Outcomes of Acute Invasive Fungal Rhinosinusitis Patients Treated with Retrobulbar Amphotericin B Injections versus Orbital Exenteration
1 Introduction
Acute invasive fungal rhinosinusitis (AIFRS) is a rare, aggressive disease process with an estimated mortality rate of 50.3% [1]. The rates of orbital invasion in AIFRS range from 40% to 60% [1, 2], and management of rhino-orbital disease remains controversial, with options ranging from orbital exenteration to tissue debridement to, more recently, transcutaneous retrobulbar amphotericin (TRAM-B) [3, 4]. In 2019, our institution began to treat rhino-orbital AIFRS primarily via TRAM-B. The objective of this study is to detail our experience with TRAM-B in the management of AIFRS and analyze patient outcomes.
Summary
- Transcutaneous retrobulbar amphotericin (TRAM-B) is a management option in orbitally invasive fungal sinusitis.
- There was no worse mortality in patients managed with TRAM-B compared with orbital exenteration.
- Progression of orbital disease despite TRAM-B is uncommon, but careful surveillance is critical.
2 Methods
IRB-approved retrospective review of patients with tissue-confirmed sinonasal AIFRS at a tertiary center from 2010 to 2024. Demographic, medical, and surgical history, imaging, and laboratory information were obtained. Patient MRIs were reviewed, and orbital involvement was defined as the presence of abnormal contrast enhancement or loss of contrast enhancement attributed to invasive fungal disease within the orbital tissues [3]. Descriptive statistics, as appropriate, were reported. Bivariate and multivariate analyses were evaluated using independent two-tailed t-testing or ANOVA for parametric data. A binary logistic regression using alive and deceased as outcomes was performed to determine the impact of various treatment-related factors on patient mortality. All tests used a significance level of ≤0.05.
2.1 TRAM-B Injection Protocol
Patients with orbital AIFRS underwent retrobulbar injection of 1 mL of 3.5 mg/mL liposomal amphotericin B compounded by the inpatient pharmacy. TRAM-B is an off-label application that is not approved by the Food and Drug Administration. The procedure was performed in conjunction with sinonasal debridement in the operating room or the inpatient wards. The globe is manually displaced laterally with direct instillation of amphotericin B into the retrobulbar space. Postinjection, manual pressure was applied to the globe, and the patient was monitored for orbital compartment syndrome. Initially, injections were performed daily for a total of three injections, but injections were transitioned to every other day intervals, due to orbital chemosis seen with daily injections.
3 Results
Ninety-five patients were included: 50 (52.6%) patients with nonorbital AIFRS, 32 orbital AIFRS patients (33.7%) received TRAM-B, 10 (10.5%) patients underwent orbital exenteration, and three (3.2%) patients received at least one dose of TRAM-B followed by exenteration. Among patients receiving TRAM-B followed by exenteration, one patient received a single injection of TRAM-B for postseptal orbital changes on MRI but developed same-day eyelid and facial soft tissue necrosis, necessitating exenteration and local debridement. Two patients received three TRAM-B injections followed by exenteration. One patient progressed to complete ophthalmoplegia and proptosis concerning clinical disease progression, and another developed complete ophthalmoplegia and proptosis with continued progression on MRI with loss of enhancement involving the optic nerve, remaining extraocular muscles, and extending toward the inferior orbital fissure.
Demographic and disease-related characteristics are in Table 1. Patients with orbital AIFRS had higher hemoglobin A1C than nonorbital AIFRS (p = 0.003), were more likely to be transferred from an outside hospital (p = 0.027), and had Rhizopus/mucor as the underlying fungal pathogen (p = 0.003). There were no differences between the TRAM-B groups or orbital exenteration groups in any demographic, comorbidity, or presenting symptoms/extent of disease.
| Nonorbital AIFRS | Retrobulbar amphotericin | Orbital exenteration | TRAM-B and exenteration | Total population | Orbital vs. nonorbital p-value | TRAM-B vs. exenteration p-value | |
|---|---|---|---|---|---|---|---|
| Number of patients (n, %) | 50 (52.6%) | 32 (33.7%) | 10 (10.5%) | 3 (3.2%) | 95 | ||
| Age (average, SD) | 56.4 ± 18 | 53.9 ± 16.3 | 55.8 ± 11.3 | 57.7 ± 14.1 | 55.6 ± 16.7 | 0.53 | 0.74 |
| Gender | 0.07 | 0.71 | |||||
| Male | 34 (68%) | 15 (46.9%) | 6 (60%) | 1 (33.3%) | 56 (59%) | ||
| Female | 16 (32%) | 17 (53.1%) | 4 (40%) | 2 (66.7%) | 39 (41%) | ||
| Race | 0.16 | 0.75 | |||||
| White | 26 (52%) | 5 (15.6%) | 5 (50%) | 2 (66.7%) | 38 (40%) | ||
| African American | 2 (4%) | 2 (6.3%) | 0 (0%) | 0 (0%) | 4 (4.2%) | ||
| Asian | 4 (8%) | 3 (9.4%) | 1 (10%) | 0 (0%) | 8 (8.4%) | ||
| Other | 9 (18%) | 10 (31.3%) | 2 (20%) | 1 (33.3%) | 22 (23.2%) | ||
| Unknown | 9 (18%) | 12 (37.5%) | 2 (20%) | 0 (0%) | 23 (24.2%) | ||
| Ethnicity | 0.21 | 1 | |||||
| Hispanic or Latino | 20 (40%) | 18 (56.3%) | 6 (60%) | 1 (33.3%) | 45 (47.4%) | ||
| Non-Hispanic or Latino | 29 (58%) | 14 (43.8%) | 4 (40%) | 2 (66.7%) | 48 (50.5%) | ||
| Primary language | 0.26 | 0.88 | |||||
| English | 37 (74%) | 19 (59.4%) | 6 (60%) | 2 (66.7%) | 64 (67.4%) | ||
| Spanish | 12 (24%) | 12 (37.5%) | 3 (30%) | 0 (0%) | 27 (28.4%) | ||
| Other | 1 (2%) | 1 (3.1%) | 1 (10%) | 1 (33.3%) | 4 (4.3%) | ||
| Comorbiditiesa | |||||||
| Diabetes mellitus | 26 (52%) | 22 (68.8%) | 7 (70%) | 3 (100%) | 58 (61.1%) | 0.06 | 0.94 |
| Hemoglobin A1C (average, SD) | 8.6 ± 3.4 | 11.7 ± 2.9 | 12.3 ± 1.3 | 8.4 ± 2.5 | 10.2 ± 3.4 | 0.002 | 0.29 |
| Diabetic ketoacidosis | 9 (18%) | 12 (37.5%) | 5 (50%) | 1 (33.3%) | 27 (28.4%) | 0.051 | 0.48 |
| Leukemia/lymphoma | 12 (24%) | 9 (28.1%) | 2 (20%) | 1 (33.3%) | 24 (25.3%) | 0.89 | 0.61 |
| Absolute neutrophil count (average, SD) (×103/mm3) | 5.6 ± 6.5 | 7.8 ± 5.2 | 10.2 ± 7.5 | 2.8 ± 1.2 | 6.8 ± 6.3 | 0.23 | 0.33 |
| Neutropenia (ANC<500 cell/mm3) | 7 (14%) | 2 (6.3%) | 1 (10%) | 0 (0%) | 10 (10.5%) | 0.25 | 0.69 |
| Solid organ transplant | 11 (22%) | 4 (12.5%) | 0 (0%) | 1 (33.3%) | 16 (16.8%) | 0.16 | 0.24 |
| Liver disease | 10 (20%) | 3 (9.4%) | 1 (10%) | 0 (0%) | 14 (14.7%) | 0.13 | 0.95 |
| End-stage renal disease | 7 (14%) | 3 (9.4%) | 0 (0%) | 0 (%) | 10 (10.5%) | 0.25 | 0.31 |
| Fungal organism isolateda | |||||||
| Rhizopus/Mucor | 22 (44%) | 26 (81.3%) | 9 (90%) | 3 (100%) | 60 (63.2%) | 0.003 | 0.52 |
| Aspergillus | 23 (46%) | 9 (28.1%) | 2 (20%) | 0 (0%) | 34 (35.8%) | 0.066 | 0.61 |
| Other species | 8 (16%) | 4 (12.5%) | 0 (0%) | 0 (0%) | 12 (12.6%) | 0.07 | 0.57 |
| Multiple fungi isolated | 4 (8%) | 6 (18.8%) | 1 (10%) | 0 (0%) | 11 (11.6%) | 0.25 | 0.65 |
| Extent of disease | |||||||
| Maxillary sinus involvement | 26 (52%) | 17 (53.1%) | 8 (80%) | 2 (66.7%) | 53 (55.8%) | 0.43 | 0.13 |
| Ethmoid sinus involvement | 16 (32%) | 17 (53.1%) | 7 (70%) | 3 (100%) | 43 (45.3%) | 0.006 | 0.34 |
| Frontal sinus involvement | 13 (26%) | 10 (31.3%) | 3 (30%) | 0 (0%) | 26 (27.4%) | 0.74 | 0.94 |
| Sphenoid sinus involvement | 4 (8%) | 6 (18.8%) | 4 (40%) | 2 (66.7%) | 16 (16.9%) | 0.02 | 0.17 |
| Pterygopalatine fossa involvement | 9 (18%) | 8 (25%) | 1 (10%) | 1 (33.3%) | 19 (20%) | 0.61 | 0.41 |
| Preseptal orbital involvement | 0 (0%) | 7 (21.9%) | 3 (30%) | 2 (66.7%) | 12 (12.6%) | 0.0001 | 0.6 |
| Postseptal orbital involvement | 0 (0%) | 28 (87.5%) | 9 (90%) | 3 (100%) | 40 (42.1%) | <0.0001 | 0.84 |
| Orbital findings at presentation | |||||||
| Vision 20/200 or better | — | 15 (46.9%) | 3 (30%) | 2 (66.7%) | 20 (21.1%) | — | 0.35 |
| Vision limited to count fingers | — | 2 (6.3%) | 0 (0%) | 0 (0%) | 2 (2.1%) | — | 0.42 |
| Vision limited to pinhole perception | — | 2 (6.3%) | 0 (0%) | 0 (0%) | 2 (2.1%) | — | 0.42 |
| Vision limited to no light perception | — | 11 (34.4%) | 6 (60%) | 1 (33.3%) | 18 (18.9%) | — | 0.15 |
| No baseline acuity reported | — | 3 (9.4%) | 1 (10%) | 0 (0%) | 4 (4.2%) | — | 0.95 |
| Elevated intraocular pressure (IOP > 21) | — | 4 (12.5%) | 3 (30%) | 1 (33.3%) | 8 (8.4%) | — | 0.19 |
| Diminished pupil reactivity | — | 16 (50%) | 7 (70%) | 1 (33.3%) | 24 (25.3%) | — | 0.27 |
| Proptosis | — | 19 (59.4%) | 5 (50%) | 1 (33.3%) | 25 (26.3%) | — | 0.6 |
| Restrictions of EOMI | — | 19 (59.4%) | 5 (50%) | 2 (66.7%) | 26 (27.4%) | — | 0.6 |
| No baseline EOMI | — | 5 (15.6%) | 1 (10%) | 0 (0%) | 6 (6.3%) | — | 0.44 |
| Transferred from outside hospital (n, %) | 15 (30%) | 15 (46.9%) | 7 (70%) | 2 (66.7%) | 39 (41.1%) | 0.027 | 0.2 |
| Treatment Outcome | 0.2 | 0.49 | |||||
| Alive | 25 (50%) | 13 (40.6%) | 2 (20%) | 1 (33.3%) | 41 (43.2%) | ||
| Deceased | 23 (46%) | 17 (53.1%) | 7 (70%) | 1 (33.3%) | 48 (50.1%) | ||
| Lost to follow-up | 2 (4%) | 2 (6.3%) | 1 (30%) | 1 (33.3%) | 6 (6.3%) | ||
- Abbreviations: AIFRS, acute invasive fungal rhinosinusitis; EOMI, extraocular movements; TRAM-B, transcutaneous retrobulbar amphotericin B; SD, standard deviation.
- a Totals for each column exceed 100%, as patients may have more than one positive response in each category.
The mortality rate for the total cohort was 50.1% (n = 48) with six (6.3%) patients lost to follow-up after discharge: 46% in the nonorbital AIFRS group, 53.1% in the TRAM-B, 70% in the orbital exenteration group, and 33.3% in patients receiving TRAM-B and exenteration. These rates were not significantly different. Binary logistic regression found no difference in odds of survival between nonorbital AIFRS, TRAM-B, or orbital exenteration patients when accounting for the severity of DM2, causative fungal organism, or transfer status (Table 2).
| Predictor | Odds ratio | 95% Confidence interval |
|---|---|---|
| Nonorbital involvement | Reference | Reference |
| Retrobulbar amphotericin | 0.7 | 0.17–2.77 |
| Orbital exenteration | 0.68 | 0.11–4.34 |
| Hemoglobin A1C > 10% | 1.00 | 0.82–1.23 |
| Transfer from outside hospital | 1.38 | 0.41–4.66 |
| Mucor/Rhizopus as fungal pathogen | 0.62 | 0.22–7.92 |
4 Discussion
There was no difference in mortality between patients undergoing orbital exenteration, TRAM-B, or nonorbital AIFRS. Other studies have examined patients with rhino-orbital AIFRS and noted a decrease in exenteration rate from 36–54% to 9–12% in patients managed with TRAM-B without differences in mortality [3, 4], which is comparable to our population where 8.6% (3 of 35 patients) receiving at least one injection of TRAM-B required exenteration. A recent meta-analysis examining the role of TRAM-B in AIFRS noted that no studies were sufficiently powered to substantiate differences in mortality, and there may be a role for TRAM-B in decreasing exenteration rates, but direct comparative studies remain limited [5].
There is a paucity of literature examining the role of orbital exenteration in survival outcomes in AIFRS patients. Turner et al. [1], in a systematic review of 807 patients, found that 20% of patients underwent exenteration without any impact on survival outcomes. Hargrove et al. [6] examined 224 cases of orbital AIFRS and found that exenteration only improved survival in patients with fevers but could identify no other prognostic factors associated with exenteration, emphasizing that alternatives to exenteration should be considered in the management of orbital AIFRS. Our data adds to the literature supporting TRAM-B as an alternative management approach to patients with AIFRS and demonstrates that these patients have no worse mortality than those undergoing exenteration.
There were three patients in our cohort that had progressive orbital AIFRS despite TRAM-B, requiring exenteration. Orbital symptoms in each patient progressed rapidly and developed progression during the course of their TRAM-B or within 24 h of completion of their treatment course. Monitoring for disease progression via clinical and/or imaging examination is necessary to ensure that treatment failures are captured early enough to determine if additional surgical intervention is required.
There are multiple limitations to this study, including the small sample size for the cohort undergoing orbital exenteration, which limits the ability to perform robust multivariate analyses. TRAM-B is a more recent treatment, and the study design may not fully account for advances in medical and anti-fungal therapy that may impact mortality. Multi-institutional studies with larger population sizes would be beneficial to evaluate these associations.
Disclosure
The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense, the Department of the Air Force, the Uniformed Services University of the Health Sciences, or any other agency of the U.S. Government.
Conflicts of Interest
The authors declare no conflicts of interest.
