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Page 1: Dimorphic fungal osteoarticular infections

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# Springer-Verlag Berlin Heidelberg 2014

Abstract The objective of this investigation was to reviewthe clinical manifestations, management, and outcome ofosteoarticular infections caused by dimorphic fungi. We ex-haustively reviewed reports of bone and joint infectionscaused by dimorphic fungi published between 1970 and2012. 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 [interquartilerange (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 timewas 175 days (IQR 60–365). Sporothrix schenckii was themost frequent pathogen (n=84), followed by Coccidioidesimmitis (n=47), Blastomyces dermatitidis (n=44),Histoplasma capsulatum (n=18), Paracoccidioidesbrasiliensis (n=16), and Penicillium marneffei (n=13). Ar-thritis occurred in 87 (58 %) cases and osteomyelitis in 64(42 %), including 19 vertebral osteomyelitis. Disseminationwas 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 desMaladies Infectieuses et Tropicales, Hôpital Necker-EnfantsMalades, Centre d’Infectiologie Necker-Pasteur, Institut Imagine,149, rue de Sèvres, 75743 Paris Cedex 15, Francee-mail: [email protected]

B. Rammaert :O. LortholaryUnité de Mycologie Moléculaire, Institut Pasteur, Paris, France

M. N. Gamaletsou :N. V. SipsasPathophysiology Department, Medical School, National andKapodistrian University of Athens, Athens, Greece

M. N. Gamaletsou : E. Roilides : B. Brause :N. V. Sipsas :T. J. WalshCenter for Osteoarticular Mycoses, Hospital for Special Surgery,New York, NY, USA

V. ZellerCentre de Référence des Infections Ostéo-Articulaires, GroupeHospitalier Diaconesses-Croix Saint-Simon, Paris, France

C. ElieUnité de Recherche Clinique Paris Centre Necker, HôpitalNecker-Enfants Malades, Sorbonne Paris Cité, APHP, UniversitéParis Descartes, Paris, France

R. PrinaporiInfectious Disease Department, San Martino di Genoa Hospital,University of Genoa, Genoa, Italy

S. J. Taj-AldeenMycology Unit, Microbiology Division, Department of LaboratoryMedicine and Pathology, Hamad Medical Corporation, Doha, Qatar

E. RoilidesThird Department of Pediatrics, Aristotle University School ofMedicine, Hippokration Hospital, Thessaloniki, Greece

D. P. KontoyiannisMD Anderson Cancer Center, Houston, TX, USA

B. Brause : T. J. WalshHospital for Special Surgery, New York, NY, USA

T. J. WalshTransplantation-Oncology Infectious Diseases Program, WeillCornell Medical Center of Cornell University, New York, NY, USA

Eur J Clin Microbiol Infect DisDOI 10.1007/s10096-014-2149-0

Page 2: Dimorphic fungal osteoarticular infections

were used in 216 (97 %) patients and in combination withsurgery in 129 (60 %). Following the Infectious DiseasesSociety of America (IDSA) guidelines, a successful initialmedical strategy was observed in 97/116 (84 %) evaluablecases. The overall mortality was 6 %, and was highest forP. marneffei (38.5 %). This study demonstrates that dimorphicosteoarticular infections have distinctive clinical presenta-tions, occur predominantly in apparently immunocompetentpatients, develop often during disseminated disease, and mayrequire surgical intervention.

Introduction

Dimorphic fungi are endemic in limited geographic regions.Although they have different clinical characteristics, all ofthese fungi share the ability to grow as hyphae at 25 °C andto invade human tissues as yeasts at 37 °C. Reports of invasivefungal diseases due to dimorphic fungi are increasing withclimate or environmental changes due to human activities,such as blastomycosis [1] or coccidioidomycosis [2]. Manydimorphic infections are associated with specific professions,outdoor leisure activities, and/or traveling into and out ofendemic areas. The acquired immunodeficiency syndrome(AIDS) epidemic as well as new immunosuppressive drugsand biotherapies used in transplantation or in chronic immu-nological disorders enable the development of histoplasmosis,coccidioidomycosis, and penicilliosis [3–5]. Bones and jointsare uncommon localizations for some of these mycoses, andare, therefore, difficult to diagnose. Whereas no osteoarticularlesions were observed in a review of 795 Vietnamese cases ofPenicillium marneffei infections [3], blastomycosis affectedbones in 18 % of the 936 cases published between 1959 and2000 [6]. In addition, bones are one of the main sites oflocalization of Histoplasma capsulatum var. duboisii infec-tion, endemic in Africa [7, 8]. To our knowledge, there is nocontemporary comprehensive literature review that analyzesthe distribution, clinical manifestations, diagnosis, treatment,and outcome of osteoarticular mycoses caused by dimorphicfungi. We have, thus, extensively reviewed the literature toprovide a better insight on dimorphic fungal osteoarticularinfections.

Literature search and criteria

We performed a PubMed search from January 1970 to June2012 using the following keywords: “bone diseases, infec-tious”, “osteomyelitis”, “vertebral osteomyelitis”, “arthritis,infectious”, crossed with “fungi” and each name of fungalspecies. We included all English, Spanish, French, and Italianarticles. We considered only reported cases with sufficientclinical, epidemiological, and mycological data, as well as a

documented absence or specific presence of medical/surgicaltreatment information (see supplemental data). Afterreviewing this initial series of reports, the individual refer-ences listed in each publication were again reviewed forascertainment 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 the2008 European Organization for the Research and Treatmentof Cancer/Mycoses Study Group (EORTC/MSG) criteriawere included [9]. Cases were classified into three groups:osteomyelitis including disk and/or vertebra involvement,arthritis with or without adjacent bone infection, and multiplebone and/or joint involvements. Dissemination was definedby the involvement of two non-contiguous sites. The diagnos-tic time was defined as the period between the first symptomsand the mycological diagnosis.

The initial medical strategy consisted of the first antifungalagent used following diagnosis with or without switch for anyoral drug (when IV formulation was initiated at baseline) inthe absence of toxicity or failure. To be evaluable, cases had toreceive the antifungal agent for at least 7 days. The subsequentmedical strategy consisted of the antifungal drug introduced incase of intolerance or failure. If unspecified, the approximateduration of amphotericin B therapy was estimated for adultpatients who only received it as a first-line therapy by dividingthe cumulative dose by 70 kg and assuming a dosage of1 mg/kg per day [10].

A complete response was defined as resolution of clinicaland radiological evidence of infection with antifungal agents,surgery, and/or local treatment. A partial response wasassigned when there was an initial improvement but incom-plete resolution or insufficient subsequent clinical and radio-logical data were available. Complete and partial responseswere considered as success. Failure was defined by infection-related death or lack of improvement. Relapse was defined byclinical and/or mycological evidence of infection followinginitial improvement and antifungal discontinuation.

We also studied the impact of available Infectious DiseasesSociety of America (IDSA) guidelines (i.e., sporotrichosis,coccidioidomycosis, and blastomycosis) on the outcome[11–13]. Although IDSA guidelines were available forH. capsulatum var. capsulatum, the number of case reportswas too limited to be analyzed [14].

Statistical analyses

Continuous variables were presented as their median andinterquartile range (IQR). Variables were compared acrossgroups using the Wilcoxon–Mann–Whitney test for continu-ous variables and the Chi-square or Fisher’s exact test for

Eur J Clin Microbiol Infect Dis

Page 3: Dimorphic fungal osteoarticular infections

categorical variables. For all analyses, statistical significancewas 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). Thedemographic patterns are shown in Table 1. Only 31 (14 %)children less than 15 years old were reported, with a medianage of 7 years (range 3–9). Male gender was predominant (n=178; 81%). Themajority of patients had no known underlyingdisease at the time of infection (n=163; 73%), whereas half ofthe patients infected with P. marneffei or Sporothrix schenckiiwere immunosuppressed (Table 1). Among the children, onlytwo 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 comorbidit ies, while those withH. 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 traumawas recorded in 31(14 %) cases, of which 58 and 29 % had infections due toS. schenckii and Coccidioides immitis, respectively, while65 % had a localized infection. Outdoor activities or contactwith soil or plants were reported in 59 (27 %) cases, morefrequently for sporotrichosis and paracoccidioidomycosis.

Diagnosis

Among the 222 cases, 206 were proven from samples ofbones and/or joints. Diagnosis was obtained for the remaining

16 cases from an extra-osteoarticular site, mainly (81 %) skinlesions. The distribution of fungal species is presented inTable 1. ForH. capsulatum, ten cases belonged to capsulatumand eight cases to duboisii varieties, respectively. Histologywas 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 thanfor other fungi, with only seven (15 %) positive results(Fig. 3). Culture was performed in 170 cases, with a positiveresult in 167 (98 %) cases. Infection was diagnosed by thedirect examination of pus only for four Blastomycesdermatitidis and one C. immitis infections (Fig. 2).

Clinical features

Fungal infections involved only one bone or joint site in 151cases (68 %). Arthritis represented 87 (58 %) cases, 55 (63 %)having adjacent bone lesion. Osteomyelitis was observed in64 (42 %) cases. The distribution of sites involved by eachfungus is presented in Table 2.

When only one site was involved, reported S. schenckiiinfection was located mostly in joints, while B. dermatitidisinfection caused osteomyelitis more frequently (Table 2).B. dermatitidis, C. immitis, and H. capsulatum infected verte-brae as a single site, whereas vertebral osteomyelitis due toS. schenckii and P. marneffei were always associated withmultiple bone involvement. Infected vertebrae could be soli-tary or multiple. Thoracic localizations (n=12/19; 63 %) weremore 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 casesof dimorphic osteoarticularinfections from 1970 to 2012according to the year ofpublication

Eur J Clin Microbiol Infect Dis

Page 4: Dimorphic fungal osteoarticular infections

site associated with bone and/or joint infection (n=67; 55 %),followed by the lungs (n=46; 37 %); one-third (n=28/84) ofsporotrichosis and 85 % (n=11/13) of penicilliosis cases hadassociated cutaneous localizations. Among the 25 patientswith S. schenckii and chronic alcohol abuse, 18 (72 %) haddisseminated infection.

The median diagnostic time, which was 175 days (IQR 60–365) for the overall population, was significantly higher forS. schenckii infections (240 days; IQR 120–540; p<0.03)compared to that for other fungi, except H. capsulatum (Ta-ble 2). Although P. marneffei infections had a similar mediandiagnostic time to those due to other fungi, infection wassignificantly more disseminated (p<0.005).When disseminat-ed, infection was not diagnosed later than what was observedfor 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, incombination with surgery in 129 (60 %) cases (Table 3). Noneof the patients with P. brasiliensis infection benefited fromsurgery. The median duration of therapy was 180 days (IQR60–365). Interestingly, penicilliosis cases had the shortestmedian treatment duration, 63 days (IQR 49–210), possiblydue to early death or discharge. A subsequent medical strategywas used in 50 (23 %) patients due to side effects or failure.Six (14 %) of them died, three having an infection-related

Table 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. capsulatuma

n=18P. 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) 5b

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/mm3 2 1 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 immunosuppressionc 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 ≥10a Ten var. capsulatum and eight var. duboisiib Two missing data in childrenc 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 osteoarticularinfections identified from bone and/or joint samples

Eur J Clin Microbiol Infect Dis

Page 5: Dimorphic fungal osteoarticular infections

death. A life-long maintenance therapy was administered ineight patients with or without history of relapse, six havingC. immitis infection. Amphotericin B and itraconazole werethe most commonly used antifungal agents for initial therapy.Cotrimoxazole was used for 9/16 paracoccidioidomycosis asthe initial or subsequent strategy; therapy was successful in allevaluable cases. There were no published data on the use ofthe new azoles, voriconazole and posaconazole, and onlyseven cases were treated with a lipid formulation ofamphotericin B.

Surgery was both diagnostic and therapeutic. Two or moredebridements were necessary in 33 (25 %) of the 131 surgicalcases (Table 3). Amputation was reported once. Surgicaltreatment 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 Binstillations and was performed in eight C. immitis and 11S. schenckii infections, in combination with either medical orsurgical 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 orfailure of the initial medical strategy for 18 (51 %). Almosthalf 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 initialmedical strategy (Table 3). Among those, the IDSA guidelineswere 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 % ofthe sporotrichosis and coccidioidomycosis cases, respectively.

The related-mortality rate was 6 %, linked to disseminatedinfection in all cases (Table 3). Few patients (n=3) who diedreceived both medical and surgical treatments, whereas fourpatients 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 advancedAIDS.

Discussion

This unique series of 222 dimorphic fungal osteoarticularinfections provides a strong foundation for understandingthese 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. Dimorphicosteoarticular infections occurred mainly in apparently immu-nocompetent patients. Unknown immunosuppression, how-eve r, shou ld be sc reened in eve ry appa ren t ly

Fig. 3 Results of culture andhistology of 206 cases ofdimorphic fungal osteoarticularinfections identified from boneand/or joint samples

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Page 6: Dimorphic fungal osteoarticular infections

immunocompetent patient, such as inherited defects in the IL-12/IFN-gamma axis [16]. In addition, the disease was oftenchronic. Arthritis with a predilection for the knees and wristsis the predominant clinical feature of all dimorphicosteoarticular mycoses. When osteomyelitis occurs, it essen-tially affects long bones and vertebrae. Disseminated infectionoccurred in more than half (55 %) of the patients. Surgery wasrequired in two-thirds of the patients in combination withmedical treatment. The median duration of treatment was6 months and 15 % of cases experienced relapse. Therelated-infection mortality rate was low.

While general observations may be inferred about dimor-phic osteoarticular mycoses as a group, each of the organismshas a unique species-dependent pathogenesis that may lead to

distinctive clinical manifestations. In addition, the distributionof risk factors described in the literature for other forms ofdimorphic fungal infections was similar here.

Osteoarticular sporotrichosis occurs in the setting of localtrauma (21 %), alcohol abuse (30 %), HIV infection, immu-nosuppression, and diabetes mellitus with single or multiplebone sites, and frequent arthritis (50 %). Osteoarticular coc-cidioidomycosis and blastomycosis occurred with virtually nocomorbidity, with predominantly single bone infection. Coc-cidioidomycosis presented with frequent arthritis (45 %),while B. dermatitidis infected especially the vertebrae. Inaddition, H. capsulatum has the particularity to have twovarieties with different epidemiological patterns. WhereasH. capsulatum var. dubois i i affec ts apparent ly

Table 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)

3 2 8 5 4 0

Flat bones 8 1 3 2 1 1 0

Small bones 15/151(24)

1 7 5 1 1 0

Vertebra 19/151(30)

0 4 13/44 (46) 2 0 0

Cervical 1 0 1 0

Thoracica 12/19 (63) 4 5 2

Lumbara 7 0 7 0

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 jointinfections

71 (32) 37 (44) 10 (21) 9 2b 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) 3b 1 11/13 (85)

Lung 46/123(21)

9 6 18/27 (41) 2c 7 4

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 ≥10aOne patient had both lumbar and thoracic infected vertebrab Solely var. duboisiic Solely var. capsulatum

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Page 7: Dimorphic fungal osteoarticular infections

Tab

le3

Managem

entand

outcom

eof

221casesof

dimorphicosteoarticular

infections

Total

S.schenckii

C.immitis

B.dermatitidis

H.capsulatum

P.brasiliensis

P.marneffei

Patientsreceivinganykind

oftreatm

ent

N=218

n=83

n=47

n=44

n=17

n=16

n=11

Surgery

alone

20

20

00

0

Antifungaltherapy

alone

85(39)

27(33)

11(23)

16(36)

516

(100)

10(91)

Bothmedicalandsurgicaltreatm

ent

129(60)

56(67)

34(72)

28(64)

12(71)

01

Intra-articular

amphotericin

Binjection

19(9)

11(13)

80

00

0

Morethan

onesurgicaldebridem

ent

33/131

(25)

19/56(34)

56

30

0

Medianduratio

nof

therapy,days

(IQR)

180(60–365)

180(52–355)

135(54–365)

180(70–359)

195(55–339)

180(180–730)

63(49–210)

Medicalstrategy

(evaluablepatients)

N=197

n=75

n=42

n=41

n=15

n=14

n=10

Initialmedicalstrategy

Itraconazole

25(13)

92

44

24

Amphotericin

B117(59)

39(52)

31(74)

31(76)

65

5

Other

agent

55(28)

27(36)

96

57

1

Success

155(79)

49(65)

33(79)

39(95)

12(80)

14(100)

8(80)

Failu

re42

(21)

26(35)

92

30

2

Subsequent

medicalstrategy

47(24)

29(39)

72

51

3

Overallresponse

attheendof

follo

w-up

N=189

n=65

n=43

n=40

n=18

n=12

n=11

Com

pleteresponse

136(72)

38(59)

31(72)

39(97.5)

14(78)

11(92)

3

Partialresponse

34(18)

18(28)

81

31

3

Failu

re19

(10)

94

01

05

Outcome

N=222

n=84

n=47

n=44

n=18

n=16

n=13

Medianfollo

w-upaftertheendof

treatm

ent,days

(IQR)

390(180–730)

540(240–730)

540(365–840)

270(165–517)

150(45–377)

540(365–730)

a

Follo

w-upaftertheendof

treatm

ent

92(42)

37(44)

21(45)

20(45)

75

2

History

ofrelapse

34(16)

21(25)

82

10

1

Death

23(10)

10(12)

41

30

5

Attributabledeath

13(6)

43

01

05

Percentagesarepresentedifthenumberof

casesconsidered

was

≥10

aOne

patient

with

90days

follo

w-upandonepatient

with

outfollow-up

Eur J Clin Microbiol Infect Dis

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immunocompetent patients and was rarely described in HIV-infected patients [17], var. capsulatum infection often occursin 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 varietyduboisii 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-infectedpatients with multiple bone and joint infections.

While osteoarticular dimorphic infections were commonlyassociated with dissemination, some features were surprisingregarding other literature data. In our series, 61 % of blasto-mycosis were disseminated, which is higher than what isobserved in other series on extra-pulmonary blastomycosis[18, 19]. In addition, 85 % of our cases of osteoarticularpenicilliosis were disseminated. Interestingly, in the largestseries of P. marneffei infection, 84 % of the 795 HIV-infected Vietnamese patients had positive blood cultures [3],but no osteoarticular localizations were reported. Sinceosteoarticular 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 truesecondary localizations localized to joints. In our cases, onlytwo patients had arthritis with acute pulmonary disease. Bothhad proven H. capsulatum var. capsulatum knee arthritis,either by percutaneous biopsy or autopsy.

While 55 % of the patients had a disseminated infectionwith bone and/or joint involvement, the related-mortality ratein our cases was very low, except for penicilliosis, whichreached 38.5 %. In a large retrospective cohort of penicilliosisincluding 795 Vietnamese HIV-infected patients, the in-

hospital mortality rate was 20 % [3]. However, our cases weremostly published in the 1990s, before the era of highly activeantiretroviral therapy. Furthermore, osteoarticular penicilliosiswas frequently disseminated and the median duration of treat-ment was shorter than that for other infections. Two reasonscan explain this shorter duration. Either the patients died fromdisseminated infection in the AIDS context or they weredischarged 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 andwas less contributive for sporotrichosis than for other infec-tions, whereas cultures yield was high. When performinghistology, specific fungal staining such as Gomori–Grocottshould be systematically done when a dimorphicosteoarticular 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 grewafter 8 days at 25 °C, whereas all the remaining cultures werepositive within 29 days [20]. For H. capsulatum, culturesbecome positive at 25 °C after several weeks, even as longas 6 weeks [21].

In our series, all the patients treated with intra-articularamphotericin B injections also received antifungal drugs orbenefited 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 ofsystemic antifungal drugs with better tolerability profiles,intra-articular amphotericin B injections may no longer benecessary for the management of dimorphic osteoarticularinfections.

The median duration of treatment in our study was shorterthan 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 twomain agents recommended by the IDSA for dimorphic infec-tions. Following these current recommendations for the initialmedical strategy, complete response occurred in more than77 % of S. schenckii, B. dermatitidis, and C. immitis infec-tions. Thus, this study confirms that both remain antifungalagents of choice for the initial therapy of dimorphicosteoarticular infections. Cotrimoxazole can also be success-fully used for paracoccidioidomycosis [23].

Voriconazole and posaconazole were not used in this caseseries. They have, however, excellent bone diffusion and havealready been used for other osteoarticular mycoses, such asaspergillosis [24, 25]. Furthermore, voriconazole has in vitroactivity against B. dermatitidis,C. immitis, andH. capsulatum[26]. In addition, in 24 patients receiving voriconazole foreither blastomycosis, coccidioidomycosis, or histoplasmosis,the outcome was favorable in 95.8 % of the cases within2 months of voriconazole initiation [27]. Voriconazole hasin vitro activity against P. marneffei and P. brasiliensis,

Fig. 4 Distribution of responses to first-line therapy when following theInfectious Diseases Society of America (IDSA) guidelines for 116evaluable patients with osteoarticular sporotrichosis, coccidioidomycosis,or blastomycosis

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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 experimentalmodel and in salvage therapy of disseminated sporotrichosis[34, 35]. Posaconazole had in vitro activity against C. immitis,B. dermatitidis, P. marneffei, H. capsulatum, andP. brasiliensis [36], and in vivo activity against C. immitis[37], B. dermatitidis [38], and both varieties ofH. capsulatum[39, 40]. The morphological changes of dimorphic fungi (i.e.,yeast in vivo/hyphae in vitro) could explain the discrepanciesbetween in vitro and in vivo antifungal activity.

This literature review, which is a combination of casereports and short case series, may carry the problem of pub-lication bias. Heterogeneity of the quality of reports has to bekept in mind. One of the main limitations of this series is thatthe follow-up duration of patients was provided in less thanhalf of the cases. We, therefore, considered the end of therapyas the endpoint for response assessment. In addition, pub-lished cases are often successful cases, and failures are oftennot published. This could have biased the overall responseinterpretation. Thus, the assessment of response followinginitial medical strategy could prevent these biases. Anotherpossible 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 thecharacteristics of dimorphic osteoarticular infections. Prospec-tive studies and clinical trials are needed in order to improvethe management of osteoarticular dimorphic fungal infections.

Acknowledgments Gyslène Lavialle and Serge Szulczewski from theJean Hamburger Library at Necker-Enfants Malades Hospital for theirvaluable help in the articles search. Dr. Walsh is a Scholar of the HenrySchueler Foundation and a Scholar of Pediatric Infectious Diseases of theSharpe Family Foundation.

Conflict of interest BR has received travel grants fromGilead sciencesand MSD. MNG has no potential conflict of interest to declare. NVS hasreceived funds for speaking at symposia organized on behalf of Astellas,Gilead, and Pfizer Hellas, and has also received research and travel grantsfrom Astellas, Gilead, and Pfeizer Hellas. OL is a consultant for GileadSciences, and has received grants or speaker’s fees from MSD, Roche,Astellas, Gilead Sciences, and Pfizer. TJW receives research grants forexperimental and clinical antimicrobial pharmacotherapeutics fromAstellas, Novartis, Merck, ContraFect, and Pfizer; he has served as aconsultant 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 QatarFoundation). The other authors have no potential conflict of interest.

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