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From theIndia (E.A.(NRCOP) (Oncology (SFacial AesthIndia (V.MOphthalmolOculoplasticSight, Jaipur

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0002-9394/$http://dx.doi.

Isolated Orbital Aspergillosis inImmunocompetent Patients: AMulticenter Study

EKTA AGGARWAL, KAUSTUBH MULAY, VIKAS MENON, GANGADHARA SUNDAR, SANTOSH G. HONAVAR,AND MUKESH SHARMA

� OBJECTIVE: To report clinicopathologic features,radiologic findings, and treatment outcomes of isolated,orbital aspergillosis.� DESIGN: Multicenter, retrospective case series.� METHODS: SETTING: Multicenter. PARTICIPANTS: Therewere 8 lesions in 8 eyes of 8 patients with isolated, orbitalaspergillosis. PROCEDURE: Review of medical records andhistopathology slides. MAIN OUTCOME MEASURES: Diseasecontrol.� RESULTS: Of 34 patients with orbital aspergillosis, 8(23.5%) had isolated orbital involvement at presentation.The mean age at presentation was 34.5 years (median, 43years: range, 0.5–72 years). Gradually progressive prop-tosis and eyelid swelling were the most common present-ing features (each 4/8). Proptosis ranged from 4 mm to9 mm (median, 5.5 mm; mean, 5.75 mm). Restrictionof ocular motility was seen in all 8 patients. Other exam-ination findings included palpable mass (2/8), conjunc-tival chemosis (2/8), hyperglobus (1/8), hypoglobus (1/8), and resistance to retropulsion (1/8). Microbial cultureresults were available in 1 patient and showedAspergillusfumigatus. Two patients were treated with complete sur-gical excision alone while 6 were treated with antifungalmedications. Complete resolution of proptosis and resto-ration of ocular motility were seen in all patientsfollowing treatment. Visual disturbances present in 1were corrected following treatment. Recurrence wasobserved in 1 patient.� CONCLUSION: Isolated orbital aspergillosis, thoughrare, should be considered in the differential diagnosisof a patient presenting with a gradually progressive orbitalmass, especially in Asian individuals. Early recognitionwill help reduce the morbidity and mortality associatedwith this disease. (Am J Ophthalmol 2016;165:125–132. � 2016 Elsevier Inc. All rights reserved.)

upplemental Material available at AJO.com.r publication Mar 4, 2016.Drishti Eye Care and Vasan Eye Care Hospitals, Hyderabad,); National Reporting Centre for Ophthalmic PathologyK.M.) and Oculoplastics, Facial Aesthetics and Ocular.G.H.), Centre For Sight, Hyderabad, India; Oculoplastics,etics and Ocular Oncology, Centre For Sight, New Delhi,.); Orbit and Oculofacial Surgery, Department ofogy, National University Hospital, Singapore (G.S.); ands, Facial Aesthetics and Ocular Oncology, Centre For, India (M.S.).o Ekta Aggarwal, Drishti Eye Care, 114/A, Srinagar Colony,da, Hyderabad 500082, India; e-mail: drektaoph@gmail.com

36.00org/10.1016/j.ajo.2016.03.007

� 2016 ELSEVIER INC. A

ASPERGILLOSIS IS A MULTIFACETED DISEASE CAUSED

by fungi of the genusAspergillus.Aspergillus spp. areubiquitous, spore-forming, dichotomously branch-

ing fungi often found in dampened soil, humid areas, agri-cultural environments, and decaying or decomposingmatter. The spectrum of aspergillosis is wide, rangingfrom mere colonization (Aspergilloma) to disseminatedinfection. Aspergillus spores are commensals of the respira-tory tract and external auditory canal. Understandably, thelungs and paranasal sinuses are the most commonly affectedsites in human beings. Orbital involvement is uncommonand often a result of contiguous spread from the oropharynxor paranasal sinuses.1–11 Isolated orbital aspergillosis isextremely rare.3,10,11 Equally rare is its occurrence inimmunocompetent, otherwise healthy individuals.10,11

We report on 8 cases of isolated, orbital aspergillosis inimmunocompetent patients and also review the literatureon this disease.

MATERIALS AND METHODS

THIS WAS A RETROSPECTIVE, CLINICOPATHOLOGIC STUDY

of 8 consecutive patients with isolated orbital aspergillosistreated at 6 centers; 5 of these were in India (Centre ForSight, Hyderabad, Delhi, and Jaipur, Vasan Eye Care Hos-pitals and Drishti Eye Care, Hyderabad) and 1 in Singapore(National University Health System, Singapore). Thisstudy was approved by the Institutional Review Board ofeach of the aforementioned institutes and was performedin accordance with the tenets of the 1964 Declaration ofHelsinki. Informed consent was obtained from the patients.A retrospective chart review of all histopathologically ormicrobiologically proven cases of orbital aspergillosis wasperformed. Only those patients who had isolated orbitalinvolvement at presentation and fungal elements withcharacteristics of aspergillosis on histopathologic examina-tion of the orbital biopsy were included in the study. Exclu-sion criteria included incomplete data, unavailability oftissue material for histopathologic review, and follow-upless than 3 months. No cases were excluded. Patient folderswere analyzed for demographic details, clinical features,imaging findings, treatment, and outcome. Patient survivalwith complete resolution of the lesion at 3month follow-upwas considered as treatment success. Histopathology slideswere reviewed in all cases.

125LL RIGHTS RESERVED.

RESULTS

THIRTY-FOUR PATIENTS HAD HISTOLOGICALLY OR MICRO-

biologically proven orbital aspergillosis at the 6 centers inthe past 33 months (January 2013 to September 2015).Of these, 8 (23.5%) had an isolated orbital involvementat presentation.

� CLINICAL FEATURES: Demographic details, clinical fea-tures, and imaging findings of all 8 patients with isolatedorbital aspergillosis are shown in the Table. Common clin-ical and radiologic features are shown in Figures 1–3.

Mean age at the time of first presentation to the clinic was34.5 years (median, 43 years; range, 6 months to 72 years).One patient presented during infancy. No sex predilectionwas observed. There were 4 male and 4 female patients.Six patients were of Indian origin; 1 was a Myanmarese,and 1 was from the Middle East, both residing in Singaporefor a considerable period.Orbital involvementwas unilateralin all patients (8/8) with no predilection for any side (right,4/8; left, 4/8). The mean duration of symptoms was5.7 months (median, 3.5 months; range, 0.5–18 months).Gradually increasing proptosis (Figure 1, Top left, andFigure 2, Top left) and eyelid fullness (Figure 2, Middle leftand Bottom left, and Figure 3, Top left) each occurred in 4of 8 patients. Other symptoms included mass (2/8), diplopia(2/8), and intermittent and transient blurring of vision (1/8).

Proptosis ranged from 4 to 9 mm (median, 5.5 mm;mean, 5.75 mm). While variable degree (mild to severe)of ocular movement restriction (Figure 1, Middle and Bot-tom panels) was seen in all patients, a nontender, nonredu-cible, and noncompressible mass (Figure 3, Top left) waspalpable in 2 patients (Cases 1 and 4). Visual acuity,colored vision, and papillary reactions (both direct andconsensual) were normal in all patients. Fungal granulomawas suspected in only 1 patient (Case 7) at the time of clin-ical examination. Differential diagnoses on clinical exam-ination included idiopathic orbital inflammation (5/8),ocular adnexal lymphoma (3/8), rhabdomyosarcoma(1/8), and lacrimal gland tumor (1/7). Intraoperatively,the mass was firm to gritty in all cases.

� IMAGING FEATURES: Computed tomography (CT) andmagnetic resonance imaging (MRI) were performed in 6and 2 patients, respectively. CT scan showed an ill-defined, infiltrative, homogenous, and hyperdense masslimited to the orbit in 4 patients (Cases 1, 6, 7, and 8) andwas well-defined, homogenous, and hyperdense in 2 (Cases2 and 4).MRI in 2 patients (Cases 3 and 5) showed themassto be isointense to the extraocular muscle on T1-weightedimages and hypointense to the muscle on T2-weighted im-ages. Contrast enhancement was mild to moderate andpatchy in 7 patients (Cases 1, 2, and 4–8). In the infant(Case 3), a diffuse, intense, and homogenous enhancementwith gadolinium was observed. The mass was extraconal in6 (Cases 1–5 and 8) and both intra- and extraconal in 2

126 AMERICAN JOURNAL OF

(Cases 6 and 7). In 3 patients (Cases 6, 7, and 8), the diseaseextended posteriorly to involve the apex (Figure 2, Topright). Bone remodeling secondary to pressure effect(Figure 2, Middle right) was seen in 3 patients (Cases 1, 6,and 8). In 1 patient (Case 6), the mass was inseparablefrom the medial rectus and closely approximated to the op-tic nerve (Figure 2, Top right). The paranasal sinuses andnasal cavity were normal in all.

� HISTOPATHOLOGIC AND MICROBIOLOGIC FINDINGS:

An incision biopsy was performed in 5 patients (Cases 1and 5–8), complete excision in 2 (Cases 2 and 4), anddebulking in 1 (Case 3). Light microscopy, in all cases,showed noncaseating, epithelioid cell granulomas withmultinucleate giant cells and lymphoplasmacytic infiltratein a densely fibrotic stroma (Figure 4, Top panel). Thin-walled, septate fungal hyphae that were relatively uniformin size and branching dichotomously at 45 degrees wereidentified in all (Figure 4, Bottom panel). These were char-acteristic of Aspergillus and stained positively with Gomorimethanamine silver (Figure 4, Bottom left) and periodicacid–Schiff stains (Figure 4, Bottom right). Variablenumbers of eosinophils were present in all patients. Afungal etiology was suspected in only 1 case (Case 7) onclinical examination. The tissue in this case grew Asper-gillus fumigatus on Sabouraud dextrose agar. In the remain-ing 7, fungal granuloma not being an initial suspicion,tissue was not preserved for microbiologic examination.Complete blood count was normal and human immuno-

deficiency virus (HIV) serology negative in all patients.

� TREATMENT AND OUTCOME: Six patients were treatedwith antifungal drugs (Table): 2 of these (Cases 1 and 7)with oral itraconazole, 1 (Case 3) with a combination ofintravenous (IV) amphotericin B and voriconazole followedby oral voriconazole, and 3 (Cases 5, 6, and 8) with acombination of IV and oral voriconazole. Two patients(Cases 2 and 4) underwent a complete excision of the massand had no systemic lesion, as a result of which they didnot receive any further treatment. Post-treatment, a com-plete resolutionof proptosis and restoration of ocularmotilitywas observed in all. Visual disturbances observed in 1 (Case5)were also corrected after completion of treatment. Follow-up duration ranged from 6 to 28 months (mean,12.5 months). One patient (Case 1) developed recurrence6 months after surgery, this time with involvement of theethmoid sinus, and was lost to follow-up before any furthertreatment could be initiated. The remaining 7 patientswere disease-free at the time of last follow-up.

DISCUSSION

ASPERGILLUS SPP. BELONG TO THE ASCOMYCETE

moulds and, together with penicillium, form the family

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TABLE. Clinical Features in Patients With Isolated Orbital Aspergillosis

Case

No. Age (y) Sex Laterality

Duration of

Symptoms (mo) Presenting Features Examination Findings Primary Management Medical Management Recurrence

1 44 Male Left 2 Lower eyelid swelling Hypoglobus mass, proptosis,

ROM (vertical gaze)

Incision biopsy Itraconazole (200 mg BD orally

for 3 months)

Yes

2 72 Female Right 3 Upper eyelid swelling ROM (vertical gaze), erythema and

tenderness of upper eyelid

Complete excision None No

3 0.5 Male Right 0.5 Upper and lower eyelid swelling ROM (all gazes), hyperglobus,

chemosis

Incision biopsy IV amphotericin B (0.25 mg/kg

for 3 weeks) followed by

voriconazole (50 mg BD orally

for 6 weeks)

No

4 13 Female Right 6 Lower eyelid swelling, anterior

orbital mass, diplopia

ROM (vertical gaze); firm,

noncompressible mass

Complete excision None No

5 12 Female Left 4 Gradually progressive

proptosis, transient blurring of

vision

ROM (vertical gaze), proptosis,

resistance to retropulsion

Incision biopsy Voriconazole (4 mg/kg IV for

6 weeks followed by 200 mg

orally for 3 months)

No

6 42 Male Left 18 Gradually progressive

proptosis, diplopia, ptosis

ROM (all gazes), proptosis Incision biopsy Voriconazole (oral; 400 mg BD

for 3 days followed by bolus

400 mg IV and then 200 mg

orally BD for 6 months)

No

7 48 Female Right 9 Gradually progressive proptosis ROM (all gazes), chemosis,

proptosis, periocular swelling

Incision biopsy Itraconazole (200 mg TID for

3 days followed by 200 mg BD

for 2 months)

No

8 45 Male Left 3 Gradually progressive proptosis ROM (all gazes), proptosis Incision biopsy Voriconazole (200 mg TID for

3 days followed by 200 mg BD

for 2 months)

No

BD ¼ twice daily; IV ¼ intravenous; ROM ¼ restricted ocular motility; TID ¼ thrice daily.

VOL.

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TED

ORBITA

LASP

ERGILLO

SIS

FIGURE 1. Clinical features of isolated orbital aspergillosis. A 42-year-old male patient with proptosis (Top left), ptosis (Top right),and restricted ocular motility (Middle, Bottom).

Aspergillaceae. Although Aspergillus fumigatus is the mostcommon pathogen in this genus to affect human beings,A niger, A flavus, and A oxyzae may also be seen. The firstmention of aspergillosis as an opportunistic infection datesback to 1953.12 Row-Jones and Moore-Gillon,13 in 1994,classified aspergillosis into 3 types: (1) noninvasive, eitheran aspergilloma or allergic type; (2) destructive, noninva-sive; and (3) invasive. While the noninvasive form maycause local tissue destruction including mucosal or bonydestruction, it does not cause tissue invasion or necrosis.The invasive form is often aggressive and associated withhigh morbidity and mortality. It may result in invasion ofadjacent tissues, necrosis, vascular invasion, or thrombosis.This form, although common in immunocompromised pa-tients, may be seen in healthy individuals as well.10,11,14,15

Predisposing factors include neutrophil disorders,corticosteroid usage, HIV infection, diabetes mellitus,organ transplants, trauma, use of prosthetic devices, andadvanced age.16 All patients in this study were otherwiseimmunocompetent, healthy individuals at the time of

128 AMERICAN JOURNAL OF

diagnosis. None were exposed to drugs or had diseasesthat compromise immunity.Orbital aspergillosis is uncommon worldwide.1–11 It is

considered to be endemic in Sudan.17 Interestingly, asignificantly large number of reports come from In-dia.1,4,6,10,11 Secondary involvement of the orbit may be aresult of contiguous spread from the paranasal sinuses orcentral nervous system or as a sequela of a disseminatedsystemic disease. A concomitant sinus disease is presentin 60%–90% of patients.10 Primary orbital aspergillosis israre, and it may remain localized or at times extend toinvolve adjacent tissues such as infratemporal fossa andcheek.3,4,10,11 In all our patients, the disease remainedlocalized to the orbit. This could possibly be a result ofspread of a latent, subclinical focus of infection in thesinuses through the fissures, which later, by itself, wascleared owing to the aeration process.Orbital aspergillosis is generally considered as a disease

of the elderly age group (mean 62.48 years).11 However, In-dian patients are affected at a significantly younger age.

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FIGURE 2. Spectrum of clinicoradiologic features in isolated orbital aspergillosis. (Top) A 48-year-old female patient: (Top left)proptosis; (Top right) computed tomography scan showing a hyperdense orbital mass extending to the apex with displacement ofthe optic nerve. (Middle) A 44-year-old male patient: (Middle left) lower eyelid fullness due to (Middle right) a homogenous, inferiororbital mass. (Bottom) A 6-month-old child: (Bottom left) upper and lower eyelid fullness; (Bottom right) magnetic resonance im-aging scan showing a homogenous orbital mass.

Two of the previously largest series on orbital aspergillosisin the Indian population have reported a mean age of 36.8years at the time of first presentation.10,11 Our study (meanage: 34.5 years) had similar observations. As explained byPushkar and associates,10 this difference may be a resultof climatic conditions in India, which are conducive tofungal growth, or occupation-related (agriculture and con-struction) exposure of younger individuals to these patho-gens. Six patients (Cases 1–3 and 6–8) in this study werefrom India, a dust-polluted region. However, none hadany specific occupation-related exposure. Only 2 cases oforbital aspergillosis have been previously reported in in-fants.10 Ours was the third such case.

Clinical presentation in orbital aspergillosis is nonspecificand may mimic several non-neoplastic and neoplasticconditions.3,8,9,18–22 Idiopathic orbital inflammation andocular adnexal lymphoma are the commonest clinicalsuspicions.10,11 As it is a chronic disease, patients tend topresent late in the disease, often with a gradually

VOL. 165 ISOLATED ORBITAL

progressive proptosis.3–5,10,11 Our results were inconcordance with these observations. Orbital involvementis usually unilateral but may be bilateral.3–5,10,11 All ourpatients had a unilateral orbital involvement. A variableamount of ocular motility restriction is seen in thesepatients.10,11 Visual disturbances, sometimes to the extentof visual loss, are not uncommon and may be a result ofinappropriate management, aggressive disease with sinusinvolvement, or compression of optic nerve.10,11,17 Bloodculture is almost always negative in patients with invasiveaspergillosis.23 Imaging features, similar to clinical ones, arenot always helpful and need careful assessment of the para-nasal sinuses, whose involvement may help suspect fungalinfection in such patients. Sivak-Callcott and associates5

suggest assessment of sphenoid sinus on MRI scans to beparticularly helpful. Presence of calcifications on CT scan,especially when their density is >2000 Hounsfield units, issuggestive of aspergillosis.24 Although fine-needle aspirationcytology has been used for the diagnosis of these lesions, its

129ASPERGILLOSIS

FIGURE 3. Additional clinical and radiologic features of isolated orbital aspergillosis. (Top) A 13-year-old Myanmarese girl with(Top left) lower eyelid fullness due to (Top right) homogenous anterior orbital mass. (Bottom) A 12-year-old Middle Eastern girlwith (Bottom left) left proptosis; (Bottom right) T-1 weighted magnetic resonance imaging scan showing a homogenous orbital mass.

FIGURE 4. Histopathologic findings of isolated orbital aspergillosis: Noncaseating epithelioid cell granulomas with multinucleategiant cells embedded in a densely fibrous stroma (Top panel). Hematoxylin-eosin; Top left3100, and Top right3400. Gomori meth-anamine silver stain demonstrating septate and dichotomously branching hyphae of Aspergillus (Bottom left). Periodic acid–Schiffstain showing fungal hyphae (Bottom right), both 3400.

role remains unclear.10,21 Biopsy is necessary for diagnosis.Sivak-Callcott and associates5 suggest that biopsies beperformed from hypodense areas to improve efficacy and ac-

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curacy. However, the organismsmay be harbored deep in themass, rendering the initial superficial biopsy noncontribu-tory. A second, deeper biopsy is required in such cases.5,18

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There exist instances where the diagnosis was missed at thetime of biopsy only to be picked up on autopsy.25,26

Suspicion at the time of initial clinical and radiologicexamination helps to plan microbiologic examination ofthese lesions. A positive culture result may obviate a repeatbiopsy. Aspergillus flavus is the commonest pathogenencountered, followed by A fumigatus.5,10,11 Aspergillusterries is rarely encountered.27 In our study, a culture resultwas available inonly 1 case; it grewA fumigatus onSabourauddextrose agar.

The mortality associated with invasive aspergillosis re-mains high but has greatly reduced in the past 2 decades.No definite treatment protocols exist for orbital aspergillosis.Complete surgical debridement is advocated as the primarytreatment in patients with orbital aspergillosis. However,involvement of bone, blood vessels, and other vital orbitalstructures limit this approach. In our study, all patientswith an ill-defined and/or extensive disease were subjectedto an incision biopsy, while those with a well-defined lesion(except the patient in Case 1, who preferred an incision bi-opsy) underwent complete excision. An extensive diseasemay at times necessitate exenteration, especially in thosewith apical and retrobulbar involvement1,11,18; however, itdoes not guarantee eradication of the disease process.Although 2 of our patients had apical involvement, noneunderwent exenteration. They continue to be disease-free

VOL. 165 ISOLATED ORBITAL

after treatment with antifungal medication. While some au-thors choose to treat patients medically even after completeexcision of the lesions, others report complete surgical exci-sion to suffice and yield favorable clinical outcomes.10,11

Two patients in our study were treated with surgicalexcision alone and continue to be disease-free. Amphoteri-cin B (0.5 mg/kg/day) used to be the preferred drug fororbital aspergillosis.10,28 However, its use is limitedbecause of the associated complications, such asnephrotoxicity. Itraconazole and voriconazole have nowreplaced amphotericin B. A large clinical trial showedvoriconazole to have a better response rate and highersurvival.28 Voriconazole has been successfully used in pa-tients with orbital aspergillosis.10,11,29 Three patients inour study were successfully treated with voriconazole.To conclude, orbital involvement in aspergillosis usually

occurs in association with a sinonasal disease. Its diagnosisrelies heavily on the clinical circumstances of the infectionand microscopic findings. A careful radiologic evaluationof sinus involvement will help suspect this disease. Isolatedorbital aspergillosis is extremely rare, often with misleadingpresentations. Yet, it should be considered in the differen-tial diagnosis of all patients presenting with gradually pro-gressive orbital mass. Early recognition is of utmostimportance to reduce the morbidity and mortality associ-ated with this disease.

FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. FINANCIAL DISCLOSURES: THE FOLLOWING AUTHORS HAVE NOfinancial disclosures: Ekta Aggarwal, Kaustubh Mulay, Vikas Menon, Gangadhara Sundar, Santosh G. Honavar, and Mukesh Sharma. All authors attestthat they meet the current ICMJE criteria for authorship.

The authors acknowledge C. Jangaiah, Centre For Sight, Hyderabad, India for helping us with the photography required during the making of thismanuscript.

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