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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.
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