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Scedosporium Infections in Transplant Recipients • CID 2005:40 (1 January) • 89
MAJOR ARTICLE
Infections Due to Scedosporium apiospermum
and Scedosporium prolificans in Transplant
Recipients: Clinical Characteristics and Impact
of Antifungal Agent Therapy on Outcome
Shahid Husain,
1
Patricia Mun˜oz,
5
Graeme Forrest,
2
Barbara D. Alexander,
3
Jyoti Somani,
4
Kathleen Brennan,
2
Marilyn M. Wagener,
1
and Nina Singh
1
1
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
2
University of Maryland, Baltimore;
3
Duke University Medical Center, Durham,
North Carolina;
4
Emory University, Atlanta, Georgia; and
5
Hospital Gregorio Maran˜o´n, Madrid, Spain
Background. Unique characteristics, impact of therapy with antifungal agents, and outcome of infections
with Scedosporium species were assessed in transplant recipients.
Methods. The patients comprised a total of 80 transplant recipients with Scedosporium infections, including
13 patients from our institutions (University of Pittsburgh Medical Center [Pittsburgh, PA], University of Maryland
[Baltimore], Duke University Medical Center [Durham, NC], Emory University [Atlanta, GA], and Hospital
Gregorio Maran˜o´n [Madrid, Spain]) and 67 reported in the literature. The transplant recipients were compared
with 190 non–transplant recipients with scedosporiosis who were described in the literature.
Results. Overall, 69% of the infections in hematopoietic stem cell transplant (HSCT) recipients and 53% of
the infections in organ transplant recipients were disseminated. HSCT recipients, compared with organ transplant
recipients, were more likely to have infections caused by Scedosporium prolificans ( ), to have an earlierP p .045
onset of infection ( ), to be neutropenic ( ), and to have fungemia ( ). Time elapsed fromP p .007 P
! .0001 P p .04
transplantation to Scedosporium infection in transplant recipients has increased in recent years ( ). TheP p .002
mortality rate among transplant recipients with scedosporiosis was 58%. In a logistic regression model using
amphotericin B as comparison treatment, voriconazole was associated with a trend towards better survival (odds
ratio [OR], 10.40; ). Presence of disseminated infection (OR, 0.20; ) predicted lower survival, andP p .08 P p .03
receipt of adjunctive surgery as treatment (OR, 5.52; ) independently predicted a better survival in thisP p .02
model.
Conclusions. Scedosporium infections in transplant recipients were associated with a high rate of dissemination
and a poor outcome overall. The use of newer triazole agents warrants consideration as a therapeutic modality
for these infections.
Scedosporium apiospermum, an anamorph or asexual
form of Pseudallescheria boydii, is a ubiquitous sapro-
phytic mold that can be readily isolated from a variety
of environmental sources (e.g., soil, sewage, polluted
water, and decaying vegetation) [1–3]. Described as a
human pathogen and as an agent of mycetoma in 1911,
S. apiospermum has since been shown to be associated
Received 30 June 2004; accepted 1 September 2004; electronically published
8 December 2004.
Reprints or correspondence: Dr. Nina Singh, Infectious Diseases Section (111E),
Veterans Affairs Medical Center, University Drive C, Pittsburgh, PA 15240
(nis5+@pitt.edu).
Clinical Infectious Diseases 2005;40:89–99
2004 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2005/4001-0014$15.00
with disseminated infections, including those involving
the CNS [2, 4–8]. The natural habitat of a related spe-
cies—Scedosporium prolificans, considered to be a de-
matiaceous fungus [9]—is less well characterized, al-
though the latter is also a soil saprophyte. The spectrum
of infections with S. prolificans ranges from localized
infections involving the bone and joints (usually in im-
munocompetent individuals) to disseminated infec-
tions (most commonly found in neutropenic patients)
[10–12].
Scedosporium species are increasingly recognized as
significant pathogens, particularly in immunocomprom-
ised hosts. These fungi now account for ∼25% of all
non-Aspergillus mold infections in organ transplant re-
cipients [13]. Scedosporium species are generally resis-
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90 • CID 2005:40 (1 January) • Husain et al.
Table 1. Clinical characteristics of 13 organ transplant recipients with Scedosporium infections from our institutions.
Patient
Age,
years Sex
Type of
transplant
Primary
ISA
Time to onset,
months after
transplantation Involvement
Scedosporium
species Antifungal therapy Outcome
1 55 M Small bowel Tacrolimus 1 Peritoneum S. prolificans Amphotericin B Died
2 40 M Kidney/pancreas Tacrolimus 17 CNS, pulmonary S. prolificans Voriconazole Survived
3 67 M Kidney Tacrolimus 36 Skin S. apiospermum Amphotericin B Survived
4 51 F Small bowel Tacrolimus 4 Aneurysm S. prolificans Amphotericin B, voricon-
azole, caspofungin
Died
5 67 M Heart Tacrolimus 158 Pulmonary, skin S. apiospermum Voriconazole Died
6 17 M Liver Tacrolimus 4.7 Pulmonary S. prolificans Voriconazole Died
7 64 M Liver CsA 1.3 CNS S. apiospermum None
a
Died
8 45 M Heart CsA 4.4 Pulmonary, skin S. apiospermem Itraconazole Died
9 56 M Liver CsA 0.8 CNS S. apiospermum Voriconazole Died
10 44 F Heart CsA 2.8 Pulmonary, skin,
sinus
S. prolificans Amphotericin B Died
11 68 M Kidney
b
Tacrolimus 10.4 Skin S. prolificans Voriconazole Survived
12 52 M Small bowel Tacrolimus 3 Pulmonary S. apiospermum Amphotericin B, voricon-
azole, caspofungin
Survived
13 62 M Kidney/pancreas Tacrolimus 5 Pulmonary S. apiospermum Voriconazole Survived
NOTE. CsA, cyclosporine A; ISA, immunosuppressive agent.
a
The patient died before therapy could be initiated.
b
The patient had undergone liver transplantation 9 years before undergoing kidney transplantation.
tant to amphotericin B. S. prolificans, in particular, is also resistant
to most currently available antifungal agents [11, 14, 15].
We report 13 cases of scedosporiosis in organ transplant
recipients that have occurred at our institutions (University of
Pittsburgh Medical Center [Pittsburgh, PA], University of
Maryland [Baltimore], Duke University Medical Center [Dur-
ham, NC], Emory University [Atlanta, GA], and Hospital Gre-
gorio Maran˜o´n [Madrid, Spain]) since 1999. In addition, data
for 44 organ transplant recipients and 23 hematopoietic stem
cell transplant (HSCT) recipients with Scedosporium infections
reported in the literature since 1985 were reviewed. Our goals
were to assess the unique clinical characteristics of, impact of
therapy with antifungal agents on, and variables influencing the
outcome of Scedosporium infections in transplant recipients.
METHODS
The present study includes 13 cases of Scedosporium infection
in transplant recipients at our institution (table 1) and cases
of scedosporiosis in the literature in patients who had under-
gone transplantation and patients who had not. For cases in
the literature, the MEDLINE database was searched for articles
published during 1985–2003 that used the terms “Scedosporium
apiospermum” and “Scedosporium prolificans.” Additional
search terms included “Pseudallescheria boydii,”“Allescheria
boydii,”“Monosporium apiospermum,”“Petriellidium boydii,”
and “Scedosporium inflatum.” The latter terms refer to prior or
other nomenclature for the 2 Scedosporium species. Additional
cases were identified by review of the bibliographies of the
original articles.
The search was limited to articles published in 1985 or after
to accurately reflect the current trends in immunosuppressive
regimens and clinical practices and to include cases involving
traditional antifungal therapy (e.g., amphotericin B therapy)
for comparison with those cases involving receipt of newer
drugs (e.g., the triazole agents). Furthermore, although S. apios-
permum has been known to be a pathogen since the early 1900s,
most early case descriptions have been descriptions of myce-
toma. Finally, S. prolificans was not recognized as a human
pathogen until 1984.
Two of the authors (S.H. and N.S.) independently extracted
the data for cases in the literature. Cases were included if my-
cologic identification of the fungus was confirmed by culture
and evidence of invasive infection was documented. Dissemi-
nation was defined as isolation of the fungus from blood cul-
tures, CNS involvement, or infection of ⭓2 noncontiguous
sites. Determination of the time to onset after receipt of trans-
plant was made on the basis of individually detailed cases;
summarized data, in which only a mean or a range for a cohort
of patients was provided, were excluded from this analysis. Time
to onset of infection for patients who received a transplant after
1999 was compared with that for those who received a trans-
plant in 1999 or thereafter. Changes in the epidemiologic char-
acteristics of invasive aspergillosis in organ transplant recipients
have previously been documented using similar intervals as a
cut-off [16].
Statistical analysis. Categorical variables were compared
using Fisher’s exact test or x
2
test. Continuous variables were
compared using Student’s t test (e.g., for age) or the Mann-
Whitney U test (e.g., for time to onset of infection). A logistic
model was developed to assess the effect of primary antifungal
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Scedosporium Infections in Transplant Recipients • CID 2005:40 (1 January) • 91
Table 2. Demographic and clinical characteristics of hematopoietic stem cell trans-
plant (HSCT) and organ transplant recipients with Scedosporium infections.
Characteristic
HSCT
recipients
(n p 23)
Organ
transplant
recipients
(n p 57)
All transplant
recipients
(n p 80)
Age,
a
mean years SD 32.9 3.3 49.5 1.7 44.9 1.7
Time to onset
Median months
b
(range) 1.3 (0.1–10.8) 4.2 (0.5–158) 4.0 (0.1–158)
⭐6 months after transplantation 75.0 (12/16) 60.7 (34/36) 63.9 (46/72)
Male sex 55.0 (11/20) 73.7 (42/57) 68.8 (53/77)
Immunosuppressive regimen
CsA 87.5 (7/8) 19.6 (10/51) 28.8 (17/59)
CsA/azathioprine 12.5 (1/8) 39.2 (20/51) 35.6 (21/59)
Tacrolimus 0 25.5 (13/51) 22.0 (13/59)
Tacrolimus/azathioprine 0 7.8 (4/51) 6.8 (4/59)
Azathioprine 0 7.8 (4/51) 6.8 (4/59)
Receipt of corticosteroids 87.5 (14/16) 98.1 (51/52) 95.6 (65/68)
Cytomegalovirus infection 15.0 (3/20) 20.4 (10/49) 18.8 (13/69)
Prior rejection episode 33.3 (7/21) 49.0 (25/51) 44.4 (32/72)
Antifungal prophylaxis
c
63.6 (14/22) 20.0 (9/45) 34.3 (23/67)
Clinical presentation
Fever 85.7 (18/21) 47.2 (17/36) 61.4 (35/57)
Pulmonary involvement 40.9 (9/22) 42.0 (21/50) 41.7 (30/72)
Skin involvement 36.4 (8/22) 32 (16/50) 33.3 ( 24/72)
CNS involvement 36.4 (8/22) 30.0 (15/50) 31.9 (23/72)
Fungemia
d
33.3 (7/21) 10.7 (6/56) 16.9 ( 13/77)
Disseminated infection 69.0 (16/23) 46.0 (23/50) 54.0 (46/85)
Neutropenia
e
66.7 (12/18) 8.5 (4/47) 24.6 (16/65)
Renal failure 18.2 (2/11) 32.7 (17/52) 30.1 (19/63)
Species isolated
f
Scedosporium prolificans 39.1 (9/23) 16.9 (9/53) 23.7 (18/76)
Scedosporium apiospermum 60.8 (14/23) 83.0 (44/53) 76.3 (58/76)
NOTE. Data are percent (ratio) of patients with the specified characteristic, unless otherwise
indicated. CsA, cyclosporine A.
a
.P p .0001
b
.P p .007
c
.P p .001
d
.P p .04
e
.P ! .0001
f
.P p .045
therapy on mortality. Factors significantly associated with out-
come (i.e., presence of disseminated infection and receipt of
adjunctive surgery) were added to the model. Treatment was
added to the model as an indicator variable set, with ampho-
tericin B as the comparison group. Patients who did not receive
antifungal therapy were excluded from the model. Stata soft-
ware, version 7.0 (Stata), was used for all statistical analysis.
RESULTS
A total of 80 cases of Scedosporium infection in transplant re-
cipients were identified; these comprised 57 cases involving
organ transplant recipients (including 13 cases at our institu-
tions) and 23 cases involving HSCT recipients [1, 2, 5, 12, 15,
17–59]. An additional 190 cases in non–transplant recipients
were identified using similar search criteria [3–9, 11, 12, 15,
21, 29, 37, 39, 40, 47, 52, 56, 59–154], and these cases are
discussed primarily to discern the unique characteristics of sce-
dosporiosis in transplant recipients, compared with other hosts.
Epidemiologic and demographic characteristics. Of 57 or-
gan transplant recipients, 20 (35%) were renal transplant re-
cipients (including 3 kidney-pancreas transplant recipients), 16
(28%) were heart transplant recipients (including 5 heart-lung
transplant recipients), 10 (18%) were liver transplant recipients,
8 (14%) were lung transplant recipients, and 3 (5%) were small
bowel transplant recipients. Fifty-five percent of the patients
had received cyclosporine A, 36% had received tacrolimus, and
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Table 3. Clinical variables in patients with Scedosporium infections stratified by the underlying host condition.
Variable
HIV-infected
patients
(n p 14)
Organ
transplant
recipients
(n p 57)
HSCT
recipients
(n p 23)
Patients with
hematologic
malignancies
(n p 69)
Other
IS patients
(n p 51)
IC patients
(n p 56)
Age,
a
mean years 37 50 33 44 51 36
Prior receipt of antifungal prophylaxis
b
46.0 (6/13) 20.0 (9/45) 64.0 (14/22) 34.0 (21/62) 4.0 (2/51) 0.0 (0/56)
Clinical presentation
CNS involvement 15.4 (2/13) 25.0 (13/53) 36.0 (8/22) 28.0 (19/67) 22.0 (11/49) 17.0 (10/56)
Pulmonary involvement
b
50.0 (7/14) 46.0 (24/52) 40.0 (8/20) 62.0 (41/66) 33.0 (16/49) 15.0 (8/53)
Skin involvement
c
7.0 (1/14) 32.0 (17/53) 38.0 (8/21) 40.0 (27/67) 31.0 (15/49) 7.0 (4/56)
Fungemia
b
23.0 (3/13) 16.0 (7/45) 25.0 (5/20) 66.0 (40/61) 6.0 (2/35) 8.0 (2/26)
Disseminated infection
b
57.0 (8/14) 55.0 (29/53) 69.0 (16/23) 86.0 (59/69) 42.0 (21/50) 20.0 (11/55)
Species isolated
Scedosporium apiospermum 71.0 (10/14) 83.0 (44/53) 60.9 (14/23) 24.6 (17/69) 82.4 (42/51) 62.5 (35/56)
Scedosporium prolificans 28.6 (4/14) 17.0 (9/53) 39.1 (9/23) 75.4 (52/69) 17.6 (9/51) 37.5 (21/56)
Neutropenia
b
39.0 (5/13) 13.0 (4/32) 67.0 (12/18) 90.0 (62/69) 4.0 (2/45) 0.0 (0/54)
Renal failure
b
0.0 (0/4) 56.0 (19/34) 18.0 (2/11) 28.0 (12/43) 20.0 (6/30) 0.0 (0/30)
Mortality 61.5 (8/13) 57.0 (31/57) 68.0 (15/22) 76.8 (53/69) 40.0 (20/50) 6.7 (9/54)
NOTE. Data are percent (ratio) of patients with the specified characteristic, unless otherwise indicated. HSCT, hematopoietic stem cell transplant;
IC, immunocompetent; IS, immunosuppressed.
a
.P p .01
b
.P ! .001
c
.P p .001
9% were receiving azathioprine without a calcineurin-inhibitor
agent (table 1). All but one of the organ transplant recipients
were receiving corticosteroids at the onset of infection. Forty-
nine percent had previously experienced rejection episodes, and
18% had received prior antifungal prophylaxis (table 2). In all,
44 (83%) of the 53 infections in organ transplant recipients
were due to S. apiospermum, and 10 (19%) were due to S.
prolificans (in 4 cases, the Scedosporium isolate was not spe-
ciated). The median time from transplantation to onset of in-
fection among organ transplant recipients was 4 months (range,
0.5–158 months) for patients with S. apiospermum infection
and 2.6 months (range, 1–17 months) for patients with S. pro-
lificans infection (table 2).
Of 23 HSCT recipients, the type of stem cell transplantation
was not specified for 2 patients; among the remaining 21 HSCT
recipients, 15 (71%) received allogeneic and 6 (29%) received
autologous transplants. Sixty-seven percent of the HSCT re-
cipients were neutropenic, and 52% had previously had graft-
versus-host disease. HSCT recipients, compared with organ
transplant recipients, were significantly more likely to have re-
ceived prior antifungal prophylaxis (64% vs.17%; ),P p .001
to be neutropenic (67% vs. 9%; ), and to have infec-P
! .0001
tions due to S. prolificans (39% vs. 17%; ) (table 2).P p .045
Scedosporium infections occurred significantly earlier after
transplantation in HSCT recipients, compared with organ
transplant recipients (median time to onset, 1.3 vs. 4 months;
). This difference may be related to the fact that neu-P p .007
tropenia occurred in HSCT recipients at the same time interval.
Overall, 75% of the infections in HSCT recipients and 61% of
the infections in organ transplant recipients occurred within 6
months after transplantation.
Patients who received transplants after 1999 (the current
cohort) were associated with a significantly longer time to onset
of Scedosporium infections after transplantation (median time
to onset, 6 months), compared with those who received trans-
plants in 1999 or earlier (the earlier cohort; median time to
onset, 1.2 months; ). Eighty-two percent of all Sce-P p .002
dosporium infections in the earlier cohort occurred within 6
months after transplantation, but in the current cohort, only
51% of Scedosporium infections occurred within 6 months
( ). For S. apiospermum infections, the median time toP p .02
onset after transplantation was 5 months in the current cohort,
compared with 2.6 months in the earlier cohort ( ). ForP p .07
S. prolificans infections, the median time to onset was 4.3
months in the current cohort and 1.0 month in the earlier
cohort ( ).P p .04
Clinical manifestations. In all, 23 (46%) of 50 Scedospor-
ium infections in organ transplant recipients were disseminated.
CNS, pulmonary, and cutaneous involvement were present in
29%, 43%, and 31% of the organ transplant recipients, re-
spectively. Other infections included those of the eye (4 pa-
tients), those of the peritoneum/abdomen (3), cardiac infec-
tions (2), mycotic aneurysm infections (2), and a sinus infection
(1). Organ transplant recipients with S. prolificans infection
were more likely to have fungemia (4 [40%] of 10), compared
with those with S. apiospermum infection (2 [4.7%] of 43)
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Scedosporium Infections in Transplant Recipients • CID 2005:40 (1 January) • 93
Table 4. Variables associated with mortality in transplant recipients with
scedosporiosis.
Characteristic
Patients
who died
(n p 46)
Patients
who survived
(n p 33) P
Age, mean years SD 42.9 2.2 47.8 2.8 NS
a
Time to onset
Median months 2.6 5.0 NS (.07)
⭐6 months after transplantation 72.5 (29/40) 54.8 (17/31) NS
Male sex 69.8 (30/43) 69.7 (23/33) NS
Cytomegalovirus infection 15.4 (6/39) 20.7 (6/29) NS
Prior rejection episode 39.0 (16/41) 53.3 (16/30) NS
Prior antifungal prophylaxis 45.4 (15/33) 23.5 (7/17) NS
Clinical presentation
Pulmonary involvment 44.4 (20/45) 38.5 (10/26) NS
CNS involvment 41.3 (19/46) 12.0 (3/25) .015
Skin involvment 28.3 (13/46) 44.0 (11/25) NS
Disseminated infection 71.7 (33/46) 19.2 (5/26)
!.0001
Fungemia 26.7 (12/45) 3.2 (1/31) .011
Neutropenia 34.3 (12/35) 13.3 (4/30) NS (.08)
Renal failure 41.7 (15/36) 14.8 (4/27) .028
Adjunctive surgery 20.0 (7/35) 56.2 (15/23) .0008
Species isolated
Scedosporium prolificans 30.4 (14/46) 13.8 (4/29) NS
Scedosporium apiospermum 69.6 (32/46) 86.2 (25/29)
Type of transplant
HSCT 32.6 (15/46) 21.2 (7/33) NS
Organ 67.4 (31/46) 78.8 (26/33)
Primary therapy
AmB 43.5 (20/46) 15.1 (5/33) .008
Itraconazole 19.6 (9/46) 48.5 (16/33) .006
Voriconazole 6.5 (3/46) 24.3 (8/33) .03
AmB and another antifungal agent
a
13.0 (6/46) 3.3 (1/33) NS
None 10.9 (5/46) 0.0 (0/33) NS
NOTE. Data are percent (ratio) of patients with the specified characteristic, unless oth-
erwise indicated. AmB, amphotericin B; HSCT, hematopoietic stem cell transplant; NS, not
significant ( ; exact P value is presented for variables with ).P
1 .05 P ! .10
a
In patients who died, other antifungal agents included miconazole (4 patients), fluconazole
(1), and itraconazole (1); one patient who survived received miconazole.
( ). Disseminated infection and CNS, pulmonary, andP p .009
cutaneous involvement were present in 69%, 36%, 41%, and
36% of HSCT recipients, respectively. Endocarditis, mycotic
aneurysm, eye infection, and joint infection were documented
in 1 patient each. Fungemia was present in 7 (33%) of 21 HSCT
recipients, compared with 6 (11%) of 56 organ transplant re-
cipients ( ).P p .04
When stratified by underlying host disease, transplant recip-
ients differed significantly from other immunosuppressed hosts
with respect to the frequency of disseminated infection, fun-
gemia, and pulmonary and skin involvement, but not with
respect to CNS infection (table 3). CNS involvement was pre-
sent in 15% of the HIV-infected patients, 17% of the immu-
nocompetent patients, 20% of the patients with hematologic
malignanies, 25% of organ transplant recipients, and 30% of
HSCT recipients ( ). Sepsis-like syndrome with hypoten-P
1 .05
sion was documented exclusively in patients with hematologic
malignancy and in HSCT recipients (in 17% and 5%, respec-
tively); it was not documented in other immunosuppressed
hosts (table 3). Thirteen percent of all neutropenic patients
were hypotensive, compared with 2.4% of the nonneutropenic
patients ( ).P p .005
Outcome. The mortality rate among all transplant recipi-
ents with scedosporiosis was 58% (46 of 79). The mortality
rate among organ transplant recipients was 54% (31 of 57)
(77.8% for patients with S. prolificans infection, and 54.5% for
patients with S. apiospermum infections). Amongst HSCT re-
cipients, the overall mortality rate was 68% (15 of 22) (61.5%
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94 • CID 2005:40 (1 January) • Husain et al.
for patients with S. apiospermum infection, and 77.8% for pa-
tients with S. prolificans infection).
When variables associated with mortality in transplant re-
cipients were analyzed, disseminated infection ( ), CNS
P
! .0001
involvement ( ), fungemia ( ), and renal failure
P p .015 P p .011
( ) were significantly associated with a higher mortality
P p .028
rate in univariate analysis. Surgery as adjunctive treatment
( ) portended lower mortality (table 4). Of patients
P p .008
with pulmonary lesions, 5 of 5 who underwent adjuvant surgery
survived, compared with 4 of 18 who did not receive surgery
( ). Among patients with CNS lesions, 1 of 2 who
P p .004
underwent surgery survived, compared with 1 of 15 without
surgery ( ).
P p .22
All transplant recipients—except for 5 who died either
shortly after diagnosis or in whom the diagnosis was established
at autopsy—had received antifungal treatment. Primary anti-
fungal therapy employed is outlined in table 4 and consisted
of amphotericin B in 25 transplant recipients, itraconazole in
25, and voriconazole in 11. In all cases, the aforementioned
antifungal agents were employed initially or within 7 days after
use of another agent and were continued as primary therapy
for the treatment of scedosporiosis. The mortality rates differed
significantly between the patients treated with amphotericin B,
itraconazole, or voriconazole (table 4). In the logistic regression
model, which considered amphotericin B to be the comparison
treatment, receipt of voriconazole was associated with a strong
trend towards better survival (OR, 0.15; 95% CI, 0.91–30.5;
. Itraconazole therapy (OR, 2.42; 95% CI, 0.60–9.68;
P p .06)
) was not significantly different from amphotericin B
P p .215
therapy with respect to survival. Disseminated infection was
the only variable associated with lower survival (OR, 0.15; 95%
CI, 0.04–0.53; ) in this model. When adjunctive sur-
P p .004
gery was added to the model, disseminated infection (OR, 0.20;
95% CI, 0.04–0.85; ) and surgery (OR, 5.52; 95% CI,
P p .03
1.32–23.7; ) independently influenced the outcome.
P p .02
The use of voriconazole, when controlled for these 2 variables,
continued to be associated with a trend towards better survival
().
P p .08
When mortality was analyzed for transplant recipients with
S. apiosper mum infections only, disseminated infection (P
!
) and CNS involvement ( ) were significantly as-.001 P p .013
sociated with greater mortality. In a logistic regression model,
using those receiving amphotericin B treatment as the com-
parison group, survival was greater among those receiving vor-
iconazole, but this difference did not attain statistical signifi-
cance (OR, 4.7; 95% CI, 0.54–40.9; ). OnlyP p .15
disseminated infection (OR, 0.10; 95% CI, 0.20–0.47; P p
) independently predicted lower survival..003
Of 18 transplant recipients with S. prolificans infection, 14
died. Fungemia ( ) and earlier onset of infection afterP p .023
transplantation ( ) correlated with a higher mortalityP p .053
rate. Of 13 patients treated with amphotericin B, 11 died. Three
patients, 1 of whom died, had received voriconazole. These
numbers, however, were too small for logistical modeling.
DISCUSSION
There are several observations that can be made from our study
with regard to Scedosporium infections in immunocomprom-
ised hosts in general and in transplant recipients in particular.
Patients with hematologic malignancy and with neutropenia
were more susceptible to infections due to S. prolificans than
to infections due to S. apiospermum. Indeed, 49% of S. proli-
ficans infections in all hosts and 62% of such infections in
immunocompromised patients were in patients with hemato-
logic malignancy (table 3). Innate immune defenses comprising
phagocytic responses play a critical role in host defense against
S. prolificans. In one study [155], mononuclear cell–mediated
hyphal damage did not differ among strains of S. prolificans
and Aspergillus fumigatus; however, polymorphonuclear cells
tended to induce more damage to S. prolificans hyphae than
to A. fumigatus. Furthermore, hyphal damage mediated by the
triazole antifungal agents against S. prolificans was synergisti-
cally enhanced by polymorphonuclear leukocytes [156]. On the
other hand, of immunosuppressed hosts, organ transplant re-
cipients and patients receiving corticosteroids had the highest
frequency of S. apiospermum infections.
Mold infections are frequently disseminated, particularly in
immunosuppressed hosts. The risk for dissemination, however,
varies for different mycelial fungi and with the type of trans-
plant. In cases of Aspergillus infection, dissemination occurs in
10%–34% of HSCT recipients and in 9%–35% of organ trans-
plant recipients [16, 157]. Higher rates, approaching 50%, have
been reported in liver transplant recipients [16]. We show that
69% of the Scedosporium infections in HSCT recipients and
46% of such infections in organ transplant recipients were dis-
seminated. Scedosporium species, unlike Aspergillus species,
have adventitial forms capable of in vivo sporulation, which
may facilitate hematogenous spread [30].
Fungemia was significantly more likely with S. prolificans
infection; 57% of S. prolificans infections but only 8% of the
S. apiospermum infections in transplant recipients were asso-
ciated with fungemia ( ). Fungemia occurred more fre-
P
! .0001
quently in HSCT recipients, compared with organ transplant
recipients ( ). That HSCT recipients were more likely
P p .04
to have S. prolificans infections—a species more likely to be
associated with fungemia—may account for this observation.
It is also plausible that host defense defects that occur in HSCT
recipients as a result of neutropenia have a more profound
impact on the susceptibility and severity of scedosporiosis than
do the immune deficits in organ transplant recipients.
Scedosporium infections may occasionally present with shock
and sepsis-like syndrome [10]. Such a presentation was ob-
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Scedosporium Infections in Transplant Recipients • CID 2005:40 (1 January) • 95
served exclusively in patients with hematologic malignancy or
in HSCT recipients and was more common in patients with S.
prolificans infections than in those with S. apiospermum infec-
tions (13% vs. 1%; ). In an animal model, S. prolificans
P
! .0001
strains have been shown to be more virulent than S. apiosper-
mum strains [158, 159]. Whereas mortality associated with S.
prolificans infections was significantly higher in mice that were
immunosuppressed with hydrocortisone than in immunocom-
petent mice, no difference in mortality associated with S. apios-
permum infection was observed in the 2 groups of animals [158].
We show that the time elapsed from transplantation to onset
of Scedosporium infection in transplant recipients has increased
in recent years. These trends largely parallel those reported for
invasive aspergillosis in HSCT recipients and organ transplant
recipients [16, 160]. It is possible that more frequent use in
recent years of antifungal prophylaxis with amphotericin B or
itraconazole after transplantation could have delayed the onset
of these infections. Antifungal prophylaxis could also have se-
lected for Scedosporium species, because these fungi have been
known to emerge as pathogens in patients receiving ampho-
tericin B, fluconazole, or itraconazole [43, 57, 100]. Our data
show that, although transplant recipients receiving antifungal
prophylaxis tended to have later onset of Scedosporium infec-
tions, compared with those who did not receive antifungal
prophylaxis (median time to onset, 4 vs. 2.3 months), the pro-
portion of patients who had received antifungal prophylaxis in
the current cohort (38%) did not differ significantly from that
in the earlier cohort of patients (40%). Whether prolonged sur-
vival of transplant patients, delayed occurrence of other risk-
factors (e.g., graft-versus-host disease), or as-yet poorly defined
factors account for the increase in time before onset of Scedos-
porium infection after transplantation remains to be determined.
Scedosporium species are resistant or have erratic suscepti-
bility to the polyene antifungal agents, such as amphotericin
B. The newer triazoles agents, however, have demonstrated su-
perior activity against S. apiospermum [14, 161–164]. Voricon-
azole was more potent than amphotericin B, fluconazole, 5
flucytosine, itraconazole, and ketoconazole [161, 163, 164]. The
MIC of voriconazole for S. apiospermum isolates has ranged
from 0.12–0.5 mg/mL [162, 163, 165]. The newer triazoles (ra-
vuconazole, posaconazole, and voriconazole) were all active
against S. apiospermum, with geometric mean MICs of 0.125,
0.08, and 0.06 mg/mL, respectively; none of these agents had
an MIC
10.25 mg/mL for any strain [164]. Cross-resistance was
found among all azoles except posaconazole, suggesting that,
for S. apiospermum, the mechanism of action for (or resistance
to) posaconazole might be different than that for the other
azoles [163]. The echinocandins also have some activity against
S. apiospermum, with MICs ranging from 0.25–4 mg/mL [166,
167]. S. prolificans, on the other hand, is largely resistant to
currently available antifungal agents. Voriconazole has shown
some in vitro activity, however, and the investigational triazole
UR-9825 (Uriach Laboratories) has had good activity against
S. prolificans [163, 164]. A combination of terbinafine and vor-
iconazole was synergistic in vitro [168].
Profound and often irreversible immunosuppression in the
host, frequent occurrence of disseminated infection, and lack
of an effective antifungal therapy render Scedosporium infec-
tions among the most difficult invasive mycoses to treat. Over-
all, the mortality rate for transplant recipients with Scedospor-
ium infections was 58% in our study. When adjusted for
disseminated infection, therapy with voriconazole, compared
with amphotericin B therapy, was associated with a lower mor-
tality rate, a difference that approached statistical significance
( ). The mortality rates associated with treatments with
P p .06
itraconazole and other antifungal agents, however, were not
significantly different from those associated with treatment with
amphotericin B. When included in the logistic regression
model, receipt of adjunctive surgery independently portended
a better survival rate among transplant recipients with scedos-
poriosis (table 4). A potential bias may nonetheless have existed
in the selection of patients to undergo surgical debridement
(e.g., they may have been selected because of better performance
status or because they had a removable focus of infection).
However, the use of voriconazole therapy, compared with am-
photericin B therapy, continued to be associated with a trend
towards lower mortality, even when controlled for surgery and
disseminated infection.
In summary, Scedosporium infections in transplant recipients
were associated with a high rate of dissemination; were asso-
ciated with a later onset in patients who received a transplant
in recent years, compared with those who received a transplant
earlier; and were associated with an overall dismal outcome.
HSCT recipients, compared with organ transplant recipients,
were more likely to have S. prolificans infections and fungemia.
The use of voriconazole therapy appeared to portend a better
outcome. We caution, however, that these data are based on a
small number of patients and are limited by bias inherent to
anecdotal reporting of cases in the literature. Nevertheless,
given the in vitro activity of the newer triazole agents, these
drugs warrant consideration as a preferred therapeutic modality
for Scedosporium infections.
Acknowledgments
Potential conflicts of interest. S.H. and G.F. are on the speaker’s bureau
for Pfizer. B.D.A. is on the speaker’s bureau for Enzon, Pfizer, Merck,
Fujisawa, and Eisai Medical Research, and she has received grant support
from Enzon and Fujisawa. J.S. has received grant support from Merck and
Fujisawa and is on the Speaker’s bureau for Pfizer, Merck, and Fujisawa.
N.S. has received grant support from Enzon and Merck. All other authors:
no conflicts.
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96 • CID 2005:40 (1 January) • Husain et al.
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