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Background: Exophiala dermatitidis is a melanized fungus isolated from many environmental sources. Infections caused by Exophiala species are typically seen in immunocompromised hosts and manifest most commonly as cutaneous or subcutaneous disease. Systemic infections are exceedingly rare and associated with significant morbidity and mortality Case presentation: A 28-year-old female originally from India presented with fevers, chills, weight loss and increasing back pain. She had a recent diffuse maculopapular rash that resulted in skin biopsy and a tentative diagnosis of sarcoidosis, leading to administration of azathioprine and prednisone. An MRI of her spine revealed a large paraspinal abscess requiring surgical intervention and hardware placement. Cultures from the paraspinal abscess grew a colony of dark pigmented mold. Microscopy of the culture revealed a melanized fungus, identified as Exophiala dermatitidis. Voriconazole was initially utilized, but due to relapse of infection involving the right iliac crest and left proximal humerus, she received a prolonged course of amphotericin B and posaconazole in combination and required 7 separate surgical interventions. Prolonged disease stability following discontinuation of therapy was achieved. Conclusions: Described is the first identified case of disseminated Exophiala dermatitidis causing osteomyelitis and septic arthritis in a patient on immunosuppressive therapy. A positive outcome was achieved through aggressive surgical intervention and prolonged treatment with broad-spectrum antifungal agents. Keywords: Exophiala dermatitidis, Phaeohyphomycosis, Wangiella dermatitidis, Disseminated, Septic arthritis, Osteomyelitis Background including osteomyelitis and septic arthritis in a previously Exophiala dermatitidis is a melanized fungus isolated healthy 28-year-old female on immunosuppressive from many environmental sources . It is a saprobe, therapy. A positive outcome was achieved through aggres- using extracellular digestion to obtain nutrients from sive surgical intervention and prolonged treatment with dead or decaying organic matter [2, 3]. Infections caused broad-spectrum antifungal agents. by Exophiala species are known as phaeohyphomycosis, due to the appearance of dark pigmented, irregular Case presentation branching, septate hyphae [1–5]. Infections are typically A previously healthy 28-year-old female presented with seen in immunocompromised hosts such as transplant complaints of increasing back pain and fevers. Originally recipients and manifest as subcutaneous disease [6, 7]. from India, she had immigrated to Canada two years Systemic infections are rare and associated with signifi- prior and within months of arrival, developed fevers cant morbidity and mortality [5, 8, 9]. associated with unintentional weight loss, and a diffuse We describe, to our knowledge, the first case of rash localized to her torso, legs and scalp. The rash was disseminated E. dermatitidis with widespread involvement annular, with dark-colored plaques and central clearing. Skin biopsy identified granulomatous inflammatory cell infiltrates with staining negative for mycobacteria and * Correspondence: email@example.com Division of Infectious Diseases, Department of Medicine, University of fungus. A diagnosis of sarcoidosis was suggested. The Saskatchewan, Regina, Saskatchewan, Canada lesions resolved spontaneously within six months with 4E - ID Clinic, Regina General Hospital, 1440 14th Avenue Regina, Regina, no specific therapy, but her fevers and weight loss Saskatchewan, Canada Full list of author information is available at the end of the article continued. © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lang et al. BMC Infectious Diseases (2018) 18:255 Page 2 of 5 The patient elected to return to India for further in- the yeast-like elements identified in the lung nodule vestigations and treatment of her ongoing symptoms. biopsy. Diffuse lymphadenopathy was identified and an inguinal Histopathology from the paravertebral collection lymph node biopsy revealed non-caseating granuloma- returned positive for yeast-like cells on PAS and GMS tous changes. Mycobacterial and fungal stains were staining, suggestive of histoplasmosis. Bacterial cultures, negative. Brucella IgM and IgG serology were positive, originally submitted for Brucella, were found to be but serum agglutination testing (SAT) to detect anti- growing a colony of dark pigmented mold. Microscopy bodies against the smooth lipopolysaccharide (S-LPS) of revealed numerous oval shaped conidia with rectangular the outer membrane was negative. While in India, she phialides in keeping with a melanized fungus, identified received empiric treatment for tuberculosis and brucel- as Exophiala species (Fig. 1). Fontana Masson staining losis with isoniazid, rifampin, pyrazinamide, ethambutol confirmed the presence of pigmented fungi in original and injectable streptomycin. After nearly eight weeks of pathology specimens (Fig. 2). Voriconazole was added therapy, she experienced no clinical change. Her antimi- empirically and liposomal amphotericin B was continued. crobials were discontinued, and she was started on high The patient developed progressive pain in her left shoulder dose prednisone with rapid resolution of her malaise and right SI joint. MRI of the pelvis revealed progression of and fevers. She returned to Canada with a presumptive an osteolytic lesion in the right iliac crest and fluid accumu- diagnosis of sarcoidosis on hydroxychloroquine, azathio- lation in the right sacro-iliac joint. Her therapy was chan- prine, and tapering prednisone initiating at 40 mg daily. ged from voriconazole to posaconazole empirically at Shortly after her return, the patient developed a large 300 mg IV daily given her ongoing disease progression. nodule on her back with progressive back pain, worsen- Multiple operative cultures and the BAL sample ing left arm pain, and ongoing fevers. She was admitted became positive for dark pigmented mold. Sequencing to hospital for further testing. Hepatosplenomegaly was of the D1-D2 region of the large (28S) ribosomal subunit noted with no appreciable lymphadenopathy. A tender of the isolate resulted in 98.6% similarity to Exophiala mass was identified medial to her left scapula. She had dermatitidis, confirming a diagnosis of Exophiala no focal neurologic deficits and the remainder of her dermatitidis . Susceptibility testing results are listed physical exam was non-contributory. in Table 1. Due to local availability of oral antifungals, Investigations revealed a white blood cell (WBC) posaconazole was changed to oral voriconazole 200 mg count of 14.3 × 10 per liter (L) and a platelet count of PO, and liposomal amphotericin B was discontinued 885 × 10 /L. Her liver enzymes and creatinine kinase following one month of combination therapy given the were within normal limits. Computed tomographic (CT) patient had experienced significant clinical improve- scanning of the spine showed a large heterogeneously ment. Prior to discharge from hospital, a trough vorico- attenuating area in the paraspinal tissue at the level of nazole level was found to be therapeutic at 2.99 mcg/mL T3-T4 along with a large nodule in the left upper lung. (target range 2–5 mcg/mL). Bone scan revealed abnormalities in the thoracic spine Three weeks following discharge, she again presented with increased uptake in the right sacroiliac (SI) joint. with an enlarging mass over her left shoulder blade and The differential diagnosis included sarcoidosis, tubercu- ultrasound revealed a thick-walled hyper-dense lesion. A losis, brucellosis, and disseminated fungal infection. Further investigations were pursued to identify the causal etiology. The lung nodule was biopsied and smear-negative for acid-fast bacilli, and culture negative for fungus, bacteria, and mycobacteria. Histopathology reported caseating granulomas and fungal elements resembling budding yeast. A CT scan of her head revealed no abnormalities. Bronchoalveolar lavage (BAL) was performed. Mycobac- terium tuberculosis complex polymerase chain reaction (PCR) and mycobacterial cultures were negative. Magnetic resonance imaging (MRI) revealed a large soft tissue mass at the spinal levels of T3-T5. Incision and drainage of this large paraspinal abscess was performed, along with a laminectomy at T4 and T5 with rod and pedicle screw placement due to involvement of the Fig. 1 Exophiala dermatitidis isolated from surgically debrided adjacent vertebral bodies. Liposomal amphotericin B was paravertebral tissue. Lactofuchsin mount, 400X started empirically, as the only etiologic clue remained Lang et al. BMC Infectious Diseases (2018) 18:255 Page 3 of 5 Fig. 2 a, b Fungal elements visualized in surgically debrided paravertebral tissue, identified from culture as Exophiala dermatitidis. H&E staining, 400X. c, d Fungal elements visualized in surgically debrided paravertebral tissue, identified from culture as Exophiala dermatitidis. Fontana-Masson stain, 400X spontaneously draining sinus from her thoracolumbar remained on posaconazole and liposomal amphotericin incision was noted. Repeat MRI of her spine and pelvis B throughout hospitalization and received a six-week revealed a bone marrow signal in the right iliac region course of combination therapy. In total, she required 7 (7.4 × 2.8 cm) and large peripherally enhancing fluid col- surgical interventions. lections extending bilaterally down the spine, enveloping Two weeks following discharge, liposomal amphoteri- the spinal hardware. She was readmitted for irrigation cin B was discontinued, and posaconazole was continued and debridement of these collections. Voriconazole was at 400 mg orally once daily. After receiving nearly discontinued, and combination therapy with liposomal 500 days of antifungal therapy following her last surgery, amphotericin B 200 mg IV daily and posaconazole with no clinical evidence of infection and normalized lab 300 mg IV daily was resumed. parameters, her posaconazole was discontinued. Over She continued to have daily fevers with worsening pain 1.5 years following discontinuation of antifungal therapy, and effusion of her left shoulder. MRI demonstrated dra- she remains disease free with normalized inflammatory matic changes suggestive of a highly aggressive process markers and continues to be followed closely by the involving the right iliac crest and left proximal humerus. infectious disease team. She has successfully received a Her spinal hardware was removed and the surrounding shoulder prosthesis to regain significant function in her area extensively debrided along with an excisional left arm. arthroplasty of the left shoulder. Operative cultures remained negative despite extended incubation. She Discussion and conclusions Several different species of Exophiala have been docu- Table 1 Antifungal Susceptibility Testing of Exophiala mented, with E. dermatitidis being known to cause cuta- dermatitidis isolate neous and subcutaneous phaeohyphomycosis . Antifungal MIC (mg/L) Systemic infections are rare with an extensive literature 5-Flucytosine 0.12 review in 2013 documenting 40 cases [5, 8, 9]. Despite identification of E. dermatitidis in environmental sam- Amphotericin B 0.5 ples globally, disseminated human infection is extremely Itraconazole 0.25 rare in North America and nearly all cases are reported Posaconazole 0.12 from Asia [7, 9]. Environmental samples have been Voriconazole 0.12 noted in abundance in public steam baths, and water Lang et al. BMC Infectious Diseases (2018) 18:255 Page 4 of 5 reservoirs, which may relate to the geographic differ- drug susceptibilities to E. dermatitidis and noted that the ences in infection . In this case, it is believed that MICs were similar between environmental and clinical the patient contracted the infection while residing in strains of the organism as well as isolates from Asia, Amer- India. Extra-cutaneous manifestations include lymph- ica and Europe . The lowest MICs were observed to adenitis, fungemia, cerebral infections, stomatitis, otitis posaconazole and itraconazole followed by voriconazole media, corneal ulcers, esophagitis, pneumonia, liver cirrho- [15, 16]. Fluconazole and amphotericin B appear to have sis, pancreatitis, inflammation of the gastrointestinal and poor activity against E. dermatitidis [2, 14, 16]. biliary systems, endocarditis and peritonitis [2, 4, 9, 12]. Li Combination therapy of caspofungin with voriconazole, et al. published a case series of seven fatal Exophiala sp. in- amphotericin or itraconazole may facilitate synergistic fections in China, two of which had bone involvement, activity against E. dermatitidis, although monotherapy however speciation revealed Exophiala spinifera as the with an echinocandin is not recommended [14, 16]. Both etiologic agent . E. dermatitidis has not previously been voriconazole and posaconazole have good cerebral pene- documented to cause bone or joint involvement. tration, ideal for treating disseminated infections. There is Of all reported cases, approximately 70% have an identi- limited data regarding the in vivo efficacy of antifungal fiable underlying risk factor such as an underlying im- therapy and there are no defined breakpoints available for munocompromised state, intravenous drug use, long-term antifungal agents . In deep-seated infections, catheters, malignancy or cystic fibrosis [1, 9]. Case reports long-term survival has only been reported when complete reveal that patients often present with hepatomegaly and surgical resection is obtained, however prognosis remains lymphadenopathy [3, 5, 7]. Biopsies of liver and lymph poor [15, 17]. The decision to discontinue therapy was nodes frequently show granulomas, which may lead to an based on demonstrated clinical stability, normalized lab early misdiagnosis of sarcoidosis, lymphoma or tubercu- parameters, expert opinion, and extensive discussion with losis [2, 3]. the patient and her immediate family members. Most infections initially involve the skin and are sus- pected to spread hematogenously . The initial skin le- Key messages sions our patient presented with may have represented cutaneous or subcutaneous fungal infection. Several case 1) Described is the first identified case of reports have described patients being diagnosed with disseminated Exophiala dermatitidis causing tinea versicolor prior to dissemination with E. dermatiti- osteomyelitis and septic arthritis in a patient on dis, leading to the belief that inoculation occurred ini- immunosuppressive therapy. tially through the skin [3–5]. Since initial biopsies 2) Exophiala dermatitidis is a dematiaceous fungus revealed non-specific granulomatous changes, empiric isolated from environmental sources. steroids and immunosuppressive agents initiated for sar- 3) Systemic infections are very rarely caused by E. coidosis may have facilitated further dissemination of dermatitidis, however when present are associated the organism. with significant morbidity and mortality. E. dermatitidis grows slowly and appears only after 4) Exophiala dermatitidis grows slowly and therefore prolonged incubation of up to seven days, with one fungal cultures need to be held for prolonged study suggesting cultures be held for at least four weeks incubation or the organism may be missed. [2, 14]. The organism may be missed if fungal cultures 5) Through aggressive surgical intervention and are not performed. Accurate identification of Exophiala prolonged antifungal therapy, a positive outcome may species is enabled by molecular diagnostics involving se- be achieved in disseminated E. dermatitidis infections. quencing of the internal transcribed space (ITS) region of the ribosomal DNA . Abbreviations A review of 20 disseminated infections from 1960 to BAL: Bronchoalveolar lavage; CT: Computed tomography; GMS: Grocott’s 1992 revealed a mortality rate of 48%, however a subse- methenamine silver stain; ITS: Internal transcribed space; MIC: Minimum inhibitory concentration; MRI: Magnetic resonance imaging; PAS: Periodic quent review between 1993 and 2011 based on 24 cases acid-Schiff stain; PCR: Polymerase chain reaction; SAT: Serum agglutination revealed a mortality rate of 25% [1, 5]. Improved out- testing; SI: Sacroiliac joint; S-LPS: Smooth lipopolysaccharide comes are believed to be due to the availability of im- proved antifungal therapies. If CNS involvement Acknowledgements develops, the survival rate is 20% . We would like to thank Dr. Tanis Dingle and the mycology department of the Provincial Laboratory for Public Health in Edmonton, Alberta, Canada for No large-scale controlled analyses of treatment options providing susceptibility testing and confirmatory identification. are available. Amphotericin B, flucytosine, itraconazole, voriconazole and posaconazole have all been used with Availability of data and materials varying degrees of success [2, 15]. In 2011, Badali et al. Data sharing is not applicable to this article as no datasets were generated performed a study comparing 11 different antifungal or analyzed during the current study. Lang et al. BMC Infectious Diseases (2018) 18:255 Page 5 of 5 Authors’ contributions 12. Gold WL, Vellend H, Salit IE, Campbell I, Summerbell R, Rinaldi M, et al. RL was involved in the literature review, planning and writing of the Successful treatment of systemic and local infections due to Exophiala manuscript. JM was the medical microbiologist who performed the species. Clin Infect Dis. 1994;19:339–41. microbiological analysis of this case. SS was involved in patient care as well 13. Li DM, Li RY, de Hoog GS, Sudhadham M, Wang DL. Fatal Exophiala infections as reviewing the manuscript. AW was the lead physician involved in patient in China, with a report of seven cases. Mycoses. 2011;54(4):e136–42. care as well as planning, writing and reviewing the manuscript. All authors 14. Horre R, Schaal KP, Siekmeier R, Sterzik B, de Hoog GS, Schnitzler N. Isolation read and approved the final manuscript. of fungi, especially Exophiala dermatitidis, in patients suffering from cystic fibrosis. A prospective Study. Respiration. 2004;71(4):360–6. Ethics approval and consent to participate 15. Sun Y, Liu W, Wan Z, Wang X, Li R. Antifungal activity of antifungal drugs, as Not applicable. well as drug combinations against Exophiala dermatitidis. Mycopathologia. 2011;171(2):111–7. Consent for publication 16. Badali H, De Hoog GS, Sudhadham M, Meis JF. Microdilution in vitro Written informed consent was obtained from the patient for publication of antifungal susceptibility of Exophiala dermatitidis a systemic opportunist. this case report and any accompanying images. A copy of the written Med Mycol. 2011;49(8):819–24. consent is available for review by the Editor of this journal. 17. Zheng JS, Sutton DA, Fothergill AW, Rinaldi MG, Harrack MJ, de Hoog GS. Spectrum of clinically relevant Exophiala species in the United States. J Clin Competing interests Microbiol. 2007;45(11):3713–20. The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Department of Medicine, University of Calgary, Calgary, Alberta, Canada. Regina Qu’Appelle Health Region, Department of Laboratory Medicine, University of Saskatchewan, College of Medicine, Regina, Saskatchewan, Canada. Division of Infectious Diseases, Department of Medicine, University of Saskatchewan, Regina, Saskatchewan, Canada. 4E - ID Clinic, Regina General Hospital, 1440 14th Avenue Regina, Regina, Saskatchewan, Canada. Received: 14 March 2018 Accepted: 28 May 2018 References 1. Suzuki K, Nakamura A, Fujieda A, Nakase K, Katayama N. Pulmonary infection caused by Exophiala dermatitidis in a patient with multiple myeloma: A case report and a review of the literature. Med Mycol Case Rep. 2012;1:95–8. 2. Alabaz D, Kibar F, Arikan S, Sancak B, Celik U, Aksaray N, et al. Systemic phaeohyphomycosis due to Exophiala (Wangiella) in an immunocompetent child. Med Mycol. 2009;47(6):653–7. 3. Oztas E, Odemis B, Kekilli M, Kurt M, Dinc BM, Parlak E, et al. 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