Curvularia—favorable response to oral itraconazole therapy in two patients with locally invasive phaeohyphomycosis

Authors

  • A. Safdar

    1. Department of Infectious Diseases, Infection Control and Employee Health, 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4095, USA
      Tel: +1 713 742 0825
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      E-mail: asafdar@mdanderson.org
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Abstract

Curvularia species are ubiquitous and occasionally lead to infections in humans. In immunosuppressed patients, infections are often serious, and systemic dissemination is not uncommon. The optimal antifungal therapy is unclear. I here present two cases, a healthy man with locally invasive, mulicentric paranasal fungal sinusitis, and a case of progressive verrucal distal onychomycosis that developed while the patient was undergoing accelerated chemotherapy for non-Hodgkin's lymphoma. Both patients showed excellent responses to treatment with itraconazole suspension. Oral itraconazole may provide a safe and effective alternative for patients with locally invasive non-disseminated mycoses due to Curvularia species.

Cases of phaeohyphomycosis due to dark-pigmented filamentous fungi such as Alternaria, Bipolaris, Curvularia, Exophiala and Scedosporium prolificans are increasing in frequency [1–3], especially in patients with severe immune dysfunction [4,5]. Curvularia is a saprobic dematiaceous mold that has been associated with a wide spectrum of human infection [1,2]. In non-immunosuppressed patients, infections frequently involve the paranasal sinus [6,7], skin and soft tissue [8,9], whereas systemic dissemination [10] and endocarditis are extremely rare [11]. The optimal antifungal therapy for curvularia infection is not known, and responses to treatment with amphotericin B, miconazole, ketoconazole, terbinafine and itraconazole have been reported [1,11,12].

In the two patients presented, excellent clinical and microbiological responses to oral itraconazole were observed for locally invasive, non-disseminated curvularia infection.

The first case involves a 41-year-old caucasian man, while undergoing accelerated chemotherapy for stage III-A nodular, poorly differentiated lymphocytic lymphoma, presented with a left great toe lesion that had been gradually progressive for ∼18 months. His symptoms commenced during the second cycle of chemotherapy, which consisted of fludarabine, mitoxantrone, dexamethasone and rituxan. Invasive distal tinea unguium with a granulomatous frail, pink verrucous excrescence was noticed on examination (Figure 1). Laboratory studies showed: a white blood cell count of 2000/µL, a platelet count of 188 000/µL, and a blood glucose level of 98 mg/dL. Serum lactic dehydrogenase, aminotransferase and chest radiograph results were normal. Blood cultures were sterile. A Curvularia species was isolated from the biopsy sample.

Figure 1.

Invasive tinea unguium involving the distal great toe in patient 1 prior to initiation of oral itraconazole therapy. A granulomatous frail, pink verrucous excrescence can be seen at the distal nail bed (inset).

Serum itraconazole and hydroxyitraconazole levels were maintained between 3.3 and 4.6 µg/mL, and 3.5 and 4.0 µg/mL, respectively. The patient tolerated a 400-mg daily dose of oral itraconazole suspension without untoward effects. Treatment with interferon-α (3 million units daily for 14 days/month) was continued. The infected verrucous lesion resolved completely after 12 weeks of therapy, and was replaced by normal toenail within 6 months after the start of antifungal therapy. Treatment was continued for 12 months. No recurrence was observed after itraconazole was discontinued.

The second case involves a 59-year-old caucasian man who had experienced recurring corticosteroid-responsive allergic rhinosinusitis over the preceding 2 years and who presented with frontal and facial pain, nasal congestion, posterior nasal drainage and progressive fatigue. He showed no response to clarithromycin, amoxycillin–clavulanic acid, moxifloxacin and cefuroxime axetil, and during these 3 months his symptoms progressed. On examination, the patient was afebrile with modest discomfort, and had minimal maxillary sinus and frontal sinus tenderness. Chest auscultation was normal. Laboratory studies showed: a white blood cell count of 5200/µL, a platelet count of 238 000/µL, and a blood glucose level of 91 mg/dL. Serum lactic dehydrogenese, aminotransferase and chest radiograph results were normal.

Owing to clinical and radiographic evidence of extensive paranasal sinus disease (Figure 2), the patient underwent endoscopic surgery. Histologic examination of the left ethamoid sinus contents showed prominent intramucosal septate hyphae, with dark brown pigments in the hyphal cell wall (Figure 3). Treatment with terbinafine (250 mg daily) was initiated after Curvularia lunata was identified. The antimicrobial susceptibility (MIC values) was determined at the University of Texas Health Science Center at San Antonio, according to the guidelines of the National Committee for Clinical Laboratory Standards [13]. The MIC values, determined at two intervals (48 and 72 h after incubation, respectively), were as follows: for amphotericin B, 0.25 and 0.5 mg/L; for ketoconazole, 2.0 and 2.0 mg/L; for terbinafine, 0.015 and 0.03 mg/L; for itraconazole, 0.5 and 1.0 mg/L; for voriconazole/UK-109,496, 2.0 and 4.0 mg/L; for ravuconazole/BMS-207147, 0.5 and 4.0 mg/L; for posaconazole/SCH-56592, 0.125 and 0.25 mg/L; and for caspofungin/MK-0991, <0.125 and <0.125 mg/L.

Figure 2.

Computed tomography scan of the paranasal sinus prior to antifungal therapy in patient 2. There is near-complete opacification of the left frontal sinus, and the right sinus mucosa shows signs of inflammation (top panel, arrows). In the middle panel, the left sphenoid sinus shows prominent signs of inflammation, compared to the right sinus (arrowhead). Similarly, the bottom panel shows bilateral maxillary sinus involvement with marked mucosal edema and thickening (arrows).

Figure 3.

Histologic examination of ethamoid sinus mucosa (Gomori's methenamine–silver (GMS) stain ×100; H&E ×400, inset). Prominent intramucosal septate, branching hyphal forms are seen that are indistinguishable from invasive hyalohyphomycosis in the GMS-stained sample. The arrowheads indicate dark-pigmented hyphae within the sinus mucosa on H&E stain, suggesting invasive phaeohyphomycosis (inset).

The patient's symptoms continued to progress, terbinafine was discontinued after nearly 8 weeks of therapy, and treatment with oral itraconazole suspension was initiated (600 mg daily for 5 days, and then 400 mg daily). Itraconazole and hydroxyitraconazole blood levels were maintained between 2.2 and 2.8 µg/mL, and 3.6 and 3.8 µg/mL, respectively. Serum transaminase levels remained stable. Four weeks after itraconazole was given, the patient's symptoms improved significantly, and symptoms resolved completely after 2 months of therapy. His energy levels gradually returned to normal.

In recent years, the incidence of systemic infections due to dematiaceous molds has risen significantly. Treatment of serious invasive mycoses, especially in the immunocompromised patient, remains a daunting task, as optimal systemic antifungal therapy has not been established [1,14]. Itraconazole has been found to be effective in most cases of non-systemic Alternaria species infections, including onychomycosis [15], disseminated and/or non-disseminated cutaneous infection [16], and non-invasive allergic fungal sinusitis [17]. A clinical response to itraconazole in patients with non-mycotic keratitis due to Curvularia species [18] is not certain. The prompt and durable responses in these two patients show the potential of treatment with oral itraconazole suspension, although it is critical to emphasize the significance of monitoring serum drug concentrations to prevent treatment failures due to suboptimal itraconazole gastrointestinal absorption.

Curvularia is the third most prevalent cause of fungal keratitis in certain regions of the USA [19]. Curvularia species are also the most common dematiaceous molds isolated from patients with corneal phaeohyphomycosis [19,20]. Nail and nail bed fungal infection are common, and dematiaceous molds are occasionally encountered; onychomycoses in this setting often involve the distal nail bed and are generally confined to a single digit, as in the case of patient 1 [21]. Black discoloration of the involved nail may suggest dematiaceous fungal infection [22], although the absence of discoloration does not eliminate the possibility of infection due to dark-pigmented fungi (patient 1; Figure 1). The verrucal curvularia onychomycosis was unusual, and this hypertrophic, locally invasive fungal infection was probably due to the host's suboptimal cellular immune response.

Curvularia species, along with other environmental molds, promote hypersensitivity disorders of the respiratory tract, especially allergic rhinosinusital disease [17,23,24]. Colonization of the tracheobronchial passages and sinus cavities serves as an endogenous supply of allergens, leading to recurring or persistent hypersensitivity responses in the susceptible individuals. In most instances, the microorganisms do not invade the mucosal surface, and antifungal therapy is usually not recommended. However, infrequently, colonizing fungi may invade the host's mucosal barriers, even in patients with no known immune defects other than systemic corticosteroid use (patient 2). Radiologically (Figure 2), fungal infections are difficult to distinguish from bacterial sinusitis, and patients often receive extended courses of broad-spectrum antibiotics before definitive histologic diagnosis is pursued, as in the case of patient 2 (Figure 3). Intrasinusital mycoses may extend to the contiguous structures, such as the orbital contents, which is an immediate threat and may cause permanent loss of vision; intracranial extension is a grave, life-threatening consequence, and cavernous sinus thrombosis and/or fungal brain abscess are often refractory to medical and/or surgical intervention [6,7,25,26]. Sinus infections may also gain intracranial access by perineural extension along the nerve sheet, and patients in this setting present with isolated, non-contiguous cranial nerve paralysis distal from the site of primary infection [26]. Treatment of locally invasive phaeohyphomycosis is often less challenging, and infections frequently respond to a wide range of antifungal agents [1]. In fact, prompt surgical debridement and sinus irrigation alone has been effective in some cases of fungal sinusitis [27]. In conclusion, oral itraconazole suspension was associated with optimal blood levels, it was tolerated without untoward effects, and satisfactory clinical resolution in these patients was encouraging. Oral itraconazole may be considered as initial therapy for patients with locally invasive susceptible Curvularia species infection.

Acknowledgments

I am grateful to our colleagues at the Fungal Testing Laboratory, The University of Texas Health Science Center at San Antonio, Texas for fungal species re-identification and antifungal susceptibility determination. I am, especially grateful to A. W. Fothergill for her diligence and interest in the field of medical mycology. I am also grateful to Field Brabham of the Media Services, Palmetto-Richland Memorial Hospital, Columbia SC, for uncompromising support in the preparation of figures for manuscripts.

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