Mycopathologia (2015) 180:257–264 DOI 10.1007/s11046-015-9911-4
Scedosporium apiospermum Otitis Complicated by a Temporomandibular Arthritis: A Case Report and Mini-Review A. Huguenin . V. Noel . A. Rogez . C. Chemla . I. Villena . D. Toubas
Received: 12 December 2014 / Accepted: 12 June 2015 / Published online: 24 June 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Scedosporium apiospermum is an ubiquitous fungus responsible for various infections in immunocompromised and immunocompetent patients. Ear infections are infrequent. We report an exceptional case of S. apiospermum external otitis complicated by temporomandibular joint arthritis. After 6 months of antibiotherapy, diagnosis was established by mycological analysis of external auditory canal and infratemporal fossae needle sampling. A satisfactory outcome was obtained after 2 months of voriconazole alone. We have reviewed 15 cases of S. apiospermum otitis. Seven of these
A. Huguenin C. Chemla I. Villena D. Toubas Parasitology-Mycology Laboratory, 45 rue Cognacq-Jay, CHU Maison Blanche, 51100 Reims, France A. Huguenin (&) Laboratoire de Parasitologie Mycologie, CHU de Reims, Universite´ Reims Champagne Ardenne, Hoˆpital Maison Blanche, 45 rue Cognacq Jay, 51092 Reims, France e-mail: [email protected] V. Noel A. Rogez Internal Medicine and Infectious Disease Unit, 45 rue Cognacq-Jay, CHU Robert Debre´, 51100 Reims, France I. Villena EA 3800, Universite´ Reims Champagne-Ardenne, Reims, France D. Toubas Equipe Me´DIAN, Unite´ MEDyC CNRS UMR 7369, Universite´ de Reims Champagne-Ardenne, Reims, France
patients were immunocompromised. Most common clinical presentation included a chronic external otitis lasting months or years before complication stage. Most common clinical features included recurrent unilateral otalgia (11/15) and purulent otorrhea (13/15). Diagnosis was often made at later stage (12/15) with local extension to bones and/or soft tissues (9/15) or cerebral lethal dissemination (3/15).The extremely low incidence of S. apiospermum otomycosis and its non-specific presentation results in a frequent diagnosis delay. A mycological investigation should be performed in case of persistent external otitis and/or osteolysis despite prolonged antibiotic treatment to prevent further extension of the disease. Keywords Scedosporium apiospermum TMJ arthritis Otomycosis Transient paraproteinemia Voriconazole
Introduction Scedosporium apiospermum is an ubiquitous saprobic fungus. In human pathology, S. apiospermum is responsible for a broad range of clinical situations [1, 2]. The most frequent is transient or persistent asymptomatic colonization of pathologic airways, particularly in cystic fibrosis [3]. S. apiospermum is increasingly incriminated in severe disseminated infections in immunocompromised patients (as bone
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marrow or solid organ transplants recipients) frequently spreading to brain, thyroid, heart or eyes. A delayed S. apiospermum pulmonary infection with secondary blood spread and particular tropism to central nervous system is described in the context of near-drowning syndrome after polluted water inhalation. Finally, local infections are reported after trauma in immunocompetent patients. Among these, the most frequent localizations may include subcutaneous tissues, eye (such as keratitis or endophthalmitis) and osteoarticular infections [1, 2]. Scedosporium apiospermum otomycosis remains a very rare localization as described below in an uncommon case of external otitis complicated with osteolysis of the temporomandibular joint (TMJ).
Case Report On January 2012, an 84-year-old man was hospitalized in the infectious disease unit of the Reims University Hospital (France) for a 6-month history of right ear recurrent infection. The patient had a past medical history of idiopathic hypertension, bilateral hip prostheses and no evidence of diabetes or immunodeficiency. He was equipped with hearing aids for bilateral transmission deafness. Up to this hospitalization, he was healthy, living in the countryside and farming poultry. However, he mentioned that since June 2011, he had been complaining of right ear pain associated with significant inflammation of the right TMJ. An external otitis was diagnosed for which he was initially treated with auricular drops of ofloxacin and PolydexaÒ (auricular solution with neomycin, polymyxin B and dexamethasone). The failure of this local treatment led to the administration of numerous systemic antibiotics (ofloxacin, amoxicillin and clavulanic acid, moxifloxacin, cefixime, pristinamycin, ciprofloxacin, clindamycin) associated with local and general corticotherapy. Two months later, the patient began complaining of an extension of the pain to the zygomatic area associated with local edema. A computerized tomography (CT) scan showed no bone lesion. On December 2011, magnetic resonance imaging (MRI) revealed arthritis of the TMJ and cellulitis of the surrounding area, without brain extension. Pseudomonas aeruginosa external malignant otitis was then suspected, and the patient received 4 weeks of parenteral antibiotic therapy (ceftazidime and
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ciprofloxacin). Symptoms abated transiently but recurred after treatment discontinuation. On admission, the patient was apyretic and presented an inflammatory and stenotic right external auditory canal (EAC) with purulent discharge. There were no signs of mastoiditis. The TMJ was painful at maximum opening of the mouth. The upper branch of the zygomatic process was swollen and painful on palpation. Laboratory data showed that C-reactive protein (CRP) was within normal range, leukocytes 7.7 g/L, hemoglobin 161 g/L, platelets 253 g/L, calcium 2.18 mmol/L, serum creatinine 104 lmol/L. Proteinuria was not significant. Serum protein electrophoresis identified hypoproteinemia (total protein 58 g/L) with decreased gammaglobulins (8.2 g/L) and a protein band. The immunofixation revealed the presence of a monoclonal band with IgG antiserum. Bence-Jones proteinuria was not detected. Within this infectious context, with low monoclonal peak and absence of end organ failure symptoms, bone marrow examination was not performed. The follow-up was based on serum electrophoresis monitoring. A CT scan confirmed the TMJ arthritis with osteolysis of the external auditory canal inner wall and a 14 9 7 mm collection of the infratemporal fossa facing the outer portion of the zygomato-temporal branch of the maxillary bone (Fig. 1). Needle aspiration of the collection and of the right EAC was performed under local anesthesia. Direct microscopic examination of the samples using Gram stain revealed
Fig. 1 Collection of the infratemporal fossae facing the outer portion of the zygomato-temporal branch of the maxillary bone (arrow). TDM at admission
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a polymorphous bacterial flora. Mycological direct examination was not performed. Culture on horse blood agar revealed several colonies of filamentous fungi and a commensal bacterial flora. Subculture of the fungal colonies on Sabouraud agar yielded greyish colonies, and microscopic examination revealed the presence of hyaline and septate vegetative hyphae and multiple oval conidia arising from hyaline cylindrical conidiogenous cells which permitted identification of the fungus as belonging to the S. apiospermum species complex. A Graphium synanamorph was observed (Fig. 2). Differential diagnosis with Lomentospora prolificans, formerly Scedosporium prolificans [4], was based on morphological features (absence of swollen conidiogenous cells) and failure to grow at 45 °C. Identification of S. apiospermum was then confirmed by sequencing the internal transcribed spacer (ITS) 1 and 2 regions of ribosomal DNA genes and b-tubulin gene area sequencing (National Reference Center for Mycoses and Antifungals, Pasteur Institute France, Genbank Accession Numbers: KT186642, KT186641). Using E-testÒ, the strain displayed low MIC to voriconazole (MIC 0.125 lg/ mL) and high MIC to amphotericin B (MIC 6 lg/mL), posaconazole (MIC 8 lg/mL) and caspofungin (MIC [ 32 lg/mL). The patient was treated with oral voriconazole (400 mg loading dose the first day then 200 mg/day) with good clinical and biological tolerance. A control electrophoresis and immunofixation 2 days after initiation of treatment showed
Fig. 2 Microscopic examination of the S. apiospermum isolate (lactophenol blue stain 9400). Coremia of a Graphium state is observed, together with obovoid conidia produced singly at the apex of cylindrical conidiogenous cells
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disappearance of the paraprotein. The search for Bence-Jones protein was also negative. The clinical outcome at 2 months was excellent, with a complete regression of ear pain and TMJ edema. Voriconazole therapy was then discontinued.
Discussion We report here a case of S. apiospermum external otitis complicated by temporomandibular joint arthritis in an immunocompetent patient with good outcome under antifungal treatment with voriconazole alone. Scedosporium spp infections (scedosporiosis) have been described in temperate and tropical zones. S. apiospermum has been recovered from many environmental samples: soil, polluted water and of birds, bats or cattle manure [1, 2]. However, in a recent study [5], it was predominantly isolated from playgrounds, agricultural areas, wastewater treatment plants or city park, suggesting a strength association with human activity. Scedosporium apiospermum has been long considered the asexual state of Pseudallescheria boydii. Nevertheless, taxonomy has been revised recently on the basis of molecular analysis combined with morphological, physiological and biochemical studies [5, 6]. Thus, it was shown that S. apiospermum and P. boydii are in fact two distinct species and three new species have been described. In addition, according to a recent publication from the international working group on Pseudallescheria/Scedosporium infections [4], the genus name Pseudallescheria should no longer be used. Therefore, S. apiospermum is now considered a species complex comprising five closely related species, i.e., S. apiospermum sensu stricto, Scedosporium boydii, Scedosporium dehoogii, Scedosporium aurantiacum and S. minutisporum. Scedosporium apiospermum is a very uncommon agent of otomycosis. Since 1899 and the first reported case of human scedosporiosis, which was strikingly an ear infection [1, 2], only about 20 cases have been reported. We have reviewed 15 literature cases of S. apiospermum or S. boydii otitis [7–21]. In cases that occurred before the molecular biology period, identification was only based on colony features and microscopic morphology. Demographic and clinical characteristics of the patients are presented in Table 1. Eleven patients were
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males (sex ratio 2.75). The age of patients ranged from 6 to 75 years (mean age 38 years, four children under 13, five patients [65 years old). Eight patients were immunocompetent, and seven were immunocompromised (AIDS, diabetes). The patients presented with chronic external otitis lasting months to years before the complication stage. The most common clinical features included recurrent unilateral otalgia (11 cases), purulent otorrhea (13 cases), granulation tissue or debris in the external auditory canal (7 cases) and local inflammatory signs (4 cases). Systemic symptoms were minimal even at complication stage: low-grade fever [6–8] and occasional mild elevation of CRP could be observed [8, 9]. Scedosporium otomycosis may be complicated by extension to adjacent bones or soft tissues (nine cases) with mastoiditis (eight cases), osteolysis of ear canal (two cases). Other localizations such as skull base osteomyelitis and conchal bowl perichondritis have been reported. To our knowledge, arthritis of the TMJ before our case has never been described. Cerebral dissemination (three cases) by loco-regional extension from chronic otomycosis is another severe complication [7, 8, 10]. The presentation is non-specific with meningo-encephalitis symptoms (intracranial hypertension syndrome, cranial nerves palsy), associated with chronic external otitis or mastoiditis. The outcome was constantly fatal in the three reviewed cases. The source of contamination remains generally unknown. In our case report, the patient, a poultry farmer, may have been contaminated while handling straw or chicken droppings. Scedosporium apiospermum contamination may lead to transient colonization or chronic colonization with saprobic involvement of the EAC or localized infection. Saprobic states in otomycosis could be triggered by several factors such as trauma, moisture, epithelial debris in the EAC and conditions such as diabetes [11]. Colonization could lead to active infection with chronic local disease. Many factors could cause the evolution to chronic invasive otomycosis in previously uncontaminated patients or patients with chronic colonization. Among these factors, local traumatisms and surgery may play an important role. In our review, three patients had history of ear surgery before infections. Bacterial external otitis and cholesteatoma
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(three patients) could also be local factors explaining this evolution. In our case, the hearing aid may have triggered an irritation of the external auditory canal making gateway through EAC skin. In this case, the only immunologic abnormality identified was the presence of the transient monoclonal gammopathy of unknown significance (MGUS), but its disappearance after only 2 days of antifungal treatment does not support its significance. Scedosporium apiospermum otitis diagnosis is difficult and may be delayed months or years. It may evolve on a torpid mode for years; diagnosis is often achieved at complication stage (10/14), because a bacterial etiology is searched in priority. An important delay may occur between the beginning of microbiological investigations and the research of a fungal etiology. It is thus very important to perform a mycological examination in case of external otitis with unfavorable evolution after empiric antibiotic treatment. In addition, S. apiospermum isolation may also be delayed due to its slow growth time. Other microorganisms present in contaminated samples may inhibit its growth. It can also be misdiagnosed as a culture contaminant [12]. Direct examination of needle aspiration sample or biopsy showing branched and septated hyphae could be particularly helpful even if it does not point to a particular genus of filamentous fungi. In our review, direct mycological examination was positive in seven among ten cases. Species identification based on culture isolation, morphological features and molecular technics is necessary in the management of otomycosis. Recently, MALDI-TOF mass spectrometry has been proposed as a fast and accurate method for species identification within the S. apiospermum complex [24]. It is particularly important to discriminate S. apiospermum from L. prolificans, due to L. prolificans resistance to voriconazole [13–16]. Scedosporium apiospermum usually shows very poor sensitivity to amphotericin B, fluconazole, ketoconazole and caspofungin. Voriconazole is the treatment of choice of S. apiospermum otomycosis [16]. Complete healing was obtained in several months in three of the four cases in which it was administered [9, 17–19]. Prolonged oral therapy is often necessary for months. Itraconazole and miconazole show in vitro and in vivo efficacy and could be used as an alternative to voriconazole [20–24]. Topical azoles seem to be an alternative to systemic treatment in uncomplicated S.
Year of report (ref.)
1997 [7]
1999 [10]
1999 [21]
1999 [20]
2001 [23]
2004 [25]
2006 [7]
2007 [17]
Patient
1
2
3
4
5
6
7
7
62, female
12, female
8, male
21, male
6, male
10, male
21, male
50, male
Age (years), gender
No
No
No
Hemophilia A AIDS (CD4 ? 90/ mm3) and C hepatitis
No
HIV, neutropenia
AIDS (CD4 ? 60/ mm3)
AIDS (CD4 ? 10/ mm3)
Comorbidities
Unilateral recurrent otorrhea since 57 years, perichondritis conchal bow abscess and superficial skin necrosis
Recurrent unilateral otorrhea since childhood, otalgia, meningeal syndrome, intracranial hypertension
Recurrent otitis since 7 years, otorrhea, white debris in the EAC
Unilateral otalgia and ear bleeding since 6 weeks, local inflammatory signs of the mastoid, granulation tissue in the EAC
Recurrent external otitis. Bilateral itching and non-purulent otorrhea
Unilateral otorrhea, granulation tissue in the EAC
Negative
Negative
No
Cholesteatoma
Radical mastoidectomy for treating cholesteatoma
Mastoiditis cerebral dissemination: extradural abscess, multiple temporal abscesses Mastoiditis
Positive
Positive
No
No
No
No
P. aeruginosa ear infection Pressure equalization tube
Mastoiditis, middle ear destruction
Positive
Osteolysis of the EAC, mastoiditis, facial nerve palsy, invasion of dura mater
No
Mastoiditis
Positive
No
Osteolysis of the EAC and mastoiditis
Unilateral otalgia, otorrhea, auditory loss, granulation tissue in the EAC Unilateral mastoid pain and swelling
Mycological direct examination
Potential local factor
Complication
Clinical features
Table 1 Description of 15 case reports of otomycosis due to Scedosporium apiospermum complex
Death
Considered cured
No
Voriconazole 6 month Incision and drainage of conchal bow abcess
Myringotomia
Radical mastoidectomy, extradural abscess drainage
Death
Considered cured
Considered cured
Amphotericin B and ketoconazole then miconazole
Topical miconazole 4 weeks
Remission with intermittent otorrhea
Topical clotrimazole, 4 weeks
Repeated surgical debridement: mastoidectomy, facial nerve decompression
No
Itraconazole, liposomal amphotericin B
Myringotomia
Death
Considered cured
Itraconazole 8 weeks and local antifungals Ketoconazole then miconazole
Outcome
Antifungal therapy
Transmastoid antrectomy
Radical mastoidectomy and meatoplasty
Surgical therapy
Mycopathologia (2015) 180:257–264 261
123
Year of report (ref.)
2006 [17]
2007 [10]
2008 [9]
2008 [18]
2009 [19]
2009 [8]
Patient
8
123
9
10
11
12
13
75, man
No
Diabetes
Diabetes
65, female
72, male
Diabetes
No
No
Comorbidities
51, male
21, female
67, female
Age (years), gender
Table 1 continued
Bilateral tympanic membrane perforation, intermittent otorrhea and otalgia since 12 years. Trigeminal and facial nerves palsy since 3 weeks
Unilateral purulent otorrhea since 6 months, stenosis of the ECA
Unilateral otalgia and purulent otorrhea since years, pruritus, debris in the ECA
Unilateral otalgia and greenish otorrhea since a month, granulation tissue in the ECA
Unilateral otalgia and otorrhea and impaired hearing since 6 months, intracranial hypertension syndrome, hemiparesis, cerebellar syndrome
Recurrent unilateral intermittent otorrhea, acute abscess of conchal bowl and meatus with skin necrosis
Clinical features
Modified radical mastoidectomy for cholesteatoma with revision and cartilage graft tympanoplasty Mastoidectomy 8 years before (chronic suppurative otitis media)
No
Perichondritis
Cerebral dissemination: cerebello-pontin angle lesion, severe brainstem edema and erosion of petrous apex Osteolysis of temporal bone, mandibular condyle and pterygoid process
Cerebral dissemination
No
Surgical exploration of the mastoid
No
Death
Considered cured
Voriconazole four weeks Surgical excision of a bone fragment in the EAC No
Osteolysis of the petrous bone, ethmoidomaxillary sinusitis Mastoiditis
Considered cured
Voriconazole
Tympanosurgery
No
Considered cured
Death Amphotericin B and ketoconazole
Voriconazole 1 month
Healing with small postauricular fistula
Voriconazole 6 months
Incision and drainage of abscess
Neurosurgical treatment: ventriculoperitoneal shunt, craniectomy and resection of cerebellopontine lesion
Outcome
Antifungal therapy
Surgical therapy
Cholesteatoma
Negative (Gram staining)
Positive
Mycological direct examination
No
Facial nerves palsy
Involvement of soft tissues (parotid, muscle)
Potential local factor
Complication
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Considered cured No No
Positive
Topical econazole nitrate (10 weeks)
Considered cured Topical itraconazole No Positive No
Surgical therapy
apiospermum otomycosis [6, 20, 24–26] but are not sufficient to treat cases with bones and soft tissues involvement or cerebral dissemination. Surgical therapy has been performed in 11 of 14 cases described in this review. Surgical debridement is associated with the medical treatment in localized infections. Complete resection of infected tissues can be impossible, requiring repeated debridement and extended antifungal therapy. In our case, surgical treatment was not necessary due to favorable outcome under medical treatment alone. In conclusion, S. apiospermum is a ubiquitous soil fungus, rarely involved in otomycosis. It may be responsible for serious complications such as bone involvement or dissemination to the brain with a very poor prognosis. A mycological examination should always be performed in case of persistent external otitis despite antibiotic treatment or in otitis complicated with osteolysis to allow early diagnosis and appropriate antifungal therapy. Acknowledgments We thank Dr. Dea Garcia-Hermoso, National Reference Center for Mycoses and Antifungals (Institut Pasteur, Paris, France), for performing molecular identification. We thank Dr. P.L. Toubas for reviewing the manuscript.
None.
No Hypoacusia for 7 years, right purulent otorrhea for 4 years followed by left purulent otorrhea 6 month after first consultation. Inflammatory ECA No 2013 [26] 15
32, male
2011 [24] 14
37, male
No
Unilateral otalgia and otorrhea since 6 months, itching, debris in the ECA
No
Conflict of interest
Year of report (ref.)
Age (years), gender
263
Compliance with ethical standards
Patient
Table 1 continued
Comorbidities
Clinical features
Complication
Potential local factor
Mycological direct examination
Antifungal therapy
Outcome
Mycopathologia (2015) 180:257–264
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Scedosporium apiospermum Otitis Complicated by a Temporomandibular Arthritis: A Case Report and Mini-Review A. Huguenin . V. Noel . A. Rogez . C. Chemla . I. Villena . D. Toubas
Received: 12 December 2014 / Accepted: 12 June 2015 / Published online: 24 June 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Scedosporium apiospermum is an ubiquitous fungus responsible for various infections in immunocompromised and immunocompetent patients. Ear infections are infrequent. We report an exceptional case of S. apiospermum external otitis complicated by temporomandibular joint arthritis. After 6 months of antibiotherapy, diagnosis was established by mycological analysis of external auditory canal and infratemporal fossae needle sampling. A satisfactory outcome was obtained after 2 months of voriconazole alone. We have reviewed 15 cases of S. apiospermum otitis. Seven of these
A. Huguenin C. Chemla I. Villena D. Toubas Parasitology-Mycology Laboratory, 45 rue Cognacq-Jay, CHU Maison Blanche, 51100 Reims, France A. Huguenin (&) Laboratoire de Parasitologie Mycologie, CHU de Reims, Universite´ Reims Champagne Ardenne, Hoˆpital Maison Blanche, 45 rue Cognacq Jay, 51092 Reims, France e-mail: [email protected] V. Noel A. Rogez Internal Medicine and Infectious Disease Unit, 45 rue Cognacq-Jay, CHU Robert Debre´, 51100 Reims, France I. Villena EA 3800, Universite´ Reims Champagne-Ardenne, Reims, France D. Toubas Equipe Me´DIAN, Unite´ MEDyC CNRS UMR 7369, Universite´ de Reims Champagne-Ardenne, Reims, France
patients were immunocompromised. Most common clinical presentation included a chronic external otitis lasting months or years before complication stage. Most common clinical features included recurrent unilateral otalgia (11/15) and purulent otorrhea (13/15). Diagnosis was often made at later stage (12/15) with local extension to bones and/or soft tissues (9/15) or cerebral lethal dissemination (3/15).The extremely low incidence of S. apiospermum otomycosis and its non-specific presentation results in a frequent diagnosis delay. A mycological investigation should be performed in case of persistent external otitis and/or osteolysis despite prolonged antibiotic treatment to prevent further extension of the disease. Keywords Scedosporium apiospermum TMJ arthritis Otomycosis Transient paraproteinemia Voriconazole
Introduction Scedosporium apiospermum is an ubiquitous saprobic fungus. In human pathology, S. apiospermum is responsible for a broad range of clinical situations [1, 2]. The most frequent is transient or persistent asymptomatic colonization of pathologic airways, particularly in cystic fibrosis [3]. S. apiospermum is increasingly incriminated in severe disseminated infections in immunocompromised patients (as bone
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marrow or solid organ transplants recipients) frequently spreading to brain, thyroid, heart or eyes. A delayed S. apiospermum pulmonary infection with secondary blood spread and particular tropism to central nervous system is described in the context of near-drowning syndrome after polluted water inhalation. Finally, local infections are reported after trauma in immunocompetent patients. Among these, the most frequent localizations may include subcutaneous tissues, eye (such as keratitis or endophthalmitis) and osteoarticular infections [1, 2]. Scedosporium apiospermum otomycosis remains a very rare localization as described below in an uncommon case of external otitis complicated with osteolysis of the temporomandibular joint (TMJ).
Case Report On January 2012, an 84-year-old man was hospitalized in the infectious disease unit of the Reims University Hospital (France) for a 6-month history of right ear recurrent infection. The patient had a past medical history of idiopathic hypertension, bilateral hip prostheses and no evidence of diabetes or immunodeficiency. He was equipped with hearing aids for bilateral transmission deafness. Up to this hospitalization, he was healthy, living in the countryside and farming poultry. However, he mentioned that since June 2011, he had been complaining of right ear pain associated with significant inflammation of the right TMJ. An external otitis was diagnosed for which he was initially treated with auricular drops of ofloxacin and PolydexaÒ (auricular solution with neomycin, polymyxin B and dexamethasone). The failure of this local treatment led to the administration of numerous systemic antibiotics (ofloxacin, amoxicillin and clavulanic acid, moxifloxacin, cefixime, pristinamycin, ciprofloxacin, clindamycin) associated with local and general corticotherapy. Two months later, the patient began complaining of an extension of the pain to the zygomatic area associated with local edema. A computerized tomography (CT) scan showed no bone lesion. On December 2011, magnetic resonance imaging (MRI) revealed arthritis of the TMJ and cellulitis of the surrounding area, without brain extension. Pseudomonas aeruginosa external malignant otitis was then suspected, and the patient received 4 weeks of parenteral antibiotic therapy (ceftazidime and
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ciprofloxacin). Symptoms abated transiently but recurred after treatment discontinuation. On admission, the patient was apyretic and presented an inflammatory and stenotic right external auditory canal (EAC) with purulent discharge. There were no signs of mastoiditis. The TMJ was painful at maximum opening of the mouth. The upper branch of the zygomatic process was swollen and painful on palpation. Laboratory data showed that C-reactive protein (CRP) was within normal range, leukocytes 7.7 g/L, hemoglobin 161 g/L, platelets 253 g/L, calcium 2.18 mmol/L, serum creatinine 104 lmol/L. Proteinuria was not significant. Serum protein electrophoresis identified hypoproteinemia (total protein 58 g/L) with decreased gammaglobulins (8.2 g/L) and a protein band. The immunofixation revealed the presence of a monoclonal band with IgG antiserum. Bence-Jones proteinuria was not detected. Within this infectious context, with low monoclonal peak and absence of end organ failure symptoms, bone marrow examination was not performed. The follow-up was based on serum electrophoresis monitoring. A CT scan confirmed the TMJ arthritis with osteolysis of the external auditory canal inner wall and a 14 9 7 mm collection of the infratemporal fossa facing the outer portion of the zygomato-temporal branch of the maxillary bone (Fig. 1). Needle aspiration of the collection and of the right EAC was performed under local anesthesia. Direct microscopic examination of the samples using Gram stain revealed
Fig. 1 Collection of the infratemporal fossae facing the outer portion of the zygomato-temporal branch of the maxillary bone (arrow). TDM at admission
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a polymorphous bacterial flora. Mycological direct examination was not performed. Culture on horse blood agar revealed several colonies of filamentous fungi and a commensal bacterial flora. Subculture of the fungal colonies on Sabouraud agar yielded greyish colonies, and microscopic examination revealed the presence of hyaline and septate vegetative hyphae and multiple oval conidia arising from hyaline cylindrical conidiogenous cells which permitted identification of the fungus as belonging to the S. apiospermum species complex. A Graphium synanamorph was observed (Fig. 2). Differential diagnosis with Lomentospora prolificans, formerly Scedosporium prolificans [4], was based on morphological features (absence of swollen conidiogenous cells) and failure to grow at 45 °C. Identification of S. apiospermum was then confirmed by sequencing the internal transcribed spacer (ITS) 1 and 2 regions of ribosomal DNA genes and b-tubulin gene area sequencing (National Reference Center for Mycoses and Antifungals, Pasteur Institute France, Genbank Accession Numbers: KT186642, KT186641). Using E-testÒ, the strain displayed low MIC to voriconazole (MIC 0.125 lg/ mL) and high MIC to amphotericin B (MIC 6 lg/mL), posaconazole (MIC 8 lg/mL) and caspofungin (MIC [ 32 lg/mL). The patient was treated with oral voriconazole (400 mg loading dose the first day then 200 mg/day) with good clinical and biological tolerance. A control electrophoresis and immunofixation 2 days after initiation of treatment showed
Fig. 2 Microscopic examination of the S. apiospermum isolate (lactophenol blue stain 9400). Coremia of a Graphium state is observed, together with obovoid conidia produced singly at the apex of cylindrical conidiogenous cells
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disappearance of the paraprotein. The search for Bence-Jones protein was also negative. The clinical outcome at 2 months was excellent, with a complete regression of ear pain and TMJ edema. Voriconazole therapy was then discontinued.
Discussion We report here a case of S. apiospermum external otitis complicated by temporomandibular joint arthritis in an immunocompetent patient with good outcome under antifungal treatment with voriconazole alone. Scedosporium spp infections (scedosporiosis) have been described in temperate and tropical zones. S. apiospermum has been recovered from many environmental samples: soil, polluted water and of birds, bats or cattle manure [1, 2]. However, in a recent study [5], it was predominantly isolated from playgrounds, agricultural areas, wastewater treatment plants or city park, suggesting a strength association with human activity. Scedosporium apiospermum has been long considered the asexual state of Pseudallescheria boydii. Nevertheless, taxonomy has been revised recently on the basis of molecular analysis combined with morphological, physiological and biochemical studies [5, 6]. Thus, it was shown that S. apiospermum and P. boydii are in fact two distinct species and three new species have been described. In addition, according to a recent publication from the international working group on Pseudallescheria/Scedosporium infections [4], the genus name Pseudallescheria should no longer be used. Therefore, S. apiospermum is now considered a species complex comprising five closely related species, i.e., S. apiospermum sensu stricto, Scedosporium boydii, Scedosporium dehoogii, Scedosporium aurantiacum and S. minutisporum. Scedosporium apiospermum is a very uncommon agent of otomycosis. Since 1899 and the first reported case of human scedosporiosis, which was strikingly an ear infection [1, 2], only about 20 cases have been reported. We have reviewed 15 literature cases of S. apiospermum or S. boydii otitis [7–21]. In cases that occurred before the molecular biology period, identification was only based on colony features and microscopic morphology. Demographic and clinical characteristics of the patients are presented in Table 1. Eleven patients were
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males (sex ratio 2.75). The age of patients ranged from 6 to 75 years (mean age 38 years, four children under 13, five patients [65 years old). Eight patients were immunocompetent, and seven were immunocompromised (AIDS, diabetes). The patients presented with chronic external otitis lasting months to years before the complication stage. The most common clinical features included recurrent unilateral otalgia (11 cases), purulent otorrhea (13 cases), granulation tissue or debris in the external auditory canal (7 cases) and local inflammatory signs (4 cases). Systemic symptoms were minimal even at complication stage: low-grade fever [6–8] and occasional mild elevation of CRP could be observed [8, 9]. Scedosporium otomycosis may be complicated by extension to adjacent bones or soft tissues (nine cases) with mastoiditis (eight cases), osteolysis of ear canal (two cases). Other localizations such as skull base osteomyelitis and conchal bowl perichondritis have been reported. To our knowledge, arthritis of the TMJ before our case has never been described. Cerebral dissemination (three cases) by loco-regional extension from chronic otomycosis is another severe complication [7, 8, 10]. The presentation is non-specific with meningo-encephalitis symptoms (intracranial hypertension syndrome, cranial nerves palsy), associated with chronic external otitis or mastoiditis. The outcome was constantly fatal in the three reviewed cases. The source of contamination remains generally unknown. In our case report, the patient, a poultry farmer, may have been contaminated while handling straw or chicken droppings. Scedosporium apiospermum contamination may lead to transient colonization or chronic colonization with saprobic involvement of the EAC or localized infection. Saprobic states in otomycosis could be triggered by several factors such as trauma, moisture, epithelial debris in the EAC and conditions such as diabetes [11]. Colonization could lead to active infection with chronic local disease. Many factors could cause the evolution to chronic invasive otomycosis in previously uncontaminated patients or patients with chronic colonization. Among these factors, local traumatisms and surgery may play an important role. In our review, three patients had history of ear surgery before infections. Bacterial external otitis and cholesteatoma
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(three patients) could also be local factors explaining this evolution. In our case, the hearing aid may have triggered an irritation of the external auditory canal making gateway through EAC skin. In this case, the only immunologic abnormality identified was the presence of the transient monoclonal gammopathy of unknown significance (MGUS), but its disappearance after only 2 days of antifungal treatment does not support its significance. Scedosporium apiospermum otitis diagnosis is difficult and may be delayed months or years. It may evolve on a torpid mode for years; diagnosis is often achieved at complication stage (10/14), because a bacterial etiology is searched in priority. An important delay may occur between the beginning of microbiological investigations and the research of a fungal etiology. It is thus very important to perform a mycological examination in case of external otitis with unfavorable evolution after empiric antibiotic treatment. In addition, S. apiospermum isolation may also be delayed due to its slow growth time. Other microorganisms present in contaminated samples may inhibit its growth. It can also be misdiagnosed as a culture contaminant [12]. Direct examination of needle aspiration sample or biopsy showing branched and septated hyphae could be particularly helpful even if it does not point to a particular genus of filamentous fungi. In our review, direct mycological examination was positive in seven among ten cases. Species identification based on culture isolation, morphological features and molecular technics is necessary in the management of otomycosis. Recently, MALDI-TOF mass spectrometry has been proposed as a fast and accurate method for species identification within the S. apiospermum complex [24]. It is particularly important to discriminate S. apiospermum from L. prolificans, due to L. prolificans resistance to voriconazole [13–16]. Scedosporium apiospermum usually shows very poor sensitivity to amphotericin B, fluconazole, ketoconazole and caspofungin. Voriconazole is the treatment of choice of S. apiospermum otomycosis [16]. Complete healing was obtained in several months in three of the four cases in which it was administered [9, 17–19]. Prolonged oral therapy is often necessary for months. Itraconazole and miconazole show in vitro and in vivo efficacy and could be used as an alternative to voriconazole [20–24]. Topical azoles seem to be an alternative to systemic treatment in uncomplicated S.
Year of report (ref.)
1997 [7]
1999 [10]
1999 [21]
1999 [20]
2001 [23]
2004 [25]
2006 [7]
2007 [17]
Patient
1
2
3
4
5
6
7
7
62, female
12, female
8, male
21, male
6, male
10, male
21, male
50, male
Age (years), gender
No
No
No
Hemophilia A AIDS (CD4 ? 90/ mm3) and C hepatitis
No
HIV, neutropenia
AIDS (CD4 ? 60/ mm3)
AIDS (CD4 ? 10/ mm3)
Comorbidities
Unilateral recurrent otorrhea since 57 years, perichondritis conchal bow abscess and superficial skin necrosis
Recurrent unilateral otorrhea since childhood, otalgia, meningeal syndrome, intracranial hypertension
Recurrent otitis since 7 years, otorrhea, white debris in the EAC
Unilateral otalgia and ear bleeding since 6 weeks, local inflammatory signs of the mastoid, granulation tissue in the EAC
Recurrent external otitis. Bilateral itching and non-purulent otorrhea
Unilateral otorrhea, granulation tissue in the EAC
Negative
Negative
No
Cholesteatoma
Radical mastoidectomy for treating cholesteatoma
Mastoiditis cerebral dissemination: extradural abscess, multiple temporal abscesses Mastoiditis
Positive
Positive
No
No
No
No
P. aeruginosa ear infection Pressure equalization tube
Mastoiditis, middle ear destruction
Positive
Osteolysis of the EAC, mastoiditis, facial nerve palsy, invasion of dura mater
No
Mastoiditis
Positive
No
Osteolysis of the EAC and mastoiditis
Unilateral otalgia, otorrhea, auditory loss, granulation tissue in the EAC Unilateral mastoid pain and swelling
Mycological direct examination
Potential local factor
Complication
Clinical features
Table 1 Description of 15 case reports of otomycosis due to Scedosporium apiospermum complex
Death
Considered cured
No
Voriconazole 6 month Incision and drainage of conchal bow abcess
Myringotomia
Radical mastoidectomy, extradural abscess drainage
Death
Considered cured
Considered cured
Amphotericin B and ketoconazole then miconazole
Topical miconazole 4 weeks
Remission with intermittent otorrhea
Topical clotrimazole, 4 weeks
Repeated surgical debridement: mastoidectomy, facial nerve decompression
No
Itraconazole, liposomal amphotericin B
Myringotomia
Death
Considered cured
Itraconazole 8 weeks and local antifungals Ketoconazole then miconazole
Outcome
Antifungal therapy
Transmastoid antrectomy
Radical mastoidectomy and meatoplasty
Surgical therapy
Mycopathologia (2015) 180:257–264 261
123
Year of report (ref.)
2006 [17]
2007 [10]
2008 [9]
2008 [18]
2009 [19]
2009 [8]
Patient
8
123
9
10
11
12
13
75, man
No
Diabetes
Diabetes
65, female
72, male
Diabetes
No
No
Comorbidities
51, male
21, female
67, female
Age (years), gender
Table 1 continued
Bilateral tympanic membrane perforation, intermittent otorrhea and otalgia since 12 years. Trigeminal and facial nerves palsy since 3 weeks
Unilateral purulent otorrhea since 6 months, stenosis of the ECA
Unilateral otalgia and purulent otorrhea since years, pruritus, debris in the ECA
Unilateral otalgia and greenish otorrhea since a month, granulation tissue in the ECA
Unilateral otalgia and otorrhea and impaired hearing since 6 months, intracranial hypertension syndrome, hemiparesis, cerebellar syndrome
Recurrent unilateral intermittent otorrhea, acute abscess of conchal bowl and meatus with skin necrosis
Clinical features
Modified radical mastoidectomy for cholesteatoma with revision and cartilage graft tympanoplasty Mastoidectomy 8 years before (chronic suppurative otitis media)
No
Perichondritis
Cerebral dissemination: cerebello-pontin angle lesion, severe brainstem edema and erosion of petrous apex Osteolysis of temporal bone, mandibular condyle and pterygoid process
Cerebral dissemination
No
Surgical exploration of the mastoid
No
Death
Considered cured
Voriconazole four weeks Surgical excision of a bone fragment in the EAC No
Osteolysis of the petrous bone, ethmoidomaxillary sinusitis Mastoiditis
Considered cured
Voriconazole
Tympanosurgery
No
Considered cured
Death Amphotericin B and ketoconazole
Voriconazole 1 month
Healing with small postauricular fistula
Voriconazole 6 months
Incision and drainage of abscess
Neurosurgical treatment: ventriculoperitoneal shunt, craniectomy and resection of cerebellopontine lesion
Outcome
Antifungal therapy
Surgical therapy
Cholesteatoma
Negative (Gram staining)
Positive
Mycological direct examination
No
Facial nerves palsy
Involvement of soft tissues (parotid, muscle)
Potential local factor
Complication
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Considered cured No No
Positive
Topical econazole nitrate (10 weeks)
Considered cured Topical itraconazole No Positive No
Surgical therapy
apiospermum otomycosis [6, 20, 24–26] but are not sufficient to treat cases with bones and soft tissues involvement or cerebral dissemination. Surgical therapy has been performed in 11 of 14 cases described in this review. Surgical debridement is associated with the medical treatment in localized infections. Complete resection of infected tissues can be impossible, requiring repeated debridement and extended antifungal therapy. In our case, surgical treatment was not necessary due to favorable outcome under medical treatment alone. In conclusion, S. apiospermum is a ubiquitous soil fungus, rarely involved in otomycosis. It may be responsible for serious complications such as bone involvement or dissemination to the brain with a very poor prognosis. A mycological examination should always be performed in case of persistent external otitis despite antibiotic treatment or in otitis complicated with osteolysis to allow early diagnosis and appropriate antifungal therapy. Acknowledgments We thank Dr. Dea Garcia-Hermoso, National Reference Center for Mycoses and Antifungals (Institut Pasteur, Paris, France), for performing molecular identification. We thank Dr. P.L. Toubas for reviewing the manuscript.
None.
No Hypoacusia for 7 years, right purulent otorrhea for 4 years followed by left purulent otorrhea 6 month after first consultation. Inflammatory ECA No 2013 [26] 15
32, male
2011 [24] 14
37, male
No
Unilateral otalgia and otorrhea since 6 months, itching, debris in the ECA
No
Conflict of interest
Year of report (ref.)
Age (years), gender
263
Compliance with ethical standards
Patient
Table 1 continued
Comorbidities
Clinical features
Complication
Potential local factor
Mycological direct examination
Antifungal therapy
Outcome
Mycopathologia (2015) 180:257–264
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