Invasive Fungal Rhinosinusitis Caused by Curvularia in a Patient With Type 1 Diabetes Mellitus: A Case Report

Abstract

Invasive fungal rhinosinusitis (IFRS) is a serious illness requiring early diagnosis, surgical debridement, and administration of antifungals. We report a case of an acute IFRS caused by Curvularia in a patient with diabetes mellitus. An 18-year-old female presented to the emergency department with an acute onset of fever, headache, facial discomfort, and a blood glucose reading of 500 mg/dL. The patient was admitted for the management of hyperosmolar hyperglycemia. Her past medical history includes uncontrolled type 1 diabetes mellitus and a recent toothache. A computed tomography scan of the facial maxillary region revealed sinus disease with bony erosion. Empiric therapy with liposomal amphotericin B 400 mg i.v. every 24 hours, piperacillin/tazobactam 4.5 g i.v. every 6 hours and vancomycin 1 g i.v. every 12 hours was started. A functional endoscopic sinus surgery revealed invasive rhinosinusitis and cultures were positive for fungal elements. The patient was discharged on liposomal amphotericin B 400 mg i.v. daily and cefuroxime 500 mg orally twice daily. However, she was readmitted for the management of acute kidney injury and was discharged on itraconazole capsules 200 mg orally twice daily. Sinus cultures grew Curvularia and itraconazole was prescribed for 6 weeks, but the patient discontinued treatment after 3 weeks and had no signs or symptoms of rhinosinusitis when she was last seen in the clinic. The possibility of IFRS should be explored in patients with diabetes and signs and symptoms of rhinosinusitis.

Keywords

Curvularia invasive fungal rhinosinusitis amphotericin B itraconazole

Introduction

Fungal rhinosinusitis encompasses a wide spectrum of immune and pathological responses, including invasive, chronic, granulomatous, and allergic disease.¹ Allergic fungal rhinosinusitis (AFRS) involves a hypersensitivity response to colonizing fungi and invasive fungal rhinosinusitis (IFRS) involves an aggressive infection.² IFRS is increasing in frequency due to the rise in the number of patients with altered immunocompetence.² IFRS can be classified as acute or chronic.² Acute IFRS has a rapid onset of signs and symptoms and usually occurs in patients with profound immunosuppression, whereas chronic IFRS has a more insidious onset and usually occurs in patients with a mild degree of immunosuppression.² The most common causative organisms are molds.² Acute infections are usually caused by Aspergillus, Fusarium, and the Mucorales such as Rhizopus and Mucor.² Chronic infections are usually caused by Aspergillus, Scedosporium, and the dematiaceous fungi such as Alternaria, Bipolaris, and Curvularia.² Diagnosis is based on histopathologic findings demonstrating fungal invasion of the tissues.² Treatment of IFRS involves surgical debridement and administration of antifungals targeted against the invading organism.²

Curvularia belongs to a group of dark-walled fungi known as dematiaceous mold commonly found worldwide in the environment, particularly in soil and on plants in tropical and subtropical regions.^3,4 Curvularia can cause a variety of human infections known as phaeohyphomycoses that can manifest as cutaneous and subcutaneous lesions, brain abscesses, AFRS, and IFRS.^3-5 When these dematiaceous fungi infect tissues, they produce hyphae, pseudohyphae, or yeast-like elements.⁶ While these infections have been reported in the immunocompetent host, fungemia and disseminated infections are more likely to occur in the immunocompromised host.³ Risk factors for acquiring Curvularia infections include trauma, allergic rhinitis, diabetes mellitus, and altered immunocompetence.³ IFRS caused by Curvularia is uncommon.³ Diagnosis requires observation of the fungi invading tissue or recovery of the fungi from an otherwise sterile site.³ Treatment usually involves surgical debridement and administration of antifungals such as amphotericin B deoxycholate, lipid preparations of amphotericin B, itraconazole, and voriconazole.³ There are no universally accepted treatment options or clinical practice guidelines to guide clinicians in managing patients with this condition. Nonetheless, there have been some case reports in the literature describing successful treatment of fungal rhinosinusitis caused by Curvularia. If antifungal therapy is warranted, amphotericin B seems to be the agent of choice for life-threatening infections, whereas itraconazole is used for mild to moderate disease.³ Voriconazole, posaconazole, isavuconazole, and caspofungin have shown in vitro activity against many of the dark-walled dematacious fungi and may be potential treatment options.^3,7 We present the case of an 18-year-old woman with type 1 diabetes mellitus and IFRS caused by Curvularia and we reviewed similar cases published in the literature to assist pharmacists and other healthcare professionals in recognizing and managing this condition.

Case report

An 18-year-old African American female presented to the emergency department with an acute onset of fever (2 days), headache, facial discomfort, congestion, and a home blood glucose reading greater than 500 mg/dL. She denies sinus discharge and any prior episode of rhinosinusitis. Her past medical history is significant for type 1 diabetes mellitus and a recent toothache. The patient states that her type 1 diabetes mellitus is uncontrolled although she is taking insulin lispro 15 units subcutaneously 3 times a day before meals and metformin 500 mg by mouth twice daily to assist in weight management. Her height is 168 cm and her weight is 80 kg resulting in a body mass index of 28.3 kg/m². She was admitted to the hospital for the management of hyperosmolar hyperglycemia, fever, and altered mental status changes. Her temperature upon arrival was 103°F, her other vital signs were stable, and her white blood cell count was 13,000 cells/mm³ (neutrophil 61%, lymphocyte 29%, monocytes 5%, eosinophils 4%, and basophils 1%). A urine drug screen was negative. A computed tomography (CT) scan of the facial maxillary region revealed complete opacification of the anterior and mid right ethmoid sinus air cells with osseous destruction, sinus disease, and bony erosion. Figure 1A shows an axial view demonstrating an opacified right maxillary sinus filled with thick material, focally invading the nasal septum. Figure 1B shows a coronal view of the aforementioned opacified sinus focally destroying the nasal septum. Blood cultures were obtained and empiric broad-spectrum antimicrobial therapy was initiated with liposomal amphotericin B (5 mg/kg) 400 mg i.v. every 24 hours, piperacillin/tazobactam 4.5 g i.v. every 6 hours, and vancomycin 1 g i.v. every 12 hours. Due to the abnormal findings on the CT scan, the patient underwent functional endoscopic sinus surgery (FESS) and a specimen was collected for pathology examination and microbiology cultures. Figure 2 shows the results of the histologic section of the right sinus contents demonstrating broad, irregular, septated, branching filamentous fungal hyphae. Blood cultures were negative, but preliminary sinus cultures were positive for coagulase negative staphylococci and negative for fungal elements. Liposomal amphotericin B and piperacillin/tazobactam were discontinued after 4 days of therapy. Vancomycin was continued to cover coagulase negative staphylococci and ceftriaxone 2 g i.v. every 24 hours was initiated to cover common upper respiratory tract infection organisms. Five days after collection, the sinus cultures revealed fungal hyphae. Intravenous antibiotics were discontinued and the patient was discharged on liposomal amphotericin B (5 mg/kg) 400 mg i.v. every 24 hours and cefuroxime 500 mg by mouth twice daily. However, 3 days later, the patient was readmitted for the management of acute kidney injury as evidenced by a rise in serum creatinine from 0.9 mg/dL to 1.8 mg/dL, and liposomal amphotericin B was discontinued as it was most likely the cause of the injury. Once the acute kidney injury resolved, liposomal amphotericin B was reinitiated in the hospital for 3 days and the patient was discharged home on itraconazole capsules 200 mg by mouth twice daily for 6 weeks.

Figure 1.

A. CT axial view demonstrating an opacified right maxillary sinus filled with thick material, focally invading the nasal septum (arrow). B. CT coronal view of the aforementioned opacified sinus focally destroying the nasal septum (arrow).

Figure 2.

Histologic section of the right sinus contents demonstrating broad, irregular, septated, branching filamentous fungal hyphae (arrows), identified as Curvularia species on fungal culture (Periodic-Acid Schiff fungal stain, original magnification 200x).

Three weeks later, sinus cultures finally grew Curvularia, but the species was never identified. The patient was diagnosed with acute IFRS and was instructed to follow up with the infectious diseases physician in the outpatient clinic 1 week after discharge and until resolution of signs and symptoms. During the second visit, the patient revealed that she has stopped taking itraconazole after 3 weeks because of nausea and resolution of signs and symptoms of rhinosinusitis. The physician determined that the patient has significantly improved and itraconazole was no longer needed. There was no clear indication for repeat imaging.

Discussion

Curvularia can cause AFRS and IFRS.^3-5 Diagnosis is based on imaging, pathology, and cultures. A CT scan or magnetic resonance imaging (MRI) usually displays sinuses filled with fluid and outward pressure on the bony sinus walls.³ CT scans have higher sensitivity than MRI for detecting bony erosions, whereas MRI has higher sensitivity for soft tissue abnormalities.⁸ Sinuses typically involved are the maxillary, ethmoid, sphenoid, and frontal.³ When these molds are present in the culture, but not invading sinus tissues, surgical removal alone can be curative and antifungal therapy is not necessary. However, when there is evidence of tissue invasion, antifungal therapy is indicated in addition to surgery.³ Although treatment options for Curvularia infections have not been universally accepted, surgical debridement is necessary to cure most patients and FESS is the most common surgical procedure in the case of rhinosinusitis.^3,9 Table 1 is a summary of published case reports of invasive and allergic fungal rhinosinusitis caused by Curvularia.^5,6,10-20 In the most recent published case of AFRS, a CT scan showed a heterogenous expansile mass in the right sphenoid sinus.¹¹ The patient underwent endoscopic sphenoidotomy and sinus cultures grew Curvularia. The patient was cured with surgical debridement and budesonide irrigation without antifungal therapy. This is an acceptable treatment strategy because the patient did not have IFRS like our patient and therefore did not require antifungal therapy. Topical corticosteroids are recommended for patients with AFRS.²¹ In another recently published case of AFRS caused by Curvularia, the patient was treated with oral itraconazole 200 mg twice daily for 4 weeks, intranasal mometasone furoate spray 100 mcg twice daily for 6 months, and normal saline irrigation.⁵ The patient was free of signs and symptoms of the disease after 2 months of treatment. This is an acceptable treatment strategy because the patient described, like our patient, had mild to moderate disease which can be successfully treated with itraconazole. In the most recent published case report of IFRS caused by Curvularia, the patient was immunocompetent.⁶ The CT scan showed bilateral opacification of the maxillary sinuses and bony destruction of the lateral wall of the maxillary sinus. The patient underwent surgical debridement and was given amphotericin B 1.0 mg/kg i.v. daily; however, treatment was discontinued after 6 weeks due to lack of resolution of symptoms. The patient then received oral itraconazole 600 mg daily for 1 week followed by 400 mg daily. After 4 weeks of treatment, the patient reported improvement and was scheduled for facial reconstruction but did not show up to scheduled appointments and was further lost to follow up. This case report had the most similar treatment approach to our case as the patient underwent surgical debridement and received amphotericin B initially followed by oral itraconazole. Most case reports included in our search describe the use of amphotericin B, itraconazole, and terbinafine as treatment options, but the more recent case reports have shown improvement of signs and symptoms of rhinosinusitis with itraconazole. Although bone infections usually require a long duration of therapy, the patient described in our case report seemed to have responded to surgical debridement and a relatively short course of antifungal therapy. Repeat imaging and monitoring of inflammatory biomarkers would have been beneficial to document clinical cure.

Table 1.

Summary of Published Cases of Invasive and Allergic Fungal Infections Caused by Curvularia.

Reference	Age	Sex	Isolate	Clinical Presentation	Comorbid Conditions	Diagnosis and Findings	Treatment	Outcomes
Gupta N¹⁰	55	M	Curvularia lunata	Fever, headache, loss of vision in the right eye, cough, mild tenderness over the frontal and maxillary sinus	Hypertension, type 2 diabetes	MRI: extensive sinusitis involving the bilateral maxillary, ethmoidal and frontal sinus with extension into the right orbit and basifrontal lobe	Surgical debridement, amphotericin B and voriconazole	Development of mucormycosis and the patient was discharged on posaconazole
Chapurin N et al¹¹	37	F	Curvularia species	Bilateral galactorrhea, occipital headaches, elevated prolactin levels	Type 2 diabetes, nasal polyps	Allergic fungal sinusitis CT: hyperdense expansile mass in the right sphenoid sinus with erosion of the sella and clivus and bony erosion	Right endoscopic sphenoidotomy with removal of polyps and debris, budesonide irrigations twice daily	Resolution Prolactin levels normalized 4 weeks after surgery
Cavanna C et al⁵	16	M	Curvularia lunata	Type 1 hypersensitivity, nasal polyposis, characteristic findings on CT scan	Bronchial asthma	Allergic fungal sinusitis CT: thickening of left side mucosa, hyperdensity of mucin in left ethmoid and maxillary sinuses and polyps in left ethmoid and maxillary sinuses	FESS, then itraconazole 200 mg twice daily for 4 weeks, mometasone nasal spray 100 mcg twice daily for 6 months, and normal saline nasal irrigations	Resolved, 19 month follow up patient was symptomless and disease free
Shetty K et al⁶	48	M	Curvularia species	Facial ulcerations, nasal congestion, drainage, fatigue	Hypothyroidism, DVT	Invasive fungal sinusitis CT: bilateral opacification of the maxillary sinuses	Debridement, amphotericin B 1mg/kg/day IV for 6 weeks with no resolution, itraconazole 600 mg daily for 1 week, then 400 mg daily for 4 weeks	Improved, lost track of patient after Hurricane Katrina
Safdar A¹²	59	M	Curvularia lunata	Frontal and facial pain, nasal congestion, posterior nasal drainage, and fatigue	Recurrent corticosteroid-responsive allergic rhinosinusitis	Invasive fungal sinusitis CT: opacification of the left frontal sinus, signs of inflammation of the right sinus mucosa, and bilateral maxillary sinus involvement	Endoscopic surgery, terbinafine 250 mg daily for about 8 weeks then discontinued due to progression of symptoms Oral itraconazole suspension was initiated at 600 mg daily for 5 days, then 400 mg daily	Symptoms improved after 4 weeks of itraconazole therapy, then completely resolved after 2 months of therapy
Willard CC et al¹³	35	M	Curvularia species	A 1-year history of right-sided progressive nasal obstruction with epiphora and anosmia		Allergic fungal sinusitisCT: soft tissue attenuation of right maxillary sinus with erosion of the medial maxillary wall and extension into the nasal cavity	Debridement, systemic or topical steroids, oral antibiotics for several weeks	Not reported
Willard CC et al¹³	31	M	C. lunata	A 6-month history of nasal congestion, chronic sinusitis, epiphora, facial swelling, proptosis		Allergic fungal sinusitisCT: large, heterogenous mixed-attenuation mass involving right maxillary sinus, right ethmoid air cells, and sphenoid and frontal sinuses	Debridement, systemic or topical steroids, oral antibiotics for several weeks	Not reported
Ebright JR et al¹⁴	46	F	C. clavata	Severe frontal headache, somnolence, bifrontal cerebritis	Asthma, hay fever, chronic sinusitis	Invasive fungal sinusitisCT: mucosal thickening in maxillary, frontal, and left sphenoid sinuses and postsurgical changes of medical aspects of both maxillary sinuses	Bilateral sphenoethmoidectomy with frontal sinusotomy and middle meatus antrostomy, amphotericin B 6mg/kg IV daily for 10 weeks, then itraconazole 400 mg twice daily for 9 months, then 200 mg twice daily for an additional 11 months	Not reported
Quraishi HA et al¹⁵	23	F	Curvularia species	A 5-month history of pressure and pain in the left cheek and progressive left-sided proptosis	Allergies, preoperative prednisone before antrotomy and ethmoidectomy	Allergic fungal sinusitisCT after 2 months of procedure: persistent opacification of left frontal sinus with aeration of left maxillary sinus	Postop: antibiotic therapy, saline lavage, aerosolized beclomethasoneAfter second CT and pendoscopic procedure: prednisone 69 mg tapered over 2 weeks, then prednisone 5 mg daily for another 2 months. Takes aerosolized beclomethasone for the past 2 years	Improved, 2 months later showed opacification but negative fungal cultures
Ismail Y et al¹⁶	46	F	C. lunata	Sudden onset of recurrent diplopia	Chronis sinusitis	Invasive fungal sinusitisCT: large mass in sphenoid sinus that extended intracranially; bone destruction	Amphotericin B 4 g IV for 4 months, followed by ketoconazole 400 mg daily for 8 months	Resolution without recurrence of symptoms after 2 month of follow-up
Killingsworth et al⁴	26	M	Curvularia species	Progressive vision loss	Allergic rhinitis with 5 intranasal polypectomies	CT: complete opacification of all sinuses with erosion of lateral wall of right ethmoid air cells and bone erosion	Caldwell-Luc surgery and left external frontoethmoidectomy, amphotericin B 1 g total dose IV for 2 months	Improvement after 8 months
Bartynski J et al¹⁷	48	M	Curvularia lunata	Recurrent sinusitis	GoutNephrolithiasisDiabetes mellitusTransphenoidal for microadenomaseasonal allergic rhinitis & vasomotor rhinitis	Allergic fungal sinusitisCT: mixed hypermucoid density or a mass filling the nasal cavity, ethmoid, sphenoid sinuses, left frontal and left maxillary sinuses	Amphotericin B for 8 days, nasal irrigations with hydrogen peroxide and saline twice daily, terbinafine 60 mg twice daily	1. Improved, but several months later patient had symptoms with cultures revealing C. lunata2. Resolved after 6 month and 1 year follow up
Nishioka G et al¹⁸	20	F	C. lunata	Left-sided facial pain with left-sided nasal stiffness and mucous drainage	Asthma	CT: large mass contained in left maxillary sinus, except for medial extension into the left nasal cavity	Caldwell-Luc procedure	Resolution
Rinaldi MG et al¹⁹	20	F	C. lunata	Nasal stuffiness and mucous drainage	Asthma	CT: large mass in left maxilliary sinus with medial extension into the nasal cavity	Caldwell-Luc procedure, no antifungal therapy	Resolved without recurrence after 1 year follow-up
Rinaldi MG et al¹⁹	23	M	C. lunata	Frontal headaches, nasal congestions, purulent nasal discharge for several years	Chronic sinusitis, nasal polyps, asthma, allergies, Caldwell-Luc procedure, polypectomy	CT: mucosal thickening and radiodense material in sinuses except sphenoid with probable bony erosion	Caldwell-Luc procedure, cefazolin then switched to cephalexin for 1 week post-surgery, no antifungal therapy	Resolved without recurrence after 14 month follow-up
Rinaldi MG et al¹⁹	11	F	C. lunata	Blockage of left nasal passage and fullness around left eye	Reye’s syndrome, surgical correction of hernia	CT: left maxillary sinus mass	Caldwell-Luc, discharged with nasal steroids and chlorpheniramine, no antifungals	Resolved without recurrence after 4 year follow-up
Rinaldi MG et al¹⁹	26	M	C. lunata	Refractory chronic pansinusitis	Smoking, chronic sinusitis	Presence of right nasal polyps	Left ethmoidectomy with left sphenoid and frontal sinusotomy, post-op treatment with cephradine for 10 days, no antifungals	Resolved without recurrence after 6 month follow-up
Rinaldi MG et al¹⁹	30	M	C. lunata	A 2-year history of nasal congestion, difficulty breathing through the nose	Allergic rhinitis, smoking	CT: large soft tissue mass in the left frontal, ethmoid, and maxillary sinuses with destruction of medial wall of left maxillary sinus	left polypectomy, ethmoidectomy, and Caldwell-Luc procedure, no antimicrobials, acetaminophen with codeine for pain	Resolved without recurrence after 6 month follow-up
Macmillian RH et al²⁰	18	F	C. lunata	Left-sided sinusitis	Asthma and bronchitisPrevious treatment: 2 months of cephalexin, ampicillin with no improvement, Caldwell-Luc procedure	CT: left pansinusitis with decreased density and increased thickness of roof of frontal sinusAllergic fungal sinusitis	Caldwell-Luc surgery, amphotericin B 980 mg total IV	Resolved without recurrence for 2 years
Macmillian RH et al²⁰	16	F	C. lunata		Multiple allergies and nasal polypectomies	Allergic fungal sinusitisOpacification of left sphenoid, ethmoid, maxillary, and front sinuses	Caldwell-Luc surgery, amphotericin B 1 g IV and 200 mg into the sinuses for 3 weeks	Resolved for 3 years

Abbreviations: CT = computed tomography scan; DVT = deep venous thrombosis; FESS = functional endoscopic sinus surgery; MRI = magnetic resonance imaging.

Conclusion

An 18-year-old woman with type 1 diabetes mellitus and IFRS was successfully treated with surgical debridement and intravenous liposomal amphotericin B for 1 week, followed by oral itraconazole for 3 weeks. The existing evidence supports this treatment strategy in immunocompetent patients with mild to moderate disease who respond quickly to oral azole antifungals. However, most patients require a longer duration of therapy.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr. Chahine serves on the speakers’ bureaus of Merck & Co, Inc. and Paratek Pharmaceuticals, Inc. Drs. Marinucci and Bush have nothing to disclose.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDP

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