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Aspergillosis Related to Long-Term Nasal Corticosteroid Use
Mayo Clin Proc, December 2002, Vol 77
Aspergillosis Related to Nasal Corticosteroid Use
1353
Case Report
Aspergillosis Related to Long-Term Nasal Corticosteroid Use ROBERT L. BRATTON, MD; PAUL W. BRAZIS, MD; WALTER C. HELLINGER, MD; ROBERT E. WHAREN, JR, MD; AND DANIEL F. BRODERICK, MD retrobulbar optic neuropathy. After extensive differential diagnostic examination, we concluded that the condition was possibly related to the long-term use of nasal corticosteroids (fluticasone propionate aqueous nasal spray). Surgical removal of solid masses of Aspergillus organisms followed by extended treatment with antifungal agents resulted in a favorable outcome. Mayo Clin Proc. 2002;77:1353-1357
Aspergillus is a ubiquitous mold that can cause several types of symptomatic infections: allergic aspergillosis, typically in young atopic patients; aspergillomas (often referred to as fungus balls); and invasive aspergillosis, typically seen in debilitated or immunocompromised patients. We describe an 85-year-old woman who was not immunocompromised but had invasive aspergillosis of the paranasal sinus that resulted in unilateral headache and
A
REPORT OF A CASE A healthy, active 85-year-old woman presented to the primary care clinic after 5 days of left-sided, temporal headaches radiating to the left postauricular area. She described the pain as shooting and intermittent. She denied any nausea, vomiting, visual changes, fever, or chills at her initial presentation. The patient had a history of chronic allergic rhinitis and sinus headaches but believed the present headaches were different in severity and character. She denied any other neurologic symptoms and reported no rashes. Her medical history was remarkable for hypothyroidism, asthma, allergic rhinitis, and degenerative joint disease. Her medications included levothyroxine sodium and aspirin; she also took a multivitamin. The patient had been applying 2 sprays per nostril per day (200 µg/d) of a fluticasone propionate aqueous nasal spray for the past 2 years. Physical examination at her initial presentation showed no specific findings; she had no visual acuity changes, no sinus or temporal tenderness, no bruits, and no focal neurologic findings. Because of the lack of physical findings, no imaging studies were performed. The working diagnosis was atypical headache (cephalgia), different from anything she had experienced before. Temporal arteritis was a possible diagnosis based on her age and presenting symptoms, although she lacked temporal tenderness. Results of blood chemistry tests were normal, and the erythrocyte sedimentation rate was 20 mm/h (reference range, 0-29 mm/h). The patient was dismissed home and instructed to use anti-inflammatory agents for symptomatic relief. She was given specific instructions regarding warning signs that would require further evaluation. She returned 1 week later with continued severe headaches and newly developed visual deficits. The patient was referred immediately
spergillosis is a fungal infection generally acquired by inhaling airborne spores (conidia) of the ubiquitous mold Aspergillus. Thus, the most frequent site of Aspergillus infection is the respiratory system. Aspergillus fumigatus and Aspergillus flavus are the most common types of Aspergillus infection associated with human disease; their spores are found on hay, grain, decaying vegetation such as leaves or compost piles, soil, and stool. Three main types of Aspergillus infections occur in humans: allergic aspergillosis, aspergillomas, and invasive aspergillosis. The diagnosis of all 3 conditions requires histopathologic confirmation, and isolation of Aspergillus from sputum or bronchoalveolar lavage fluid suggests colonization or infection. In many patients, biopsy is necessary for definitive diagnosis. Immunocompromised or immunosuppressed patients, such as patients with acquired immunodeficiency syndrome (AIDS), patients who receive glucocorticoids or cytotoxic drugs such as cyclosporine, and patients who have an underlying malignancy or are otherwise debilitated, have an increased risk for developing Aspergillus-related infections. We describe a relatively healthy elderly woman who presented with severe headaches and visual disturbances. After an extensive differential diagnostic process involving many conditions commonly encountered in a primary care clinic and participation by various specialists, invasive aspergillosis, possibly related to long-term use of nasal corticosteroids, was identified as the cause. From the Department of Family Medicine (R.L.B.), Department of Ophthalmology (P.W.B.), Division of Infectious Diseases (W.C.H.), Department of Neurosurgery (R.E.W.), and Department of Radiology (D.F.B.), Mayo Clinic, Jacksonville, Fla. Address reprint request and correspondence to Robert L. Bratton, MD, Department of Family Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224. Mayo Clin Proc. 2002;77:1353-1357
1353
© 2002 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
1354
Aspergillosis Related to Nasal Corticosteroid Use
Figure 1. Axial T1-weighted (450/12/1 [repetition time/echo time/excitations]) magnetic resonance image shows an abnormal isointense mass at the anterosuperior aspect of the left sphenoid sinus (arrow), immediately medial and adjacent to the left optic nerve (arrowhead).
to the ophthalmology department, where examination showed a left relative afferent pupillary defect and a profound visual field deficit in the left eye. The optic nerve appeared normal. Treatment with systemic (oral) cortico-
Figure 2. Axial T1-weighted contrast-enhanced (621/12/1 [repetition time/echo time/excitations]) magnetic resonance image with fat saturation shows abnormal enhancement within the left sphenoid sinus (arrow) and lateral to the left optic nerve (arrowhead).
Mayo Clin Proc, December 2002, Vol 77
steroids (prednisone, 60 mg/d) was initiated for the presumptive diagnosis of giant cell arteritis. Bilateral temporal artery biopsies were performed the next day; results showed no evidence of temporal arteritis. The patient’s headache was completely alleviated with the high-dose corticosteroid treatment, but her vision improved only modestly. Because the visual deficits persisted after the temporal artery biopsies, further consultation was requested. Examination by a neuro-ophthalmologist confirmed a left relative afferent pupillary defect and visual field impairment consistent with retrobulbar optic neuropathy. At this point, the differential diagnosis included an infiltrative or infectious process (eg, sarcoidosis, Wegener granulomatosis, or carcinomatous meningitis). Further laboratory tests failed to identify an infiltrative disease process. The corticosteroid treatment was continued and was tapered rapidly. The patient was followed up 2 weeks later. Her headache had returned after reduction of the corticosteroid dose, and the left vision field deficit was becoming progressively worse. Because of the improvement with higher-dose corticosteroids, the prednisone dosage was increased from 10 to 20 mg/d. Magnetic resonance imaging of the orbits, performed with and without contrast, showed an abnormal enhancing mass that involved the anterosuperior aspect of the left sphenoid sinus, adjacent bone, dura mater, and possibly the meningeal covering of the left optic nerve (Figures 1-3). The patient was referred immediately to the neurosurgery department and underwent a left frontal craniotomy on the same day. Surgical exploration showed a wellcircumscribed grayish mass medial to the left optic nerve, with involvement of a thickened dura mater encasing the optic nerve and extending into the optic canal. The optic canal was decompressed by removing the optic roof. Additionally, the grayish mass and the dura mater were resected with use of microsurgical techniques. Periodic acid–Schiff and Grocott-Gomori methenamine–silver nitrate stains were positive for fungal elements that showed characteristic septa and branching. A culture of the mass grew A fumigatus. Treatment with intravenous amphotericin B was initiated. A conventional formulation of amphotericin (amphotericin B deoxycholate) was used initially at a dosage of 30 mg/d (0.5 mg/kg per day). The preparation was subsequently changed to a lipid formulation of amphotericin at a dosage of 300 mg/d (5 mg/kg per day) because of gastrointestinal adverse effects and renal insufficiency. The patient received a total of 6 weeks of amphotericin treatment in the form of either the conventional amphotericin or the amphotericin B lipid complex. To ensure eradication,
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, December 2002, Vol 77
Aspergillosis Related to Nasal Corticosteroid Use
1355
Figure 3. Left and Right, Coronal T1-weighted contrast-enhanced (475/12/1 [repetition time/echo time/excitations]) magnetic resonance images with fat saturation show abnormal enhancement within the left sphenoid sinus (arrow) and the overlying dura mater (arrowhead), obscuring the left optic nerve. The right optic nerve is normal (open arrow).
this treatment was followed empirically with 2 months of oral treatment with a less expensive, more easily tolerated antifungal agent (itraconazole). The patient recovered fully. Magnetic resonance imaging was repeated after completion of therapy and showed only postsurgical changes. At follow-up, the patient’s vision had improved considerably, and her headaches had resolved. DISCUSSION Our patient presented with unilateral headaches, visual field deficits, and an afferent pupillary defect. New onset of headaches can signal a potentially serious medical condition, particularly in the elderly population. The differential diagnosis is extensive and includes temporal arteritis, tumor, subdural hematoma, subarachnoid hemorrhage, uncontrolled hypertension, glaucoma, meningitis, encephalitis, and other infections or infiltrative and inflammatory conditions.1 Visual disturbances are also a serious symptom that should be evaluated further, with the differential diagnosis including cataracts, glaucoma, macular degeneration, retinal disturbances, floaters, vascular disease, neurologic disease, and infection or infiltrative and inflammatory states.2 Our patient was initially believed to have presenting signs and symptoms of an expanding tumor or an infiltrative process compressing the optic nerve. Magnetic resonance imaging of the orbits supported the diagno-
sis of an expanding neoplasm or an infiltrative process. Only after surgical resection and histopathologic confirmation was the diagnosis of a locally invasive aspergillosis infection successfully made. Of the 3 main types of Aspergillus infection, allergic aspergillosis typically affects younger atopic patients. That condition is due to immediate and late hypersensitivity reactions to Aspergillus antigens and results in classic allergic symptoms such as rhinitis, sinusitis, erythematous pruritic rashes, and wheezing; the condition may be associated with a history of nasal polyposis, asthma, and chronic rhinitis.3 Clinically important eosinophilia is often present. Radiographic examination with computed tomography shows characteristic findings of acute or chronic sinusitis with thickening or clouding of the paranasal sinuses. Rarely, in severe cases with sinus consolidation, neuroophthalmologic findings may include an afferent pupillary defect due to optic nerve compression, extraocular muscle dysfunction, periorbital edema, or proptosis. Diagnosis of allergic aspergillosis may be facilitated when Charcot-Leyden crystals (proteinaceous crystals that occur when eosinophilic leukocytes undergo fragmentation, eg, in asthma or intestinal parasitism) can be identified in mucus secretions. Case studies have shown that treatment with systemic corticosteroids and antifungal therapy is beneficial4; surgical débridement of sinus consolidation may be necessary for
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
1356
Aspergillosis Related to Nasal Corticosteroid Use
severe cases.5,6 If no evidence of invasion is found, antifungal therapy is probably unnecessary.7,8 Prognosis is usually excellent, even in patients with visual loss.4,9,10 Aspergillomas (also known as mycetomas or fungus balls) typically affect the lungs, although they may also affect the paranasal sinuses. They are usually solitary lesions that develop in healthy individuals in areas of anatomical or functional deformity and grow for months or years without symptoms or systemic spread. In most patients, unless they extend beyond the sinuses, aspergillomas that develop in the paranasal sinuses result only in nasal congestion and breathing difficulty, without evidence of infection or systemic symptoms. They are solid masses of Aspergillus organisms and are demarcated from normal tissue by varying degrees of exudate.11 The treatment is surgical excision of the solid masses followed by antifungal therapy. In some patients, particularly those with nasal aspergillomas, only surgical removal of the fungus ball is necessary.12 Most patients with solitary aspergillomas are initially thought to have a slow-growing neoplasm. In invasive aspergillosis, the portal of entry is usually the lung, where Aspergillus colonizes and gives rise to multiple necrotic granulomatous lesions. Subsequently, the infection may spread to the bloodstream and the central nervous system. Symptoms initially include fever, cough, hemoptysis, and dyspnea. Pneumonia may develop, resulting in respiratory decompensation. The differential diagnosis includes various subacute bacterial respiratory infections, nocardiosis, mycobacterial pulmonary infection, other fungal infections, and aseptic inflammatory or malignant disease processes affecting the lower respiratory tract. Treatment of invasive aspergillosis requires the use of antifungal agents, including intravenous amphotericin B or itraconazole; tapering and elimination, as far as possible, of immunosuppressive therapies; and surgical débridement when feasible. Aspergillus infections, particularly invasive aspergillosis, are most likely to occur in patients undergoing immunosuppression or who are immunocompromised, such as patients with AIDS, patients who receive glucocorticoids or cytotoxic drugs such as cyclosporine, and patients who have an underlying malignancy or are otherwise debilitated.13 Although our patient was elderly, she was not in an immunosuppressed or debilitated state. In retrospect, we surmised that the long-term use of nasal corticosteroids (fluticasone propionate) over a period of several years may have contributed to the development of Aspergillus colonization, which was followed by a local invasion. Both pulmonary and laryngeal aspergillosis have been reported after the use of inhaled (oral) fluticasone propionate.14,15 Although no reports relate the use of nasal corticosteroids to Aspergillus, the long-term use of these drugs might have contributed to
Mayo Clin Proc, December 2002, Vol 77
the growth of Aspergillus in the sinus cavity and the subsequent Aspergillus invasion. According to product information for available nasal fluticasone propionate preparations, adverse effects may include headache, pharyngitis, hoarseness, nasal burning, epistaxis, nasal congestion, and cough, and the recommended dosage had no effect on adrenal function in clinical trials. Interestingly, our patient’s condition improved with the use of high-dose oral corticosteroids. This may have been due to anti-inflammatory effects on the inflammation that likely surrounded the locally invasive aspergillosis infection. Because the diagnosis was made soon after the initiation of corticosteroid therapy and this treatment was discontinued, the immunosuppressant properties of the corticosteroids were minimized. With prolonged use of corticosteroids, the patient’s condition might have been exacerbated. A review of published literature revealed a case report of a 74-year-old man with a history of atherosclerosis and chronic lymphocytic leukemia who presented with symptoms similar to those in our patient.16 As in our patient, temporal arteritis was suspected but not confirmed. However, in contrast to our patient, the addition of corticosteroids did not improve his symptoms, and surgical excision (Lynch-type cutaneous incision) was performed. That patient was also treated with amphotericin B, but he died as a result of a streptococcal (pneumonia) infection. Aspergillus infection was present in the orbital region at the time of his death. No established guidelines exist for the duration of antifungal therapy for invasive aspergillosis. Duration of intravenous amphotericin is directed by clinical response. Oral itraconazole treatment after parenteral administration of amphotericin is often advised for immunocompromised patients and for patients with critically situated disease.17 However, mortality is high when Aspergillus infection remains untreated. If the disease is limited to the orbit, the death rate is approximately 28%; with central nervous system involvement, the death rate is 80%.18 Thus, as in our patient, early diagnosis and aggressive treatment may prevent considerable morbidity and mortality. CONCLUSIONS Nasal corticosteroids are commonly used by patients of various ages to treat chronic and allergic nasal rhinitis. Despite the drugs’ relative safety, clinicians must remain alert to potential complications that could arise from their use. In our patient, severe consequences (ie, loss of vision, cerebral aspergillosis) could have occurred had no diagnosis been made. In most patients, Aspergillus infections are treated with surgery followed by an extended course of antifungal therapy. As a result of a timely and coordinated
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, December 2002, Vol 77
effort among multiple specialties, our patient recovered without substantial deficits.
Aspergillosis Related to Nasal Corticosteroid Use
10.
11.
REFERENCES 1. 2. 3. 4.
5. 6.
7. 8.
9.
Clinch CR. Evaluation of acute headaches in adults. Am Fam Physician. 2001;63:685-692. Quillen DA. Common causes of vision loss in elderly patients. Am Fam Physician. 1999;60:99-108. Gourley DS. Allergic fungal sinusitis. Insights Allergy. 1989;4:1-7. Brown P, Demaerel P, McNaught A, et al. Neuro-ophthalmological presentation of non-invasive Aspergillus sinus disease in the nonimmunocompromised host. J Neurol Neurosurg Psychiatry. 1994; 57:234-237. Hartwick RW, Batsakis JG. Sinus aspergillosis and allergic fungal sinusitis. Ann Otol Rhinol Laryngol. 1991;100:427-430. Mannes GP, van der Heide S, van Aalderen WM, Gerritsen J. Itraconazole and allergic bronchopulmonary aspergillosis in twin brothers with cystic fibrosis [letter]. Lancet. 1993;341:492. Jacobson M, Galetta SL, Atlas SW, Curtis MT, Wulc AW. Bipolarisinduced orbital cellulitis. J Clin Neuroophthalmol. 1992; 12:250-256. Chang WJ, Shields CL, Shields JA, et al. Bilateral orbital involvement with massive allergic fungal sinusitis [letter]. Arch Ophthalmol. 1996;114:767-768. Dunlop IS, Billson FA. Visual failure in allergic aspergillus sinusitis: case report. Br J Ophthalmol. 1988;72:127-130.
12.
13.
14.
15.
16.
17.
18.
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Stefanyszyn MA. Aspergillosis of the sphenoid sinus presenting as a suprasellar mass. Presented at: Orbital Society Meeting; April 3, 1993; Snowbird, Utah. Scaravilli F. Parasitic and fungal infections of the nervous system. In: Adams JH, Corsellis JAN, Duchen LW, eds. Greenfield’s Neuropathology. 4th ed. New York, NY: John Wiley & Sons; 1984: 304-337. Bennett JE. Aspergillosis. In: Isselbacher RJ, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2002:1156-1157. Arnold AC. Fungi and mycotic diseases. In: Miller NR, Newman NJ, eds. Walsh and Hoyt’s Clinical Neuro-Ophthalmology. Vol 4. 5th ed. Baltimore, Md: Williams & Wilkins; 1998:4286- 4317. Leav BA, Fanburg B, Hadley S. Invasive pulmonary aspergillosis associated with high-dose inhaled fluticasone [letter]. N Engl J Med. 2000;343:586. Fairfax AJ, David V, Douce G. Laryngeal aspergillosis following high dose inhaled fluticasone therapy for asthma. Thorax. 1999; 54:860-861. Scully RE, Mark EJ, McNeely WF, McNeely BU. Case records of the Massachussetts General Hospital. N Engl J Med. 1991;325:494504. Mandell GL, Bennett JE, Dolin R. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000:2674-2684. Hedges TR, Leung LS. Parasellar and orbital apex syndrome caused by aspergillosis. Neurology. 1976;26:117-120.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Aspergillosis Related to Nasal Corticosteroid Use
1353
Case Report
Aspergillosis Related to Long-Term Nasal Corticosteroid Use ROBERT L. BRATTON, MD; PAUL W. BRAZIS, MD; WALTER C. HELLINGER, MD; ROBERT E. WHAREN, JR, MD; AND DANIEL F. BRODERICK, MD retrobulbar optic neuropathy. After extensive differential diagnostic examination, we concluded that the condition was possibly related to the long-term use of nasal corticosteroids (fluticasone propionate aqueous nasal spray). Surgical removal of solid masses of Aspergillus organisms followed by extended treatment with antifungal agents resulted in a favorable outcome. Mayo Clin Proc. 2002;77:1353-1357
Aspergillus is a ubiquitous mold that can cause several types of symptomatic infections: allergic aspergillosis, typically in young atopic patients; aspergillomas (often referred to as fungus balls); and invasive aspergillosis, typically seen in debilitated or immunocompromised patients. We describe an 85-year-old woman who was not immunocompromised but had invasive aspergillosis of the paranasal sinus that resulted in unilateral headache and
A
REPORT OF A CASE A healthy, active 85-year-old woman presented to the primary care clinic after 5 days of left-sided, temporal headaches radiating to the left postauricular area. She described the pain as shooting and intermittent. She denied any nausea, vomiting, visual changes, fever, or chills at her initial presentation. The patient had a history of chronic allergic rhinitis and sinus headaches but believed the present headaches were different in severity and character. She denied any other neurologic symptoms and reported no rashes. Her medical history was remarkable for hypothyroidism, asthma, allergic rhinitis, and degenerative joint disease. Her medications included levothyroxine sodium and aspirin; she also took a multivitamin. The patient had been applying 2 sprays per nostril per day (200 µg/d) of a fluticasone propionate aqueous nasal spray for the past 2 years. Physical examination at her initial presentation showed no specific findings; she had no visual acuity changes, no sinus or temporal tenderness, no bruits, and no focal neurologic findings. Because of the lack of physical findings, no imaging studies were performed. The working diagnosis was atypical headache (cephalgia), different from anything she had experienced before. Temporal arteritis was a possible diagnosis based on her age and presenting symptoms, although she lacked temporal tenderness. Results of blood chemistry tests were normal, and the erythrocyte sedimentation rate was 20 mm/h (reference range, 0-29 mm/h). The patient was dismissed home and instructed to use anti-inflammatory agents for symptomatic relief. She was given specific instructions regarding warning signs that would require further evaluation. She returned 1 week later with continued severe headaches and newly developed visual deficits. The patient was referred immediately
spergillosis is a fungal infection generally acquired by inhaling airborne spores (conidia) of the ubiquitous mold Aspergillus. Thus, the most frequent site of Aspergillus infection is the respiratory system. Aspergillus fumigatus and Aspergillus flavus are the most common types of Aspergillus infection associated with human disease; their spores are found on hay, grain, decaying vegetation such as leaves or compost piles, soil, and stool. Three main types of Aspergillus infections occur in humans: allergic aspergillosis, aspergillomas, and invasive aspergillosis. The diagnosis of all 3 conditions requires histopathologic confirmation, and isolation of Aspergillus from sputum or bronchoalveolar lavage fluid suggests colonization or infection. In many patients, biopsy is necessary for definitive diagnosis. Immunocompromised or immunosuppressed patients, such as patients with acquired immunodeficiency syndrome (AIDS), patients who receive glucocorticoids or cytotoxic drugs such as cyclosporine, and patients who have an underlying malignancy or are otherwise debilitated, have an increased risk for developing Aspergillus-related infections. We describe a relatively healthy elderly woman who presented with severe headaches and visual disturbances. After an extensive differential diagnostic process involving many conditions commonly encountered in a primary care clinic and participation by various specialists, invasive aspergillosis, possibly related to long-term use of nasal corticosteroids, was identified as the cause. From the Department of Family Medicine (R.L.B.), Department of Ophthalmology (P.W.B.), Division of Infectious Diseases (W.C.H.), Department of Neurosurgery (R.E.W.), and Department of Radiology (D.F.B.), Mayo Clinic, Jacksonville, Fla. Address reprint request and correspondence to Robert L. Bratton, MD, Department of Family Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224. Mayo Clin Proc. 2002;77:1353-1357
1353
© 2002 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
1354
Aspergillosis Related to Nasal Corticosteroid Use
Figure 1. Axial T1-weighted (450/12/1 [repetition time/echo time/excitations]) magnetic resonance image shows an abnormal isointense mass at the anterosuperior aspect of the left sphenoid sinus (arrow), immediately medial and adjacent to the left optic nerve (arrowhead).
to the ophthalmology department, where examination showed a left relative afferent pupillary defect and a profound visual field deficit in the left eye. The optic nerve appeared normal. Treatment with systemic (oral) cortico-
Figure 2. Axial T1-weighted contrast-enhanced (621/12/1 [repetition time/echo time/excitations]) magnetic resonance image with fat saturation shows abnormal enhancement within the left sphenoid sinus (arrow) and lateral to the left optic nerve (arrowhead).
Mayo Clin Proc, December 2002, Vol 77
steroids (prednisone, 60 mg/d) was initiated for the presumptive diagnosis of giant cell arteritis. Bilateral temporal artery biopsies were performed the next day; results showed no evidence of temporal arteritis. The patient’s headache was completely alleviated with the high-dose corticosteroid treatment, but her vision improved only modestly. Because the visual deficits persisted after the temporal artery biopsies, further consultation was requested. Examination by a neuro-ophthalmologist confirmed a left relative afferent pupillary defect and visual field impairment consistent with retrobulbar optic neuropathy. At this point, the differential diagnosis included an infiltrative or infectious process (eg, sarcoidosis, Wegener granulomatosis, or carcinomatous meningitis). Further laboratory tests failed to identify an infiltrative disease process. The corticosteroid treatment was continued and was tapered rapidly. The patient was followed up 2 weeks later. Her headache had returned after reduction of the corticosteroid dose, and the left vision field deficit was becoming progressively worse. Because of the improvement with higher-dose corticosteroids, the prednisone dosage was increased from 10 to 20 mg/d. Magnetic resonance imaging of the orbits, performed with and without contrast, showed an abnormal enhancing mass that involved the anterosuperior aspect of the left sphenoid sinus, adjacent bone, dura mater, and possibly the meningeal covering of the left optic nerve (Figures 1-3). The patient was referred immediately to the neurosurgery department and underwent a left frontal craniotomy on the same day. Surgical exploration showed a wellcircumscribed grayish mass medial to the left optic nerve, with involvement of a thickened dura mater encasing the optic nerve and extending into the optic canal. The optic canal was decompressed by removing the optic roof. Additionally, the grayish mass and the dura mater were resected with use of microsurgical techniques. Periodic acid–Schiff and Grocott-Gomori methenamine–silver nitrate stains were positive for fungal elements that showed characteristic septa and branching. A culture of the mass grew A fumigatus. Treatment with intravenous amphotericin B was initiated. A conventional formulation of amphotericin (amphotericin B deoxycholate) was used initially at a dosage of 30 mg/d (0.5 mg/kg per day). The preparation was subsequently changed to a lipid formulation of amphotericin at a dosage of 300 mg/d (5 mg/kg per day) because of gastrointestinal adverse effects and renal insufficiency. The patient received a total of 6 weeks of amphotericin treatment in the form of either the conventional amphotericin or the amphotericin B lipid complex. To ensure eradication,
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, December 2002, Vol 77
Aspergillosis Related to Nasal Corticosteroid Use
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Figure 3. Left and Right, Coronal T1-weighted contrast-enhanced (475/12/1 [repetition time/echo time/excitations]) magnetic resonance images with fat saturation show abnormal enhancement within the left sphenoid sinus (arrow) and the overlying dura mater (arrowhead), obscuring the left optic nerve. The right optic nerve is normal (open arrow).
this treatment was followed empirically with 2 months of oral treatment with a less expensive, more easily tolerated antifungal agent (itraconazole). The patient recovered fully. Magnetic resonance imaging was repeated after completion of therapy and showed only postsurgical changes. At follow-up, the patient’s vision had improved considerably, and her headaches had resolved. DISCUSSION Our patient presented with unilateral headaches, visual field deficits, and an afferent pupillary defect. New onset of headaches can signal a potentially serious medical condition, particularly in the elderly population. The differential diagnosis is extensive and includes temporal arteritis, tumor, subdural hematoma, subarachnoid hemorrhage, uncontrolled hypertension, glaucoma, meningitis, encephalitis, and other infections or infiltrative and inflammatory conditions.1 Visual disturbances are also a serious symptom that should be evaluated further, with the differential diagnosis including cataracts, glaucoma, macular degeneration, retinal disturbances, floaters, vascular disease, neurologic disease, and infection or infiltrative and inflammatory states.2 Our patient was initially believed to have presenting signs and symptoms of an expanding tumor or an infiltrative process compressing the optic nerve. Magnetic resonance imaging of the orbits supported the diagno-
sis of an expanding neoplasm or an infiltrative process. Only after surgical resection and histopathologic confirmation was the diagnosis of a locally invasive aspergillosis infection successfully made. Of the 3 main types of Aspergillus infection, allergic aspergillosis typically affects younger atopic patients. That condition is due to immediate and late hypersensitivity reactions to Aspergillus antigens and results in classic allergic symptoms such as rhinitis, sinusitis, erythematous pruritic rashes, and wheezing; the condition may be associated with a history of nasal polyposis, asthma, and chronic rhinitis.3 Clinically important eosinophilia is often present. Radiographic examination with computed tomography shows characteristic findings of acute or chronic sinusitis with thickening or clouding of the paranasal sinuses. Rarely, in severe cases with sinus consolidation, neuroophthalmologic findings may include an afferent pupillary defect due to optic nerve compression, extraocular muscle dysfunction, periorbital edema, or proptosis. Diagnosis of allergic aspergillosis may be facilitated when Charcot-Leyden crystals (proteinaceous crystals that occur when eosinophilic leukocytes undergo fragmentation, eg, in asthma or intestinal parasitism) can be identified in mucus secretions. Case studies have shown that treatment with systemic corticosteroids and antifungal therapy is beneficial4; surgical débridement of sinus consolidation may be necessary for
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
1356
Aspergillosis Related to Nasal Corticosteroid Use
severe cases.5,6 If no evidence of invasion is found, antifungal therapy is probably unnecessary.7,8 Prognosis is usually excellent, even in patients with visual loss.4,9,10 Aspergillomas (also known as mycetomas or fungus balls) typically affect the lungs, although they may also affect the paranasal sinuses. They are usually solitary lesions that develop in healthy individuals in areas of anatomical or functional deformity and grow for months or years without symptoms or systemic spread. In most patients, unless they extend beyond the sinuses, aspergillomas that develop in the paranasal sinuses result only in nasal congestion and breathing difficulty, without evidence of infection or systemic symptoms. They are solid masses of Aspergillus organisms and are demarcated from normal tissue by varying degrees of exudate.11 The treatment is surgical excision of the solid masses followed by antifungal therapy. In some patients, particularly those with nasal aspergillomas, only surgical removal of the fungus ball is necessary.12 Most patients with solitary aspergillomas are initially thought to have a slow-growing neoplasm. In invasive aspergillosis, the portal of entry is usually the lung, where Aspergillus colonizes and gives rise to multiple necrotic granulomatous lesions. Subsequently, the infection may spread to the bloodstream and the central nervous system. Symptoms initially include fever, cough, hemoptysis, and dyspnea. Pneumonia may develop, resulting in respiratory decompensation. The differential diagnosis includes various subacute bacterial respiratory infections, nocardiosis, mycobacterial pulmonary infection, other fungal infections, and aseptic inflammatory or malignant disease processes affecting the lower respiratory tract. Treatment of invasive aspergillosis requires the use of antifungal agents, including intravenous amphotericin B or itraconazole; tapering and elimination, as far as possible, of immunosuppressive therapies; and surgical débridement when feasible. Aspergillus infections, particularly invasive aspergillosis, are most likely to occur in patients undergoing immunosuppression or who are immunocompromised, such as patients with AIDS, patients who receive glucocorticoids or cytotoxic drugs such as cyclosporine, and patients who have an underlying malignancy or are otherwise debilitated.13 Although our patient was elderly, she was not in an immunosuppressed or debilitated state. In retrospect, we surmised that the long-term use of nasal corticosteroids (fluticasone propionate) over a period of several years may have contributed to the development of Aspergillus colonization, which was followed by a local invasion. Both pulmonary and laryngeal aspergillosis have been reported after the use of inhaled (oral) fluticasone propionate.14,15 Although no reports relate the use of nasal corticosteroids to Aspergillus, the long-term use of these drugs might have contributed to
Mayo Clin Proc, December 2002, Vol 77
the growth of Aspergillus in the sinus cavity and the subsequent Aspergillus invasion. According to product information for available nasal fluticasone propionate preparations, adverse effects may include headache, pharyngitis, hoarseness, nasal burning, epistaxis, nasal congestion, and cough, and the recommended dosage had no effect on adrenal function in clinical trials. Interestingly, our patient’s condition improved with the use of high-dose oral corticosteroids. This may have been due to anti-inflammatory effects on the inflammation that likely surrounded the locally invasive aspergillosis infection. Because the diagnosis was made soon after the initiation of corticosteroid therapy and this treatment was discontinued, the immunosuppressant properties of the corticosteroids were minimized. With prolonged use of corticosteroids, the patient’s condition might have been exacerbated. A review of published literature revealed a case report of a 74-year-old man with a history of atherosclerosis and chronic lymphocytic leukemia who presented with symptoms similar to those in our patient.16 As in our patient, temporal arteritis was suspected but not confirmed. However, in contrast to our patient, the addition of corticosteroids did not improve his symptoms, and surgical excision (Lynch-type cutaneous incision) was performed. That patient was also treated with amphotericin B, but he died as a result of a streptococcal (pneumonia) infection. Aspergillus infection was present in the orbital region at the time of his death. No established guidelines exist for the duration of antifungal therapy for invasive aspergillosis. Duration of intravenous amphotericin is directed by clinical response. Oral itraconazole treatment after parenteral administration of amphotericin is often advised for immunocompromised patients and for patients with critically situated disease.17 However, mortality is high when Aspergillus infection remains untreated. If the disease is limited to the orbit, the death rate is approximately 28%; with central nervous system involvement, the death rate is 80%.18 Thus, as in our patient, early diagnosis and aggressive treatment may prevent considerable morbidity and mortality. CONCLUSIONS Nasal corticosteroids are commonly used by patients of various ages to treat chronic and allergic nasal rhinitis. Despite the drugs’ relative safety, clinicians must remain alert to potential complications that could arise from their use. In our patient, severe consequences (ie, loss of vision, cerebral aspergillosis) could have occurred had no diagnosis been made. In most patients, Aspergillus infections are treated with surgery followed by an extended course of antifungal therapy. As a result of a timely and coordinated
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effort among multiple specialties, our patient recovered without substantial deficits.
Aspergillosis Related to Nasal Corticosteroid Use
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