[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.197.65.227. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Download PDF
Figure 1.
Patient 1. Axial computed tomographic scan of a 32-year-old woman with invasive sino-orbital aspergillosis extending into left orbit and brain.

Patient 1. Axial computed tomographic scan of a 32-year-old woman with invasive sino-orbital aspergillosis extending into left orbit and brain.

Figure 2.
Patient 2. Coronal computed tomographic scan of a 35-year-old woman with invasive aspergillosis involving both ethmoid sinuses and right orbit, with intracranial extension of the infection (arrow).

Patient 2. Coronal computed tomographic scan of a 35-year-old woman with invasive aspergillosis involving both ethmoid sinuses and right orbit, with intracranial extension of the infection (arrow).

Figure 3.
Patient 3. A 38-year-old man following frontal sinus surgery with proptosis and downward displacement in the right eye secondary to invasive aspergillosis.

Patient 3. A 38-year-old man following frontal sinus surgery with proptosis and downward displacement in the right eye secondary to invasive aspergillosis.

Figure 4.
Patient 3. Histopathologic section of orbital tissue exhibits numerous hyphal elements with septae and dichotomous branching, typical of aspergillus (Gomori methenamine silver stain, original magnification ×400).

Patient 3. Histopathologic section of orbital tissue exhibits numerous hyphal elements with septae and dichotomous branching, typical of aspergillus (Gomori methenamine silver stain, original magnification ×400).

Figure 5.
Patient 3. Non–contrast-enhanced axial computed tomographic scan showing recurrent heterogeneous mass filling the right orbit and ethmoid sinus.

Patient 3. Non–contrast-enhanced axial computed tomographic scan showing recurrent heterogeneous mass filling the right orbit and ethmoid sinus.

Figure 6.
Patient 4. A 34-year-old woman nearly blind in the right eye secondary to cytomegalovirus retinitis and dense cataract, and with proptosis in the left eye due to left sino-orbital aspergillosis. A drain is in place from previous frontal sinus surgery.

Patient 4. A 34-year-old woman nearly blind in the right eye secondary to cytomegalovirus retinitis and dense cataract, and with proptosis in the left eye due to left sino-orbital aspergillosis. A drain is in place from previous frontal sinus surgery.

Figure 7.
Patient 4. Magnetic resonance imaging (T1-weighted) demonstrates hypointense lesion involving both ethmoid sinuses and invading the left orbit.

Patient 4. Magnetic resonance imaging (T1-weighted) demonstrates hypointense lesion involving both ethmoid sinuses and invading the left orbit.

Figure 8.
Patient 4. Magnetic resonance imaging (T2-weighted) also demonstrates hypointensity (arrow) of the left sino-orbital aspergilloma.

Patient 4. Magnetic resonance imaging (T2-weighted) also demonstrates hypointensity (arrow) of the left sino-orbital aspergilloma.

Figure 9.
Patient 4. Magnetic resonance imaging (T1-weighted) with gadolinium contrast shows enhancing left sino-orbital mass with areas of necrosis.

Patient 4. Magnetic resonance imaging (T1-weighted) with gadolinium contrast shows enhancing left sino-orbital mass with areas of necrosis.

Figure 10.
Patient 5. Coronal computed tomographic scan of a 31-year-old man with extensive sinus involvement with aspergillosis eroding into the right orbit and brain. Intracranial air is seen (arrow).

Patient 5. Coronal computed tomographic scan of a 31-year-old man with extensive sinus involvement with aspergillosis eroding into the right orbit and brain. Intracranial air is seen (arrow).

Clinical Summary of Patients With AIDS and Sino-orbital Aspergillosis*
Clinical Summary of Patients With AIDS and Sino-orbital Aspergillosis*
1.
Kronish  JWJohnson  TEGilberg  SMCorrent  GFMcLeish  WMScott  KR Orbital infections in patients with human immunodeficiency virus infection. Ophthalmology. 1996;1031483- 1492Article
2.
Brown  PDemaerel  PMcNaught  ARevesz  TGraham  EKendall  BEPlant  G Neuro-ophthalmological presentation of non-invasive aspergillus sinus disease in the non-immunocompromised host. J Neurol Neurosurg Psychiatry. 1994;57234- 237Article
3.
Glass  RBJHertzanu  YMendelsohn  DBPosen  J Paranasal sinus aspergillosis: a case report with computed tomogram findings. J Laryngol Otol. 1984;98199- 205Article
4.
Green  WRFont  RLZimmerman  LE Aspergillosis of the orbit: report of ten cases and review of the literature. Arch Ophthalmol. 1969;82302- 313Article
5.
Vitale  ATSpaide  RFWarren  FAMoussouris  HFD'Amico  RA Orbital aspergillosis in an immunocompromised host. Am J Ophthalmol. 1992;113725- 726
6.
Cahill  KVHogan  CDKoletar  SLGersman  M Intraorbital injection of amphotericin B for palliative treatment of aspergillosis orbital abscess. Ophthal Plast Reconstr Surg. 1994;10276- 277Article
7.
Teh  WMatti  BSMarisiddaiah  HMinamoto  GY Aspergillus sinusitis in patients with AIDS: report of three cases and review. Clin Infect Dis. 1995;21529- 535Article
8.
Meyer  RDGaultier  CRYamashita  JTBabapour  RPitchon  HEWolfe  PR Fungal sinusitis in patients with AIDS: report of 4 cases and review of the literature. Medicine. 1994;7369- 78Article
9.
Levin  LAAvery  RShore  JWWoog  JJBaker  AS The spectrum of orbital aspergillosis: a clinicopathological review. Surv Ophthalmol. 1996;41142- 154Article
10.
Rudwan  MASheikh  HA Aspergilloma of paranasal sinuses: a common cause of unilateral proptosis in Sudan. Clin Radiol. 1976;27497- 502Article
11.
Milosev  Bel-Mahgoub  SAal  AOel-Hassan  AM Primary aspergilloma of paranasal sinuses in the Sudan: a review of seventeen cases. Br J Surg. 1969;56132- 137Article
12.
Massry  GGHornblass  AHarrison  W Itraconazole in the treatment of orbital aspergillosis. Ophthalmology. 1196;1031467- 1470Article
13.
Houle  TVJEllis  PP Aspergillosis of the orbit with immunosuppressive therapy. Surv Ophthalmol. 1975;2035- 42Article
14.
Khoo  SHDenning  DW Invasive aspergillosis in patients with AIDS. Clin Infect Dis. 1994;19(suppl)S41- S48Article
15.
McGill  TJSimpson  GHealy  G Fulminant aspergillosis of the nose and paranasal sinuses: a new clinical entity. Laryngoscope. 1980;90748- 754Article
16.
Harris  GJWill  BR Orbital aspergillosis: conservative debridement and local amphotericin irrigation. Ophthalmic Plast Reconstr Surg. 1989;5207- 211Article
17.
Rosenberg  ZFFauci  AS Immunopathogenesis of HIV infection. DeVita  VTHellman  SRosenberg  SAedsAIDS: Etiology, Diagnosis, Treatment, and Prevention. 3rd ed. Philadelphia, Pa JB Lippincott1992;61- 76
18.
Germain  RN Antigen processing and CD-4+ T cell depletion in AIDS. Cell. 1988;54441Article
19.
Orellana  JLieberman  RMTeich  SA Color Atlas of Ocular Manifestations of AIDS: Diagnosis and Management.  New York, NY Igaku-Shoin Medical Publishers1995;46
20.
Kupperman  BDPetty  JGRichman  DD  et al.  Correlation between CD4+ counts and prevalence of cytomegalovirus retinitis and human immunodeficiency virus–related noninfectious retinal vasculopathy in patients with acquired immunodeficiency syndrome. Am J Opthalmol. 1993;115575- 582
21.
Zurlo  JJFeuerstein  IMLebovics  RLane  HC Sinusitis in HIV-1 infection. Am J Med. 1992;93157- 162Article
22.
Mauriello  JAYepez  NMostafavi  R  et al.  Invasive rhinosino-orbital aspergillosis with precipitous visual loss. Can J Ophthalmol. 1995;30124- 130
23.
Reifler  DMWarzynski  MJBlount  WR  et al.  Orbital lymphoma associated with acquired immune deficiency syndrome. Surv Ophthalmol. 1994;38371- 380Article
24.
Font  RLLaucirica  RPatrinely  JR Immunoblastic B-cell malignant lymphoma involving the orbit and maxillary sinus in a patient with acquired immune deficiency syndrome. Ophthalmology. 1993;100966- 970Article
25.
Zinreich  SJKennedy  DWMalat  J Fungal sinusitis: diagnosis with CT and MR imaging. Radiology. 1988;169439- 444
26.
Mansour  AM Adnexal findings in AIDS. Ophthalmic Plast Reconstr Surg. 1993;9273- 279Article
27.
Hay  RJ Liposomal amphotericin B, AmBisome. J Infect. 1994;28(suppl 1)35- 43Article
28.
Denning  DWLee  JYHostetle  JS  et al.  NIAID Mycoses Study Group Multicenter Trial of oral itraconazole therapy for invasive aspergillosis [published correction appears in Am J Med. 1994;97:497]. Am J Med. 1994;97135- 144Article
29.
Denning  DWTucker  RMHanson  LHStevens  DA Treatment of invasive aspergillosis with itraconazole. Am J Med. 1989;86791- 800Article
30.
Weber  RSLopez-Berestein  G Treatment of invasive aspergillus sinusitis with liposomal amphotericin B. Laryngoscope. 1987;97937- 941Article
31.
Deeks  SGSmith  MHolodniy  MKahn  JO HIV-1 protease inhibitors: a review for clinicians. JAMA. 1997;277145- 153Article
32.
Murphy  MArmstrong  DSepkowitz  KAAhkami  RNMyskowski  PL Regression of AIDS-related Kaposi's sarcoma following treatment with an HIV-1 protease inhibitor. AIDS. 1997;11261- 262
33.
Reed  JBSchwab  IRGordon  JMorse  LS Regression of cytomegalovirus retinitis associated with protease-inhibitor treatment in patients with AIDS. Am J Ophthalmol. 1997;124199- 205
34.
Zingman  BS Resolution of refractory AIDS-related mucosal candidiasis after initiation of didanosine plus saquinavir. N Engl J Med. 1996;3341674- 1675Article
35.
Stephenson  J The art of "HAART": researchers probe the potential and limits of aggressive HIV treatments. JAMA. 1997;277614- 616Article
36.
Ferry  APAbedi  S Diagnosis and management of rhino-orbitocerebral mucormycosis (phycomycosis): a report of 16 personally observed cases. Ophthalmology. 1983;901096- 1104Article
37.
Chusid  MJGelfand  JANutter  CFauci  AS Pulmonary aspergillosis, inhalation of contaminated marijuana smoke, chronic granulomatous disease. Ann Intern Med. 1975;82682- 683Article
38.
Llamas  RHart  DRSchneider  NS Allergic bronchopulmonary aspergillosis associated with smoking moldy marihuana. Chest. 1978;73871- 872Article
39.
Kagen  SL Aspergillus: an inhalable contaminant of marihuana. N Engl J Med. 1981;304483- 484
40.
Marks  WHFlorence  LLieberman  J  et al.  Successfully treated invasive pulmonary aspergillosis associated with smoking marijuana in a renal transplant recipient. Transplantation. 1996;611771- 1774Article
Clinical Sciences
January 1999

Sino-orbital Aspergillosis in Acquired Immunodeficiency Syndrome

Author Affiliations

From the Department of Ophthalmology, Bascom Palmer Eye Institute (Drs Johnson, Kronish, Tse, Meldrum, and Chang), and the Department of Otolaryngology, University of Miami School of Medicine (Dr Casiano), Miami, Fla.

Arch Ophthalmol. 1999;117(1):57-64. doi:10.1001/archopht.117.1.57
Abstract

Objective  To describe the clinical features, causes, imaging characteristics, treatment, and outcome of patients with the acquired immunodeficiency syndrome (AIDS) and sino-orbital aspergillosis.

Design  Records of 5 patients were reviewed. Results of imaging and histopathologic examinations and clinical courses of the patients were studied.

Results  There were 3 women and 2 men (mean age, 34.0 years). All had received a diagnosis of AIDS, and mean CD4+ cell count was 0.014×109/L (14 cells/mm3). Computed tomographic scanning exhibited heterogeneous, enhancing sino-orbital soft tissue lesions with bony erosion, and magnetic resonance imaging disclosed soft tissue masses hypointense on T1- and T2-weighted images. The infection involved 1 or more paranasal sinuses, with extension into the right orbit in 3 patients and into the left orbit in 2. Patients were treated with aggressive surgical debridement and intravenous antifungal agents. In addition, local irrigation of amphotericin B was performed in 3 patients. Aspergillus fumigatus was found to be the cause in all 5 patients. Intracranial extension developed in 4 patients, and all subsequently died. The 2 longest surviving patients were the only ones being treated with protease inhibitors. Three patients had a history of frequent marijuana smoking.

Conclusions  Sino-orbital aspergillosis is a progressive, relentless, and usually fatal opportunistic infection of advanced AIDS. Patients are first seen with longstanding headache and proptosis with minimal external inflammatory signs. Marijuana smoking may increase the risk for development of sino-orbital aspergillosis in these patients. Aggressive surgical and medical treatment, combined with newer combination therapies using protease inhibitors, may improve the longevity of these patients.

ORBITAL INFECTIONS are relatively uncommon in patients infected with the human immunodeficiency virus (HIV), but when present, they cause significant morbidity and mortality.1Aspergillus, a fungus ubiquitous in our environment, can cause noninvasive or invasive infections in immunocompetent and immunocompromised patients.24 Recently, the association between acquired immunodeficiency syndrome (AIDS) and sino-orbital aspergillosis has been described.1,58 We reviewed 5 patients with sino-orbital aspergillosis and AIDS and studied the predisposing factors, clinical presentations, imaging characteristics, treatments, and outcomes.

PATIENTS AND METHODS

The 5 patients with AIDS and sino-orbital aspergillosis underwent evaluation and treatment at the University of Miami Bascom Palmer Eye Institute and Jackson Memorial Hospital, Miami, Fla, from January 1, 1994, to December 31, 1998. All patients underwent a complete history, physical examination, and ophthalmic evaluation. Diagnostic tests included CD4+ lymphocyte counts; computed tomographic (CT) scans of the sinuses, orbits, and brain; and fungal cultures of surgically excised tissues. Magnetic resonance imaging (MRI) was performed in 3 patients.

RESULTS

We studied 3 women and 2 men with a mean age of 34 years at initial examination. All patients had received a previous diagnosis of AIDS and had been seropositive for HIV from 3 to 10 years (mean duration, 6.4 years). The mean CD4+ cell count was 0.014×109/L (14 cells/mm3). The infections involved 1 or more paranasal sinuses and extended into the right orbit in 3 patients and into the left orbit in 2. Computed tomographic findings included heterogeneous, enhancing sino-orbital masses with bony destruction and calcifications; MRI exhibited soft tissue–enhancing masses, hypointense on T1- and T2-weighted images. None of the patients had concomitant pulmonary infection. Surgical excision or debulking of the sino-orbital mass was performed in all patients, and tissue was cultured and examined histopathologically. Fungal cultures in all patients yielded Aspergillus fumigatus, and secondary bacterial infections were found in 3 patients. All patients were treated with systemic antifungal agents in the perioperative period, and all were available for follow-up. Intracranial extension developed in 4 patients. Three were found to have intracranial extension at initial examination, and intracranial spread developed later in the other one, despite aggressive therapy. All 4 patients with intracranial extension died of fungal proliferation, refractory to aggressive therapies. Only 1 patient is still alive. Two patients underwent orbital exenteration. Intracranial extension developed in 1 of these patients 7 months after sinus and orbital exenteration, and orbital recurrences developed in the other patient 3, 6, and 12 months after initial surgical debridement. The second patient finally underwent orbital exenteration (Table 1).

REPORT OF CASES
PATIENT 1

A 32-year-old woman sought care because of a 4-month history of headache and a recent onset of nausea, vomiting, and decreased vision in the left eye. She had been seropositive for HIV for 4 years and had a CD4+ cell count of 0.010×109/L (10 cells/mm3). Previous AIDS-related diseases included Pneumocystis carinii pneumonia, disseminated Mycobacterium avium-intracelluare complex, cryptococcal meningitis, recurrent varicella zoster, and herpes zoster ophthalmicus in the right eye. Her social history included frequent marijuana smoking. Endoscopic biopsy of the ethmoid sinus performed previously at a community hospital revealed a fungal sinusitis. On admission, her visual acuity was 20/30 OD and 20/50 OS. There was 3 mm of left axial proptosis and a left afferent pupillary defect. Ocular motility was restricted in all fields in the left eye, and results of funduscopic examination revealed a swollen left optic disc. Orbital CT scan showed a soft tissue mass with bony destruction involving ethmoid and sphenoid sinuses, extending into the medial left orbit and brain (Figure 1). An endoscopic bilateral total ethmoidectomy, septectomy, sphenoid and frontal sinusotomy, orbital decompression, and debulking of the intraorbital and intracranial mass were performed. Fungal cultures yielded A fumigatus, and bacterial cultures disclosed a light growth of Pseudomonas aeruginosa. Intravenous amphotericin B, at doses of 25 to 35 mg/d, was administered, and daily transnasal sinus irrigation with amphotericin B (1 mg/mL) was performed. In addition, intravenous ofloxacillin was given. She remained disease free for 12 months, but then began experiencing severe right-sided headaches, and MRI disclosed an abscess of the right frontal lobe. Despite debridement of the abscess and treatment with systemic amphotericin B, she died 2 months later of intracranial extension of the infection.

PATIENT 2

A 35-year-old woman was first seen by us with fever and right periorbital swelling for 1 month. She had a history of chronic sinusitis, had been seropositive for HIV for 4 years, and had a CD4+ cell count of 0.001×109/L (1 cell/mm3). On admission, her visual acuity was 20/20 OU. She had 5 mm of right axial proptosis, without an afferent pupillary defect. Ocular motility was restricted on upgaze in the right eye. Results of funduscopic examination revealed scattered cotton-wool spots in both eyes. An orbital CT scan showed an enhancing lesion involving both ethmoid sinuses with bony destruction and intracranial and right intraorbital extension (Figure 2). She underwent bilateral endoscopic ethmoidectomy, right medial orbitotomy, and intravenous amphotericin B therapy at doses of 50 to 70 mg/d. In addition, local irrigation with amphotericin B was performed. A potassium hydroxide wet mount revealed fungal elements, and fungal cultures yielded A fumigatus. Bacterial cultures showed a light growth of coagulase-negative Staphylococcus. She died of recurrent intracranial disease involving the left frontal lobe 7 months later.

PATIENT 3

A 38-year-old man who had been seropositive for HIV for 11 years and had a CD4+ count of 0.012×109/L (12 cells/mm3) was first seen by us with pain in the right eye, proptosis, and epistaxis of 1 month's duration in April 1996. His social history was positive for frequent marijuana smoking. Past AIDS-related illnesses included systemic lymphoma and cytomegalovirus (CMV) retinitis in the right eye. Previous frontal sinus surgery revealed invasive aspergillosis. On admission, he was afebrile, and visual acuity was 20/40 OD and 20/20 OS. The right eye revealed 5 mm of proptosis and displacement down and out, with minimal external inflammation (Figure 3). A CT scan showed opacification of the right frontal, ethmoid, and sphenoid sinuses, with a dehiscence of the right orbital roof and intraorbital extension of the mass. He underwent a right endoscopic total ethmoidectomy, frontal and sphenoid sinusotomy, and right orbitotomy with debulking of the lesion. Fungal cultures yielded A fumigatus, and results of histopathologic examination showed typical Aspergillus hyphae. (Figure 4). After several debulking surgeries and treatment with intravenous and local irrigation of amphotericin B, he lost all light perception in the right eye due to massive orbital and sinus recurrence (Figure 5). He underwent orbital and sinus exenteration in May 1997. During hospitalization, he was treated with intravenous amphotericin B lipid complex at a dose of 300 mg/d, and started oral itraconazole therapy, 300 mg twice a day, which he continued after discharge. Seven months later, he was found to have asymptomatic intracranial extension on MRI. He underwent a craniotomy with extensive debridement of the infection in December 1997, and cultures confirmed infection with A fumigatus. He was without clinical evidence of disease in June 1998, and was being treated with weekly socket irrigation with amphotericin B, 50 mg/50 mL. His systemic medications include saquinavir mesylate, a protease inhibitor, started in June 1996; 2 nucleoside reverse transcriptase inhibitors, stavudine and lamivudine; and oral itraconazole. In October 1997, his CD4+ count had increased to 0.148×109/L (148 cells/mm3), and viral load (HIV-1 RNA detected using polymerase chain reaction analysis) was less than 400 RNA copies/mL, considered nondetectable. Recurrent intracranial disease developed in July 1998, and he underwent repeated craniotomy with debridement, but he died of intracranial extension in August 1998.

PATIENT 4

A 34-year-old woman was first seen by us in July 1997 with severe pain in the left eye of 4 weeks' duration and a 6-month history of severe headaches, sinus problems, and left-sided proptosis. She had been seropositive for HIV for at least 10 years, and her CD4+ count was 0.037×109/L (37 cells/mm3). Her social history was positive for frequent marijuana smoking. Previous AIDS-related illnesses included P carinii pneumonia and CMV retinitis in the right eye. On admission, she was afebrile with visual acuity of light perception in the right eye and 20/25 OS. There was a right exotropia, as well as a dense cataract and afferent pupillary defect in the right eye. The left eye revealed 4 mm of proptosis with minimal inflammatory signs (Figure 6). Magnetic resonance imaging showed an enhancing soft tissue mass involving both ethmoid sinuses with extension into the left orbit (Figure 7, Figure 8, and Figure 9). She underwent endoscopic total ethmoidectomy, frontal sinusotomy, and orbital decompression. Fungus cultures yielded A fumigatus. Three months following sinus and orbital drainage, and despite daily intravenous liposomal amphotericin B therapy, recurrent orbital disease developed, and she underwent repeated medial orbitotomy and debridement. Another recurrence developed 3 months later, and she underwent an inferior orbitotomy with debridement. Fungal cultures yielded A fumigatus, and bacterial cultures were negative. She continued treatment with daily intravenous amphotericin B lipid complex at a dose of 5 mg/kg per day. Her systemic medications also included indinavir sulfate, a protease inhibitor started in May 1997, and zidovudine and lamivudine. Her HIV-1 RNA level was 100,222 copies/mL in December 1997. Another orbital recurrence developed in April 1998, and she underwent lateral orbitotomy with drainage of liquid pus and removal of copious cheesy material. Fungal cultures again yielded A fumigatus, and bacterial cultures were negative. There was no evidence of intracranial extension. Despite continuous therapy with liposomal amphotericin B, massive recurrent disease developed in her left orbit, she lost all light perception, and she underwent orbital exenteration in August 1998.

PATIENT 5

A 31-year-old man was first seen by us with facial pain and swelling for 5 days, proptosis and blurred vision in the right eye for 3 days, fever for 24 hours, and epistaxis. He had been seropositive for HIV for 3 years and had a CD4+ count of 0.011×109/L (11 cells/mm3). He stopped taking all antiviral medications 2 weeks before admission. He denied any history of marijuana smoking. Previous AIDS-related illnesses included P carinii pneumonia. He was febrile with a temperature of 38.5°C (101.3°F). Visual acuity was 20/25−3 OD and 20/20 OS. His right eye revealed 4 mm of proptosis, with decreased abduction and without afferent pupillary defect. Computed tomographic scan showed bilateral opacification of the ethmoid, maxillary, and sphenoid sinuses, with right intraorbital extension. Erosion of the cribriform plate and intracranial extension with intracranial air were present (Figure 10). He underwent endoscopic bilateral total ethmoidectomies; maxillary, frontal, and sphenoid sinusotomies; and orbital and intracranial decompression. A potassium hydroxide wet mount of excised tissues showed septate hyphae consistent with Aspergillus, and fungal cultures yielded A fumigatus. Bacterial cultures disclosed a moderate growth of P aeruginosa and light growth of coagulase-negative Staphylococcus. Despite intensive treatment with systemic amphotericin B, with doses ranging from 30 to 70 mg/d, and broad-spectrum intravenous antibiotics, he died of progressive intracranial disease 2 weeks later.

COMMENT

Aspergillus is usually considered a harmless saprophyte, which is ubiquitous in our environment.3 It uncommonly causes infection in immunocompetent hosts, where it can be invasive or noninvasive. Noninvasive infections include allergic Aspergillus sinusitis and sinonasal aspergilloma.9 Most invasive infections in immunocompetent individuals have been reported from hot humid climates and Sudan,4,10 where the infection starts in the paranasal sinuses and initiates a fibrosing, granulomatous reaction.4 Secondary orbital and intracranial extension is due to the slow, progressive, and often painless nature of the disease.1012Aspergillus flavus is the usual causative organism.10 This invasive fungal infection is difficult to eradicate using surgical debridement combined with systemic and local antifungal agents, and there is a high mortality rate due to intracranial extension.4

Invasive aspergillosis occurs more often in immunocompromised hosts, including patients undergoing transplantation, neutropenic patients receiving chemotherapy,13 and patients with AIDS.14 Pulmonary infections are the most common,14 but other organs can be infected, including brain, paranasal sinuses, and orbit. Immunocompromised individuals can have a slowly progressive or an abrupt onset of orbital inflammation, proptosis, and pain.9,13,15 Fulminant Aspergillus infection of the nose, paranasal sinuses, and orbit, often associated with intracranial extension, has been reported to develop in immunocompromised patients without AIDS.15 Treatment includes extensive surgical debridement and/or exenteration, combined with aggressive intravenous antifungal treatment and local irrigation or packing with amphotericin B. Despite this aggressive therapy, the mortality rate is high.16

Infection with HIV results in a selective loss of a critical component of the immune system, the population of T-helper (CD4+) lymphocytes, and low CD4+ cell counts are associated with the development of opportunistic infections.17,18 Most patients with AIDS and CMV retinitis have CD4+ counts below 0.050×109/L (50 cells/mm3).19,20 Sinusitis is common in HIV-infected patients,21 and fungal sinusitis more commonly affects patients in the later stages of AIDS, when the CD4+ count is less than 0.050×109/L (50 cells/mm3). Aspergillus is the usual fungal pathogen.8

The clinical findings in our patients with AIDS and sino-orbital aspergillosis were usually not abrupt, but slowly progressive. Most patients complained of moderate to severe headaches, which preceded the onset of proptosis, visual changes, and motility disturbances by months. All 5 patients had advanced AIDS, and the mean CD4+ count was 0.014×109/L (14 cells/mm3). On clinical examination, there were minimal external inflammatory signs. Visual acuity was minimally affected, with visual acuity on initial examination ranging from 20/20 to 20/50. It appears that patients with AIDS and invasive sino-orbital aspergillosis have a different clinical course compared with those not infected with HIV. Mauriello et al22 described 5 patients without AIDS and with invasive sino-orbital aspergillosis. Risk factors in their patients included alcohol abuse, steroid therapy, diabetes mellitus, and advanced age. Their patients had the abrupt onset of proptosis and debilitating periorbital pain, with precipitous visual loss. Similar to our patients with AIDS, their patients showed minimal external inflammatory signs, fungal cultures in all yielded A fumigatus, and secondary bacterial infections developed in many.22

Imaging studies are helpful in differentiating sino-orbital aspergillosis from other disease processes. Findings on CT scans included heterogeneous soft tissue masses with bony erosion and calcifications. Orbital lymphoma in patients with AIDS can be accompanied by bone erosion also, when the tumor extends to or from a paranasal sinus.23,24 Magnetic resonance imaging exhibited contrast-enhancing soft tissue sino-orbital masses hypointense on T1- and T2-weighted images, with surrounding mucosal inflammation. Zinreich et al25 described CT and MRI findings in patients with fungal sinusitis and found fungal sinusitis to be characterized by serpiginous areas of increased attenuation on CT scan. The heterogeneous image may be attributable to the presence of iron, manganese, or calcium in fungal concretions. Bone destruction is thought to be due to pressure necrosis and destructive effects by multiple mediators of inflammation released by eosinophils. Magnetic resonance imaging demonstrates contrast-enhancing lesions, which are hypointense on both T1- and T2-weighted images, surrounded by mucosal inflammation. In contrast, neoplasms and bacterial infections are hyperintense on T2-weighted images.25

Definitive diagnosis of aspergillosis is based on fungal culture findings, and all 5 of our patients were found to be infected with A fumigatus. A potassium hydroxide preparation is useful in confirming a fungal infection while awaiting final culture results. Two previous case reports of sino-orbital aspergillosis in patients with AIDS found A fumigatus to be the causative organism,5,6 and another study found 13 of 14 patients with AIDS and Aspergillus sinusitis were also infected with A fumigatus.7 In addition, bacterial cultures of the orbit and sinuses yielded positive results in 3 patients in this study, including infections with P aeruginosa and coagulase-negative Staphylococcus. All patients were treated with broad-spectrum intravenous antibiotics during the perioperative period.

ORBITAL INFECTIONS are uncommon in patients with AIDS, whereas opportunistic infections involving the eye occur much more frequently.1 The differential diagnosis in an HIV-infected individual with an orbital mass includes lymphoma, bacterial orbital cellulitis, orbital cellulitis due to toxoplasmic panophthalmitis, orbital infection with P carinii, and sino-orbital aspergillosis.26

Treatment of invasive sino-orbital aspergillosis involves aggressive surgical debridement combined with systemic antifungal agents.12 Intravenous amphotericin B has been the mainstay of medical therapy, but toxic side effects, especially renal, require discontinuing the medication in some patients. New systemic antifungal medications include liposomal amphotericin B preparations, with fewer renal toxic effects,27 and oral itraconazole.12,28,29 Liposomal amphotericin B, a formulation of liposome-encapsulated amphotericin B, was reported to be successful in the treatment of Aspergillus rhinosinusitis after therapy with conventional amphotericin B failed.30 Oral itraconazole, a synthetic triazole antifungal agent, is an alternative therapy for invasive aspergillosis, and response rates are reported to be comparable with those of amphotericin B.28 This medication was successfully used in the treatment of recurrent sino-orbital aspergillosis in an immunocompetent woman after combined surgery and intravenous amphotericin B failed, and was recommended for use in patients who are unable to tolerate amphotericin B.12 Adjuvant local irrigation of amphotericin B also has been recommended.16 For patients unable or unwilling to undergo surgery, intralesional injection of amphotericin B has been used successfully as a palliative treatment.6 Four patients in our series were treated in the perioperative period with intravenous amphotericin B. Two were later treated with intravenous liposomal amphotericin B and continued to receive this medication at home after discharge from the hospital. Both of the surviving patients have been maintained with oral itraconazole after discontinuation of intravenous liposomal amphotericin B therapy. Three patients underwent frequent sinus and orbital irrigation with amphotericin B at a concentration of 1 mg/mL.

Patients with AIDS and invasive pulmonary aspergillosis have a dismal prognosis, usually dying within 2 to 4 months of diagnosis.14 Patients with AIDS and sino-orbital aspergillosis are also reported to have a poor prognosis, with most dying of intracranial extension even after aggressive medical and surgical treatment.1,57 Teh et al7 described 3 patients with AIDS and invasive Aspergillus sinusitis, and reviewed 15 additional patients described in the literature. Seven of the 18 had brain involvement, 3 had orbital extension, 3 had concomitant invasive pulmonary aspergillosis, and 6 had a history of sinusitis. Despite aggressive surgical intervention and systemic antifungal therapy, nearly all patients died as a result of aspergillosis.7 Intracranial extension of the infection developed in 4 patients in our study, and all 4 have died as a result. Recently, a new class of compounds, HIV-1 protease inhibitors, have been found to suppress HIV-1 replication, reduce HIV disease progression, and reduce mortality in patients with AIDS when used in combination with reverse transcriptase inhibitors.31 Regression of AIDS-related Kaposi sarcoma, CMV retinitis, and refractory AIDS-related mucosal candidiasis have been reported following treatment with protease inhibitors.3234 These new drug combinations that include a potent protease inhibitor are called "highly active antiretroviral therapy (HAART)."35 The 2 patients in our study who survived the longest after diagnosis with this infection were the only 2 who had been treated with protease inhibitors combined with other antiretroviral medications. Both started therapy with protease inhibitors after the diagnosis of sino-orbital aspergillosis had already been made. This infection did not develop in any patient while taking protease inhibitors. The 3 patients who were never treated with protease inhibitors all died from 3 weeks to 14 months (average, 26 weeks) after diagnosis with this infection. One patient treated with a protease inhibitor survived 28 months, and the only remaining living patient has survived 13 months after diagnosis with sino-orbital aspergillosis. Although these numbers are small, these data indicate that combination therapy with protease inhibitors may improve the longevity of patients with AIDS and sino-orbital aspergillosis. The longest surviving patients were not cured of this devastating infection, but the length and quality of their lives were enhanced by offering an aggressive surgical debridement approach, supplemented with systemic and local antifungal agents and newer antiretroviral combination therapies.

Orbital exenteration is often required in the treatment of debilitated patients with another sino-orbital fungal infection, mucormycosis. These patients can survive if the underlying metabolic abnormality is corrected, systemic antifungal agents are administered, and infected tissue is excised.36 Due to the relentless progression of sino-orbital aspergillosis in AIDS with frequent development of intracranial extension, one must consider the role of early orbital exenteration. The 2 longest-surviving patients in our study required sino-orbital exenteration after a blind, painful eye with massive orbital involvement developed, both having undergone multiple orbital debridements. One survived more than 1 year after exenteration before dying of intracranial extension. The only remaining living patient had aspergillosis localized in the orbit containing her only seeing eye, having lost all vision in the other eye from complications of CMV retinitis, and it was difficult to justify early exenteration. However, she too eventually lost all light perception and required orbital exenteration for relief of pain. Further study is needed to determine if early exenteration of the sinuses and orbit can possibly eradicate this infection in HIV-infected individuals.

Marijuana smoking may increase the risk for development of sino-orbital aspergillosis.3740 Marijuana can be a highly contaminated source of Aspergillus.39,40 This fungus has been cultured from marijuana cigarettes.39 Marijuana has been considered the likely source of infection in immunocompromised patients with invasive pulmonary aspergillosis40 or allergic bronchopulmonary aspergillosis.38 Three of our patients admitted to habitual use of marijuana. One patient was not specifically asked about marijuana use, but had a history of intravenous drug use and may have smoked marijuana. One patient denied marijuana use. Patients with advanced AIDS, especially those with low CD4+ counts, should be warned of the possible association between marijuana smoking and the development of invasive aspergillosis.

Back to top
Article Information

Accepted for publication September 16, 1998.

This investigation was supported in part by Research to Prevent Blindness Inc, New York, NY.

Abstract presented in poster form at the 28th Annual Scientific Symposium of the American Society of Ophthalmic Plastic and Reconstructive Surgery, San Francisco, Calif, October 25, 1997.

Corresponding author: Thomas E. Johnson, MD, 900 NW 17th St, Miami, FL 33136 (e-mail: tjohnson@bpei.med.miami.edu).

References
1.
Kronish  JWJohnson  TEGilberg  SMCorrent  GFMcLeish  WMScott  KR Orbital infections in patients with human immunodeficiency virus infection. Ophthalmology. 1996;1031483- 1492Article
2.
Brown  PDemaerel  PMcNaught  ARevesz  TGraham  EKendall  BEPlant  G Neuro-ophthalmological presentation of non-invasive aspergillus sinus disease in the non-immunocompromised host. J Neurol Neurosurg Psychiatry. 1994;57234- 237Article
3.
Glass  RBJHertzanu  YMendelsohn  DBPosen  J Paranasal sinus aspergillosis: a case report with computed tomogram findings. J Laryngol Otol. 1984;98199- 205Article
4.
Green  WRFont  RLZimmerman  LE Aspergillosis of the orbit: report of ten cases and review of the literature. Arch Ophthalmol. 1969;82302- 313Article
5.
Vitale  ATSpaide  RFWarren  FAMoussouris  HFD'Amico  RA Orbital aspergillosis in an immunocompromised host. Am J Ophthalmol. 1992;113725- 726
6.
Cahill  KVHogan  CDKoletar  SLGersman  M Intraorbital injection of amphotericin B for palliative treatment of aspergillosis orbital abscess. Ophthal Plast Reconstr Surg. 1994;10276- 277Article
7.
Teh  WMatti  BSMarisiddaiah  HMinamoto  GY Aspergillus sinusitis in patients with AIDS: report of three cases and review. Clin Infect Dis. 1995;21529- 535Article
8.
Meyer  RDGaultier  CRYamashita  JTBabapour  RPitchon  HEWolfe  PR Fungal sinusitis in patients with AIDS: report of 4 cases and review of the literature. Medicine. 1994;7369- 78Article
9.
Levin  LAAvery  RShore  JWWoog  JJBaker  AS The spectrum of orbital aspergillosis: a clinicopathological review. Surv Ophthalmol. 1996;41142- 154Article
10.
Rudwan  MASheikh  HA Aspergilloma of paranasal sinuses: a common cause of unilateral proptosis in Sudan. Clin Radiol. 1976;27497- 502Article
11.
Milosev  Bel-Mahgoub  SAal  AOel-Hassan  AM Primary aspergilloma of paranasal sinuses in the Sudan: a review of seventeen cases. Br J Surg. 1969;56132- 137Article
12.
Massry  GGHornblass  AHarrison  W Itraconazole in the treatment of orbital aspergillosis. Ophthalmology. 1196;1031467- 1470Article
13.
Houle  TVJEllis  PP Aspergillosis of the orbit with immunosuppressive therapy. Surv Ophthalmol. 1975;2035- 42Article
14.
Khoo  SHDenning  DW Invasive aspergillosis in patients with AIDS. Clin Infect Dis. 1994;19(suppl)S41- S48Article
15.
McGill  TJSimpson  GHealy  G Fulminant aspergillosis of the nose and paranasal sinuses: a new clinical entity. Laryngoscope. 1980;90748- 754Article
16.
Harris  GJWill  BR Orbital aspergillosis: conservative debridement and local amphotericin irrigation. Ophthalmic Plast Reconstr Surg. 1989;5207- 211Article
17.
Rosenberg  ZFFauci  AS Immunopathogenesis of HIV infection. DeVita  VTHellman  SRosenberg  SAedsAIDS: Etiology, Diagnosis, Treatment, and Prevention. 3rd ed. Philadelphia, Pa JB Lippincott1992;61- 76
18.
Germain  RN Antigen processing and CD-4+ T cell depletion in AIDS. Cell. 1988;54441Article
19.
Orellana  JLieberman  RMTeich  SA Color Atlas of Ocular Manifestations of AIDS: Diagnosis and Management.  New York, NY Igaku-Shoin Medical Publishers1995;46
20.
Kupperman  BDPetty  JGRichman  DD  et al.  Correlation between CD4+ counts and prevalence of cytomegalovirus retinitis and human immunodeficiency virus–related noninfectious retinal vasculopathy in patients with acquired immunodeficiency syndrome. Am J Opthalmol. 1993;115575- 582
21.
Zurlo  JJFeuerstein  IMLebovics  RLane  HC Sinusitis in HIV-1 infection. Am J Med. 1992;93157- 162Article
22.
Mauriello  JAYepez  NMostafavi  R  et al.  Invasive rhinosino-orbital aspergillosis with precipitous visual loss. Can J Ophthalmol. 1995;30124- 130
23.
Reifler  DMWarzynski  MJBlount  WR  et al.  Orbital lymphoma associated with acquired immune deficiency syndrome. Surv Ophthalmol. 1994;38371- 380Article
24.
Font  RLLaucirica  RPatrinely  JR Immunoblastic B-cell malignant lymphoma involving the orbit and maxillary sinus in a patient with acquired immune deficiency syndrome. Ophthalmology. 1993;100966- 970Article
25.
Zinreich  SJKennedy  DWMalat  J Fungal sinusitis: diagnosis with CT and MR imaging. Radiology. 1988;169439- 444
26.
Mansour  AM Adnexal findings in AIDS. Ophthalmic Plast Reconstr Surg. 1993;9273- 279Article
27.
Hay  RJ Liposomal amphotericin B, AmBisome. J Infect. 1994;28(suppl 1)35- 43Article
28.
Denning  DWLee  JYHostetle  JS  et al.  NIAID Mycoses Study Group Multicenter Trial of oral itraconazole therapy for invasive aspergillosis [published correction appears in Am J Med. 1994;97:497]. Am J Med. 1994;97135- 144Article
29.
Denning  DWTucker  RMHanson  LHStevens  DA Treatment of invasive aspergillosis with itraconazole. Am J Med. 1989;86791- 800Article
30.
Weber  RSLopez-Berestein  G Treatment of invasive aspergillus sinusitis with liposomal amphotericin B. Laryngoscope. 1987;97937- 941Article
31.
Deeks  SGSmith  MHolodniy  MKahn  JO HIV-1 protease inhibitors: a review for clinicians. JAMA. 1997;277145- 153Article
32.
Murphy  MArmstrong  DSepkowitz  KAAhkami  RNMyskowski  PL Regression of AIDS-related Kaposi's sarcoma following treatment with an HIV-1 protease inhibitor. AIDS. 1997;11261- 262
33.
Reed  JBSchwab  IRGordon  JMorse  LS Regression of cytomegalovirus retinitis associated with protease-inhibitor treatment in patients with AIDS. Am J Ophthalmol. 1997;124199- 205
34.
Zingman  BS Resolution of refractory AIDS-related mucosal candidiasis after initiation of didanosine plus saquinavir. N Engl J Med. 1996;3341674- 1675Article
35.
Stephenson  J The art of "HAART": researchers probe the potential and limits of aggressive HIV treatments. JAMA. 1997;277614- 616Article
36.
Ferry  APAbedi  S Diagnosis and management of rhino-orbitocerebral mucormycosis (phycomycosis): a report of 16 personally observed cases. Ophthalmology. 1983;901096- 1104Article
37.
Chusid  MJGelfand  JANutter  CFauci  AS Pulmonary aspergillosis, inhalation of contaminated marijuana smoke, chronic granulomatous disease. Ann Intern Med. 1975;82682- 683Article
38.
Llamas  RHart  DRSchneider  NS Allergic bronchopulmonary aspergillosis associated with smoking moldy marihuana. Chest. 1978;73871- 872Article
39.
Kagen  SL Aspergillus: an inhalable contaminant of marihuana. N Engl J Med. 1981;304483- 484
40.
Marks  WHFlorence  LLieberman  J  et al.  Successfully treated invasive pulmonary aspergillosis associated with smoking marijuana in a renal transplant recipient. Transplantation. 1996;611771- 1774Article
×