Downloaded from http://bjo.bmj.com/ on February 18, 2016 - Published by group.bmj.com Clinical science Invasive fungal disease of the sinus and orbit: a comparison between mucormycosis and Aspergillus Danielle Trief,1,2 Stacey T Gray,1,3 Frederick A Jakobiec,1,2,4 Marlene L Durand,1,5 Aaron Fay,1,2 Suzanne K Freitag,1,2 N Grace Lee,1,2 Daniel R Lefebvre,1,2 Eric Holbrook,1,3 Benjamin Bleier,1,3 Peter Sadow,1,3 Alia Rashid,1,2,4 Nipun Chhabra,1,3 Michael K Yoon1,2

▸ Additional material is ABSTRACT affecting patients without any risk factors for – published online only. To view Background/aims Invasive fungal infections of the immunocompromise are decidedly rare.8 10 please visit the journal online (http://dx.doi.org/10.1136/ head and neck are rare life-threatening infections where The rarity of these infections may prevent early bjophthalmol-2015-306945). prompt diagnosis and intervention is critical for survival. recognition by clinicians. Presenting symptoms may The aim of this study is to determine the clinical initially be subtle, often resembling acute bacterial 1Massachusetts Eye and Ear Infirmary, Boston, characteristics and outcomes of invasive fungal disease infections of the orbit or sinuses, non-infectious Massachusetts, USA of the sinus and orbit, and to compare mucormycosis orbital inflammatory conditions (eg, idiopathic 2Department of Ophthalmology, and Aspergillus infection. orbital inflammation) or facial nerve palsy.11 Harvard Medical School, Boston, Methods A retrospective review was conducted from a Misdiagnosis can cause delay in treatment or incor- Massachusetts, USA 3 single tertiary care eye and ear hospital over 20 years rect treatment with corticosteroids, which may Department of 712 Otolaryngology, Harvard (1994–2014). Twenty-four patients with a confirmed worsen the infection. Medical School, Boston, pathological diagnosis of invasive fungal disease of the Treatment is directed at limiting the progression Massachusetts, USA fi 4 sinus and/or orbit were identi ed and their medical of infection with a combination of surgical debride- David G. Cogan Laboratory records were reviewed. The main outcome measures ment, antifungal therapy and reversal of immuno- of Ophthalmic Pathology, Massachusetts Eye and were type of fungus, location of disease, mortality and compromising factors, when possible. However, Ear Infirmary, Boston, visual outcome. given the rarity of this infection, the optimal treat- Massachusetts, USA Results Patients with orbital involvement had a higher ment regimen has not been clearly defined.13 5 Department of Medicine, mortality and higher likelihood of mucormycosis infection Current clinical recommendations are based on Massachusetts General 14 15 Hospital, Boston, compared with those with sinus-only disease (78.6% vs small case series and retrospective reviews. Massachusetts, USA 20%, p=0.01; 86% vs 30%, p=0.01, respectively). While invasive Aspergillosis and mucormycosis Patients with mucormycosis had a higher mortality infections are often grouped together under the Correspondence to (71%) than patients with Aspergillus (29%); however, umbrella of IFS, studies have found very different Dr Michael K Yoon, this was not statistically significant (p=0.16). All clinical outcomes between these two fungal infec- Ophthalmic Plastic Surgery, 1 10th Floor, Massachusetts Eye patients with orbital involvement and/or mucormycosis tions. Given the limited nature of published reports, and Ear Infirmary, 243 Charles infections were immunosuppressed or had inadequately the purpose of this study is to review our institution’s Street, Boston, MA 02114, controlled diabetes, and had a cranial neuropathy or experience treating patients with IFS. Differences USA; Michael_Yoon@meei. ocular motility dysfunction. All five post-transplant between the clinical course for patients with invasive harvard.edu patients with orbital infections died, while the two mucormycosis and aspergillosis and the differences Received 2 April 2015 transplant patients with sinus infections survived. between outcomes for patients with orbital and sinus Revised 15 May 2015 Conclusions Patients with orbital fungal infections are involvement were specifically analysed. Accepted 30 May 2015 more likely to be infected with mucormycosis compared Published Online First with Aspergillus and have a higher mortality compared 25 June 2015 PATIENTS AND METHODS with infections sparing the orbit. History of transplant A retrospective review of patients with a diagnosis portends a dismal prognosis in orbital infections. of invasive fungal disease of the orbit and Invasive fungal disease should be considered in any sinonasal cavity treated by the Ophthalmology and immunocompromised patient presenting with a new Otolaryngology services of Massachusetts Eye and cranial neuropathy or ocular motility abnormality. Ear Infirmary from January 1994 through February 2014 was conducted. For inclusion in this study, patients required a histopathological diagnosis of invasive fungal INTRODUCTION disease, defined as histopathological evidence of Invasive fungal sinusitis (IFS) is a severe and often angioinvasion or invasion of surrounding soft life-threatening infection. Affected patients almost tissue (figure 1). Data collected included past universally have systemic immunosuppression or medical history, with an emphasis on immunocom- alteration, which is the primary risk factor for this promising factors such as malignancy or diabetes, infection. Even with rapid diagnosis and initiation age, gender, presenting signs and symptoms of treatment, prognosis is poor with mortality (including cranial neuropathies and central retinal – ranging from 21% to 80%.1 5 Haematological artery occlusion (CRAO)), medical and surgical To cite: Trief D, Gray ST, malignancy, diabetes, immunosuppressive therapy treatments, time from symptom onset to diagnosis Jakobiec FA, et al. Br J after solid organ and bone marrow transplantation, and time to death where applicable. The outcome Ophthalmol 2016;100:184– AIDS, haemochromatosis and long-term cortico- of a patient who was discharged on hospice care – 188. steroid use are all risk factors for IFS.5 7 Cases was counted as a mortality.

184 Trief D, et al. Br J Ophthalmol 2016;100:184–188. doi:10.1136/bjophthalmol-2015-306945 Downloaded from http://bjo.bmj.com/ on February 18, 2016 - Published by group.bmj.com Clinical science

dematiaceous fungus in 1 and indeterminate fungus in 1. In total, 13 patients (54%) had a fatal outcome, 11 of whom had orbital disease. Of the patients who died, 10 had a pathological diagnosis of mucormycosis, 2 had Aspergillus and 1 had a fungal infection of indeterminate species. The majority (11 of 14) of the orbital infections were secondary to mucormycosis, and the majority of orbit sparing sinus infections (6 of 10) were second- ary to Aspergillus.

Risk factors While 13 of the patients (54%) carried a diagnosis of diabetes, 8 of these 13 also had medication-related immunosuppression (chemotherapy or post-transplant antirejection medications). Of the five patients who had diabetes without other risk factors, three survived. All five patients with diabetes as their only risk factor had poorly controlled diabetes. Three of the five had a recent haemoglobin A1c >9.5. The other two patients, in whom a haemoglobin A1c was not recorded, had multiple epi- sodes of diabetic ketoacidosis or finger stick readings of 400 mg/ dL. There were seven patients who had a history of solid organ or stem cell transplant. Five had orbital infections (all mucormy- cosis), and they all died from their infection. Four of the trans- plant recipients had no other risk factors, and three of the four died. The one transplant patient without other risk factors who survived did not have orbital disease. Chronic intranasal steroid use for chronic sinusitis was the only apparent risk factor for two patients; both had invasive sinus disease without orbital involvement and both survived. Nine of the 24 patients had a haematological malignancy or dysplasia. Seven carried a diagno- sis of leukaemia, one patient had multiple myeloma and one patient had myelodysplastic syndrome. No other active malig- nancies were present.

Signs and symptoms Figure 1 Histopathological photomicrographs of fungal infections. (Top) Mucormycosis (zygomycosis). The hyphae are readily seen in the All patients with orbital involvement (14) had an optic neur- wall of an orbital vessel in a H&E stained section and are non-septate, opathy, cranial neuropathy or ocular motility dysfunction. wide (7–30 μm), and often branch at 90° angles. The inset displays the Twelve (85.7%) reported decreased vision, and six ultimately density of the matted hyphal elements (H&E, ×100, inset ×200). declined to no light perception. Twelve patients (85.7%) had (Bottom) Aspergillus. Hyphae of Aspergillus are narrow (2–4 μm) and motility deficits, and 10 (71.4%) had proptosis on presenta- septate. They branch at acute, often 45° (insert) angles (Grocott’s tion. Notably, all patients with visual loss also had ophthal- methenamine silver, ×200, inset ×400). moplegia and/or proptosis. Six patients had a documented CRAO, all of whom had a diagnosis of mucormycosis (one had both mucormycosis and Aspergillus), and five of whom Infections were analysed based on their causative fungal (83%) died. organism and the presence or absence of orbital involvement, Of the 10 patients with orbit sparing disease, 8 (80%) fi fi de ned by clinical ndings (ie, the presence of ophthalmoplegia reported sinus pain or pressure. One patient with AIDS was and/or proptosis) and supported by radiographic evidence of admitted for persistent vomiting and developed periorbital swel- orbital invasion. One patient with concomitant mucormycosis ling during her hospital course. Another patient was admitted and aspergillosis, one patient with dematiaceous without further for febrile neutropenia in the setting of leukaemia and devel- speciation and one patient infected with an indeterminate oped facial swelling, a facial droop and nose bleeds during his fungal species were excluded from the subanalysis of the fungal admission. genera. For indeterminate fungal species, histopathological, The average time from symptom onset to diagnosis was fi immunohistochemical and genetic testing could not de nitively 10.3 days for patients with orbital involvement and an indeter- ’ determine the fungal species. Fisher s exact tests were used to minate duration for patients with orbit sparing disease since fi calculate statistical signi cance between the groups. many of these patients had symptoms from chronic sinus disease for years. RESULTS Twenty-four patients with invasive fungal sinus with or without Treatment orbital disease were identified (see online supplementary table). Of the 24 patients, 23 were initially treated with antibiotics for There were 16 men and 8 women ranging in age from 30 to presumed bacterial sinusitis and/or orbital cellulitis. Five patients 80 years (mean 55). Fourteen patients had disease affecting the were treated with steroids, two of whom were treated for pre- orbit while 10 spared the orbit. The fungal aetiology was sumed giant cell arteritis (GCA). an agent of mucormycosis in 14 patients (58%), Aspergillus in Also, 20 of the 24 patients (83.3%) received liposomal 7 (29%), both mucormycosis and Aspergillus in 1 (4%), amphotericin B (AmBisome, Astellas Pharma, Northbrook,

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Table 1 Characteristics of patients with mucormycosis compared with Aspergillus Mucormycosis Aspergillus

Total patients (male) 14 (9) 7 (5) Mean age (range) 54 (33–80) 50 (30–68) Mortality 10/14 2/7 Time from diagnosis to death 26.6 days (mean) Mean 47 days (3 days in one patient, 3 months in one patient) Risk factor (mortality) Diabetes: 5 (2) Diabetes: 0 Diabetes+immunosuppression: 3 (3) Diabetes+immunosuppression: 3 (1) Transplant without diabetes: 3 (3) Transplant without diabetes: 1 (0) Other immunosuppression: 3 (2) Other immunosuppression: 2 (1) Sinusitis without other risk factors: 0 (0) Sinusitis without other risk factors: 1 (0) Orbital invasion 11/14 1/7 Mortality in orbital cases 9/11 1/1 Three patients were excluded from this table: one patient with indeterminate fungus, one with dematiaceous and one with concomitant mucormycosis and Aspergillus.

Illinois), including all patients with a diagnosis of mucormy- more likely to be infected by mucormycosis alone than orbit cosis. In patients where a diagnosis of invasive Aspergillus sparing disease (79 vs 30%, respectively, p=0.01). Conversely, was made, amphotericin was switched to voriconazole patients with orbit sparing disease were more likely to be infected after this agent was demonstrated to be superior. The mean by Aspergillus alone (7% vs 60%, respectively, p<0.01). number of surgeries was 2.5 for patients with orbital involvement and 2 for patients with orbit sparing disease. All patients had endoscopic sinus debridement except one patient who elected for palliative care after a bedside intra- DISCUSSION nasal biopsy was diagnostic for mucormycosis. Four patients This 20-year retrospective case series represents one of the underwent orbital exenteration, three of whom had a fatal largest series of invasive fungal sinus and sino-orbital disease outcome. from a single institution. In total, 14 of our 24 patients had Four patients with orbital mucormycosis received hyperbaric orbital disease, and these patients had a higher mortality com- oxygen treatments. Three of these four patients died. pared with orbit sparing disease (78.6% vs 20%, respectively, p=0.01). The vast majority of patients with orbital disease were infected by mucormycosis alone (79%) while the majority of Mucormycosis vs Aspergillus patients with orbit sparing disease were infected by Aspergillus Patients with mucormycosis had a higher mortality (71.4%) (60%). than patients with Aspergillus (28.5%); however, this was not There are several hypotheses why patients with orbital disease fi statistically signi cant (p=0.16) (table 1). All patients with has a poorer outcome than those with orbit sparing disease. mucormycosis had systemic immunosuppression or uncontrolled Mucormycosis is known to cause a more aggressive fungal infec- diabetes, whereas one of the patients with angioinvasive asper- tion,1 and in the current study, there was a higher proportion of gillosis had chronic sinus disease without other risk factors. patients with orbital disease infected with it. However, mucor- fi A signi cantly higher number of patients with mucormycosis mycosis infection compared with other fungi did not lead to a had orbital invasion compared with Aspergillus (78.6% vs statistically higher mortality rate in our study. A second explan- 14.2%, respectively, p=0.02). ation is that once the fungus enters the orbit it can easily access the intracranial space through the ophthalmic artery, optic canal Orbital disease vs orbit sparing (sinus-only) disease or superior orbital fissure.6 A third theory is that the fungal Patients with orbital infection had a higher mortality compared infections that have demonstrated a propensity to spread with those with orbit sparing disease (78.6% vs 20%, respect- beyond the confines of the sinuses and into surrounding spaces ively, p=0.01) (table 2). Patients with orbital involvement were may be more inherently virulent.716

Table 2 Characteristics of patients with orbital and orbit sparing disease Orbital disease Orbit sparing (sinus-only) disease

Total patients (male) 14 (9) 10 (7) Mean age (range) 55 (34–80) 55 (30–75) Organism Mucormycosis: 11 Mucormycosis: 3 Aspergillus:1 Aspergillus:6 Mucormycosis+Aspergillus: 1 Dematiaceous: 1 Indeterminate: 1 Mortality 11/14 (78.6%) 2/10 (20%) Risk factor: number (mortality) Diabetes: 4 (2) Diabetes: 1 (0) Diabetes+immunosuppression: 5 (4) Diabetes+immunosuppression: 3 (0) Transplant without diabetes: 3 (3) Transplant without diabetes: 1 (0) Other immunosuppression (chemotherapy): 2 (2) Other immunosuppression (chemotherapy): 3 (2) Sinusitis without other risk factors: 0 (0) Sinusitis without other risk factors: 2 (0)

186 Trief D, et al. Br J Ophthalmol 2016;100:184–188. doi:10.1136/bjophthalmol-2015-306945 Downloaded from http://bjo.bmj.com/ on February 18, 2016 - Published by group.bmj.com Clinical science

Thirteen of the patients in the current study (54.1%) had a Interestingly, 6 of the 14 orbital cases had evidence of retinal diagnosis of diabetes mellitus. Five had uncontrolled diabetes ischaemia on initial examination (CRAO), and all of these without other concomitant immunocompromising conditions. patients had mucormycosis infections. This points to the Uncontrolled diabetics are known to have poor humoral immun- angioinvasive nature of mucormycosis. If a CRAO is seen in an ity and neutrophilic dysfunction.17 An environment of low immunosuppressed patient, IFS, specifically mucormycosis, oxygen tension, hyperglycaemia and ketosis provides an excellent should be considered. medium for the fungus to thrive.6 Diabetics also have poor iron Of the 24 patients, 23 underwent endoscopic sinus debride- metabolism.16 Iron overload is a risk factor for mucormycosis ment. Surgical debridement (endoscopic or open sinus surgery infection and patients with iron overload (haemochromatosis) or and/or orbitofacial debridement) of IFS has been shown to lead who are treated with iron chelating agents such as deferoxamine to increased survival.4 Antifungal agents take time to be effect- are at higher risk of developing invasive fungal infections.18 19 ive. The advantages of surgical debridement are multifaceted: Patients with diabetes as their only risk factor fared better than (1) removal of devitalised tissue; (2) debulking of infected patients with other immunocompromising conditions (40% mor- tissue, theoretically allowing for faster action of antifungals tality). This finding may reflect the potential reversibility of dia- against a smaller burden of fungi; and (3) provision of speci- betic immune dysfunction.414 mens for culture and pathology to confirm aetiology.5 In contrast, 75% of patients who were organ transplant reci- Only four patients in this study underwent exenteration, pients without other risk factors died from the disease. three of whom succumbed to the infection. All four of these Transplant patients had the worst prognosis. This likely reflects patients were infected with mucormycosis. Exenteration of the the severe and sometimes irreversible immunosuppression in orbit is aimed at local control prior to spread of fungus intracra- these patients.20 nially, where intravascular invasion can be lethal. The role of All patients with mucormycosis were immunosuppressed or exenteration in orbital fungal disease has been contested. It is a had diabetes. There are few case reports of invasive mucormy- disfiguring procedure, although radical debridement of affected cosis in immunocompetent hosts: these infections were second- tissue may be life saving. While some studies have failed to ary to trauma21 or high exposure load.9 In contrast, there were show a statistical benefit,4 another found a benefit in patients two patients in our study with Aspergillus whose only apparent who presented with fever.14 We advocate that the decision of risk factor for IFS was chronic intranasal steroid use. While exenteration should be made by the multidisciplinary team invasive aspergillosis is most commonly seen in immunosup- caring for the individual patient. pressed individuals, there have been reports of infection in All patients with mucormycosis were treated with liposomal immunocompetent individuals22 and these individuals tend to amphotericin B. Doses ranged from 5 to 10 mg/kg. Liposomal have much higher survival rates.810Additionally, compared amphotericin appears to be superior to amphotericin B deoxy- with immunosuppressed patients, immunocompetent patients cholate in the treatment of mucormycosis.18 We recommend with IFS tend to have more chronic or indolent presentations. that if there is suspicion for IFS, systemic amphotericin be admi- In one study of 35 immunocompetent patients with invasive nistered empirically (prior to tissue diagnosis) in consultation orbital Aspergillus, symptoms persisted for an average of 1 year with infectious disease specialists. prior to diagnosis.10 Our two immunocompetent patients with The majority of patients with Aspergillus without mucor were invasive Aspergillus both had a diagnosis of chronic sinusitis and treated with voriconazole. In a randomised clinical trial of reported sinus pain for months prior to diagnosis of fungal patients infected with Aspergillus, initial therapy with voricona- infection. The immunocompromised or uncontrolled diabetics zole led to better response and improved survival compared had a much more rapid disease course. with amphotericin B.24 Patients were placed on liposomal Haematological malignancy or dysplasia was seen in 9 of the amphotericin and then switched to voriconazole if the patho- 24 patients (5 of whom had mucormycosis infections). logical diagnosis or culture revealed Aspergillus. Although haematological malignancies are classically associated Several case reports and series have reported survival benefits with Aspergillus infections, they may be associated with mucor- of treatment with hyperbaric oxygen.725Hyperbaric oxygen is mycosis as well.2 Consistent with previous studies, the current thought to improve flow to ischaemic tissue and alleviate acid- study found a male predominance.16 The clinical significance of osis. The complications of hyperbaric oxygen include pneumo- this is unknown. thorax, seizures, nausea, tinnitus and visual abnormalities.13 In In total, 23 of the 24 patients were initially treated for bacter- the present study, four patients with orbital mucormycosis ial sinusitis. As sinus symptoms progressed despite broad- received hyperbaric oxygen treatments, and three of the four spectrum antibiotics, patients were reimaged and sinus biopsies died. It is difficult to determine whether this was a failure in were taken, leading to the diagnosis of invasive fungal infection. treatment or selection bias for patients with worse disease. In contrast, all patients with orbital disease had an optic neur- Future studies are needed to clearly define the role of hyperbaric opathy, trigeminal hypesthesia or ocular motility dysfunction. oxygen in invasive fungal disease. Also, 5 of the 14 orbital cases were initially given high-dose The mortality rate for both mucormycosis and Aspergillus con- steroids for presumed GCA, idiopathic orbital inflammation or tinues to be high. The treatment regimen has remained similar, presumed bacterial sinusitis with concurrent antibiotics. Given that is, debridement (endoscopic and/or open) with antifungal the rare nature of IFS and the fact that orbital fungal infections medication, although pharmacological developments (liposomal can have similar presentations to non-infectious inflammatory amphotericin and voriconazole) have been made. Studies have conditions, misdiagnosis is quite commonly reported in the routinely found survival benefit when fungal infections are identi- literature.23 However, delay in diagnosis or treatment of these fied early. Early diagnosis is often challenging as patients may potentially deadly infections with steroids can lead to reduced present with subtle and non-specific findings. However, as survival.12 Clinicians should maintain a high suspicion for demonstrated by our study, careful consideration of fungal infec- fungal infections in immunocompromised or diabetic patients tion should be given to any immunosuppressed patient presenting who present with a new cranial neuropathy and orbital with a new optic neuropathy, cranial neuropathy or ocular motil- findings. ity dysfunction. High-dose steroid treatment must be reserved

Trief D, et al. Br J Ophthalmol 2016;100:184–188. doi:10.1136/bjophthalmol-2015-306945 187 Downloaded from http://bjo.bmj.com/ on February 18, 2016 - Published by group.bmj.com Clinical science until fungal disease is ruled out. Transplant and systemically 9 Schutz P, Behbehani JH, Khan ZU, et al. Fatal rhino-orbito-cerebral zygomycosis immunosuppressed patients are especially vulnerable to IFS, and caused by Apophysomyces elegans in a healthy patient. J Oral Maxillofac Surg 2006;64:1795–802. this infection should be considered in this population, along with 10 Mody KH, Ali MJ, Vemuganti GK, et al. Orbital aspergillosis in immunocompetent diabetics, when this clinical scenario arises. patients. Br J Ophthalmol 2014;98:1379–84. 11 Sohail MA, Al Khabori M, Hyder J, et al. Acute fulminant fungal sinusitis: clinical Contributors All authors made substantial contributions to the conception of the work presentation, radiological findings and treatment. Acta Trop 2001;80:177–85. or to the acquisition/analysis/interpretation of the data. All authors gave final approval of 12 Choi HS, Choi JY, Yoon JS, et al. Clinical characteristics and prognosis of orbital the version published and agree to be accountable for all aspects of the work. invasive aspergillosis. Ophthal Plast Reconstr Surg 2008;24:454–9. Competing interests None declared. 13 Thomas PA. Current perspectives on ophthalmic mycoses. Clin Microbiol Rev 2003;16:730–97. fi Ethics approval Massachusetts Eye and Ear In rmary Institutional Review Board. 14 Hargrove RN, Wesley RE, Klippenstein KA, et al. Indications for orbital exenteration The study was HIPAA compliant and adhered to the tenets of the Declaration of in mucormycosis. Ophthal Plast Reconstr Surg 2006;22:286–91. Helsinki. 15 Tacke D, Koehler P, Markiefka B, et al. Our 2014 approach to mucormycosis. Provenance and peer review Not commissioned; externally peer reviewed. Mycoses 2014;57:519–24. 16 Gamaletsou MN, Sipsas NV, Roilides E, et al. Rhino-orbital-cerebral mucormycosis. Curr Infect Dis Rep 2012;14:423–34. REFERENCES 17 Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. 1 Ingley AP, Parikh SL, DelGaudio JM. Orbital and cranial nerve presentations and Clin Microbiol Rev 2000;13:236–301. sequelae are hallmarks of invasive fungal sinusitis caused by Mucor in contrast to 18 Ibrahim AS, Kontoyiannis DP. Update on mucormycosis pathogenesis. Curr Opin Aspergillus. Am J Rhinol 2008;22:155–8. Infect Dis 2013;26:508–15. 2 Chen CY, Sheng WH, Cheng A, et al. Invasive fungal sinusitis in patients with 19 McNab AA, McKelvie P. Iron overload is a risk factor for zygomycosis. hematological malignancy: 15 years experience in a single university hospital in Arch Ophthalmol 1997;115:919–21. Taiwan. BMC Infect Dis 2011;11:250. 20 Lanternier F, Sun HY, Ribaud P, et al. Mucormycosis in organ and stem cell 3 Monroe MM, McLean M, Sautter N, et al. Invasive fungal rhinosinusitis: a 15-year transplant recipients. Clin Infect Dis 2012;54:1629–36. experience with 29 patients. Laryngoscope 2013;123:1583–7. 21 Fairley C, Sullivan TJ, Bartley P, et al. Survival after rhino-orbital-cerebral 4 Turner JH, Soudry E, Nayak JV, et al. Survival outcomes in acute invasive fungal mucormycosis in an immunocompetent patient. Ophthalmology 2000;107: sinusitis: a systematic review and quantitative synthesis of published evidence. 555–8. Laryngoscope 2013;123:1112–18. 22 Sivak-Callcott JA, Livesley N, Nugent RA, et al. Localised invasive sino-orbital 5 Zuniga MG, Turner JH. Treatment outcomes in acute invasive fungal rhinosinusitis. aspergillosis: characteristic features. Br J Ophthalmol 2004;88:681–7. Curr Opin Otolaryngol Head Neck Surg 2014;22:242–8. 23 Gillespie MB, O’Malley BW. An algorithmic approach to the diagnosis and 6 Wali U, Balkhair A, Al-Mujaini A. Cerebro-rhino orbital mucormycosis: an update. management of invasive fungal rhinosinusitis in the immunocompromised patient. J Infect Public Health 2012;5:116–26. Otolaryngol Clin North Am 2000;33:323–34. 7 Yohai RA, Bullock JD, Aziz AA, et al. Survival factors in rhino-orbital-cerebral 24 Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin mucormycosis. Surv Ophthalmol 1994;39:3–22. B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 8 Pushker N, Meel R, Kashyap S, et al. Invasive aspergillosis of orbit in 347:408–15. immunocompetent patients: treatment and outcome. Ophthalmology 25 John BV, Chamilos G, Kontoyiannis DP. Hyperbaric oxygen as an adjunctive 2011;118:1886–91. treatment for zygomycosis. Clin Microbiol Infect 2005;11:515–17.

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Invasive fungal disease of the sinus and orbit: a comparison between mucormycosis and Aspergillus Danielle Trief, Stacey T Gray, Frederick A Jakobiec, Marlene L Durand, Aaron Fay, Suzanne K Freitag, N Grace Lee, Daniel R Lefebvre, Eric Holbrook, Benjamin Bleier, Peter Sadow, Alia Rashid, Nipun Chhabra and Michael K Yoon

Br J Ophthalmol 2016 100: 184-188 originally published online June 25, 2015 doi: 10.1136/bjophthalmol-2015-306945

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