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ABSTRACT Curvulatia is a saprobic dematiaceous mold that has been associated with a wide spectrum of human infection. In non-immunosuppressed patients, infec- tions frequently involve the paranasal sinus, skin, and soft tissue, whereas mternic dissemination and endocarditis are extremely rare. The optimal antifun- gal therapy for Curvularia infection is not known, and responses to treatment with arnphotericin 6, miconazole, keto- conazole, terbinafine, and itraconatole have been reported. We describe a patient with an invasive dematiaceous fungal sinusitis who was immunocompe- tent and was infected with curvu/eri8. The patient was successfully treated with oral itraconazole by otolaryngology and the infectious disease service.

Chronic craniofacial dematiaceous fungal infection: A case report Kishore Shetty, DDS, MS, MRCS;” Peter Giannini, DDS, MS;2 Ronald Achong, DDS, MD3 lMedically Complex Patient Clinic, Department of Restorative Dentistry, The University of Texas Dental Branch at Houston; ’University of Nebraska Medical Center College of Dentistry, Lincoln, Nebraska; 3Private Practice limited to Oral and Maxillofacial Surgery, Orlando, Florida. *Corresponding author: kishore.shetty@uth.tmc.edu

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I n t r o d u c t i o n Dematiaceous fungi or those that contain melanin cause chromoblastomycosis, phaeo- hyphomycosis, and eumycetoma.’ Phaeohyphomycosis refers to a wide range of infections caused by dematiaceous fungi that, in tissue, produce hyphae, pseudohy- phae, or yeastlike elements.2 More than 100 genera of fungi cause phaeohyphomycosis. The most common fungi within the dematiaceous genera include: Exophiala, Cuwularia, Bipolaris, Exserohilum, Coelomycetes, and Alternaria. Although Cuwularia species are predominantly found on plants and numerous substrata worldwide, they are also frequent human pathogen^.^ There are about 40 known species of Curvularia. Some of the more commonly isolated human pathogenic species of Cuwularia include C lunata, C senegalensis, Cfallax, and C verucufosa.’ Cuwularia infection most often occurs during hot and humid weather. Cuwularia is a saprobic dematiaceous mold that has been associated with a wide spectrum of human disease. In immunocompetent patients, infections frequently involve the paranasal sinus, skin, and soft tissue, whereas systemic dissemination and endocarditis are extremely rare5 Most cases of Cuwularia infection in immunocompetent patients present in a noninvasive fashion as an allergic fungal sinusitis. Most of these cases can be successfully treated with debridement and aeration of the involved sinusesb The disease may be disseminated viscerally in the immunocompromised patient and sites of involvement have included the lower respiratory tract, skin and subcutaneous tissue, paranasal sinus, nasal septum, and cornea.’f The typical portal of entry of this fungus is either local implanta- tion following trauma with vegetable matter or inhalationy

Since invasive Cuwularia infection is extremely rare, no specific therapeutic guidelines are available in the literature to date.Io There is a lack of standardized testing of antifungal agents. Furthermore, it has been observed that the response of this fungus to antifungal agents differs in vivo and in vitro.” In vitro studies have shown that the fungus is susceptible to amphotericin B, micona- zole, ketoconazole, and itraconazole only in high concentrations.” However, failure

with these drugs has also been reported, even with high dosages1 Not only can such high drug concentrations cause complications, including decreased renal function (with amphotericin B) and thrombophlebitis (with intravenous miconazole), but the Cuwularia infection can recur even after apparent initial suc- cess with drug therapy.” Hence, the definitive treatment consists of early and complete surgical removal of diseased tissue and antifungal drug therapy.I3

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Locally invasive Curvularia has been suc- cessfully treated with oral itraconazole. In 2003, Safdar" documented successful treatment approaches with itraconazole in two patients. One such patient was a 41-year-old Caucasian male who was undergoing treatment for lymphocytic lymphoma. Another patient was an oth- erwise healthy 59-year-old Caucasian male whose chief complaint was recur- rent allergic rhinosinusitis. Initially treatment was instituted with terbinafine. The patient's symptoms progressed which led to the discontinuation of terbinafine and the addition of oral itra- conazole with complete resolution in two months. Regardless of the therapy, long- term observation is necessary to detect possible recurrences or dissemination. In this paper we describe the problems and treatment of an immunocompetent patient infected with Curvulavia.

C a s e R e p o r t A 48-year-old African-American male was referred to the oral and maxillofacial surgery clinic at the Medical Center of New Orleans for facial ulcerations he had been exhibiting for four to five months. He also reported nasal congestion, poste- rior nasal drainage, and fatigue. The patient had been prescribed multiple antibiotics (clarithromycin, cefuroxime and amoxicillidclavulanic acid) by his primary care physician with no resolu- tion of the lesions. A physical examination identified generalized facial ulceration and crusting throughout the lower and middle face extending superi- orly to the nasal dorsum and the infra-orbital region (Figure 1). Laterally, the pretragal regions were involved with extension along the inferior border of the mandible bilaterally connecting at the midline. The nasal alar base was edema- tous and widened; however, the nasal passages were clear with mild erythema of the inferior turbinates. No ulcerations or masses were noted intranasally. The nasolabial folds were blunted with marked edema of the upper and lower lips. Crusted ulcerations extended into the labial mucosa. Neurological examina- tion showed cranial nerves 2 to 12 were

Figure 1. Generalized facial ulceration and crusting throughout the lower and middle face on a patient with Curvu/aria.

Figure 2. An ulcerative lesion on the hard palate, sized 0.5 X 0.5 cm.

intact. The patient's fundi and visual fields were normal. Corneal sensation was intact. The external auditory canal was normal and hearing was preserved. There were no cerebellar deficits. The patient reported tenderness bilaterally over the maxillary sinuses. An intraoral examination established that the patient had poor oral hygiene with generalized periodontitis. There was no evidence of caries, purulence, or masses. Ulcerations were noted on the hard palate (0.8 cm x 0.5 cm); however, there was no commu- nication into the nasal floor (Figure 2). The posterior pharynx was without apparent pathology and the submandibu-

Figure 3. A C T scan of the face showed bilat- eral opacification of the maxillary sinuses. There was diffuse soft tissue swelling of the mid and lower face with bony destruction of the lat- eral wall of the maxillary sinus and the palate.

Figure 4. An MRI sagittal view of the head reveals mucosal thickening and obliteration of the maxillary sinuses. There was soft tissue edema in the lower and middle face.

lar and parotid ducts were patent bilater- ally. No lymphadenopathy was noted in the head and neck region. The remainder of the physical examination was unre- markable. The patient's vital signs were within normal limits, and he was afebrile. On questioning, the patient reported a past medical history of hypothyroidism, deep venous thrombosis of the right leg, Cuwulavia infection of

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Figure 5. Septate hyphae of Curvularia organ- ism stained with GMS (4OOX).

the left turbinate, and anemia. The patient was allergic to tetracycline and metronidazole. He denied any drug, tobacco, or alcohol abuse. The patient was evaluated and found not to have dia- betes. A Western blot and polymerase chain reaction (PCR) tests for Human Immunodeficiency Virus (HIV) were negative. A tuberculin purified protein derivative (PPD) test for tuberculosis was also negative. His white blood cell count was 19.8 (granulocytes 79%, lympho- cytes 13%, monocytes 7% and eosinophils 1%). Electrolytes, blood glu- cose level, hematocrit, platelet count, liver function tests, and albumin levels were all within normal limits. An evalua- tion of a computed tomography scan of the face showed bilateral opacification of the maxillary sinuses. There was diffuse soft tissue swelling of the mid and lower face with bony destruction of the lateral wall of the maxillary sinus and palate (Figure 3 ) . An evaluation of a Sagittal Magnetic Resonance Imaging (MRI) of the head revealed mucosal thickening and obliteration of the maxillary sinuses. There was soft tissue edema in the lower and middle face (Figure 4). No masses or lesions were noted on the chest radi- ograph. Chest auscultation was normal.

Thus, clinical and radiographic evi- dence showed extensive disease in the maxillary sinus and the dermis of the face. Subsequently, the patient under- went endoscopic surgery of the maxillary sinus and incisional biopsies of the facial dermis. Histological evaluation of the sinus contents showed prominent intra- mucosal septate hyphae, with dark brown pigments in the hyphal cell wall. Both Gomori‘s methenamine silver

Figure 6. Septate hyphae of Curvularia organ- ism stained with PAS (4OOX).

(GMS) and periodic acid-Schiff (PAS) stains were utilized to identify the dema- tiaceous fungal organisms (Sigma-Aldrich: St. Louis, Missouri, USA, http://www.sigmaaldrich. corn). Evaluation of hematoxilyn and eosin (HQE) stained specimens revealed multi- ple granulomas in the dermal tissues. Fungal organisms were also visible within the multinucleated giant cells. The septate fungal hyphae were better visualized with the GMS and PAS stains where multiple Cuwularia organisms were visible within the connective tissue (Figures 5 and 6). Confirmation of the diagnosis of Cuwularia was achieved by culturing the organism on Sabouraud dextrose agar (Newcomer Supply: Middleton, Wisc., USA, http://www.new- comersupply.com). Blood cultures for fungi were negative. IgG and IgM levels were within normal range.

aid of otolaryngology and infectious dis- ease medical services. Extensive surgical debridement was carried out by remov- ing all necrotic material from the maxillary sinuses and the dermis of the face. Intravenous amphotericin B treat- ment was begun (1.0 mg/kg per day) but the patient’s symptoms continued to progress. Amphotericin B was subse- quently discontinued after six weeks of therapy, and treatment with oral itra- conazole was initiated (600 mg daily for one week and then 400 mg daily). Four weeks after commencing itraconazole therapy, the patient reported slight improvement in his symptoms and was scheduled for facial reconstruction in the maxillofacial surgery clinic but did not show up for scheduled visits. The infec-

The patient was managed with the

tious disease clinic subsequently lost track of the patient following Hurricane Katrina. The New Orleans hospital was extensively damaged during the hurri- cane and remains closed.

Discussion Several case histories of invasive Cuwularia infection have been previously reported in immunocompetent patients. One patient15 presented as a necrotizing cellulitis on the anterior region of both thighs in a 58-year-old male patient. The infection involved the subcutaneous adi- pose and fascia, and was ultimately successfully treated with surgical debride- ment and intravenous amphotericin B. Another person16 with an invasive Cuwularia infection presented as sinusitis in a 46-year-old female with additional erosion of the cribiform plate and bifrontal cerebritis. This patient was suc- cessfully treated with amphotericin B and itraconazole. A similar report” of a person with invasive Curvularia infection occurred in a 46-year-old female patient who presented with similar symptoms as an invasive sinusitis with intracranial extension. The isolated species in this patient was Curvularia lunata. The patient initially reported with a chief complaint of a sudden onset of recurrent diplopia. She was treated with surgical debride- ment, as well as intravenous amphotericin B, and oral ketoconazole. A more recent example of invasive Curvularia infection was reported in an otherwise healthy 26-year-old male who presented with a slowly growing forehead mass. The initial clinical impression was that of an epidermoid cyst. Upon further examination, a diagnosis of eosinophilic fungal rhinosinusitis was made, which on further investigation was due to Curvularia lunata. The process initially involved the frontal sinus but also extended to the right frontal calvarium with displacement of the frontal lobe pos- teriorly. In addition, there was involvement of the ethmoid and maxil- lary sinuses along with the nasal cavity. The patient was successfully treated with surgery and itraconazole.lR

The first case of Curvularia in

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humans was reported in the cornea of the eye.’’ The most frequent etiology for ocular infections is trauma.” Cuwularia species are the most common form of fungal keratitis among the dematiaceous family.L’ ’’ Most patients who have ocular keratitis due to Curvularia are success- fully treated with topical natamycin. Oral ketoconazole or itraconazole are added for more severe infections of keratitis.’? An unusual presentation of fungal kerati- tis as a result of Curvularia followed a laser-assisted in situ keratomileusis (LASIK) procedure. This particular infec- tion was traced to a fungal skin infection due to the patient’s cat. The infection was treated with topical natamycin, cefazolin, and scopolamine.2i Although ocular Curvularia infection most often affects the cornea, two unusual case reports of infection with Curvularia localized to the lacrimal sac have also been described. Both of the patients were not immuno- compromised.’6 All previously reported infections by ocular mycosis as a result of Cuwularia have occurred in the cornea. Both patients were successfully treated with oral fluconazole.

In this paper we present a patient who had an unusual chronic invasive craniofacial dematiaceous fungal infec- tion and who was immunocompetent. To treat this form of aggressive disease, cli- nicians must rely on the results of empirical data so that they can provide optimal therapy for management and prevent future recurrence. Our patient was ultimately successfully managed with oral itraconazole therapy.

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