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ARTICLE
Dimorphic fungal osteoarticular infections
B. Rammaert &M. N. Gamaletsou &V. Zeller &C. Elie &R. Prinapori &S. J. Taj-Aldeen &
E. Roilides &D. P. Kontoyiannis &B. Brause &N. V. Sipsas &T. J. Walsh &O. Lortholary
Received: 16 March 2014 /Accepted: 29 April 2014 /Published online: 18 June 2014
#Springer-Verlag Berlin Heidelberg 2014
Abstract The objective of this investigation was to review
the clinical manifestations, management, and outcome of
osteoarticular infections caused by dimorphic fungi. We ex-
haustively reviewed reports of bone and joint infections
caused by dimorphic fungi published between 1970 and
2012. Underlying conditions, microbiological features, histo-
logical characteristics, clinical manifestations, antifungal ther-
apy, and outcome were analyzed in 222 evaluable cases.
Among 222 proven cases (median age 41 years [interquartile
range (IQR) 26–57]), 73 % had no predisposing condition.
Histopathology performed in 128 (57 %) cases and culture in
170 confirmed diagnosis in 63 % and 98 % of the cases,
respectively. Diagnosis was obtained from an extra-
osteoarticular site in 16 cases. The median diagnostic time
was 175 days (IQR 60–365). Sporothrix schenckii was the
most frequent pathogen (n=84), followed by Coccidioides
immitis (n=47), Blastomyces dermatitidis (n=44),
Histoplasma capsulatum (n=18), Paracoccidioides
brasiliensis (n=16), and Penicillium marneffei (n=13). Ar-
thritis occurred in 87 (58 %) cases and osteomyelitis in 64
(42 %), including 19 vertebral osteomyelitis. Dissemination
was reported in 123 (55 %) cases. Systemic antifungal agents
Electronic supplementary material The online version of this article
(doi:10.1007/s10096-014-2149-0) contains supplementary material,
which is available to authorized users.
B. Rammaert :O. Lortholary (*)
Université Paris-Descartes, Sorbonne Paris Cité, APHP, Service des
Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants
Malades, Centre d’Infectiologie Necker-Pasteur, Institut Imagine,
149, rue de Sèvres, 75743 Paris Cedex 15, France
e-mail: olortho@pasteur.fr
B. Rammaert:O. Lortholary
Unité de Mycologie Moléculaire, Institut Pasteur, Paris, France
M. N. Gamaletsou :N. V. Sipsas
Pathophysiology Department, Medical School, National and
Kapodistrian University of Athens, Athens, Greece
M. N. Gamaletsou :E. Roilides :B. Brause :N. V. Sipsas:
T. J. Walsh
Center for Osteoarticular Mycoses, Hospital for Special Surgery,
New York, NY, USA
V. Z e l l e r
Centre de Référence des Infections Ostéo-Articulaires, Groupe
Hospitalier Diaconesses-Croix Saint-Simon, Paris, France
C. Elie
Unité de Recherche Clinique Paris Centre Necker, Hôpital
Necker-Enfants Malades, Sorbonne Paris Cité, APHP, Université
Paris Descartes, Paris, France
R. Prinapori
Infectious Disease Department, San Martino di Genoa Hospital,
University of Genoa, Genoa, Italy
S. J. Taj-Aldeen
Mycology Unit, Microbiology Division, Department of Laboratory
Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar
E. Roilides
Third Department of Pediatrics, Aristotle University School of
Medicine, Hippokration Hospital, Thessaloniki, Greece
D. P. Kontoyiannis
MD Anderson Cancer Center, Houston, TX, USA
B. Brause :T. J. Walsh
Hospital for Special Surgery, New York, NY, USA
T. J. Walsh
Transplantation-Oncology Infectious Diseases Program, Weill
Cornell Medical Center of Cornell University, New York, NY, USA
Eur J Clin Microbiol Infect Dis (2014) 33:2131–2140
DOI 10.1007/s10096-014-2149-0
were used in 216 (97 %) patients and in combination with
surgery in 129 (60 %). Following the Infectious Diseases
Society of America (IDSA) guidelines, a successful initial
medical strategy was observed in 97/116 (84 %) evaluable
cases. The overall mortality was 6 %, and was highest for
P. marneffei (38.5 %). This study demonstrates that dimorphic
osteoarticular infections have distinctive clinical presenta-
tions, occur predominantly in apparently immunocompetent
patients, develop often during disseminated disease, and may
require surgical intervention.
Introduction
Dimorphic fungi are endemic in limited geographic regions.
Although they have different clinical characteristics, all of
these fungi share the ability to grow as hyphae at 25 °C and
to invade human tissues as yeasts at 37 °C. Reports of invasive
fungal diseases due to dimorphic fungi are increasing with
climate or environmental changes due to human activities,
such as blastomycosis [1] or coccidioidomycosis [2]. Many
dimorphic infections are associated with specific professions,
outdoor leisure activities, and/or traveling into and out of
endemic areas. The acquired immunodeficiency syndrome
(AIDS) epidemic as well as new immunosuppressive drugs
and biotherapies used in transplantation or in chronic immu-
nological disorders enable the development of histoplasmosis,
coccidioidomycosis, and penicilliosis [3–5]. Bones and joints
are uncommon localizations for some of these mycoses, and
are, therefore, difficult to diagnose. Whereas no osteoarticular
lesions were observed in a review of 795 Vietnamese cases of
Penicillium marneffei infections [3], blastomycosis affected
bones in 18 % of the 936 cases published between 1959 and
2000 [6]. In addition, bones are one of the main sites of
localization of Histoplasma capsulatum var. duboisii infec-
tion, endemic in Africa [7,8]. To our knowledge, there is no
contemporary comprehensive literature review that analyzes
the distribution, clinical manifestations, diagnosis, treatment,
and outcome of osteoarticular mycoses caused by dimorphic
fungi. We have, thus, extensively reviewed the literature to
provide a better insight on dimorphic fungal osteoarticular
infections.
Literature search and criteria
We performed a PubMed search from January 1970 to June
2012 using the following keywords: “bone diseases, infec-
tious”,“osteomyelitis”,“vertebral osteomyelitis”,“arthritis,
infectious”, crossed with “fungi”and each name of fungal
species. We included all English, Spanish, French, and Italian
articles. We considered only reported cases with sufficient
clinical, epidemiological, and mycological data, as well as a
documented absence or specific presence of medical/surgical
treatment information (see supplemental data). After
reviewing this initial series of reports, the individual refer-
ences listed in each publication were again reviewed for
ascertainment of additional articles. We excluded all publica-
tions on invasive sinusitis, invasive otitis, isolated tenosyno-
vitis, and fungal mycetoma.
Only proven cases of dimorphic infections following the
2008 European Organization for the Research and Treatment
of Cancer/Mycoses Study Group (EORTC/MSG) criteria
were included [9]. Cases were classified into three groups:
osteomyelitis including disk and/or vertebra involvement,
arthritis with or without adjacent bone infection, and multiple
bone and/or joint involvements. Dissemination was defined
by the involvement of two non-contiguous sites. The diagnos-
tic time was defined as the period between the first symptoms
and the mycological diagnosis.
The initial medical strategy consisted of the first antifungal
agent used following diagnosis with or without switch for any
oral drug (when IV formulation was initiated at baseline) in
the absence of toxicity or failure. To be evaluable, cases had to
receive the antifungal agent for at least 7 days. The subsequent
medical strategy consisted of the antifungal drugintroduced in
case of intolerance or failure. If unspecified, the approximate
duration of amphotericin B therapy was estimated for adult
patients who only received itas a first-line therapy by dividing
the cumulative dose by 70 kg and assuming a dosage of
1 mg/kg per day [10].
A complete response was defined as resolution of clinical
and radiological evidence of infection with antifungal agents,
surgery, and/or local treatment. A partial response was
assigned when there was an initial improvement but incom-
plete resolution or insufficient subsequent clinical and radio-
logical data were available. Complete and partial responses
were considered as success. Failure was defined by infection-
related death or lack of improvement. Relapse was defined by
clinical and/or mycological evidence of infection following
initial improvement and antifungal discontinuation.
We also studied the impact of available Infectious Diseases
Society of America (IDSA) guidelines (i.e., sporotrichosis,
coccidioidomycosis, and blastomycosis) on the outcome
[11–13]. Although IDSA guidelines were available for
H. capsulatum var. capsulatum, the number of case reports
wastoolimitedtobeanalyzed[14].
Statistical analyses
Continuous variables were presented as their median and
interquartile range (IQR). Variables were compared across
groups using the Wilcoxon–Mann–Whitney test for continu-
ous variables and the Chi-square or Fisher’s exact test for
2132 Eur J Clin Microbiol Infect Dis (2014) 33:2131–2140
categorical variables. For all analyses, statistical significance
was defined at p<0.05.
Results
Demographic characteristics
A total of 222 cases were reported from 142 publications;
most of those were published in the 1990s (Fig. 1). The
demographic patterns are shown in Table 1.Only31(14%)
children less than 15 years old were reported, with a median
age of 7 years (range 3–9). Male gender was predominant (n=
178; 81 %). The majority of patients had no known underlying
disease at the time of infection (n=163; 73 %), whereas half of
the patients infected with P. marneffei or Sporothrix schenckii
were immunosuppressed (Table 1). Among the children, only
two had an underlying condition leading to human immuno-
deficiency virus (HIV)-related penicilliosis. When consider-
ing H. capsulatum, 6/10 cases infected by H. capsulatum var.
capsulatum had comorbidities, while those with
H. capsulatum var. duboisii did not. Of note, among the 27
(12 %) cases associated with alcohol abuse, 93 % were infect-
ed by S. schenckii. A previous local trauma was recorded in 31
(14 %) cases, of which 58 and 29 % had infections due to
S. schenckii and Coccidioides immitis, respectively, while
65 % had a localized infection. Outdoor activities or contact
with soil or plants were reported in 59 (27 %) cases, more
frequently for sporotrichosis and paracoccidioidomycosis.
Diagnosis
Among the 222 cases, 206 were proven from samples of
bones and/or joints. Diagnosis was obtained for the remaining
16 cases from an extra-osteoarticular site, mainly (81 %) skin
lesions. The distribution of fungal species is presented in
Tab le 1.ForH. capsulatum, ten cases belonged to capsulatum
and eight cases to duboisii varieties, respectively. Histology
was performed in 128 (57 %) cases and was contributive in 81
(63 %) cases. Histology was the only diagnostic tool in 35
(16 %) cases (Fig. 2). In osteoarticular sporotrichosis, histol-
ogy was performed in 45 cases and was less contributive than
for other fungi, with only seven (15 %) positive results
(Fig. 3). Culture was performed in 170 cases, with a positive
result in 167 (98 %) cases. Infection was diagnosed by the
direct examination of pus only for four Blastomyces
dermatitidis and one C. immitis infections (Fig. 2).
Clinical features
Fungal infections involved only one bone or joint site in 151
cases (68 %). Arthritis represented 87 (58 %) cases, 55 (63 %)
having adjacent bone lesion. Osteomyelitis was observed in
64 (42 %) cases. The distribution of sites involved by each
fungus is presented in Table 2.
When only one site was involved, reported S. schenckii
infection was located mostly in joints, while B. dermatitidis
infection caused osteomyelitis more frequently (Table 2).
B. dermatitidis,C. immitis,andH. capsulatum infected verte-
brae as a single site, whereas vertebral osteomyelitis due to
S. schenckii and P. marneffei were always associated with
multiple bone involvement. Infected vertebrae could be soli-
tary or multiple. Thoracic localizations (n=12/19; 63 %)were
more frequent than lumbar or cervical localizations (Table 2).
Knees were the most common localizations for arthritis
(n=54; 62 %), while long bones were more frequently in-
volved during osteomyelitis (n=22; 34 %). Among the 123
(55 %) disseminated infections, skin was the most frequent
Fig. 1 Distribution of 221 cases
of dimorphic osteoarticular
infections from 1970 to 2012
according to the year of
publication
Eur J Clin Microbiol Infect Dis (2014) 33:2131–2140 2133
site associated with bone and/or joint infection (n=67; 55 %),
followed by the lungs (n=46; 37 %); one-third (n=28/84) of
sporotrichosis and 85 % (n=11/13) of penicilliosis cases had
associated cutaneous localizations. Among the 25 patients
with S. schenckii and chronic alcohol abuse, 18 (72 %) had
disseminated infection.
The median diagnostic time, which was 175 days (IQR 60–
365) for the overall population, was significantly higher for
S. schenckii infections (240 days; IQR 120–540; p<0.03)
compared to that for other fungi, except H. capsulatum (Ta-
ble 2). Although P. m a r n ef f e i infections had a similar median
diagnostic time to those due to other fungi, infection was
significantly more disseminated (p<0.005). When disseminat-
ed, infection was not diagnosed later than what was observed
for isolated osteoarticular infection cases (134 days [60–270]
vs. 180 days [90–442]; p=0.16).
Treatment
An initial medical strategy was used in 215 (97 %) patients, in
combination with surgery in 129 (60 %) cases (Table 3). None
of the patients with P. brasiliensis infection benefited from
surgery. The median duration of therapy was 180 days (IQR
60–365). Interestingly, penicilliosis cases had the shortest
median treatment duration, 63 days (IQR 49–210), possibly
due to early death or discharge. A subsequent medical strategy
was used in 50 (23 %) patients due to side effects or failure.
Six (14 %) of them died, three having an infection-related
Tabl e 1 General population characteristics of dimorphic osteoarticular infections
Demographic data Total, N=
222
S. schenckii,
n=84
C. immitis,
n=47
B. dermatitidis,
n=44
H. capsulatum
a
n=18
P. brasiliensis,
n=16
P. marneffei,
n=13
Adult >15 years 191 (86) 82 (98) 39 (83) 32 (73) 15 (83) 12 (75) 11 (85)
Median adult age, years (IQR) 41 (26–
57)
50 (40.5–60) 33 (20–51) 33.5 (15–56) 40 (30–54) 38 (16.5–47.5) 30 (21–37)
Children ≤15 years 31 (14) 2 8 12 (27) 3 4 2
<5 years 11 (37) 0 5 2 1 1 2
Neonates <2 months 1 0 1 0 0 0 0
Male gender (%) 178 (81) 75 (89) 42 (89) 30 (68) 12 (67) 14 (87.5) 5
b
Outdoor activities or contact with soil,
wood, or plants
59 (27) 35 (42) 9 2 2 9 2
Prosthesis 5 3 1 0 1 0 0
Trauma 32 (14) 18 (21) 9 1 2 2 0
No known comorbidity 163 (73) 44 (52) 46 (98) 41 (93) 12 (67) 14 (87.5) 6
≥1 comorbidity 59 (27) 40 (49) 1 3 6 2 7
Diabetes 11 (5) 7 1 2 1 0 0
Insulin-dependent diabetes 6 4 1 0 1 0 0
Hematological malignancy 6 4 0 0 2 0 0
Neutropenia <500/mm
3
21 0 0 1 0 0
HIV 13 (6) 5 0 0 1 1 6
Alcohol abuse 27 (12) 25 (30) 0 1 0 1 0
Other immunosuppression
c
11 (5) 6 1 0 2 1 1
Long-term corticosteroids use 5 3 0 0 2 0 0
Percentages are presented if the number of cases considered was ≥10
a
Ten v ar. capsulatum and eight var. duboisii
b
Two missing data in children
c
Including cancer (n=3), autoimmune disorder (n=3), chronic renal failure (n=2), kidney transplant recipient (n=1), postnecrosis cirrhosis (n=1)
Positive
histology
N=33
Positive
direct
examination
N=5
Positive
culture
N=105
N=38 N=0
N=16
N=9
Fig. 2 Mycological diagnosis of 206 cases of dimorphic osteoarticular
infections identified from bone and/or joint samples
2134 Eur J Clin Microbiol Infect Dis (2014) 33:2131–2140
death. A life-long maintenance therapy was administered in
eight patients with or without history of relapse, six having
C. immitis infection. Amphotericin B and itraconazole were
the most commonly used antifungal agents for initial therapy.
Cotrimoxazole was used for 9/16 paracoccidioidomycosis as
the initial or subsequent strategy; therapy was successful in all
evaluable cases. There were no published data on the use of
the new azoles, voriconazole and posaconazole, and only
seven cases were treated with a lipid formulation of
amphotericin B.
Surgery was both diagnostic and therapeutic. Two or more
debridements were necessary in 33 (25 %) of the 131 surgical
cases (Table 3). Amputation was reported once. Surgical
treatment for knee (n=2) and hip (n=3) prosthesis was con-
servative, except in one case leading to arthrodesis.
Local treatment consisted of intra-articular amphotericin B
instillations and was performed in eight C. immitis and 11
S. schenckii infections, in combination with either medical or
surgical treatment in all cases.
Outcome
An overall complete response was noticed in 136 (73 %)
cases, a partial response in 34 (18 %), and failure in 19
(10 %) cases (Table 3). Dissemination was more often asso-
ciated with failure than isolated osteomyelitis or arthritis
([20 % vs. 0 %, p<0.001] and [20 % vs. 5 %, p<0.001],
respectively). A clinical or mycological relapse occurred in 34
(16 %) cases, due to either premature discontinuation or
failure of the initial medical strategy for 18 (51 %). Almost
half of the relapses (n=14; 41 %) occurred in patients with
underlying comorbidities; S. schenckii was frequently in-
volved in relapses.
A total of 197 patients were evaluable for response to initial
medical strategy (Table 3). Among those, the IDSA guidelines
were followed in 116 (73 %) of the 158 patients with sporo-
trichosis, coccidioidomycosis, or blastomycosis. Success ob-
tained with the initial medical strategy was observed in 97
(84 %) cases (Fig. 4). Failure was observed in 23 and 21 % of
the sporotrichosis and coccidioidomycosis cases, respectively.
The related-mortality rate was 6 %, linked to disseminated
infection in all cases (Table 3). Few patients (n=3) who died
received both medical and surgical treatments, whereas four
patients did not receive any treatment because of late diagno-
sis. Penicilliosis was the most severe infection, with a related-
mortality rate of 38.5 %, mostly in the context of advanced
AIDS.
Discussion
This unique series of 222 dimorphic fungal osteoarticular
infections provides a strong foundation for understanding
these debilitating diseases. This study has elucidated impor-
tant general patterns that are interesting to delineate.
As previously known for dimorphic fungal infections ex-
cept sporotrichosis [15], we found here a male predominance
(81 %) in case of osteoarticular localizations. Dimorphic
osteoarticular infections occurred mainly in apparently immu-
nocompetent patients. Unknown immunosuppression, how-
ever, should be screened in every apparently
Fig. 3 Results of culture and
histology of 206 cases of
dimorphic fungal osteoarticular
infections identified from bone
and/or joint samples
Eur J Clin Microbiol Infect Dis (2014) 33:2131–2140 2135
immunocompetent patient, such as inherited defects in the IL-
12/IFN-gamma axis [16]. In addition, the disease was often
chronic. Arthritis with a predilection for the knees and wrists
is the predominant clinical feature of all dimorphic
osteoarticular mycoses. When osteomyelitis occurs, it essen-
tially affects long bones and vertebrae. Disseminated infection
occurred in more than half (55 %) of the patients. Surgery was
required in two-thirds of the patients in combination with
medical treatment. The median duration of treatment was
6 months and 15 % of cases experienced relapse. The
related-infection mortality rate was low.
While general observations may be inferred about dimor-
phic osteoarticular mycoses as a group, each of the organisms
has a unique species-dependent pathogenesis that may lead to
distinctive clinical manifestations. In addition, the distribution
of risk factors described in the literature for other forms of
dimorphic fungal infections was similar here.
Osteoarticular sporotrichosis occurs in the setting of local
trauma (21 %), alcohol abuse (30 %), HIV infection, immu-
nosuppression, and diabetes mellitus with single or multiple
bone sites, and frequent arthritis (50 %). Osteoarticular coc-
cidioidomycosis and blastomycosis occurred with virtually no
comorbidity, with predominantly single bone infection. Coc-
cidioidomycosis presented with frequent arthritis (45 %),
while B. dermatitidis infected especially the vertebrae. In
addition, H. capsulatum has the particularity to have two
varieties with different epidemiological patterns. Whereas
H. capsulatum var. duboisii affects apparently
Tabl e 2 Distribution of clinical sites in 221 cases of dimorphic osteoarticular infections
Clinical data Total, N=
222
S. schenckii,
n=84
C. immitis,
n=47
B. dermatitidis,
n=44
H. capsulatum,
n=18
P. brasiliensis,
n=16
P. marneffei,
n=13
Single bone or joint infection 151 (68) 47 (56) 37 (79) 35 (80) 16 (89) 14 (87.5) 2
Osteomyelitis 64/151
(42)
5 16/47 (34) 28/44 (64) 9 6 0
Long bones 22/151
(34)
328 5 4 0
Flat bones 8 1 3 2 1 1 0
Small bones 15/151
(24)
175 1 1 0
Vertebra 19/151
(30)
0 4 13/44 (46) 2 0 0
Cervical 1 0 1 0
Thoracic
a
12/19 (63) 4 5 2
Lumbar
a
7070
Arthritis 87(58) 42(50) 21(45) 7 7 8 2
Large joints 85/87 (98) 41/42 (97) 21/21 (100) 7 7 8 1
Knee 54/87 (64) 26/42 (62) 16/21 (76) 2 4 5 1
Wrist 16/87 (19) 10/42 (24) 2 1 1 2 0
Ankle 5 2 1 2 0 0 0
Elbow 5 3 1 1 0 0 0
Hip 3 0 1 1 1 0 0
Shoulder 2 0 0 0 1 1 0
Small joints (hands, feet) 2 1 0 0 0 0 1
Multiple bone or joint
infections
71 (32) 37 (44) 10 (21) 9 2
b
2 11 (85)
Dissemination 123 (55) 45 (54) 21 (45) 27 (61) 7 10 (62.5) 13 (100)
Skin 67/123
(30)
28 (33) 11 (23) 13/27 (30) 3
b
1 11/13 (85)
Lung 46/123
(21)
9 6 18/27 (41) 2
c
74
Median time for diagnosis,
days (IQR)
175 (60–
365)
240 (120–540) 120 (30–315) 105 (54–210) 120 (44–365) 75 (14–153) 135 (18–227)
Percentages are presented if the number of cases considered was ≥10
a
One patient had both lumbar and thoracic infected vertebra
b
Solely var. duboisii
c
Solely var. capsulatum
2136 Eur J Clin Microbiol Infect Dis (2014) 33:2131–2140
Tab l e 3 Management and outcome of 221 cases of dimorphic osteoarticular infections
Tot al S. schenckii C. immitis B. dermatitidis H. capsulatum P. brasiliensis P. marneffei
Patients receiving anykindoftreatment N= 218 n=83 n=47 n=44 n=17 n=16 n=11
Surgeryalone 2020000
Antifungal therapy alone 85 (39) 27 (33) 11 (23) 16 (36) 5 16 (100) 10 (91)
Both medical and surgical treatment 129 (60) 56 (67) 34 (72) 28 (64) 12 (71) 0 1
Intra-articular amphotericin B injection 19 (9) 11 (13) 8 0 0 0 0
More than one surgical debridement 33/131 (25) 19/56 (34) 5 6 3 0 0
Median duration of therapy, days (IQR) 180 (60–365) 180 (52–355) 135 (54–365) 180 (70–359) 195 (55–339) 180 (180–730) 63 (49–210)
Medical strategy (evaluable patients) N=197 n=75 n=42 n=41 n=15 n=14 n=10
Initial medical strategy
Itraconazole 25 (13) 9 2 4 4 2 4
Amphotericin B 117 (59) 39 (52) 31 (74) 31 (76) 6 5 5
Other agent 55 (28) 27 (36) 9 6 5 7 1
Success 155 (79) 49 (65) 33 (79) 39 (95) 12 (80) 14 (100) 8 (80)
Failure 42 (21) 26 (35) 9 2 3 0 2
Subsequent medical strategy 47 (24) 29 (39) 7 2 5 1 3
Overall response at the end of follow-up N=189 n=65 n=43 n=40 n=18 n=12 n=11
Complete response 136 (72) 38 (59) 31 (72) 39 (97.5) 14 (78) 11 (92) 3
Partial response 34 (18) 18 (28) 8 1 3 1 3
Failure 19 (10) 9 4 0 1 0 5
Outcome N=222 n=84 n=47 n=44 n=18 n=16 n=13
Median follow-up after the end of treatment, days (IQR) 390 (180–730) 540 (240–730) 540 (365–840) 270 (165–517) 150 (45–377) 540 (365–730)
a
Follow-up after the end of treatment 92 (42) 37 (44) 21 (45) 20 (45) 7 5 2
History of relapse 34 (16) 21 (25) 8 2 1 0 1
Death 23 (10) 10 (12) 4 1 3 0 5
Attributable death 13 (6) 4 3 0 1 0 5
Percentages are presented if the number of cases considered was ≥10
a
One patient with 90 days follow-up and one patient without follow-up
Eur J Clin Microbiol Infect Dis (2014) 33:2131–2140 2137
immunocompetent patients and was rarely described in HIV-
infected patients [17], var. capsulatum infection often occurs
in immunocompromised hosts with disseminated diseases [4].
In our cohort, all patients suffering from H. capsulatum var.
duboisii had no comorbidity, whereas 4/10 with var.
capsulatum infection were immunocompromised.
Osteoarticular histoplasmosis, however, presented as a soli-
tary bone or joint lesion in 89 % of cases. Only the variety
duboisii provided multiple bone lesions. P. brasiliensis oc-
curred in immunocompetent patients as predominantly (88 %)
non-vertebral single bone and joint infection. Finally,
osteoarticular penicilliosis presented mainly in HIV-infected
patients with multiple bone and joint infections.
While osteoarticular dimorphic infections were commonly
associated with dissemination, some features were surprising
regarding other literature data. In our series, 61 % of blasto-
mycosis were disseminated, which is higher than what is
observed in other series on extra-pulmonary blastomycosis
[18,19]. In addition, 85 % of our cases of osteoarticular
penicilliosis were disseminated. Interestingly, in the largest
series of P. marneffei infection, 84 % of the 795 HIV-
infected Vietnamese patients had positive blood cultures [3],
but no osteoarticular localizations were reported. Since
osteoarticular localizations were not systematically examined,
their incidence may be underestimated.
The literature mentioned articular inflammation as a sys-
temic inflammatory response to acute pulmonary histoplas-
mosis [14]. However, clinicians have to be aware of true
secondary localizations localized to joints. In our cases, only
two patients had arthritis with acute pulmonary disease. Both
had proven H. capsulatum var. capsulatum knee arthritis,
either by percutaneous biopsy or autopsy.
While 55 % of the patients had a disseminated infection
with bone and/or joint involvement, the related-mortality rate
in our cases was very low, except for penicilliosis, which
reached 38.5 %. In a large retrospective cohort of penicilliosis
including 795 Vietnamese HIV-infected patients, the in-
hospital mortality rate was 20 % [3]. However, our cases were
mostly published in the 1990s, before the era of highly active
antiretroviral therapy. Furthermore, osteoarticular penicilliosis
was frequently disseminated and the median duration of treat-
ment was shorter than that for other infections. Two reasons
can explain this shorter duration. Either the patients died from
disseminated infection in the AIDS context or they were
discharged rapidly without further follow-up.
The diagnosis of dimorphic osteoarticular infection is dif-
ficult. The median time for diagnosis was almost 6 months.
Histological analysis was not systematically performed and
was less contributive for sporotrichosis than for other infec-
tions, whereas cultures yield was high. When performing
histology, specific fungal staining such as Gomori–Grocott
should be systematically done when a dimorphic
osteoarticular infection is suspected in an endemic area. Cul-
tures have to be kept days or weeks, depending on the dimor-
phic fungus. For example, 89 % of S. schenckii isolates grew
after 8 days at 25 °C, whereas all the remaining cultures were
positive within 29 days [20]. For H. capsulatum, cultures
become positive at 25 °C after several weeks, even as long
as 6 weeks [21].
In our series, all the patients treated with intra-articular
amphotericin B injections also received antifungal drugs or
benefited from surgery. While not reported in humans, intra-
articular amphotericin B injections are known to induce asep-
tic arthritis in animals [22]. Thus, due to the availability of
systemic antifungal drugs with better tolerability profiles,
intra-articular amphotericin B injections may no longer be
necessary for the management of dimorphic osteoarticular
infections.
The median duration of treatment in our study was shorter
than that advocated by the IDSA. For osteoarticular blasto-
mycosis or sporotrichosis, 12 months duration is recommend-
ed [11,12]. Itraconazole and amphotericin B were the two
main agents recommended by the IDSA for dimorphic infec-
tions. Following these current recommendations for the initial
medical strategy, complete response occurred in more than
77 % of S. schenckii,B. dermatitidis,andC. immitis infec-
tions. Thus, this study confirms that both remain antifungal
agents of choice for the initial therapy of dimorphic
osteoarticular infections. Cotrimoxazole can also be success-
fully used for paracoccidioidomycosis [23].
Voriconazole and posaconazole were not used in this case
series. They have, however, excellent bone diffusion and have
already been used for other osteoarticular mycoses, such as
aspergillosis [24,25]. Furthermore, voriconazole has in vitro
activity against B. dermatitidis,C. immitis,andH. capsulatum
[26]. In addition, in 24 patients receiving voriconazole for
either blastomycosis, coccidioidomycosis, or histoplasmosis,
the outcome was favorable in 95.8 % of the cases within
2 months of voriconazole initiation [27]. Voriconazole has
in vitro activity against P. m a r n e f f e i and P. brasiliensis,
Fig. 4 Distribution of responses to first-line therapy when following the
Infectious Diseases Society of America (IDSA) guidelines for 116
evaluable patients with osteoarticular sporotrichosis, coccidioidomycosis,
or blastomycosis
2138 Eur J Clin Microbiol Infect Dis (2014) 33:2131–2140
consistent with the clinical data [28–31]. On the contrary,
voriconazole is not active against S. schenckii in vitro [32],
whereas posaconazole does have activity in vitro [33].
Voriconazole is also effective in vivo in a murine experimental
model and in salvage therapy of disseminated sporotrichosis
[34,35]. Posaconazole had in vitro activity against C. immitis,
B. dermatitidis,P. marneffei,H. capsulatum,and
P. brasiliensis [36], and in vivo activity against C. immitis
[37], B. dermatitidis [38], and both varieties of H. capsulatum
[39,40]. The morphological changes of dimorphic fungi (i.e.,
yeast in vivo/hyphae in vitro) could explain the discrepancies
between in vitro and in vivo antifungal activity.
This literature review, which is a combination of case
reports and short case series, may carry the problem of pub-
lication bias. Heterogeneity of the quality of reports has to be
kept in mind. One of the main limitations of this series is that
the follow-up duration of patients was provided in less than
half of the cases. We, therefore, considered the end of therapy
as the endpoint for response assessment. In addition, pub-
lished cases are often successful cases, and failures are often
not published. This could have biased the overall response
interpretation. Thus, the assessment of response following
initial medical strategy could prevent these biases. Another
possible limitation is that all the relapses are not fully docu-
mented with culture or histological evidence. We consider,
however, that this series provides a better insight on the
characteristics of dimorphic osteoarticular infections. Prospec-
tive studies and clinical trials are needed in order to improve
the management of osteoarticular dimorphic fungal infections.
Acknowledgments Gyslène Lavialle and Serge Szulczewski from the
Jean Hamburger Library at Necker-Enfants Malades Hospital for their
valuable help in the articles search. Dr. Walsh is a Scholar of the Henry
Schueler Foundation and a Scholar of Pediatric Infectious Diseases of the
Sharpe Family Foundation.
Conflict of interest BR has received travel grants from Gilead sciences
and MSD. MNG has no potential conflict of interest to declare. NVS has
received funds for speaking at symposia organized on behalf of Astellas,
Gilead, and Pfizer Hellas, and has also received research and travel grants
from Astellas, Gilead, and Pfeizer Hellas. OL is a consultant for Gilead
Sciences, and has received grants or speaker’s fees from MSD, Roche,
Astellas, Gilead Sciences, and Pfizer. TJW receives research grants for
experimental and clinical antimicrobial pharmacotherapeutics from
Astellas, Novartis, Merck, ContraFect, and Pfizer; he has served as a
consultant to Astellas, ContraFect, Drais, iCo, Novartis, Pfizer,
Methylgene, Sigma-Tau, and Trius. SJT-A received NPRP grant 5-298-
3-086 from the Qatar National Research Fund (a member of the Qatar
Foundation). The other authors have no potential conflict of interest.
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