. Resolution of granulocytopenia deaths. Emergency surgery had an impact on six
may permit the administration of lower doses until cases that might otherwise have been fatal. A useful
the completion of therapy. retrospective review from a center with considerable
The optimal duration of therapy is not clear. In experience in the clinical care of patients with asper-
general, with the treatment of deep mycoses (partic- gillosis has been published [54]; 10 (38%) of 26 pa-
ularly life-threatening ones), it may pay to be con- tients had minor hemoptysis (<50 mL of blood) dur-
servative and to err on the side of overtreatment. ing the course of pulmonary aspergillosis, and four
Courses of 1.5-4 g of AmB have usually been recom- (15%) had major (life-threatening) hemoptysis. In
mended. In granulocytopenic patents, the resolution all four of the latter patients, granulocytopenia had
of infection often follows bone marrow recovery and recently resolved, platelet counts were >38 x 109/L,
leukemia remission. If no further cytotoxic chemo- and coagulation parameters were normal. In three
therapy is planned, a shorter course of treatment may of the four patients, cavitary lesions had appeared
be appropriate, e.g., 4-6 weeks after full hematologic on the chest roentgenogram 1 or 2 days before the
recovery. As some studies have suggested that the hemorrhage. Eight other patients had cavitary lung
renal toxicity of AmB is dose dependent, a finite lesions but did not hemorrhage. TWo of the four pa-
amount of AmB-between 1.5 and 4 g-is usually tients with major hemoptysis first had minor hemop-
chosen. With newer, less toxic agents that are given tysis; in the other two cases, there was no warning.
orally, such as itraconazole, these questions become The three patients who survived in this series under-
less vexing. If radiologic improvement is not achieved went emergency rigid bronchoscopy to localize the
fairly rapidly after hematologic recovery (1-2 bleeding site and subsequent lobectomy. At least two
months), surgery or an alternative agent should be patients have died awaiting removal of a "fungal ball"
considered; however, full radiologic resolution can [3, 55]. It is unclear whether embolization techniques
take months [60]. to control hemoptysis (like those used in patients
Another consideration is the relapse of disease with pulmonary aspergillomas [73]) will be helpful.
during subsequent episodes of neutropenia. Further (2) BMT recipients. Mortality from IPA in BMT
cytotoxic chemotherapy is often necessary to achieve recipients approaches 100%. Of 109 patients reported
or maintain remission of leukemia. Recent data sug- in the literature, 102 (94%) died [55, 57, 71, 74-83].
gest that the frequency of relapse of aspergillus pneu- Not all of these infections were diagnosed antemor-
monia during neutropenia, even after large doses of tem, and some survivors may have had disease not
AmB, is high [61]. Relapse carries a considerable risk at pulmonary but at other sites. This figure reflects
of death, which may be averted by the prophylactic the massive compromise of the immune systems of
administration of high-dose AmB (1 mg/[kg-d]) be- these patients. In allogeneic transplants profound,
ginning at the same time as cytotoxic chemotherapy. prolonged neutropenia is followed by the immuno-
Even in this context, pulmonary disease may flare suppression of graft-vs.-host disease compounded
(as judged by computed tomography) but not with by cyclosporin and corticosteroid treatment. Cyto-
fatal results; there were two relapses in 13 episodes megalovirus pneumonia is common and is also im-
of neutropenia in nine patients in one small series munosuppressive but did not alter the acquisition
[62]. Although itraconazole has been successful in of aspergillosis in one study [81]. Each phase of im-
uncontrolled prophylactic studies of de novo gran- munosuppression is probably a risk for these pa-
ulocytopenic patients [63], it is not known whether tients; this point may be illustrated by the time after
this agent will be successful in this setting. One anec- transplantation when these infections occurred in
dotal experience with hepatic aspergillosis suggests one series of 14 patients: 50 ? 24 days [79]. Although
that it may be [48]. air filtration may reduce the incidence of aspergil-
Another major problem area in the care of these losis [79], exposure to Aspergillus conidia cannot be
patients is the relatively high incidence of severe he- avoided after discharge from the hospital, and early
moptysis after apparently successful antifungal che- recognition of disease and effective therapy are
motherapy. The vasculotropic nature of aspergilli clearly needed. All 16 patients evaluated with respect
to to medium AmB
treatment doses. Use of lower doses to
failed is
one prompted by fear of
received 1 nephrotoxicity
mg/[k made worse by
alone, and one received itraconazole (with low se- the use of cyclosporin [87], although many of these
rum concentrations). cases occurred in the pre-cyclosporin era. Low and
In another study [80], two children (the details ofmedium AmB doses also failed but apparently less
whose treatment were not given) survived with a mix- frequently than in neutropenic patients. One patient
ture of medical and surgical therapy (lobectomy). It responded with radiologic resolution, only to die of
was significant that these patients had evidence of disseminated aspergillosis 6 months after stopping
marrow engraftment at the time of diagnosis. AmB treatment. The role of flucytosine is unclear
(3) Other transplant recipients. In reports of from these data, because all responders received at
other transplant recipients reviewed here, successful least moderate AmB doses; moreover, all of the cases
therapy was more frequent than failure. Pulmonary that responded to the combination of AmB and
disease may be less aggressive in these hosts if the flucytosine were treated at a single institution [4].
infection is not already disseminated; in fact, pul- Three of the patients in this same series [4] un-
monary aspergillosis can be well controlled with the derwent resection of single pulmonary lesions with
appropriate dose of an appropriate antifungal agent. subsequent short-course AmB therapy and a good
In one series 82% of patients survived, and five of outcome. Unfortunately, we do not know the dose
the nine survivors retained their renal allograft [4]. of AmB used in these cases. This approach - surgery
Of the 400 most recent heart transplant recipients followed by short-course AmB -is worthy of con-
at Stanford University Medical Center, 55 (13.80o) sideration and is amenable to a controlled trial.
have developed aspergillosis (authors' unpublished Among successfully treated renal transplant re-
data). In 19 cases the infection was disseminated at cipients, graft loss was relatively frequent. Six of 15
presentation, and two cases that were treated later such patients lost the graft, usually because im-
disseminated. All patients with disseminated disease munosuppression was reduced or eliminated. The
died. Of the 36 patients who presented with a pneu- concurrent use of AmB and cyclosporin usually
monic process, 10 (28%) are still alive; many of the causes considerable renal toxicity [87], potentially
deaths were attributable to a cause other than asper- jeopardizing a renal graft. Maintenance of low blood
gillosis. Aspergillosis also occurs after liver trans- cyclosporin concentrations may reduce this problem.
plantation, but no successfully treated cases have Whether a more potent antifungal agent would ob-
been reported. Of course, the immune deficit in viate the need to reduce immunosuppression is not
transplant patients does not wane substantially; in known.
this respect transplant recipients differ from leukemic Itraconazole was evaluated for three transplant
patients, in whom recovery of neutrophils presages recipients, two of whom responded [47, 88]. Ther-
recovery of immune function. apy failed in a renal transplant recipient with a rela-
A problem in transplant cases is that aspergillosis tively resistant organism; the MIC was 6.3 mg/mL,
may be silent for longer and may be associated with and serum concentrations never attained this value
a lower frequency of radiographically overt pulmo- [47]. One cardiac transplant recipient responded to
nary disease; thus diagnosis may be difficult until L-AmB [89].
a catastrophic event occurs, such as the development (4) Other groups of patients. Patients with
of cerebral aspergillosis. Such an infection usually chronic granulomatous disease (CGD) usually re-
appears 1-4 months after transplantation [84-86], spond to AmB. Many receive concurrent granulo-
when the patient may be at home; in contrast, this
cyte infusions and/or rifampin treatment. Four of
type of infection occurs in the leukemic patient the 12 patients whose cases are reviewed here received
during granulocytopenia under medical supervisionhigh-dose AmB; this observation may be important
in the hospital. for this group, as several deaths due to pulmonary
In general, lower doses of AmB (with or without aspergillosis in CGD patients are recorded in the liter-
flucytosine) were more efficacious in transplant ature. In a group of 14 cases reported from France
recipients than in neutropenic patients. Ten of the [90], the success rate was 50% (as was the mortal-
26 transplant recipients successfully treated (table ity); in most cases a combination of AmB and
2) received <30 mg of AmB daily, in some cases with flucytosine was used, and this regimen was followed
other therapeutic measures. All the rest responded by ketoconazole treatment in the survivors. Doses
7keatment of Aspergillosis 1159
and durations of therapy were not given. Three pa- AmB [95, 96]. TWo patients responded to flucyto-
tients with CGD remained free of disease while tak- sine alone [921. Others have responded to local ther-
ing itraconazole after responding to AmB [91]. apy with AmB or nystatin. Of the three patients
Likewise, patients with mild immune deficits (e.g., treated with instillations of AmB [98-100], one failed
patients who were not neutropenic and not recipients to respond [98] but subsequently did respond to nys-
of transplants) and those with no apparent immune tatin. The MIC of nystatin against this organism was
defect did very well with a variety of therapies if lower than that of AmB. One patient with a bron-
aspergillosis was diagnosed early. Treatment with chopleural fistula responded to iv and topical
flucytosine alone was successful in four cases [55, miconazole treatment [101].
92] and unsuccessful in one [93]. One patient treated Surgical therapy is occasionally curative. One pa-
with flucytosine alone relapsed after improvement; tient had bronchial stump aspergillosis after a pneu-
at relapse, her Aspergillus isolate had developed re- monectomy, with aspergillus in the pleural cavity
sistance to flucytosine, whereas her previous isolate [102]. Removal of the silk thread-the nidus-
had been susceptible [92]. Two of three patients in resulted in cure (see the next section). The other pa-
this group responded to itraconazole [47, 88, 94]. The tient, a 14-year-old boy, underwent pleural decorti-
one patient in this assorted group whose therapy cation [103] and then received 21 days of low-dose
failed had granulomatous mediastinitis, which AmB (236 mg). He was cured, probably by the
recurred shortly after completion of therapy with surgery.
AmB and flucytosine. Three patients with pleural aspergillosis were
Pleural aspergillosis. Most cases of pleural asper- treated with itraconazole. One who had previously
gillosis are related to pulmonary aspergillomas, had tuberculosis responded dramatically, with reso-
which frequently develop secondary to pulmonary lution of fever, chest roentgenographic abnormali-
tuberculosis and old cavitary disease. Tvo cases of ties, and raised sedimentation rate [94]. Another pa-
pleural disease have been reported in association withtient, who had had Hodgkin's disease, did not
chemotherapy for acute lymphocytic leukemia improve during 2 weeks of therapy with itracona-
(ALL) [95, 96], and one has been described follow- zole, despite having had a surgical procedure as well
ing radiation to the thorax for Hodgkin's lymphoma [97]; itraconazole therapy was discontinued, and the
[97]. Direct spread from the lung is almost certainly patient was treated with AmB. This therapy also
the cause in the vast majority of cases. Many cases failed, and the patient subsequently died; pleural
are related to bronchopulmonary fistulae. With re- histologic examination at autopsy showed Asper-
spect to the latter, we have included those cases in gillus. The third patient, wh4o had a bronchopleural
which the evidence in favor of the diagnosis was un- cutaneous fistula, responded to treatment with
equivocal and not merely a reflection of endobron- itraconazole [47]. Tissue cultures became negative
chial colonization. after 7 weeks of therapy (having been positive at 3
Most cases of pleural aspergillosis have responded weeks), but histologic examination gave a positive
to therapy (table 3, appendix table 2A). The two pa- result until 13 weeks.
tients with leukemia responded to medium-dose Pleural aspergillosis, more common in the nonim-
Table 3. Summary table of treatment results for pleural aspergillosis.

indicated medical treatment*
indicated type(s) of treatment AmB (mg/d) Total no.

and 5FC of sites
Surgical Medical Medical and Local treated
Group only only surgical only <30 31-59 Itr (%)
Responders 1 10 3 4 2 2 2 14 (88)
Nonresponders 0 1 1 1 0 0 1 2 (12)
NOTE. Full details are given in appendix table 2A.

* 5FC = flucytosine; Itr = itraconazole.
munocompromised patient, responds well to ther- Aspergillosis of the sinuses. Aspergillus infection
apy. Pleural biopsy is necessary for diagnosis, espe- of the sinuses is almost certainly airborne, and any
cially in cases with endobronchial colonization. sinus may be involved. The most common site of in-
Surgical decortication is appropriate if disease is ex- fection is the maxillary sinus, although the ethmoi-
tensive. Otherwise, medical therapy- either systemic dal sinuses are frequently involved concurrently. The
or local - is likely to be effective. Local therapy disease, which is usually indolent and slowly progres-
should be the mainstay of management if progress sive, is common in tropical climes such as the Su-
can be made while systemic therapy is withheld or dan. Complications include intracerebral, major ar-
tapered; thus the toxicity of systemic therapy may terial, and orbital extension of disease. In the
be avoided. If a bronchopleural fistula is present in neutropenic host, aspergillus sinusitis is a much more
the context of a previous lobectomy and/or pneu- aggressive disease, causing septal perforation and ex-
monectomy, surgical drainage (leaving a broncho- tending to skin, palate, and intracerebral sites. Few
pleural cutaneous fistula) combined with medical cases of sinus aspergillosis have been reported in
therapy is appropriate. transplant recipients, and we include only one trans-
Bronchial stump aspergillosis. Of the 10 reports plant recipient and one steroid-treated patient here.
of bronchial stump aspergillosis in the English- On the other hand, leukemia and/or neutropenia
language literature, nine were in a single Japanese seems to be a major risk factor for this disease. Thus
study [104]. These patients presented 6-12 months evaluations of granulocyte recovery and leukemia
after pulmonary resection. Cough, sputum produc- remission are essential in an assessment of antifun-
tion, and expectoration of thread with a putrid mass gal therapy. A new clinical complex of allergic asper-
of hyphae characterized the disorder. In the one pa- gillus sinusitis has recently been described [110, 111].
tient with this illness in the United States [102], the (1) Nonimmunocompromisedpatients. From ta-
presentation was that of an empyema. In the Japa- ble 4 (and appendix table 3A), it is apparent that
nese series, the most frequent species isolated were surgical treatment alone is satisfactory for the vast
Aspergillus oryzae and Aspergillus tamarii, both of majority of nonimmunocompromised patients with
which are used in the fermentation of soy sauce. aspergillus sinusitis. Issues concerning the localiza-
In all cases, including that in the United States, tion of disease by nasal endoscopy and tomography
resolution followed the removal of silk thread. No or computed tomography, along with appropriate
antifungal therapy was given in the Japanese cases, surgical procedures, have been addressed thought-
and the two local instillations of AmB into the fully and in detail by Stammberger [112]. He details
results in 48 patients with fungal sinusitis and pro-
pleural cavity in the case from the United States prob-
ably did not influence outcome. vides a rationale for endoscopic nasal surgery of the
In an analogous infection in the urinary pelvis frequently diseased ethmoids. A report from Aus-
[105], medical therapy failed. Only after nephrectomy tria [113] presents data on patients with solitary max-
was the reason apparent: persistent sutures were act- illary sinusitis who had undergone preceding dental
ing as a nidus for infection. work on the upper teeth. Radiologic appearance was
The Japanese investigators studied the type of pathognomonic, and zinc oxide and paraformalde-
thread likely to produce this problem and concluded hyde were found in the antrum of 33 of 34 patients.
that silk was a much more likely cause than All of these patients responded to surgical debride-
monofilament nylon. ment alone. Surgery probably cured two infections
Upper airway aspergillosis. Aspergillosis of the in patients who received low-dose AmB for 2 weeks
trachea and bronchi, either as a necrotizing bron- [114] or 3 weeks [115].
chitis or as a mass in the trachea, has been reported Combined surgical and medical therapy failed in
[1061, but no results of treatment have been de- three cases [116, 1171, two of which were in patients
scribed. To our knowledge, three cases of laryngeal with sphenoid disease; nevertheless, five other pa-
aspergillosis diagnosed antemortem have been tients with sphenoid disease did well with surgery
reported, all in nonimmunocompromised patients. alone [118-120], another responded to itraconazole
IWo cases responded to local surgical debridement and surgery [47], and a seventh responded to sur-
by direct laryngoscopy [107, 108]. The outcome gery, of AmB, and rifampin [1211. One of the patients
the third case was not described. Aspergillus epiglot-in whom combined therapy failed was given low-dose
titis in a neutropenic patient [109] ended in death.AmB (25 mg daily) for 2 months [116] and devel-
Table 4. Summary table of treatment results for sinus aspergillosis.

indicated type(s)

Neutropeniat
Responders 0 11 2 2 4 2 0 0 0 5 0 13 (46)
Nonresponders 0 7 8 0 6 7 0 0 1 1 0 15 (54)
BMT
Responders 0 1 1 0 1 1 0 0 0 0 0 2 (40)
Nonresponders 0 2 1 0 2 1 0 0 0 0 0 3 (60)
Other
Responders 52 0 11 4 2 0 1 1 0 0 1 63 (91)
Nonresponders 3 0 3 1 1 0 0 0 0 1 0 6 (9)

t The neutropenia group includes all patients in whom neutropenia had been documented; however, this condition was no
oped carotid and cavernous sinus thrombosis. In AML and aspergillus sinusitis were evaluable; four
vitro studies suggested resistance of the pathogen to responded to therapy and three did not. The two
AmB, and this patient's condition improved after responders [114, 127] who received low-dose AmB
flucytosine was added to the AmB regimen, despite were not neutropenic; a third responder who received
the absence of in vitro synergy. The organism iso- higher doses of AmB was neutropenic [3] but gained
lated from the patient was susceptible to flucytosine hematologic remission. No details were given for the
(MIC not given). A second patient also failed to re- fourth patient [128]. Two nonresponders were neu-
spond to AmB [117] and was found to be infected tropenic [3, 129]. One of these had an AmB-
with an organism relatively resistant to this drug; sub- susceptible isolate and received 1.2 mg of AmB/
sequently however, he responded to a combination (kg-d), granulocyte transfusions, and rifampin. This
of AmB, rifampin, and flucytosine, though in vitro patient died with active fungal disease of the sphe-
synergy was not demonstrated. The pathogen was noid despite more than 2 weeks of therapy [129]. The
susceptible to flucytosine in vitro. The third failure nonneutropenic patient in whom therapy failed died
involved a case in which first AmB therapy (the full with disseminated aspergillosis after 4 months of
details of which were not given) and then L-AmB therapy.
therapy had previously failed [1221. More patients with ALL and sinus and/or nasal
Patients with mild immunocompromising factors aspergillosis have been reported. In general, the che-
also may do well with surgery alone. One diabetic motherapeutic regimens used for ALL are less likely
patient required three procedures to cure her sinus than the therapy for other leukemias to cause pro-
disease [123]. She received no antifungal chemother- longed granulocytopenia. Of 14 treatment courses
apy. Her diabetic control (through diet only) was evaluated, six were successful and eight unsuccess-
probably inadequate, and this circumstance may have ful. In a series of four cases in children [130], all failed
accounted for these problems. Another diabetic pa- to respond to antifungal therapy, were neutropenic,
tient taking insulin with good glucose control [124] and remained sountil death. In contrast, in two other
and an alcoholic patient [125] did well with surgery children [131], recovery probably coincided with
alone. One steroid-dependent patient with sphenoid recovery of granulocyte counts, and failure in a third
sinusitis responded to a combination of surgery and [6] coincided with relapse of leukemia. Higher doses
AmB treatment [126]. of AmB may not be helpful if neutropenia or leuke-
(2) Neutropenic patients. Seven patients with mia persists. In ALL antifungal therapy may be less
important than the status of the underlying disease, or dose per kilogram of body weight was. No sus-
although more effective antifungal therapy could al- ceptibility data were given.
ter the situation. TWo of three patients with ALL It is not clear from the available data what role
responded to L-AmB. surgery plays in sinus aspergillosis in the neutropenic
Of three patients with aplastic anemia, two did leukemic patient. The data shown in table 4 suggest
not respond to AmB treatment [122, 131] and were that mortality is increased by surgery (usually a
probably neutropenic. One of these patients subse- Caldwell-Luc procedure). Most of these patients were
quently responded to therapy with L-AmB, only to thrombocytopenic, and at least two patients suffered
die I month later of unspecified sepsis [122]. One major delayed hemorrhage postoperatively from the
patient with chronic lymphocytic leukemia (CLL) site of surgery [74, 129]; this hemorrhaging caused
failed to respond to AmB but did respond to L-AmB death in both instances. Whether the apparent in-
[122]. One patient with chronic myeloid leukemia crease in mortality following surgery reflects more
(CML) was unresponsive to 330 mg of AmB but then severe disease (patients in whom medical therapy is
responded to L-AmB [122]. perceived to be failing) is not clear. However, local
One series of four patients who developed asper- therapy with AmB in packing materials is not possi-
gillus sinusitis after BMT has been reported [74]. One ble without surgery. Whether local therapy is a valu-
patient responded to systemic and topical AmB ther- able adjunctive measure remains unclear. A biopsy
apy. Response in one instance did not occur until is necessary for diagnosis, and no complications have
surgery, which left a 2.5-cm oral-antral communi- been reported from biopsy procedures, as opposed
cation. A subsequent response to local AmB ther- to major therapeutic surgical procedures.
apy and high-dose systemic AmB treatment was Ocular aspergillosis. As Doft et al. [133] noted
noted. Another patient died of a hemorrhage 2 weeksin their discussion of aspergillus endophthalmitis,
after a Caldwell-Luc procedure and had cultures the first patient to regain her sight after treatment
positive for aspergilli at autopsy despite high-dose for this disease was one of their two patients (table
AmB. 5, appendix table 4A). In the other 21 cases reported
The observation of responses in two of five pain the literature up to that time (1980), the diagnosis
tients is more encouraging than the results obtained was usually made only by enucleation or at autopsy.
in pulmonary aspergillosis in BMT recipients. Since that time, one newborn in India with proba-
Rifampin was given with AmB to four patients ble bilateral disease has retained useful vision in the
and granulocyte transfusions to two patients. These right eye after systemic AmB treatment, although
ancillary forms of therapy will be covered in general the diagnosis was made on enucleation of the left
terms in the Discussion. eye [134]. Three other patients with successfully
In a large series not included in the table because treated aspergillus endophthalmitis have now been
of lack of detail about individual cases, 21 patients reported [135-137].
with cancer developed aspergillus sinusitis at the Diagnosis of intraocular aspergillosis is not easy.
Maryland Cancer Center [132]. Eleven patients had Aspiration of the vitreous is sometimes helpful in
AML, eight had ALL, and two had CML with blast that bacterial infection can usually be diagnosed in
crisis. Aspergillus flavus accounted for 14 of the this manner, but Aspergillus may not grow or a sin-
cases. A good response to AmB therapy was obtained gle colony of doubtful significance may grow. In the
in 100/o of those treated within 9 days of the devel- cases studied by Doft and colleagues, culture of the
opment of symptoms of sinusitis. With a delayed di- whole vitrectomy specimen was helpful in diagno-
agnosis, only four (57%) of seven patients responded sis. These authors also argue cogently, as others have
and the other three had generalized disease at au- [135, 138], that in fungal endophthalmitis vitrecto-
topsy. The authors stressed, however, that relapse is my is an important if not essential part of manage-
common after treatment and was not correlated with ment. Vitreoretinal traction and subsequent retinal
the total dose of AmB administered. Of the 18 pa- detachment may be prevented by vitrectomy. In one
tients originally responding, 11 relapsed and all had of the more recent successfully treated cases [135],
generalized aspergillosis at autopsy. Relapse usually an initial closed vitrectomy was followed 72 hours
coincided with relapse of leukemia and reinduction later by lensectomy and vitreous washout with exci-
chemotherapy. It was not stated whether surgery was sion of retrolental and cyclitic membranes. A core
performed in any case or what the daily AmB dose vitrectomy with intravitreal AmB treatment was also
ieatment of Aspergillosis 1163
Table 5. Summary table of treatment results for aspergillus endophthalmitis.
No. of infection sites with No. of infection sites with indicated medical treatment*
indicated type(s) of treatment Total no.
Intravitreal AmB (mg/d) AmB of sites
Surgical Medical Medical and AmB given (30 mg/d) treated
Group only only surgical > twice 430 31-59 and 5FC (%)
Responders 0 1 3 2 2 1 1 4 (40)
Nonresponders 1 3 2 0 1 2 0 6 (60)

* 5FC = flucytosine.
should include diagnostic vitrectomy (for both fun-

successful [137]. Early diagnosis (during the initial
operative procedure) may be achieved by Giemsa gal culture and histology), intraocular AmB treat-
staining of the vitrectomy aspirate [136]. ment (probably repeated at least once), systemic ther-
Because the penetration of AmB into the eye is apy with AmB (or another antifungal agent), and
poor [26], intraocular AmB therapy is almost cer- possibly repeated surgery for debridement. Whether
tainly an essential part of management. Up to 10 >ig the new azole fluconazole or the less toxic L-AmB
may be safely given at any one time if administered will be efficacious remains to be seen.
slowly into the vitreous; larger doses are retinotoxic The management of scleral abscesses due to
in a rabbit model but not in a rhesus monkey model; Aspergillus merits a brief discussion. TWo such cases
in the latter, 30 tg was tolerated without permanent have been reported. The first patient was an automo-
retinal toxicity [33]. L-AmB is markedly less toxic bile mechanic who frequently had foreign bodies in
to the eyes: a dose of L-AmB fourfold higher than his eyes and developed a 2.5-mm x 1.5-mm fluctu-
that of AmB was just as well tolerated in the rhesus ant mass in the sclera [1411. Hyphae noted at biopsy
monkey [33] and rabbit eye. In successfully treated responded to subconjunctival and topical AmB given
cases (except that in the neonate), vitreal injections over 30 days. The second patient had had aspergillus
of AmB were given once [136, 137], twice [135], or meningitis 5 years previously [142]. The original sin-
three times [133]. A total of 50 .g was given in one gle area of episcleritis, which appeared after blunt
case over 6 months without serious retinal toxicity trauma, extended during topical therapy with pred-
[139]. It is unclear whether subconjunctival AmB nisolone. Treatment with topical and subconjunc-
tival AmB followed by iv AmB with oral flucytosine
offers any additional benefit in terms of higher in-
traocular levels, but it is certainly an irritant. Al- was given during 8 months (total dose of AmB, 2,600
though levels have not been determined, flucytosine mg) for a probable coexisting bone focus of asper-
probably penetrates reasonably well into the human gillosis. The eye lesions resolved over the first 3
vitreous; the levels in the aqueous are 20%-30% of months. From the data available,no clear recom-
those in serum [37, 38]. In rabbits, levels of flucyto- mendations as to therapy are possible. Both flucyto-
sine in the aqueous are 75% and those in vitreous sine and itraconazole may prove to be good first
are 90lo of serum levels [140]. The use of flucyto-
choices for this entity.
sine is a logical approach to therapy, although ex- Cerebral aspergillosis. The 33 assessable cases of
perience to date is confined to one patient (described cerebral aspergillosis are presented in table 6 (and
by Doft et al. [133]) who received several other modes appendix table 5A). Most cases in the literature could
of treatment. The penetration of L-AmB into the not be included here, either because the diagnosis
aqueous and vitreous humors is not known, that of was first made at autopsy or because the patient re-
miconazole [21] and fluconazole [51] is good, that ceived only a few doses of AmB. For example, in two
of ketoconazole is moderate [51], and that of recent reviews of 24 patients from university hospi-
itraconazole is poor [51]. tals, only four patients received any AmB and even
Aspergillus endophthalmitis is a rare disease. Im- in those instances treatment was given for only a few
provements in therapy will not come until clinicians days [85, 86]; no patients survived. All of a group
are much more aggressive in their investigation and of nine renal transplant recipients died, despite treat-
management of suspected cases. The measures taken ment in four cases [4]. Likewise, mortality was 1000/o
Table 6. Summary table of results of treatment of cerebral aspergillosis.

indicated type(s)

Neutropeniat
Responders 0 0 2 0 1 0 1 0 0 0 0 2 (18)
Nonresponders 0 9 0 2 4 1 0 0 1 1 0 9 (82)
Transplant
Responders 0 1 0 0 1 0 0 0 0 0 0 1 (10)
Nonresponders 0 9 0 2 5 0 0 1 0 0 1 9 (90)
Other
Responders 1 2 2 1 0 0 1 0 2 0 0 5 (42)
Nonresponders 1 4 2 1 4 0 0 0 0 0 0 7 (58)
NOTE. Full details are given in appendi

t The neutropenia group includes all patie
among 10 heart transplant recipients, five of whom In two cases excisional surgery was a key factor
received AmB treatment [5]. Our data summary sug- in success. In one a frontal "tumor" was removed
gests a 24% response to therapy, likely weighted in and no medical therapy was given [148]. Nearly 4
favor of the well-documented but few survivors. A years later this patient remained well. Aspergillus ver-
critical reading of the literature and our own ex- sicolor was isolated. In the other case (in an alco-
perience suggest a mortality exceeding 95%, with a holic), a temporal mass that yielded A. fumigatus
value that may be nearer 1000/ in the significantly was excised and 450 mg of AmB was given [149]. Ad-
immunocompromised. This discrepancy reflects the verse reactions necessitated interruption of AmB
difficulty of antemortem diagnosis and the exclu- therapy, and it is unlikely that this small dose had
sion of patients who did not receive 14 days of an- major impact on the patient's disease.
tifungal therapy. Based on the literature, the following tentative con-
Survivors may be left with neurologic sequelae. clusions can be drawn with respect to surgical treat-
A neonate who survived was grossly damaged fol- ment of cerebral aspergillosis. There is no clear ad-
lowing this illness and had many neurologic han- vantage of a combined medical-surgical approach
dicaps [143]. It is not clear what role local therapy over a medical one alone. Lack of response to medi-
(AmB inserted into a cavity catheter) or concurrent cal therapy alone was in one case [144] followed by
treatment with flucytosine and rifampin played in success with both therapeutic modalities. Surgery
this case. One other child who received postopera- alone may be adequate for well-encapsulated single
tive local therapy-albeit for only 4 days-with lesions in less immunocompromised individuals.
flucytosine and systemic AmB also survived [144]; With respect to medical therapy, greater success has
previous treatment with AmB alone had failed in this been reported with a combination of flucytosine and
instance. Of three other patients given flucytosine, AmB than with AmB alone: four of seven therapy
two were cured of their infections. One was a pa- successes and four of 23 therapy failures were at-
tient with a pituitary abscess that was surgically tributable to flucytosine with AmB. The data on
drained prior to medical therapy [145]. A 74-year- aspergillus meningitis also support this view. In con-
old patient did well with a long (15-month) course trast, the results for pulmonary aspergillosis indicate
of high-dose AmB (total, 6.4 g) and flucytosine [146]. that the addition of flucytosine offers no advantage
Catheter drainage together with AmB therapy (50 over treatment with AmB alone. This difference may
mg/d) was successful in a patient after treatment for reflect tissue penetration differences for the most
AML [147]. part. Since three of the four patients treated with ri-
fampin and AmB failed to respond, there appears given with flucytosine and rifampin, although his
to be no clear advantage for this combination. The leukemia was in remission [152].
data do not suggest that a high dose of AmB is more No broad conclusions about therapy for asper-
efficacious than an intermediate or low dose. Local gillus meningitis can be based on these four patients
treatment with AmB may be helpful if given directly alone. Therapy with unstated amounts of AmB failed
into the site of disease. Too few data are available to elicit a response from three other patients reported
to evaluate L-AmB or itraconazole. The animal in the literature. Combined with the data on cere-
model data indicating synergy between itraconazolebral aspergillosis, this information strongly suggests
and flucytosine [13] may point the way toward fu- that flucytosine may be an important component of
ture progress in this difficult area. therapy for CNS aspergillosis.
Aspergillus meningitis. Only four evaluable Aspergillus epidural abscess. The majority of
cases of aspergillus meningitis have been reported: cases of aspergillus epidural abscess have been as-
one in a nonimmunocompromised patient [1501, one sociated with contiguous infection, usually of a ver-
in a drug addict [151], one in a neutropenic patient tebral body. These infections may be relatively si-
[152], and one following corticosteroid therapy [921.lent until neurologic disease appears. Fourteen cases
Three patients responded to treatment: one to AmB could be evaluated. As in all cases of progressive fo-
alone, one to AmB with flucytosine, and one to cal disease affecting the spinal cord, surgical decom-
flucytosine alone. Treatment failed in one case. The pression is appropriate for diagnostic and therapeutic
drug addict received flucytosine and AmB (17 mg reasons. In only one case [153] was the spinal cord
iv daily) for 3 months, with 0.3 mg of AmB given invaded by hyphae. However, two children who had
on alternate days via an Ommaya reservoir into the CGD with typical features of epidural extension of
right lateral ventricle (total AmB dose, 13.5 mg) [151]. thoracic vertebral osteomyelitis responded to medi-
The organism (A. oryzae) was susceptible to both cal therapy alone (high-dose AmB). In contrast, one
agents. Follow-up data in a separate report indicatedof the other patients did poorly with medical ther-
that this patient relapsed 5 years later with bilateral apy alone but later responded to operative interven-
necrotizing scleritis and a thoracic focus of infection and further AmB treatment [154].
tion [1421. She did not have meningitis at this time. The other patients received a combination of med-
A previously healthy patient responded to treatment ical and surgical therapy (table 7, appendix table 6A).
with 3 g of AmB (30 mg daily) plus flucytosine [150]; The five who responded (including one with an in-
no follow-up data were provided. The third patient, tracranial extradural lesion) were not immunocom-
who had sarcoidosis, received steroids and then de- promised and received slightly larger doses of AmB
veloped A. fumigatus meningitis, with CSF cultures than those who did not respond. Because only the
positive on three occasions. His condition improved total dose - and not the daily dose - of AmB was
during 3 weeks of treatment with flucytosine alone, stated in two of these cases, no great importance can
and he received a total of 3 months of therapy. He be attached to the dose of AmB in terms of the suc-
did not relapse over the next 2 years. The fourth pa- cess of management. Of the six patients who did
tient also had pulmonary disease and was neutro- poorly, three were immunocompromised. One of
penic; he failed to respond to AmB (1 mg/[kg.d]) these patients - a renal transplant recipient [153] -
Table 7. Summary table of treatment results for epidural aspergillosis.

Medical AmB (mg/d) of sites
Surgical Medical and treated
Group only only surgical (30 31-59 >60 -30 31-59 L-AmB (%)
Responders 0 2 5 1 1 4 0 1 0 7 (44)
Nonresponders 0 3 6 4 2 0 1 1 1 9 (56)

was infected by an organism that was apparently direct extension from brain or sinus disease but in
resistant to AmB, and renal impairment prevented three of these cases appeared to arise from otitis
optimal dosing of AmB. In an alcoholic patient, the [156-158]. Except for the three cases of otitis included
diagnosis of thoracic aspergillus osteomyelitis was in the tables, no case was reported in enough detail
delayed by >2 weeks (until paraplegia developed); for a separate discussion of the response of infected
postoperative renal failure curtailed therapy with cranial bone to therapy. Interested readers can refer
AmB. In a diabetic patient, both diagnosis and sur- to the original articles [74, 114, 118, 122, 126, 131,
gery were delayed [154]. In another nonimmunocom- 159-162]. All cases of rib infection except one
promised patient [155], toxicity of AmB precluded postoperative case were in patients with CGD, and
its use; despite surgery and ketoconazole treatment, these cases are considered separately below. Cases
the patient died. of epidural disease with bone involvement are con-
We believe that surgical intervention has a central sidereci in the preceding section, and the three cases
role in the management of aspergillus epidural ab- of fulminant skin, soft tissue, and (presumably) bone
scess. In CGD aggressive medical therapy alone may infection after major trauma are considered in the
be efficacious, although data are available for only later section on cutaneous aspergillosis.
two patients. Diagnosis should not be delayed, and Of the 38 courses of therapy, 24 were successful
early surgical intervention can be helpful in this re- and 14 failed. Fifteen of the 19 initially responding
spect. Medical therapy should be as aggressive as pos- patients had no immunocompromising factors,
sible, given the neurologic sequelae should therapy whereas 10 of 14 initial nonresponders were immuno-
fail. Treatment entails high-dose AmB at present. compromised to some degree. Among responders
Any role for flucytosine remains unclarified. Ex- 59% underwent a combination of medical and sur-
perience with a single patient indicates that gical treatment, whereas only 38% of nonresponders
ketoconazole is not helpful, and both itraconazole underwent surgery. iWo patients in whom medical
and L-AmB remain untried as primary therapy. therapy alone failed were cured with surgery and
However, one patient with CGD who had extensive AmB. These results imply that surgical intervention
vertebral body aspergillosis and paraplegia could not is an important part of the management of bone
tolerate >8 g of AmB and continued to improve dur- aspergillosis. Since concentrations of AmB in bone
ing itraconazole treatment, with resolution of are low and the pathology of aspergillosis involves
paraplegia [91]. infarction and necrosis, which result in poor drug
Bone aspergillosis. Included in table 8 (and ap- delivery to tissue, the need for surgery is emphasized.
pendix table 7A) are 33 evaluable cases of bony (1) Vertebral aspergillosis. Vertebral osteomyelitis
aspergillosis involving vertebrae, sternum, and long
is the most frequent type of bone infection caused
bones. TWo patients received two courses and one by Aspergillus species. It is not apparent from the
patient received three courses of therapy. Aspergillus literature what procedure is best for patients with
infection of these bones is acquired hematogenously vertebral aspergillosis or when a procedure should
via trauma or surgery. Sixteen other patients had be performed. Most patients underwent simple
cranial bone infection, which is usually acquired by debridement [154, 163-167], usually as part of an ini-
Table 8. Summary table of treatment results for bone aspergillosis.

No. of infection sites with indicated medical treatment*
indicated type(s) of treatment
AmB (mg/d) ~~~Total no.
Surgical Medical and - treated
Group only only surgical <3O 331-59 >60 <30 31-59 Itr (%)
Responders 0 9 15 3 10 1 3 1 3 24 (63)
Nonresponders 0 9 5 2 6 0 1 3 1 14 (37)
NOTE. Full details are given in appendix tab

tial diagnostic procedure. Others had the diagnosis long-bone infections as about diskitis. However, ex-
made by a percutaneous biopsy with, for example, perience in these areas is severely limited [174, 175].
a Craig needle. Later surgery consisted of radical (4) Rib aspergillosis. Infection of the ribs by
debridement with bone grafting; usually a rib strut Aspergillus is very uncommon and occurs almost ex-
was used [47, 154, 164, 165, 167, 168], and sometimes clusively in CGD patients as a result of contiguous
stabilization from Harrington rods was employed spread from the lung. Few patients with this condi-
[47, 166]. In these cases the time of surgery with re- tion have been reported [170, 176-178], and knowl-
spect to AmB therapy varied considerably, ranging edge of appropriate therapy is lacking. Careful scru-
from the time of diagnosis to 5 months later. Grafts tiny of the literature on patients with CGD indicates
apparently are accepted regardless of a local infec- that failure of therapy- either failure of initial ther-
tious process if concurrent systemic antifungal che- apy or relapse after some (usually slight) improve-
motherapy is given. In the stabilization of the spine, ment-is common. Surgery for this condition (e.g.,
an early grafting procedure probably speeds recov- rib resection) creates considerable deformity and may
ery. TWo patients for whom medical therapy alone leave the underlying lung unprotected. There is there-
failed but who subsequently responded to combined fore a definite need for early, aggressive diagnosis
therapy have been mentioned in the preceding para- despite the paucity of clinical signs. Even if surgery
graph [154, 166]. is delayed, we would still recommend a combination
Confidence in antifungal therapy allows more rad- of medical and surgical therapy. TWo patients with
ical surgical procedures for vertebral aspergillosis. CGD have been maintained in remission with
Unfortunately, the data available provide few clues itraconazole [91] after primary AmB treatment.
as to the best medical therapy. It is notable that three Joint aspergillosis. Little is known of this entity,
of four patients treated with itraconazole have done of which there are only two documented cases. In
well, two without surgery (although one required the first patient a total hip replacement became pain-
stabilization of his spine after 4 months of itracona- ful 9 years after surgery, and Aspergillus niger was
zole therapy when histology and cultures were nega- isolated from aspirated hip fluid [165]. Intraopera-
tive). The one patient in whom this agent failed was tive cultures and acetabular bone scrapings yielded
taking a low daily dose (200 mg) and had suboptimal the same organism, and histologic examination re-
serum concentrations. Two of three patients not in- vealed hyphal elements. A new prosthesis was in-
cluded in the tables because of a lack of detail serted, and 36 mg of AmB was given daily for 2 weeks
responded to 200 mg of itraconazole daily [169]. postoperatively. The patient remained well 18 months
With regard to AmB, there is no clear advantage to after this second operation. The second patient was
higher doses; however, such doses (>I mg/[kg.d]) diabetic and was infected by Aspergillus glaucus [47].
have not been used in this disease despite poor He responded to itraconazole, but 3 months after
penetration into bone. Lower AmB doses were ef- the completion of 1 year of therapy, swelling and er-
fective when given in combination with flucytosine, ythema of the knee developed. Because the patient
and, because of the good penetration of flucytosine refused to undergo further investigation, it is unclear
into bone, this agent would seem to be a logical ad- whether he did actually relapse.
dition to an AmB regimen. Two patients have been No definitive conclusions can be drawn from these
cured with 3 months of therapy with flucytosine two cases. A trial of medical therapy - plus surgery
alone [170, 1711. for removal of infected bone, if present -may be a
(2) Aspergillus diskitis. The distinction between reasonable approach to this problem.
vertebral osteomyelitis and diskitis is ill defined; in Invasive external otitis. Five evaluable cases of
some cases very little involvement of the adjacent invasive external otitis have been reported [47,
bone has been apparent, but in others the infection 156-158, 179]. The finding of Aspergillus species in
has clearly spread into bone and intervertebral disk. a culture from the external ear canal is of little sig-
There are three reports of this entity [154, 172, 173]; nificance; this organism is both a commensal and
in two, the authors recommend a combination of a cause of external otitis without invasion. Those
medical and surgical therapy [154, 172]. cases without invasion are not discussed further here.
(3) Long-bone aspergillosis. By extrapolation, One patient with AML improved with 2 g of AmB
much the same recommendations can be made about given over an unstated period, although his facial
palsy remained [158]. An elderly, nonimmunocom- cur with disseminated disease. In profoundly im-
promised patient had progressive loss of cranial nervemunocompromised patients dissemination may fol-
function over the first 3 weeks of a 5-week course low cutaneous inoculation. It is curious that a large
of therapy with AmB (43 mg/d); function then re- number of children with cutaneous disease have been
mained stable. Invasive cerebral disease was not reported; adults predominate numerically in cases
shown at autopsy 2 months later [179]. of aspergillosis at other sites.
AmB therapy probably failed in two other cases. Of the 29 episodes reported in sufficient detail,
One patient had CLL and, despite the administra- 23 were successfully treated (table 9 and appendix
tion of AmB (30-40 mg/d) and flucytosine over 2 table 8A). These included two pre-1970 cases in
weeks, reexploration of the mastoid yielded a speci- nonimmunocompromised patients: one from Egypt
men that grew A. fumigatus [157]. The patient died [180] and one from South Africa [181]; both
of concurrent cryptococcal meningitis and Pneu- responded to oral nystatin therapy. Although many
isolates of Aspergillus are susceptible to nystatin, oral
mocystis carinii pneumonia; autopsy (after rv4 weeks
of treatment with AmB and flucytosine) did not re-absorption is very poor. We believe that these cases
veal persistent infection with Aspergillus of the reflect the ease with which cutaneous disease may
debrided mastoid. The other patient, with no im- be treated if no grossly immunocompromising fac-
munocompromising factors except his age (85 years), tors are present. The cure rate was much higher for
received AmB (43 mg/d) for 5 weeks after surgery, cutaneous disease than for disease at any other site.
with some improvement [156]. Three weeks after he Even three out of four cases of hematogenously ac-
stopped taking AmB, he developed a symptomatic quired cutaneous disease responded [4, 182, 183].
recurrence that did not appear to respond to AmB One patient with CGD did not respond to high-dose
(48 mg/d) and rifampin. AmB despite the susceptibility of the infecting or-
The one patient (nonimmunocompromised) who ganism [184].
was treated with itraconazole responded, although In a recent series of nine patients with cutaneous
mastoidectomy may have played a part in the re- infection associated with Hickman catheters, all but
sponse [47]. two patients responded to high-dose AmB and
It is not clear what the best therapy is in these flucytosine after removal of the catheter [9]. Five pa-
cases, which include two responders, one partial re- tients also had pulmonary disease. The two patients
sponder, and two failures of combined medical and who remained neutropenic failed to respond to treat-
surgical treatment. ment and died with disseminated aspergillosis. The
Cutaneous aspergillosis. Most cases of cutane- organism involved in eight of nine cases was A. fla-
ous aspergillosis are acquired by direct inoculation. vus. No susceptibility data were given.
Only occasionally do cutaneous manifestations oc- Cutaneous aspergillosis may respond better than
Table 9. Summary table of treatment results for cutaneous aspergillosis.

No. of infection sites with indicated medical treatment*
Host factor, Surgical Medical

Am1B only (mg/d) Am1B of sites
Medical and (60 mg/d) treated
group only only surgical (30 31-59 >60 and 5FC (%)
Neutropeniat
Responders 0 10 1 0 3 1 7 11 (79)
Nonresponders 0 2 1 0 0 1 2 3 (21)
Other
Responders 2 7 3 3 3 0 0 12 (80)
Nonresponders 2 1 0 0 0 1 0 3 (20)

t The neutropenia group includes all patients in whom neutropenia had been documented; however, this condition was not
TReatment of Aspergillosis 1169
other forms of aspergillosis because the abnormal- AmB treatment failed to cure the infection in a 6-
ity is recognized early; appropriate, relatively safe year-old; a right hip disarticulation was finally re-
diagnostic steps are taken; and treatment is instituted quired. Clearly in these cases there was infection of
quickly. In addition, most cases have been reported deep tissue and presumably bone in addition to skin,
in leukemic patients, in whom neutropenia resolved but the poor response to AmB (dose not clearly
soon after antifungal treatment was initiated. In the stated) is similar to that seen in burn patients.
two neutropenic patients whose therapy failed, neu- Aspergillus endocarditis. Endocarditis due to
tropenia was not reversed; these patients died with Aspergillus occurs de novo or, more usually, after
disseminated disease. surgery. Occasionally it is seen as part of dissemi-
(1) Burn wound aspergillosis. Aspergillus species nated aspergillosis. The diagnosis is generally
may colonize or infect burn wounds. Presentation delayed; in most cases diagnosed antemortem, the
includes significant fever (above that usually seen examination of tissue removed at embolectomy has
with the burn itself) and a change in character of provided the diagnostic clue. Blood cultures are rarely
the burn, including "conversion" from a partial- to positive in disseminated aspergillosis or endocardi-
a full-thickness injury. Swelling, induration, and tis, probably because fungemia is intermittent. Reli-
tenderness are frequently seen. The pace of infec- ance on a positive blood culture for diagnosis is un-
tion may be slow or fulminant. Mortality varies from wise. For these reasons diagnosis is often delayed or
"'30% [185] to 78% [186]. Data for 1982-1985 indi- not made at all before death. The clinical features
cate that 24 (77%) of 31 infected patients and nine of aspergillus endocarditis have been reviewed [190].
(47tVo) of 19 colonized patients died [186]. One case of mural endocarditis has been reported
Therapy for this entity is unsatisfactory. Success- [125]. We found only 15 cases for which we can re-
fully treated patients have always undergone exten- view therapy.
sive, radical surgery, often with amputation [185, It is clear from table 10 (and appendix table 9A)
187]. Local recurrence has often followed conserva- that all patients who received medical therapy alone
tive debridement [187]. Excision of multiple distant died, despite the use of high-dose AmB in two cases
areas of involvement is not always successful [188]. [191, 192]. Of those treated both medically and sur-
Even radical excision has been unsuccessful in many gically, three (43!70) of seven survived; follow-up data
cases, and recurrence has been noted even in three covered only the first 80 days after surgery for one
of seven patients treated by open amputation [187]. survivor [191]. One surgical patient [193] received no
The infection was suppressed with iv AmB (dose un- medical therapy at all and survived, although perti-
stated) but was never eradicated [187]. Patients with nent histopathologic details of this case were not
more severe burns fared less well. given. Early surgical intervention is clearly impor-
(2) Posttraumatic soft tissue aspergillosis. In a tant in these patients. This conclusion is supported
series of four children with extensive soft tissue by the very low penetration of AmB into cardiac
aspergillus infection (three were victims of major vegetations [25]. Penetration of penicillin into vege-
trauma), control was achieved only with radical sur- tations depends on the relative gradient between
gery [189]. TWo patients-aged 2 and 10 years- blood concentrations and vegetations. If this is also
required hemipelvectomies. Knee disarticulation and true for AmB and a fungal vegetation, then more
Table 10. Summary table of treatment results for aspergillus endocarditis.
indicated type(s) of treatment
AmB (mg/d) ~~~Total no.
Medical AAiB (mg/d) of sites
Group only only surgical K30 31-59 >60 (30 31-59 Itr (%)
Responders 1 0 3 0 1 1 1 0 0 4 (27)
Nonresponders 0 7 4 0 5 2 1 2 1 11 (73)

rapid administration of AmB (e.g., over 45 minutes), patient, who also had pulmonary disease, relapsed
with a higher peak level, may result in higher con- twice after two courses of medium-dose AmB [195].
centrations in vegetations. It is not clear what dose All patients who died had disseminated disease
of AmB is optimal. at autopsy. All were leukopenic, although in one, who
The penetration of flucytosine into vegetations is also received corticosteroids [72], the granulocyte
likely to be higher but has not been measured. One count was 700 x 106/L just prior to death. This pa-
renal transplant recipient thought to have only pul- tient also underwent surgery for the creation of a
monary disease died after 5 weeks of itraconazole pericardial window; this procedure obviously did not
therapy [47] and had endocarditis at autopsy. The improve the outcome, but a rather low dose of AmB
infecting organism was relatively resistant to itra- was used in this case.
conazole, and serum levels never exceeded the MIC. Arterial aspergillosis. One of the remarkable fea-
Early diagnosis by surgery and valve replacement tures of aspergilli is their predilection for blood ves-
is the cornerstone of successful therapy. Diagnosis sels. Invasion of small pulmonary vessels is charac-
may be made only at surgery. Surgery may also pre- teristic and often results in pulmonary infarction.
vent major embolic events since these events are Many of the clinical features of cerebral aspergillo-
much less frequent after excision of the infected valve
sis, hemorrhage, and infarction are due to this prop-
[194]. erty of the fungus. A few cases have been reported
Pericarditis. Pericarditis is a relatively rare com- in which major arteries were diseased as a result of
plication of disseminated aspergillosis, comprising aspergillus infection. Some patients have developed
4% of cases in the series described by Young et al. mycotic aneurysms; others have shown complete or
[1]. This entity may occur because of rupture of a partial occlusion of the artery. The scanty literature
myocardial abscess, contiguous spread from the lung, on fungal mycotic aneurysms of the cranial vessels
or (occasionally) hematogenous spread. Symptoms, has been reviewed by Mielke et al. [196].
signs, and electrocardiographic abnormalities may We can include three cases of bona fide arterial
be absent. aspergillosis occurring as a discrete entity. One was
Only three patients who have survived this com- a postoperative infection of an aortobifemoral Da-
plication of aspergillosis have been described (table cron graft- [197]. This infection extended into adja-
11 and appendix table IOA). One was a heart trans- cent vertebrae. Resection of the aneurysm with lower
plant recipient with serous pericarditis [88], one was limb vascular supply from an axillobifemoral graft
a patient with constrictive pericarditis and mediasti- and the administration of 2 g of AmB effected a good
nal disease 5 years after treatment for Hodgkin's dis- response. TWo other patients had carotid artery oc-
ease [47], and one had no discernible immuno- clusion caused by Aspergillus. One, whose disease
compromising factors [195]. Both patients given also involved the sphenoid cavernous sinuses, under-
itraconazole responded, although in one case the went angiographic visualization before and after a
Aspergillus isolate showed only borderline suscep- 2-month course of AmB (25 mg/d), but the proce-
dure revealed no evidence of improvement [116]. The
tibility (MIC, 6.3 gg/mL); one of these infections
was probably cured: no relapse has occurred in the organism isolated was relatively resistant to AmB.
9 months since cessation of therapy [47]. The third A further course of AmB with flucytosine (to which
Table 11. Summary table of treatment results for pericardial aspergillosis.
indicated type(s) of treatment - -
AmB (mg/d)
Group only only surgical -30 31-59 >60 - 430 31-59 Itr (%)
Responders 0 2 1 0 1 0 0 0 2 3 (27)
Nonresponders 0 7 1 1 4 1 0 2 0 8 (73)
NOTE. Full details are given in appendix table IOA.

the organism was susceptible) and rifampin resulted portant risk factor and is more often associated with
in improvement, but the carotid artery was not pelvic than with parenchymal disease. Parenchymal
visualized further. This 37-year-old patient was not disease is more common in patients with leukemia
immunocompromised. The third patient, also young, and CGD and may not be as rare as the literature
was a renal transplant recipient who also had sinus suggests. In the series described by Young et al. [1],
and cerebral aspergillosis that progressed during 12 of 98 cases - mostly in patients with leukemia and
treatment with AmB [471. He then received itracona-lymphoma-had renal involvement at autopsy. Pa-
zole by nasogastric tube and gavage (poor delivery renchymal disease is usually silent, whereas pelvic
modes because of the difficulty in passing drug down disease presents with the passage of fungal balls and
the tube). Concentrations of itraconazole in the renal colic.
blood never exceeded the MIC for the infecting or- With 18 cases reported (20 courses of therapy),
ganism. The patient died of gastrointestinal bleed- therapy was successful in all but one instance (in a
ing. Autopsy showed occlusion of his right carotid patient who had disseminated disease [72]); eight
artery by aspergilli. cases required surgical removal of one kidney as the
Poor drug delivery to the site of disease is a ma- means of cure (table 12 and appendix table IIA).
jor problem in this entity, even if very active agents Most patients treated medically responded to medi-
become available. Vessel occlusion with distal infarc- cal therapy alone, including local irrigation with
tion or hemorrhagic infarction may make the use of AmB in two cases. (One of the latter patients also
thrombolytic therapy (surgical or pharmacologic) received AmB and flucytosine systemically, while the
hazardous in this setting. On the other hand, it is other received local therapy alone.) Three patients
not easy to see how outcome can be improved with- had surgical procedures other than nephrectomy: two
out such therapy. One of the newly reported agents had pyelotomy for removal of aspergillomas from
that do not cause much additional bleeding - tissue the renal pelvis, and the other underwent partial
plasminogen activator or anisoylated plasminogen nephrectomy.
streptokinase activator complex -may be useful in Systemic antifungal therapy failed in two patients.
this regard. The careful study of an animal model One had probably acquired her infection from air-
may provide at least a partial solution to this borne spores at the time of a pyelolithotomy 3 years
problem. before [105]; the suture material had provided a ni-
Urinary tract aspergillosis. Aspergillus renal dis-dus of infection that almost certainly would never
ease takes two main forms: parenchymal disease and have responded to medical therapy alone. This in-
fection was cured with nephrectomy. In the other pa-
pelvic disease. Infection at this site is usually blood-
borne. Although the authors of one report have tient, who had bilateral disease [198], infection in
claimed an ascending route of infection [1981, the the right kidney may have been mycologically cured,
evidence is not strong. However, a single case of fun- but such fibrosis developed after removal of asper-
gal balls in the bladder without upper tract disease gillomas from the pelvis and systemic treatment with
has been described [199]. Diabetes is the most im- AmB that the kidney completely stopped function-
Table 12. Summary table of treatment results for renal aspergillosis.

indicated type(s) of treatment No. of infection sites with indicated medical treatment* Total no.

Group only only surgical <30 31-59 >60 <30 31-59 >60 (%)
Responders 9t 5 3 3 3 0 0 1 1 17 (85)
Nonresponders 0 2 1 1 1 0 1 0 03 (15)
NOTE. Full details are given in appen

t All patients underwent nephrectomy.
ing. The left kidney, which was less diseased initially, five had solitary lesions, while the fifth patient had
responded to local irrigations of AmB through a multiple lesions. In the series described by Young et
nephrostomy tube. al. [1], 12 of 98 patients had hepatic involvement,
In general, renal pelvic aspergillosis is not immedi- and two had such extensive involvement of hepatic
ately life-threatening; therefore, diagnosis and treat- veins that a Budd-Chiari syndrome developed.
ment are not as urgent as in many other forms of There have been three well-documented treated
aspergillosis. Nonetheless, inadequate therapy or late cases of hepatosplenic aspergillosis. All three patients
diagnosis may result in loss of a kidney. Based on failed to respond to AmB; one subsequently
the 13 cases reported, the following synthesis appears responded to L-AmB [68] and one to itraconazole
pertinent. Three of six patients who responded to [47]. In one patient with ALL, hepatosplenic asper-
treatment received local irrigations of AmB through gillosis was diagnosed by histopathology [24]. Af-
nephrostomy tubes. Four of six who responded re- ter the administration of 1,752 mg of AmB over a
ceived medium- or high-dose AmB, although two of period of 37 days (mean, 47 mg daily), hepatic and
these four also received flucytosine (and one of these splenic concentrations of AmB at autopsy were 166
rifampin as well). We recommend the use of high- and 48 gg/g of tissue, respectively, as measured by
dose AmB; however, cure may be possible with low high-performance liquid chromatography of an eth-
doses [200, 201]. The use of flucytosine may be help- anol extract of tissue. These concentrations greatly
ful since the latter agent is excreted in high concen- exceed the MIC for the isolate (40.4 gg/mL), yet
tration in the urine. If the disease follows an open treatment failed.
renal procedure, implantation aspergillosis in an al- In a patient with lymphoma [68], infection per-
ready diseased and scarred kidney is likely, and cure sisted despite administration of a total of 6.9 g of
is unlikely with medical therapy alone. Whether AmB over 9 months with flucytosine, miconazole,
fluconazole, which achieves high urinary concentra- and ketoconazole. New lesions appeared that were
tions, will be efficacious remains to be seen. histologically shown to be due to Aspergillus spe-
One case of A. flavus prostatic aspergillosis was cies. During 57 days of L-AmB treatment, the pa-
successfully treated with surgical removal of a fleshy tient's condition improved markedly; both a liver bi-
protuberance arising from the prostate and seen on opsy after treatment and autopsy 9 months later
cystoscopy [202]. showed no evidence of fungal disease.
Adrenal aspergillosis. Of the 98 patients whose A patient with AML developed pulmonary asper-
autopsy results were reported by Young et al. [1], only
gillosis during prolonged neutropenia and responded
one had evidence of adrenal disease. A single case to 2 g of AmB given over "'6 weeks [47]. On follow-
of adrenal aspergillosis diagnosed in life has been up her liver function tests became abnormal, and
reported [203]. This patient with sarcoidosis was computed tomography showed hepatosplenic asper-
treated with prednisone and underwent partial gillosis, which was confirmed histologically. The pa-
removal of an adrenal mass that was later shown to tient responded to itraconazole treatment over the
be due to A. fumigatus. After "'2 weeks of ketocona- next 2-3 months (which included a second period
zole therapy, thrombosis of the inferior vena cava of profound neutropenia lasting for 3 weeks), with
was found and anticoagulation was begun. A week normalization of liver function tests and great im-
later, the patient died suddenly of massive hemop- provement in computed tomographic appearances.
tysis. Autopsy revealed a large fungal abscess that Although limited, the data available for these cases
had penetrated the inferior vena cava. Ketoconazole, are exceptional in quality. For reasons that are un-
which penetrates the adrenal well, had clearly failed clear, AmB appears to be a poor agent for the treat-
to arrest this infection. The organism was resistant ment of hepatic aspergillosis. Alternative therapy
in vitro. with L-AmB or itraconazole should be considered
Hepatosplenic aspergillosis. This entity is only early in the course of this illness. Both of the latter
rarely recognized antemortem. In a series from agents reach high concentrations in the liver, a char-
Memorial Sloan-Kettering Cancer Center, five of 93 acteristic that nmay explain their success.
cases had hepatic involvement as a prominent fea- Aspergillus peritonitis. We found only one suc-
ture of disseminated aspergillosis [204]. All patients cessfully treated case of peritoneal aspergillosis in
had abnormal hepatic function, especially elevations the literature [205]. This infection occurred in a
of bilirubin and alkaline phosphatase. Four of the patient undergoing continuous cycling peritoneal
Theatment of Aspergillosis 1173
dialysis and was due to Aspergillus terreus. Initial gillus can ever be the gastrointestinal tract. The
therapy (12 days) with ip AmB (1 mg/L) was unsuc- conidia are extremely widespread, hardy, and able
cessful. The Tenckhoff catheter was therefore re- to survive for years in hostile conditions. Moisture
moved, and the patient was given iv AmB to a total and warmth are two prime stimuli for germination.
of 30 mg/kg with hemodialysis. Subsequent attempts A gastrointestinal mode of infection has never been
to replace the peritoneal catheter were thwarted by demonstrated but seems feasible. However, 18 of 21
many adhesions. cases in the series described by Young et al. had
Of the five other patients described, four had ful-prominent pulmonary involvement as well, suggest-
minant illnesses and died in <1 week. In one case ing airborne spread as the mode of acquisition [1].
the diagnosis was delayed by lack of fungal growth Filtering of conidia by the nose and swallowing of
from the peritoneal fluid. In another, due to A. niger, nasopharyngeal mucus may be another possible
local administration of AmB, removal of the cathe- mode of acquisition. It is also unclear what treat-
ter, and iv treatment with AmB (0.5 mg/[kg-d]) were ment is appropriate and whether orally administered
unsuccessful in averting death for longer than 3 antifungal agents, particularly nonabsorbable anti-
weeks [206]. In some cases of fungal peritonitis due biotics, would be efficacious in this setting.
to Candida species, local instillation of AmB was Lymph node aspergillosis. Aspergillus infection
unsuccessful but removal of the peritoneal catheter of the lymph nodes seems to be rare. In one case that
was curative alone. In aspergillus peritonitis, cathe- followed infection of the soft tissues and bone of
ter removal appears to be mandatory. The continued the lower leg of a CGD patient, inguinal and
use of the catheter allows ip therapy and may theo- popliteal nodes were infected [184]. This infection
retically prevent adhesions, but the presence of a for- occurred despite the administration of AmB (1
eign body may prevent effective therapy. Continued mg/[kg.d] for 1 month). The MIC of AmB for the
use of the catheter may have been a significant fac- organism was 1.2 g.g/mL, and serum concentrations
tor in several of the fatal cases reported. of AmB were unusually high (1.7-4.5 mg/mL). Cure
Gastrointestinal aspergillosis. This disease entity was effected by surgical removal of the nodes.
is only rarely recognized antemortem. Of the 91 cases Aspergillus thyroiditis. Despite the relatively
whose pathology was studied by Young et al. [11, 21 high frequency of aspergillus thyroiditis at autopsy
had evidence of gastrointestinal aspergillosis. The in patients with disseminated aspergillosis (9O/o-150o)
ranking of frequency of infection in different parts [1, 2041, very few individual case reports have been
of the gastrointestinal tract is as follows: esophagus published. In one renal transplant recipient, the di-
(10 cases), colon (nine), jejunum (five), stomach agnosis was made antemortem by aspiration (with
(five), tongue (three), ileum (two), soft palate (two),
ultrasound guidance) of a nodule [208]. The aspirate
and hypopharynx (two). In another series of 93 pa- grew A. fumigatus. TNelve days of therapy with AmB
tients, nine had gastrointestinal involvement [204]. (0.5 mg/[kg-d]) and flucytosine resulted in clinical
Only one patient with a possible antemortem diag- improvement, but the patient died of bacterial pneu-
nosis of gastrointestinal tract aspergillosis has been monia. Autopsy showed disseminated, culture-posi-
reported [183]. This diagnosis was based on the clin- tive aspergillosis.
ical features of abdominal pain and ileus with a stool To our knowledge, only one case of successful
culture positive for A. niger in a neutropenic patient treatment of aspergillus thyroiditis is on record. A
with AML. The same organism was isolated from boy with CGD developed fever, thyrotoxicosis, and
sputum; lower-lobe pneumonitis was present concur- a tender, erythematous thyroid swelling [209]. Sur-
rently. Low-dose AmB (<10 mg/d) with granulocyte gical incision drained 10 mL of pus, which grew A.
transfusions was given for 2 weeks. The patient re- fumigatus. The boy received 5 weeks of treatment
covered and her leukemia went into remission for with AmB (20 mg, or rvO.6 mg/kg, daily) and re-
1 year. At autopsy more than a year after antifungal covered completely. No relapse had occurred 6
treatment, liver histology showed granulomata and months later.
fungi consistent with Aspergillus organisms, indi-
cating probable previous dissemination. One other
Discussion
patient developed a bronchoesophageal fistula re-
lated to pulmonary aspergillosis [207]. This review has detailed results of therapy in 379
It is not clear whether the portal of entry of Asper- evaluable patients and 440 courses of therapy for dis-
ease at different sites, including all forms of inva- For others, there is very little published information.
sive aspergillosis. The discussion attempts to focus In patients with leukemia who develop pulmonary
on individual antifungal agents, other treatment aspergillosis and require further chemotherapy or
measures (surgery and granulocyte transfusions), and transplantation, resection of a localized area of
in vitro susceptibility testing of aspergilli and to drawaspergillosis (as judged by computed tomography)
some conclusions about the place of each in ther- may be lifesaving.
apy for aspergillosis. As medical therapy for invasive aspergillosis im-
proves, the indications for and types of surgical ther-
apy will probably change. An example might be new
Surgery
medical therapy for pulmonary aspergillosis that pre-
Aspergillosis is characterized histologically by infarc-vents tissue infarction, obviating the need for resec-
tion and necrosis. Probably for this reason many pa- tion of residual pulmonary disease. Only two types
tients have apparently responded to surgical debride- of invasive aspergillosis can be handled surgically
ment of tissue in combination with antifungal without medical therapy: sinusitis in the nonim-
chemotherapy. We have tabulated the major indica-munocompromised host and bronchial stump asper-
tions for surgery in table 13; in some cases surgicalgillosis. These indications for surgery probably will
therapy is so important that we have deemed it es- not alter in the near future.
sential. In other cases it may well be important, but
the data available are poor. Some surgical approaches
AmB
have not been tried and are worthy of consideration.
AmB has been used since 1957 and remains one of
the most toxic drugs administered to patients, with
the exception of the cytotoxic chemotherapy agents.
Table 13. Indications for surgery in invasive aspergillosis.
More experience has been accumulated in the
Disease process Operative procedure management of aspergillosis with AmB than with
Essential for management any other agent. It is the major iv agent available
Endocarditis Valve replacement (miconazole and flucytosine being the others).
Endophthalmitis Vitrectomy and AmB instillation The overall efficacy of AmB is not very impres-
Hemoptysis in pulmonary
sive. For the patients included in this review, the over-
disease Resection of nodule(s)
all response rate was 55% (176 responses in 320 sites).
Sinusitis in normal host Drainage and aeration of affected
sinuses Clearly this figure includes patients who did not un-
Epidural abscess Decompression of spinal cord dergo surgery that might have been beneficial in
Posttraumatic soft tissue some cases. In this review our exclusion of patients
infection Radical debridement
treated for <14 days may have obscured many early
Burn wound aspergillosis Radical debridement/amputation
failures. AmB doses were virtually the same in
Peritonitis Removal of catheter
Bronchial stump responders and nonresponders. This fact emphasizes
aspergillosis Removal of infected suture material the heterogeneity of both the patient population and
Desirable for management the infecting organisms in terms of in vivo suscepti-
Bony aspergillosis Debridement with immediate bone
bility of AmB.
grafting, if appropriate
Extensive pleural disease Decortication
The data we have reviewed do not indicate clearly
Possibly helpful, but data what the dosage of AmB should be. For pulmonary
limited aspergillosis, lower doses have been more successful
Cerebral aspergillosis Diagnostic and therapeutic resection in transplant recipients and relatively nonim-
Invasive external otitis Debridement
munocompromised patients than in neutropenic pa-
Lymph node disease Resection
Localized pulmonary
tients. In the last group early initiation of therapy
aspergillosis Resection (especially prior to and use of daily doses of 1 mg/kg combined with
transplantation or further flucytosine administration have reduced mortality
chemotherapy) at some centers during recent years. Invasive pulmo-
Laryngeal aspergillosis Excision
nary aspergillosis developed in many of these pa-
NOTE. See text for details, especially as the procedure may be tients during treatment with 0.5 mg of AmB/(kg.d).
diagnostic as well as therapeutic. For these reasons we believe that high-dose AmB (at
least 1 mg/[kg promised d]) [931, is and the other had undergone bone
appropriate
tients with thismarrow transplantation [551.
disease Because in vitro sus- itr
unless
is shown to be superior. Lower doses are adequate ceptibility data were given in only two of these reports
for most patients who are not neutropenic. High [92, 93], clinical response cannot be correlated with
doses also achieve good results in neutropenic pa- susceptibility.
tients with cutaneous disease if neutropenia resolves, A total of 63 patients were treated with a combi-
Topical therapy with AmB has been used infre- nation of flucytosine and AmB (table 14). Two-thirds
quently, and the only setting in which it appears es- responded to the combination, including 11 (58%)
sential is that of aspergillus endophthalmitis, in of 19 patients with acute leukemia. Fourteen (88%)
which two or three intravitreal doses have proved of 16 nonimmunocompromised patients and nine
sight-saving if combined with vitrectomy. The use (82%) of 11 renal transplant recipients responded.
of nephrostomy infusions of AmB in renal pelvis For several reasons the data favor the empiric use
aspergillosis is probably justified. Local instillations of flucytosine with AmB in all cases of invasive
of AmB (or nystatin or miconazole) into the pleural aspergillosis: in animal models the combination of
space for pleural aspergillosis have also been effec- flucytosine with AmB is often synergistic or at worst
tive and, in terms of toxicity, are preferable to iv dos- indifferent; penetration of AmB into CSF, vitreous,
ing. It is not clear whether local therapy for sinusi- and bone is poor, whereas that of flucytosine is bet-
tis is helpful or whether the placement of catheters ter; potentially therapeutic tissue concentrations of
in infected areas of lung or brain, with subsequent flucytosine (unlike those of AmB) are reached rap-
local irrigation of AmB, is beneficial. Use of AmB idly; and the above data on single-drug therapy and
irrigation in peritoneal infection is likely to lead to combination therapy are favorably inclined towards
rapid death; removal of the catheter and adminis- flucytosine. (The last point is based on a series of
tration of iv AmB may lower the current high mor- anecdotal cases and should be interpreted in that
tality. light). If serum flucytosine concentrations cannot
AmB remains the treatment of choice for most be monitored rapidly, the drug probably should not
forms of invasive aspergillosis. Its record is gener- be used with AmB in order to prevent toxicity. No
ally poor, however; and the results of therapy in some data suggest that doses of flucytosine giving ther-
settings, such as cerebral aspergillosis or bone mar- apeutic serum concentrations have any undesirable
row transplantation, are dismal. The efficacy of effect on recovery of bone marrow function during
AmB may be improved by combination with flucyto-chemotherapy-induced granulocytopenia. If, after
sine or rifampin. Although its toxicity has probablyempiric therapy with flucytosine and AmB has be-
been overestimated, AmB is toxic and generally gun, the isolate turns out to be resistant to flucyto-
poorly tolerated by patients. Despite such problems, sine or is not affected synergistically by flucytosine
it may be several years before this drug is supplanted
in combination with AmB, then the continued use
by newer agents. of flucytosine in that patient may no longer be
justified.
Recent work has focused on the combination of
Flucytosine Alone or in Combination
flucytosine and itraconazole [13, 231]. This oral com-
Only 12 patients reviewed here were treated with bination may be markedly synergistic in vitro and
flucytosine alone, and 10 of the 12 responded [55, may prove useful in the future for the treatment of
92, 93, 170, 171, 210]. Six of these 10 patients were some forms of invasive aspergillosis. However, no
described in one report [92]; the group included one patients who have received the combination have
patient with meningitis and two with pleural disease. been described.
Relapse probably occurred in one case of pulmonary
disease in which the isolate became resistant during
Rifampin and AmB
therapy.
Of the other six patients, four responded: one each Both in vitro and animal model data suggest that
with invasive pulmonary aspergillosis [55] and sinus- rifampin and AmB are synergistic or additive when
itis [210] and two with bony disease [170, 171]. Both used together. The data in table 14 show that 65%
patients in whom therapy failed had invasive pul- of patients given this combination responded; this
monary aspergillosis; one was not immunocom- result may be better than that obtained with AmB
Table 14. Combination, adjunctive, and novel therapy for invasive aspergillosis.
Granulocyte transfusions with antifungal
therapy Rif and AmB 5FC and AmB L-A
Underlying condition R NR T R NR T R NR T R N
AML 67, 183(x2) 3, 131 5 67, 158, 211, 129, 152 6 9-1, 9-4, 9-7, 9-6, 57, 71, 12 6
212 9-8, 213-2, 152, 157,
214 213-8
ALL 66, 130, 3 9-2, 9-3, 9-5, 122, 130 7 68-2, 122-1, 122-6
215 144, 216 122-4
CL 71, 157 2 122-3, 122-7 2 47-2

AA 9-9 1 122-5 1
BMT 76-2, 217(x2) 3 72 1 57 1
Lymphoma 60 66 2 47-10 9
Solid tumor 94-4, 164 94-4 3 94-4
Renal transplant 218-2, 218-3 2 4-7, 4-8, 4-19, 4-24 12
4-10, 4-12,
4-13, 4-15,
4-16, 4-17,
219-2,
219-3
Heart transplant 219-2 219-1 2 89 1 88-

Neonatal state 143 1 143 1
Diabetes 220 159 2 220 105, 154-3 3
Alcoholism 221 1
COD 178, 222, 223-2 223-3 4 176, 177, 222 3
Steroid treatment 92, 224-2 2 47-7
Postoperative period 154-1, 165, 226 4
225
Previous TB 94-
Drug addiction 133, 151 2
None 116, 117, 167, 156 6 92, 116, 117, 228 10 122-2 1
168, 121 145, 146, 47
150, 168, 47
229, 230 47
Total no. (%) 6 (50) 6 (50) 12 17 (65) 9 (35) 26 43 (68) 20 (32) 63 7 (70) 3 (30)
NOTE. Except for totals, data are given as reference numbers followed by either (1) a hyphen and (if given) the case num
in parentheses, indicating the total number of relevant cases. Abbreviations: R = response; NR = no response; T = total; Rif
ALL = acute lymphocytic leukemia; CL = chronic leukemia; AA = aplastic anemia; and TB = tuberculosis.
alone. However, among neutropenic patients whose of AmB treatment were inadequate for an evalua-
pulmonary aspergillosis was treated with AmB and tion of response.
rifampin, only four of nine (44'P/) survived; in con- There is a clear need for a less toxic iv alternative
trast, 45 (65%) of 69 neutropenic patients whose pul- to AmB. It is difficult, given all these considerations
monary aspergillosis was treated with AmB alone and those discussed in the Results section, to assess
survived. The use of rifampin poses problems for whether liposomal or lipid-complexed AmB repre-
some patients because of its potent enzyme-inducing sents an advance in therapy for aspergillosis. In sum-
properties. Transplant recipients in particular, by vir- mary, these preparations appear to be less effective
tue of their dependence on cyclosporin and steroids, but also less toxic than AmB in similar doses. We
may be placed in a disadvantageous position. One hope that the latter benefit will outweigh the former
such patient suffered cardiac rejection and died, pos- disadvantage, the result being a better therapeutic
sibly as a direct result of rifampin administration index.
[2191. We do not believe that rifampin should be used
empirically in the treatment of aspergillosis when
Miconazole
drug interaction problems are a consideration, as in
transplantation. Its use may also preclude the sub- Details on two patients whose invasive aspergillosis
sequent use of itraconazole because of enzyme in- was successfully treated with miconazole have been
duction. published [1011. In view of its greater activity,
itraconazole would appear to be a preferable agent
if absorption is assured. As an alternative iv prepa-
L-AmB
ration, miconazole is certainly worth consideration,
Too few patients treated with L-AmB (i.e., 10) have if, for example, AmB cannot be given because of tox-
been reported for a full appraisal of the potential icity or allergy.
of this agent in aspergillosis. The available data sug-
gest that larger doses of AmB, e.g., 2 mg/(kg-d), can
Ketoconazole
be given in this form with little acute toxicity. This
observation, if supported by a demonstration of in- Although there have been occasional reports of suc-
creased efficacy, would represent a major step for- cess with ketoconazole in treating aspergillomas, we
ward in antifungal chemotherapy. It is also clear that found only three documented cases of invasive dis-
the exact chemical formulation of the AmB in lipo- ease treated with this agent. One of these involved
somes is critical to efficacy and toxicity and that the a nonimmunocompromised patient with sinus dis-
formulation, transportation, and storage of this ease who was given ketoconazole postoperatively
product are far from easy. These problems may be [233]. As we know that the majority of these cases
resolved as nationwide studies with lipid delivery ve- are treated successfully by surgery alone, this case
hicles are beginning in the United States. Evaluation lacks evidence of efficacy. The other patients treated
of any studies with any one of these new agents re- with ketoconazole had abscesses -one epidpural [155]
quires attention to the details of preparation and the and one adrenal [2031-that were surgically de-
characteristics of the final product. brided. Ketoconazole failed to halt infection in both
The results of therapy in the small group of pa- cases. Thus we do not recommend ketoconazole for
tients reviewed here suggest that L-AmB is effica- treating aspergillosis.
cious; seven of 10 patients responded (table 14). At
a symposium in 1988 in Stockholm, Lopez-Berestein
Itraconazole
summarized his current results with L-AmB in asper-
gillosis as eight successes and 11 failures [232]. Fur-The data reviewed here indicate that itraconazole is
ther details are awaited. In some settings L-AmB has effective in most cases (possibly as many as 78%)
cured patients after failure of therapy with AmB. of invasive aspergillosis. Its success is particularly
However, we cannot conclude that L-AmB is even notable in invasive pulmonary aspergillosis, with 11
equal to AmB in activity because the numbers of (79%) of 14 cases responding completely [47, 78, 88,
treated patients are small, the failure of conventional94, 971, and in bone and joint disease, with four of
therapy was not completely documented in every five cases responding [47, 48, 88, 94, 2271. Serum
case, and in some instances the dose and duration itraconazole concentrations were low in all four of
the patients who did not respond to therapy and in failures were thought to relate to low serum levels.
whom they were measured. In an open series of cases In addition, many of the failures cited here were as-
of invasive and other forms of aspergillosis [169], sociated with low serum drug levels. Thus the deter-
only eight of 35 patients had histologically demon- mination of serum levels during therapy may be im-
strated pulmonary disease, and 63% of patients portant in predicting outcome. Serum levels fall
(both those with definite pulmonary disease and during concurrent rifampin, phenytoin, or car-
overall) apparently responded to itraconazole (50- bamazepine therapy (authors' unpublished data).
400 mg daily). Lack of detail prevents adequate ap- Doses above 400 mg daily have only rarely been used,
praisal of these cases, but all the data taken together and it is not clear that absorption increases with in-
indicate that itraconazole is active in human inva- creasing oral doses. The data in mice given a differ-
sive pulmonary aspergillosis. This agent is presently ent solubilizing vehicle suggest that the relation be-
available only in an oral formulation and is proba- tween absorption and oral dose is not linear but that
bly the oral agent of choice for aspergillosis (the only serum concentrations do increase with increased dos-
other option being flucytosine). One study of pro- age [11, 97]. It is also clear that in animals tissue con-
phylaxis of aspergillosis and other fungal infections centrations exceed serum concentrations, but those
in neutropenic patients indicated that itraconazole relations have not been clearly defined for humans.
did prevent invasive aspergillosis if serum concen- Itraconazole probably is a significant advance in
trations were high enough [63]. Recent data, pre- therapy for aspergillosis in that it is both an addi-
sented only in abstract form to date, support this con- tional choice for patients in whom conventional ther-
clusion, even in bone marrow transplant recipients apy fails and a relatively nontoxic oral formulation
[234]. that has shown clear-cut efficacy in fully documented
No reports have appeared on the use of itracona- cases of invasive disease. Its place in primary ther-
zole for treatment - as opposed to prophylaxis - of apy, follow-up therapy, or salvage therapy is not yet
pulmonary aspergillosis during neutropenia. Neither clearly defined. Work in progress is addressing these
has efficacy in invasive sinusitis or cerebral disease issues.
been demonstrated. We cannot conclude that itra-
conazole is equal to AmB against the most lethal
Granulocyte Ihansfusions
forms of invasive aspergillosis because very few such
cases have been treated. Follow-up of treated cases Granulocyte transfusions have been used in two set-
is limited, and it is not clear whether the complete tings: persistent neutropenia and CGD. As noted in
responses seen will turn out to be cures or whether table 14, only 12 evaluable patients have been treated
relapse will be a problem. with this modality. In neutropenic patients two of
A major problem with itraconazole may be the five infections did not respond; none of three BMT
marked interpatient variation in serum levels 148], recipients responded. Exact numbers of granulocytes
if these levels do in fact reflect tissue concentrations.infused were not given for these cases. Several
The long half-life of itraconazole (25-40 hours) authors have noted better responses in patients who
means that it takes 2 weeks for serum levels to reachreceived more granulocytes; in one study 4 x 1010
steady state; although the drug accumulates in many granulocytes/m2 was the minimum required for re-
tissues (including lung and brain), concentrations sponse [236]. These poor results are, however, in ac-
may take time to plateau. This may not be a prob- cord with those in a controlled trial by Winston et
lem if the disease is insidious in onset, but some cases al. [237], who showed no benefit in 38 BMT recip-
of aspergillosis are rapidly progressive. Few data are ients given prophylactic granulocyte transfusions.
available on whether loading doses raise serum lev- One concern regarding the administration of gran-
els more rapidly. The absorption of itraconazole is ulocytes with AmB is the reported occurrence of se-
also variable, giving serum levels of <1-25 gg/mL. vere (occasionally lethal) pulmonary reactions. The
Why this variability occurs has not been carefully data available are conflicting. The most thorough
studied. Some workers believe that antacids reduce clinical study of this problem [238] showed a clear
absorption, but little information is available as yet relation between such dual therapy and these seri-
and a study with cimetidine and ranitidine in volun- ous reactions, although the study group included all
teers did not support this contention [235]. In the patients receiving granulocytes (57 granulocyte trans-
studies of prophylaxis referred to above, treatment fusion courses). No patients receiving AmB only
were included in the analysis. A similar phenome- respect to AmB, Aspergillus has been isolated at au-
non of pulmonary decompensation has been seen topsy from organs in which the drug concentration
in patients given AmB without granulocytes [239, vastly exceeded the MIC for the infecting organism
240]. In another BMT center where AmB and gran- [241. With respect to itraconazole, low blood con-
ulocytes were used together, pulmonary decompen- centrations may be observed more frequently in pa-
sation was not seen, possibly because of concomi- tients failing to respond to therapy or developing dis-
tant corticosteroid use [241]. Another center argued ease despite a prophylactic regimen; this pattern
the case for more severe reactions in the presence of suggests a minimum effective concentration, but this
bacteremia, suggesting a role for endotoxin, possi- concentration has not yet been determined in vitro.
bly in conjunction with AmB and/or granulocytes These discrepancies probably involve two related
[242]. An in vivo study showed that nylon-wool-fiber- points. The first is that the optimal method for in
damaged granulocytes caused severe pulmonary vitro susceptibility testing has yet to be defined for
Aspergillus species. The second is that antifungal
reactions in rabbits given AmB [243]; this result sug-
gested that it is the combination of activated granu-concentrations at different cellular sites may be crit-
locytes (however they are activated) with AmB that ical; for example, itraconazole is concentrated within
produces the problem. Another in vivo study found macrophages [245] and therefore may reach higher
that complement activation in combination with concentrations in the vicinity of hyphae than free
AmB treatment promotes pulmonary sequestration drug would. The same may not be true for flucyto-
of granulocytes [244], suggesting a different but al-sine, which is highly soluble in water. AmB does not
lied mechanism. accumulate in macrophages but does activate them
The available data indicate that granulocyte infu- to some extent (although L-AmB may not) [246]. The
sions are not required for bacterial sepsis in neutro- intracellular fate of all of these drugs within neu-
penic patients -a reflection of the many excellent trophils has not been studied. In addition, host fac-
antibiotics available. The relatively poor activity of tors constitute a critical determinant of success or
AmB and the generally poor results of therapy in failure in the treatment of aspergillosis and may over-
prolonged neutropenia (the key point in this discus- shadow the efficacy or lack of efficacy of a drug or
sion) makes us unwilling to dismiss the possibility combination of drugs.
that granulocytes may be useful in aspergillosis in We believe, however, that susceptibility testing
neutropenic patients, despite the figures given in ta- does yield clinically useful data. The acquisition of
ble 14. Likewise, their value in patients with CGD these data in the present will enable us to determine
is not known, although three of four patients ap- in the future whether or not there is a good correla-
peared to benefit. This area needs clarification, tion with outcome and which method(s) yield op-
which can probably be accomplished only through timal data for which drugs. In an ideal world, we
multicenter studies. Any study may be superseded would recommend testing of all clinically relevant
by the introduction of better antifungal agents isolates in reference laboratories. The primary em-
and/or recombinant colony-stimulating factors to in-piric treatment regimen chosen should be tested, as
crease granulocyte production. should a backup regimen if the patient is potentially
mortally ill. The backup regimen will be helpful
should the first regimen prove unsatisfactory (e.g.,
Role of in Vitro Susceptibility Testing
toxic, inefficacious). Ideally, both the MIC and the
At the present state of knowledge, it is not possible MFC (minimal fungicidal concentration) should be
to be definitive as to the relation of in vitro suscep- determined, although which value has more mean-
tibility data and the outcome of therapy in patients. ing in any given clinical situation is unclear.
For this reason no in vitro data are presented here In a less than ideal world, the following more
as a basis for clinical decision making. Flucytosine limited indications for in vitro testing are recom-
is an example of an agent for which there is a wide mended as a minimum: (1) all cases in which ther-
spectrum of susceptibility among isolates; no con- apy is failing, even if immunosuppressive factors do
clusion regarding the value of in vitro testing is pos- not favor success; (2) infections due to Aspergillus
sible because so few patients have been treated with species for which data are negligible, e.g., species
this agent alone for infection caused by isolates other than A. fumigatus, A. flavus, or A. niger, (3)
whose susceptibility data have been published. With cases in which flucytosine is being used or contem-
plated for use (in our experience only 35% of iso- should be included (with details about the timing
lates are susceptible, and synergy and antagonism of administration and sampling and about the du-
with AmB are seen with equal frequency); (4) cases ration of therapy). Response to therapy should be
in which ketoconazole or miconazole is being con- given (with relevant dates) for each site of disease;
sidered for therapy; (5) cases of endocarditis or ar- this information is often best presented in tabular
terial diseases (MFC desirable); (6) cases in BMT form. If the patient dies, details of all organ systems
involved at autopsy and results of cultures of those
recipients and other patients with markedly impaired
immune defenses, e.g., neutropenic AIDS patients organs should be given. Follow-up of surviving pa-
(MFC desirable); and (7) cases of relapse. tients should be sufficient, usually on the order of
Laboratories should not discard isolates for at 1-2 years. Longer follow-up is desirable, since relapse
least 4 weeks because a failure of therapy may not can occur even after 5 years [142, 151].
be manifest for some time. As the turnaround time In fungal disease the rarity of most manifestations
for susceptibility testing is usually at least 5 days (and makes comparative trials very difficult. There is a
may be as long as 3 weeks if the organism is slow need for well-documented case reports detailing both
to sporulate), clinicians need to think ahead about success and failure of therapy. Too much of the liter-
these issues, preferably at the time of diagnosis. At ature fails to provide basic facts about individual
present, different reference laboratories use differ- cases and therefore adds nothing to our understand-
ent methodologies, but attempts are under way both ing of the best form of therapy. It may be helpful
nationally and internationally to standardize meth- to study examples of valuable case reports with all
odology. Correlations of susceptibility data with in relevant information included (for example, see [74,
vivo outcome in an animal model are possible, and 105, 135, 226]).
data of this sort have begun to appear. However, the
use of clinical outcome to validate in vitro results
Concluding Remarks
is complex. For all fungal diseases, this area of study
is in its infancy. No controlled trials of treatment of invasive asper-
gillosis have been done. Substantial difficulties are
involved in such trials, and, until recently, the lack
Guidelines for Authors of Future Case Reports
of alternative agents available has meant that the re-
of Aspergiflosis
turn is not worth the effort. One of the major
Case reports or small collections of cases will con- difficulties with any trial in this group of diseases
tinue to make important contributions to the litera- is to make an early, definitive diagnosis. If only late
ture on fungal disease. Thus we would urge prospec- cases are studied (because the diagnosis in these cases
tive authors and editors to include the following was definitive), bias against early therapy is intro-
minimal data so that treatment outcome can be fully duced and may cloud differences between regimens.
evaluated. Therefore, efforts aimed at early, definitive diag-
The details of the underlying disease should be nosis - e.g., use of serum antigen detection- are im-
well documented, with specifics given about doses portant to the design of a good comparative study.
of immunosuppressive agents, exact duration and We believe that it will be possible for dedicated, ex-
degree of neutropenia (preferably with dates), and perienced investigators to perform controlled trials
history of previous immunocompromising infections of the treatment of aspergillosis on a multicenter
(such as cytomegalovirus pneumonitis). Precise de- basis.
tails as to the means of diagnosis of aspergillosis, We are hopeful that the critical review presented
including pertinent positive and negative cultures, here will provide something analogous to a histori-
microscopy, and description of histopathologic and cal control for future studies. For example, the mor-
radiologic findings, are essential. Speciation of the tality from cerebral aspergillosis is so close to 100%
organism and results of in vitro susceptibility test- that a new treatment yielding 20% survival would
ing (with methods described or referenced) are highly likely be a significant advance. We recognize that the
desirable. Exact details of therapy, including dura- data as they stand are inconclusive in many areas,
tion, dose, and milligrams of drug used per kilogram, but we hope that the synthesis presented here will
should be given. Surgical details should also be com- allow clinicians and investigators to focus clearly on
plete. If drug concentrations are assayed, these values the central questions for each case or study.
Reatment of Aspergillosis 1181
Invasive aspergillosis is becoming more common Appendix Tables

as more patients become immunocompromised.
The appendix tables are divided into two main sec-
Poor results of the treatment of fungal diseases in
tions: the three columns on the left indicate whether
general are influencing the success of new modes of
surgical therapy, medical therapy, or both were suc-
therapy for other potentially fatal diseases. The two
cessful or otherwise, and the eight columns on the
new antifungal agents now being studied in humans,
right detail the medical therapy if it included iv AmB,
itraconazole and L-AmB, are encouraging new de-
AmB plus flucytosine, L-AmB, or itraconazole. Med-
velopments. Additional agents that may be even
ical therapy that was given locally or that consisted
more potent are emerging from the laboratory. Af-
only of flucytosine, ketoconazole, or miconazole (or
ter many years of discouraging results, invasive asper-
older agents) is indicated by a superscript.
gillosis may soon become a less devastating disease,
Each entry is made up of reference numbers, with
although decisions about treatment will become
additional information detailed in footnotes. Case
harder to make as the number of new agents in-
numbers are those given in the reference. References
creases [247].
numbered above 247 are cited only in the appendix
tables and not in the text.
Rows and columns for totals refer to the total num-
ber of evaluable sites of infection treated with any
given course. Multiple entries are therefore possible
for separate sites treated with one course, the same
site treated again, or both.
Appendix Table IA. Tteatment of pulmonary aspergillosis.
Cases with indicated type(s) of treatment Cases with indicated medical treatment
Group, Medical AmB only (mg/d) AmB (mg/d) and

underlying Surgical Medical and
condition only only surgical (30 31-59 >60 630 31-59 >60 L-Am
Responders
AML 55-1, 55-2, 3-1, 3-3, 3-4, 3a-5, 207 3-3, 3a-6, 65, 3-1, 3-4, 8(x4), 211f 2139-2 2
204 3a-6, 8(x4), 9-1, 67cf, 3a-5, 95-1, 9-7
9-4, 9-7, 9-8, 55b-7, 183c-2, 95-2, 9-
65, 67cf, 95-1, 95-2, 2489 l83c-1,
97-6, l01ae, 183C-1, 207, 212f
183C-2, 211f, 212f,
2139-2, 214, 2489
ALL lh(x2), 9-2, 47-3, 68-2, 249 lh(x2), 144i 9-2 68-2 4
88-2, 95-3, 95-4, 96, 95-3,
144i, 249 95-4, 96
CL 47-2, 88-1 47-2, 8

Lymphoma 60, 250(x2) 250 (x
Solid tumor 251 78-2, 94-6, 224-3 224-3 94
Renal transplant 4jk-7, 4j-8, 4k1 10, 4jJ11, 84-1, 84k-2, 4j-11 253 4ij1
4jk-12, 4j-14, 4jk-16, 4i-15, 253k-2 4j-17, 4jk1 J0,
84-1, 84k-2, 4j-I7 218fkm-2, 4jk-12,
218fk--2, 2180-3, 2180-3 4j-14,
252, 253k-2 4ijk-16
Heart transplant 5-34, 5-140, 5-144, 5-34, 254n-3, 5-140, 5-144, 8
5-172, 88-3, 88-4, 2549-4 5-172,
88j-3, 89, 219f-2, 88j-3,
254n-3, 2549-4 219f-2
CGD 176fi, 177fi, 178fi, 184i, 255 177fi, 178ci, 176

222ci, 223cij2, 223i-1, 222ci
223-1, 223il-2, 255, 223il-2,
256 223cii-2,
256
Alcoholism 221, 257-1, 258 257-1 2

Steroid treatment 47-7, 224-2 259 259 224
None 260, 261 92-3, 92b-4, 92b-8, 1951, 261P 92-3, 230
92bJ-3, 94-3, 182b?,
195', 261P, 220P, 230
Total no. 6 95 5 17 30 9 10 9 5 2
Appendix Table IA. (Continued)
Group, Medical AmB only (mg/d) AmB (mg/d) and 5

condition only only surgical S30 31-59 >60 430 31-59 >60 L-Am
Nonresponders
AML 8, 9-6, 53, 57-1, 62, 65 8, 53, 68j-12, 213g-8 57-1 9-6,
65, 68-12, 68j-12, 71j-4, 152f
71i-4, 71i-6, 97j-6, 71j-6,
101, 152f, 2139-8, 97i-6, 101,
217hj 217hi
ALL Ih, 24-1, 24-2, 66f-1, 1h, 24-1, 66fn-
68i-2, 215f 24-2, 2isf
CL 57-4, 71i-3 57-4, 71
AA 9-9 9-9
BMT 55b-lJ, 57-2, 57-6, 57-2, 72f 57-8, 71j-2, 78-3 57
57-8, 71j-2, 71j-5, 76-1, 76-2,
72f, 76-1, 76-2, 76-3, 76-3,
78-3, 83(x2), 83(x2),
217c(x2) 217C(x2)
Renal transplant 4i-13, 4j-19, 4j-24, 84-3, 262-3 4i-13 4i-19, 4

47m-S, 84-3, 262-3
Heart transplant 219tl, 2549-5 2549-5
CGD 223ci-3, 263 223ci-3,
None 88-6, 93b, 228 228 8
Total no. 52 5 25, 26 5 1 6 4
NOTE. Except for totals, data

indicating the total niumber
granulomatous disease; AA = aplastic anemia; BMT = bone marrow transplant.
a Response, but autopsy showed Aspergillus.
b Received only SFC.
c Also received granulocyte transfusions.
e Intravenous miconazole.
f Also received rifampin.
g Received nystatin by inhalation.
h Underlying disease assumed.
Dose adjusted for body weight (child).
AmB dose assumed.
k Graft lost.
I Relapsed.
m Immunosuppression stopped.
n AmB given into cavity.
o Received nystatin orally.
P Local AmB given (inhalations).
q Low serum concentrations.
Appendix Table 2A. Treatment of pleural aspergillosis.

condition only only surgical 3 0 3 1-59 >60 3 0 3 1-59 >60 L-Am
Responders
ALL 95-4, 96 95-4,
Diabetes 92a-
Previous TB 94-3, 92a-JO, 98b,9
99b..6, 99c..9, 264b
Sarcoidosis 10OOC IO
None 102 loid 47-8, 103 103
Total no. 1 10 3 2 2
Nonresponders
Lymphoma 97-23 97-
Previous TB 98cI
Total no. 1 1
NOTE. Except
flucytosine; I
a 5FC only.
b Nystatin giv
c AmiB into p
d Miconazole
Appendix Table 3A. Treatment of sinus aspergillosis.

condition only only surgical <30 31-59 >60 630 31-59 >60 L-Am
Responders
AML 3-2, 114-5 127, 128a-2 114-5, 127 3-2
ALL 95b-3, 95b_4, 122-1, 95b-3, 131a-4 122-
122-4, 131c-3, 95b-4,
131a-4 131c-3
CL 122-3, 122-7 122-3, 12
AA 122-5 126-
BMT 74ad-. 74de.3 74ad-I 74
Diabetes 123f-/, 124, 120 16
Alcoholism 125 265Ch 26

Steroids 126 12
None 113(x31), 47-9, 114-3, 114-3, 115, 116i 1l
1 14-2, 1 14-3, 1 1 5, 1 16i, 121,i 2339
114-6, 114-7, 117i,
1 18(x3), 210, 121i,
266, 267, 2339,
268, 269, 210i
270, 271(x4)
Total no. 52 12 14 6 7 3 1 1
Nonresponders
AML 3k-10 129ik, 131-2 3k-10 1
131-2
ALL 6a, 122-6, 122c-1, 130a-2, 6a, 122c-1, 130a-2, 130a

122c-4, 130ai-j 130a-4, 122c-4 130a-4,
130a-5 130a-5
CL 122c-3 122c-
AA 122c-5 131-1 l22c-5 13
BMT 74de-2, 83 102-4 74de-2, 83
Solid tumor 130a-2 130
Diabetes 123f-1, 123f
None 233 116, 117C, 116 117c 1
122-2
Total no. 3 9 12 1 9 8 1
NOTE. Except for totals,

sign and a number in p
lymphocytic leukemia;
a Dose adjusted g Receivedfor oral ketoconazole. bod
b Nasal infection. h Relapsed.
c AmB dose assumed.
i Also received rifampin.
d Also received i Received 5FC only.
topical th
e Medical therapy alone failed; response after a Caldwell-Luc procedure. k Also received granulocyte transfusions.
f First and second surgical procedures failed; response to third.
Appendix Table 4A. Treatment of aspergillus endophthalmitis.
Group, Medical AmB only (mg/d) AmB (mgld) and 5

condition only only surgical 3 0 3 1-59 >60O ~ 3O 3 1-59 >60 L-A
Responders
Neonatal state 134a 13
Drug addiction 133b-2, 136c 136c 1
Ocular trauma 135d 135dI
Total no. 1 3 2 1
Nonresponders
Renal transplant 84,c 252c
Diabetes 272 272 252cI
Steroid treatment 273eI
Drug addiction 133c-J 274c
Total no. 1 3 2 1 2
NOTE. Except f
5FC = flucytosine; Itr = itraconazole.
a Bilateral disease; diagnosis made on enucleated left eye.
b AmB given into vitreous three times and subconjunctivally.
cAmB given into vitreous once after 10 days of iv therapy.
d AmB given into vitreous twice.
eAmB given into vitreous once and subconjunctivally.
Appendix Table SA. Treatment of cerebral aspergillosis.

underlying Surgical Medical and -
condition only only surgical 630 31-59 >60 <30 31-59 >60 L-Am
Responders
AML 147a 147
ALL 144b 144b
Renal transplant 84
Neonatal state 143bcd 143
Alcoholism 149 14
None 148-1 146 145 145
Totalno. 1 3 4 1 2 2
Nonresponders
AML 129,C 152c 129c 1
ALL I,e 24, 66,c 122-6, 144b le 24, 66c 144
BMT 76-3, 83 76-3,
Renal transplant 4f-19, 479-5, 85, 262 85 262 4f-
Heart transplant 5-34, 5-140, 5-144, 5-34 5-140
5-172, 254-5 5-172, 254-5
CGD 263 263
Diabetes 159c 159
None 148-2 272, 275 160h-4, 276 272, 27
Total no. 1 22 2 5 13 1 1 1
NOTE. Except for totals, data are given as reference numbers followed by a hyphen and (if given) the case number (in italics) used in the orig
flucytosine; Itr = itraconazole; ALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; BMT = bone marrow transplant; and CGD
a Surgery consisted of stereotactic biopsy, aspiration, and percutaneous drainage.
b Dose adjusted for body weight (child).
c Also received rifampin.
d Also received local therapy.
e Underlying disease assumed.
f AmB dose assumed.
g Immunosuppression stopped.
h Given B-diethylaminoethylfencholate and dehydroxystilbamidine in 1953.
Appendix Table 6A. Treatment of epidural aspergillosis.
Group, Medical AmB only (mg/d) AmB (mg/d) and

condition only only surgical <30 31-59 >60 <30 31-59 >60 L-Am
Responders
CGD 277a( x 2) 277a( x
None 122bc, 154b1, 162a 154b 1 122bc,
154b-2, 162a, 278 278
Total no. 2 5 1 1 4
Nonresponders
Solid tumor 166 166 166
Renal transplant 153 1
Diabetes 154b_3 154
Alcoholism 279 28
None 122-2, 154bd-1 155e, 167 155e, 167 154bd
Total no. 3 6 4 2 1 1

sign and a number in p
a Dose adjusted for body
b AmB dose assumed.
c Relapsed 9 months later.
d Medical therapy alone failed; response to combined medical and surgical treatment.
e Also received ketoconazole after only 230 mg of AmB.
Appendix Table 7A. Treatment of bone aspergillosis (vertebral, sternal, and long-bone disease only).
Cases with indicated medical treatment
Group, Cases with indicated type(s) of treatment Am ny(gd m m

underlying Medical and Am ny(gd m m/)ad
condition Medical only surgical <(30 3 1-59 >60 <30 31-59 >60 L-A
Responders
AML 158ab iSSa
Solid tumor 94-4, 94ac-4, 166 166 94ac
Heart transplant 88-S 8
CGD 170d-6
Alcoholism 280 280
Steroid treatment 260e 260eI
Drug addiction 164-2 164-1 164-2,
Postoperative state 171d, 197a 154ae-1, 165-2, 197a 1540-1, 16
165a-1, 28fg 282
282
None 47-1 154ae..2, 163, 167h, 167h 154a-2, 163, 175 1
168ah, 174, 175 174
Total no. 9 15 3 9 1 3 2
Nonresponders
AML 213 213
CL 157b 157b
AA 2831 83
Solid tumor 166-1 94a..4 166-1
Renal transplant 153 1
Alcoholism 279 27
Diabetes 154ae-3 154a
Steroid treatment 165-3, 227-7 165-3
Postoperative state 154ae-1, 165a-1 281f 154ae-
None 156bh 156b
Total no. 9 5 2 5 1 3
NOTE. Except for totals, da
flucytosine; Itr = itracona
a AmB dose assumed.
b Temporal bone infections w
cRelapsed.
d Received 5FC only.
e Diskitis and vertebral disease.
fLocal AmB only.
g More radical surgery after previous failure.
h Also received rifampin.
i Dose adjusted for body weight (child).
Appendix Table 8A. Treatment of cutaneous aspergillosis.

condition only only surgical <30 31-59 >60 <30 31-59 >60 L-Am
Responders
AML 9-1, 9-4, 9-7, 9-8, 189b-3 183a, 284b 189b-3
183a, 284b 9-7, 9-8
ALL 9-2, 9-5 9-2, 9
AEL 9-3 9-3
BMT 83 83
Renal transplant 4c-9, 4C-15 4c-15
Burn 185d, 188-
CGD 255 255
None 180e, 181e, 182f, 189bh/1, 189bh-2, 286 1
2859 286 189bh-2
Total no. 2 17 4 3 6 1
Nonresponders
AML 9L6 287b 287b 9

AA 9-L9 9L9
CGD 184 184
Burn 185d, 188-1
Total no. 2 3 1 2
NOTE. Except fo
flucytosine; Itr =
chronic granulomatous disease; and AA = aplastic anemia.
a Also received granulocyte transfusions.
b Dose adjusted for body weight (child).
c AmB dose assumed.
d First limited procedure failed; amputation of hand curative.
e Responded to oral nystatin.
f Responded to inhaled nystatin.
5 Responded to topical copper solution.
h Trauma victims.
i No hematologic recovery.
Appendix Table 9A. Treatment of aspergillus endocarditis.

condition only only surgical 430 31-59 >60 430 31-59 >60 L-Am
Responders
Postoperative state 193-6 225, 288a 28
None l91b-1 l91b
Total no. 1 3 1 1
Nonresponders
ALL 215c 215
Renal transplant 47d_5 47
Diabetes 272 27
Alcoholism 192 192
Steroid treatment 289c 2
Postoperative state 190e, 226f, 290 190e, 2
None l9lb-1, 275 291 275 l91b-
Total no. 7 4 5 2 1 1
flucvtosine; Itr = itracon
a d Immunosuppression stopped.
Received 5FC late in co
b Medical e Dose adjusted for body weight (child).
therapy alone fa
c Also received rifampin. f Highly resistant organism.
Appendix Table IOA. Treatment of pericardial aspergillosis.
Group, Medical Am ny(gd m m/)ad5C
underlyingy Surgical Medical and Am ny(gd m m/)
condition only only surgical 430 3 1-59 ~ 6 0 ,3O0 3 1-59 >.60 L-A
Responders
Lymphoma 47-JO 47-
Heart transplant 88-3
None 195a 195
Total no. 2 1 1
Nonresponders
AML 71b-4, 7lb-6 7lb-4 7l
CL 7lb-3 71b-
BMT 7lb-2, 7lb-5, 76-1 72C 72c 7lb-2, 76-
CGD 223de-3 223de
Total no. 7 1 1 4 1
NOTE. Except for

flucytosine; Itr =
a Relapsed. d Dose adjusted for body weight (child).
b AmB dose assumed. e Also received granulocyte transfusions.
c Also received rifampin.
Appendix Table 11A. Treatment of renal aspergillosis.
Cases with indicated type(s) of treatment Cases with indicated medical treatmen

condition only only surgical <30 3 1-59 >60 <3O 3 1-59 >60 L-A
Responders
ALL 292ab 216ac 292ab 21
HCL 293d
Lymphoma 294
Diabetes 105de-1, 198d(R), 295,d 296 198bf(L), 200, 201 220bfgh 200, 201 19
CGD 297d-J
Drug addiction 298b 299 299
None 300,d 301
Total no. 9 5 3 3 3 1
Nonresponders
BMT 72g 72g
Diabetes 105be-J 198bfh(R) 198bfh(R)
Total no. 2 1 1 1
NOTE. Except fo
on whether the
chronic granulomatous disease; and BMT = bone marrow transplant.
a Dose adjusted for body weight (child).
b Local pelvic irrigations of AmB given.
c Partial nephrectomy.
d Nephrectomy.
e Foreign body related.

f Bilateral.
g Also received rifampin.
h Pyelotomy.
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Antifungal and Surgical Treatment of Invasive Aspergillosis: Review of 2,121 Published

Antifungal and Surgical TReatment of Invasive Aspergillosis:

Results immediately after infection [13]. In an earlier set of

Clinical Data only those with a definitive diagnosis and those in

Table 2. Summary table of treatment results for pulmonary aspergillosis.

No. of infection sites with

Medical AmB only (mg/d) AmB (mg/d) and 5FC of sites

NOTE. Full details are given in appendix table IA.

Table 3. Summary table of treatment results for pleural aspergillosis.

No. of infection sites with

indicated type(s) of treatment AmB (mg/d) Total no.

NOTE. Full details are given in appendix table 2A.

Table 4. Summary table of treatment results for sinus aspergillosis.

No. of infection sites with

Medical AmB only (mg/d) AmB (mg/d) and 5FC of sites

NOTE. Full details are given in appendix table 3A.

Table 5. Summary table of treatment results for aspergillus endophthalmitis.

NOTE. Full details are given in appendix table 4A.

should include diagnostic vitrectomy (for both fun-

Table 6. Summary table of results of treatment of cerebral aspergillosis.

No. of infection sites with

Medical AmB only (mg/d) AmB (mg/d) and 5FC of sites

NOTE. Full details are given in appendi

Table 7. Summary table of treatment results for epidural aspergillosis.

indicated type(s) of treatment Total no.

NOTE. Full details are given in appendix table 6A.

Table 8. Summary table of treatment results for bone aspergillosis.

No. of infection sites with

NOTE. Full details are given in appendix tab

Table 9. Summary table of treatment results for cutaneous aspergillosis.

No. of infection sites with

Host factor, Surgical Medical

NOTE. Full details are given in appendix table 8A.

Table 10. Summary table of treatment results for aspergillus endocarditis.

NOTE. Full details are given in appendix table 9A.

Table 11. Summary table of treatment results for pericardial aspergillosis.

NOTE. Full details are given in appendix table IOA.

Table 12. Summary table of treatment results for renal aspergillosis.

No. of infection sites with

Medical AmB only (mg/d) AmB (mg/d) and 5FC of sites

NOTE. Full details are given in appen

CL 71, 157 2 122-3, 122-7 2 47-2

Heart transplant 219-2 219-1 2 89 1 88-

Invasive aspergillosis is becoming more common Appendix Tables

Group, Medical AmB only (mg/d) AmB (mg/d) and

CL 47-2, 88-1 47-2, 8

CGD 176fi, 177fi, 178fi, 184i, 255 177fi, 178ci, 176

Alcoholism 221, 257-1, 258 257-1 2

Group, Medical AmB only (mg/d) AmB (mg/d) and 5

Renal transplant 4i-13, 4j-19, 4j-24, 84-3, 262-3 4i-13 4i-19, 4

NOTE. Except for totals, data

Group, Medical AmB only (mg/d) AmB (mg/d) and 5

Group, Medical AmB only (mg/d) AmB (mg/d) and 5

Alcoholism 125 265Ch 26

ALL 6a, 122-6, 122c-1, 130a-2, 6a, 122c-1, 130a-2, 130a

NOTE. Except for totals,

Group, Medical AmB only (mg/d) AmB (mgld) and 5

Group, Medical AmB only (mg/d) AmB (mg/d) and 5

Group, Medical AmB only (mg/d) AmB (mg/d) and

NOTE. Except for totals,

Group, Cases with indicated type(s) of treatment Am ny(gd m m

Group, Medical AmB only (mg/d) AmB (mg/d) and 5

AML 9L6 287b 287b 9