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The Laryngoscope C 2014 The American Laryngological, V Rhinological and Otological Society, Inc. Case Report Invasive Fungal Sinusitis in a Healthy Athlete due to Long-term Anabolic Steroid Use Irene A. Kim, MD; Christopher F. Thompson, MD; Paul A. Kedeshian, MD; Fernando Palma-Diaz, MD; Jeffrey D. Suh, MD Invasive fungal rhinosinusitis is a potentially fatal infection that affects immunocompromised patients. Prognosis is generally poor despite aggressive medical and surgical treatments. We present the first reported case of invasive fungal sinusitis in a healthy 18-year-old male athlete who was taking anabolic androgenic steroids (AAS). The effects of excessive AAS use on the immune system are not fully understood, but there may be consequences at supraphysiological concentrations. This case demonstrates potential immunomodulatory effects of anabolic steroids and highlights a previously unknown cause of invasive fungal sinusitis. Key Words: Invasive fungal sinusitis, Aspergillus, aspergillosis, sinus, surgery, anabolic, steroids. Laryngoscope, 124:1756–1759, 2014 INTRODUCTION Invasive fungal rhinosinusitis (IFRS) is a potentially fatal infection that almost exclusively affects immunocompromised patients, such as those with poorly controlled diabetes mellitus, chronic corticosteroid use, and history of organ transplantation or hematologic malignancy.1,2 Clinical presentation includes rapidly progressive facial pressure and swelling, nasal congestion, ophthalmoplegia, paresthesias, proptosis, and fever.1 Prompt histopathological diagnosis revealing fungal invasion into the sinonasal tissues is critical so that surgery and systemic antifungal treatment may be initiated. Despite aggressive medical and surgical treatments, prognosis is generally poor, with a mortality rate as high as 50% to 80%.1,3 The most common fungal pathogens in IFRS are the zygomycetes (Rhizopus, Mucor, Rhizomucor) and Aspergillus species.1 We present the first reported case of Aspergillus IFRS in a healthy 18-year-old male ath- From the Department of Head & Neck Surgery (I.A.K., C.F.T., P.A.K., and the Department of Pathology (F.P.-D.), University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, U.S.A. Editor’s Note: This Manuscript was accepted for publication January 21, 2014. Presented as a poster at the American Rhinologic Society 59th Annual Meeting, Vancouver, British Columbia, Canada, September 28, 2013. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Irene A. Kim, MD, Department of Head & Neck Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., CHS 62-142, Los Angeles, CA 90095. E-mail: [email protected] J.D.S.) DOI: 10.1002/lary.24608 Laryngoscope 124: August 2014 1756 lete taking anabolic androgenic steroids (AAS), highlighting the potential immunomodulatory effects of AAS.4–6 CASE REPORT We present the case of an 18-year-old male athlete with a long history of bilateral nasal obstruction, hyposmia, and postnasal drainage secondary to allergic fungal rhinosinusitis. Figure 1A illustrates the initial computed tomography (CT) scan. He underwent endoscopic sinus surgery and was found to have extensive polyposis with allergic mucin and fungal debris. After this surgery, his symptoms initially improved but then worsened over the next 4 months when he developed a sudden onset of progressive left-sided facial pain, pressure, and headaches. He had no visual complaints at that time. A preoperative CT scan showed diffuse sinonasal opacification (Fig. 1A) with bony erosion at the left pterygopalatine fossa and orbital apex. The patient was taken to the operating room for tissue biopsy. Extensive polyposis and fungal debris were again debrided from the left sinonasal cavity. Pathology at this surgery demonstrated chronic sinusitis with noninvasive Aspergillus organisms, with no evidence of tumor. Two weeks after the second surgery, he developed new complaints of rapidly progressive left facial numbness, diplopia, left eye proptosis, retro-orbital pain, fevers, chills, and worsening occipital headaches. He was then referred our tertiary care rhinology center for management. His past medical history was otherwise unremarkable except for long-term use of AAS. Laboratory values on admission were within normal limits, except for an Kim et al.: Invasive Fungal Sinusitis due to AAS Use Fig. 1. Preoperative and postoperative axial computed tomography (CT). (A) Initial axial CT scan shows pansinusitis with heterogeneous areas of signal intensity in the maxillary and ethmoid sinuses consistent with allergic fungal sinusitis. (B) Later axial CT image shows a destructive soft tissue mass in the left maxillary sinus with extension into the pterygopalatine fossa. #High density, expansile fungal debris in the right maxillary sinus. *Erosion of the posterior wall of the left maxillary sinus due to invasive Aspergillus. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] elevated immunoglobulin E (IgE) level (795 U/mL), consistent with his history of atopic allergy. Tests for human immunodeficiency virus were negative. Physical examination was significant for proptosis of the left eye, abducens nerve palsy, and complete left maxillary nerve anesthesia. Ophthalmologic evaluation revealed moderate abduction and mild adduction restriction of left eye movement, as well as 3-mm proptosis. There was no evidence of optic nerve dysfunction, as visual acuity was not affected. Nasal endoscopy revealed substantial mucosal edema and purulent drainage. CT (Fig. 1B) and magnetic resonance imaging (Fig. 2) revealed a destructive sinonasal lesion in the left maxillary sinus, with extension into the pterygopalatine fossa, bilateral sphenoid sinuses, bilateral posterior ethmoid air cells, and orbital apex. There was also enhancement of the maxillary nerve in the foramen rotundum confirming perineural invasion, as well as enhancement along the inferior orbital fissure, infraorbital nerve, and the margins of the left cavernous sinus. Due to the rapid onset of symptoms and concerning radiologic findings, the patient was urgently taken to Fig. 2. (A) Pretreatment coronal magnetic resonance imaging (MRI) shows a mass extending into the pterygopalatine fossa, into the inferior orbital fissure, through the foramen rotundum into the middle cranial fossa, along the margins of the cavernous sinus, and partially into the superior orbital fissure. Optic nerves and extraocular muscles are grossly normal. (B) Pretreatment axial MRI shows a mass extending into the pterygopalatine fossa, into the inferior orbital fissure, through the foramen rotundum into the middle cranial fossa, along the margins of the cavernous sinus, and partially into the superior orbital fissure. Optic nerves and extraocular muscles are grossly normal. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] Laryngoscope 124: August 2014 Kim et al.: Invasive Fungal Sinusitis due to AAS Use 1757 Fig. 3. Invasive Aspergillus fumigatus. Gomori methenamine silver stain highlights the septated fungal hyphae with acute angle branching (340). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] the operating room for definitive diagnosis and surgical debulking. Surgery included a left-sided medial maxillectomy, middle turbinate resection, and completion ethmoidectomy and frontal sinusotomy. Intraoperative biopsies demonstrated the presence of invasive Aspergillus fumigatus within necrotic tissue. The characteristic, septated, acute angle branching of hyphae was morphologically consistent with the Aspergillus species (Fig. 3). After surgery, the patient was started on intravenous (IV) amphotericin B, IV caspofungin, and oral voriconazole. Two weeks later, he was taken back to the operating room for further debridement of the pterygopalatine fossa and orbital apex. There was bony dehiscence at the orbital apex, but the periorbita was intact. One week after this surgery, ophthalmologic evaluation showed marked improvement with only mild left abduction restriction and no optic nerve dysfunction. Six months postoperatively, he has had a remarkable clinical and radiographic improvement with resolution of diplopia and slow return of maxillary nerve V2 sensation (Fig. 4). He has completed 6 months of IV caspofungin and will continue oral voriconazole with close clinical follow-up for at least 6 additional months. behavioral changes, increased risk for myocardial infarctions and strokes, and sterility.4 The effects of excessive AAS use on the immune system are not fully understood, but there may be consequences at supraphysiological concentrations.4 T cells regulate the secretion of cytokines, which can both activate and deactivate fungicidal phagocytes.9 Several murine and in vitro studies have shown that high levels of AAS interfere with the Th1/Th2 balance of immune regulation and the maturation of lymphocytes, thus disrupting the production and secretion of critical cytokines needed to combat fungal invasion.4,9 Aspergillus organisms are ubiquitous, and both T-lymphocyte–regulated immunity and nonspecific cellular immunity mediated by macrophages, neutrophils, and natural killer cells are usually well adapted to defend the body against such fungal infections in immunocompetent individuals.9 However, high doses of AAS have been shown to suppress natural killer cell activity, the oxidative capacity of neutrophils, and lymphocyte maturation into effector and memory cells.4 Specifically, supraphysiologic doses of AAS decrease interferon-c (IFN-c) and interleukin-2 (IL-2) secretion by T helper 1 cells.4 IFN-c is important in the phagocytosis of invading microorganisms, whereas IL-2 is an essential component of generating memory lymphocytes to recognize and clear pathogens.4 IL-2 production may be suppressed because AAS inhibit the activities of endogenous adrenal androgens such as dehydroepiandrosterone, which normally promote IL-2 production and subsequent inhibition of viral and fungal infections.5,6 In fact, one study demonstrated that IL-2 was a protective factor against pulmonary invasive A fumigatus when administered as an adjuvant therapeutic agent with amphotericin B in immunosuppressed mice.10 DISCUSSION IFRS, such as that caused by Aspergillus, almost exclusively affects immunocompromised patients with poorly controlled diabetes mellitus, malignancy, chronic corticosteroid use, or history of solid organ transplantation.1,2,7 Rarely have Aspergillus infections been reported to convert from allergic fungal sinusitis (AFS) to IFRS in otherwise immunocompetent individuals.2 We present the first case of IFRS attributed to the use of AAS in an otherwise healthy 18-year-old male athlete with a history of AFS. AAS are derivatives of testosterone; there are over 40 different oral and injectable forms.8 Known side effects of these performance-enhancing drugs include Laryngoscope 124: August 2014 1758 Fig. 4. Post-treatment axial magnetic resonance imaging (MRI). Most recent postoperative axial MRI image shows improvement of previously seen disease. There is decreased enhancement of left foramen rotundum, left masticator muscle, superior orbital fissure, and left maxillary sinus. *Left maxillary sinus. [Color figure can be viewed in the online issue, which is available at www. laryngoscope.com.] Kim et al.: Invasive Fungal Sinusitis due to AAS Use In addition to the in vitro and animal studies investigating the negative immunomodulating impact of AAS, one human subject study by Calabrese et al.5 analyzed the immunological effects of AAS on bodybuilder athletes. They found that bodybuilders using AAS had reduced serum immunoglobulin levels compared to those who were not using AAS. Specifically, the most profound reduction occurred with immunoglobulin A (IgA) levels.5 IgA plays a critical role in mucosal immunity, as it is produced by plasma cells in mucosal linings and is integral in preventing antigen adherence and absorption in the sinonasal and respiratory tracts. Although the exact mechanism of how AAS modulates the immune system has not been fully elucidated, our case highlights the potential life-threatening infection that can result with AAS abuse. Our patient may have been at increased risk for conversion to IFRS because he was already suffering from Aspergillus AFS. However, AFS is an indolent, benign, IgE-driven, eosinophilic inflammatory condition thought to affect those with a hypersensitivity to fungal antigens, and only rare cases of concurrent AFS and IFRS have been described.2,5,11 Most of the reported cases of “mixed fungal sinusitis” involve chronic invasive fungal sinusitis with AFS.11 Our patient is only the second reported case of AFS converting to acute IFRS.2 In the only previously reported case, the patient developed IFRS with Rhizopus 2 weeks after revision endoscopic sinus surgery for AFS that was complicated by concurrent repair of bilateral cribiform cerebrospinal fluid leaks resulting from a traumatic skateboarding accident.2 Our patient was an otherwise healthy 18-year-old athlete who underwent an uncomplicated revision sinus surgery 2 weeks prior to presentation. His only notable immunomodulating risk factor was long-term use of AAS. Laryngoscope 124: August 2014 CONCLUSION The long-term outcomes of patients with invasive fungal sinusitis are poor, and early diagnosis and treatment are essential. Treatment entails surgical debridement, antifungal medications, and reversing the cause of immunosuppression when possible. We report a case of long-term anabolic steroid abuse likely facilitating the conversion from AFS to life-threatening IFRS. Although further research is needed to determine the exact mechanism that AAS has in modulating the immune system, our case illustrates the potential danger of AAS suppressing the immune system and causing serious infections. BIBLIOGRAPHY 1. Turner JH, Soudry E, Nayak JV, Hwang PH. Survival outcomes in acute invasive fungal sinusitis: a systematic review and quantitative synthesis of published evidence. Laryngoscope 2013;123:1112–1118. 2. Chaaban MR, Bell W, Woodworth BA. Invasive mucormycosis in an immunocompetent patient with allergic fungal rhinosinusitis. Otolaryngol Head Neck Surg 2013;148:174–175. 3. Suslu AE, Ogremenoglu O, Suslu N, Yucel OT, Onerci TM. Acute invasive fungal rhinosinusitis: our experience with 19 patients. Eur Arch Otorhinolaryngol 2009;266:77–82. 4. Brenu EW, McNaughton L, Marshall-Gradisnik SM. Is there a potential immune dysfunction with anabolic androgenic steroid use? A Review. Mini Rev Med Chem 2011;11:438–445. 5. Calabrese LH, Kleiner SM, Barna BP, et al. The effects of anabolic steroids and strength training on the human immune response. Med Sci Sports Exerc 1989;21:386–392. 6. Mendenhall CL, Grossman CJ, Roselle GA, et al. Anabolic steroid effects on immune function: differences between analogs. J Steroid Biochem Mol Biol 1990;37:71–76. 7. Thompson GR, Patterson TF. Fungal disease of the nose and paranasal sinuses. J Allergy Clin Immunol 2012;129:321–326. 8. Hughes TK, Rady PL, Smith EM. Potential for the effects of anabolic steroid abuse in the immune and neuroendrocrine axis. J Neuroimmunol 1998;83:162–167. 9. Romani L. The T cell response against fungal infections. Curr Opin Immunol 1997;9:484–490. 10. Zhang CR, Tang YC, Kawakami K, Zhang TT, Zhang KX, Zhu JX. An experimental study of the therapeutic effect of interleukin-2 and interleukin-12 with and without amphotericin B on pulmonary fungal infection [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi 2004;27:234–236. 11. Rupa V, Thomas M. Different type of fungal sinusitis occurring concurrently: implications for therapy. Eur Arch Otorhinolaryngol 2013;270:603–608. Kim et al.: Invasive Fungal Sinusitis due to AAS Use 1759