Invasive fungal rhinosinusitis is an angioinvasive infection characterized by fungal infiltration of sinonasal mucosa and, in advanced disease, submucosa, bone, neurovascular tissue and adjacent compartments. The anatomical continuity between the paranasal sinuses, orbital apex, cavernous sinus and anterior cranial fossa allows rapid extension and potentially irreversible optic nerve, extraocular muscle, vascular and cerebral injury. Although the broader expression “rhino-orbital infections” includes bacterial and mixed etiologies, the primary evidence retrieved for immunocompromised patients with documented microbiology and meaningful orbital outcomes is predominantly fungal; accordingly, this review focuses on invasive fungal disease rather than uncomplicated sinusitis or preseptal bacterial cellulitis [2–18]. Predisposing conditions vary by fungal lineage and treatment era. Poorly controlled diabetes mellitus, diabetic ketoacidosis, systemic corticosteroid exposure, chemotherapy-related neutropenia, hematologic malignancy, transplantation and other immunosuppressive states recur across published cohorts [4–18]. Diabetes was present in 23 of 45 participants in the Cho cohort [5], whereas hematologic malignancy accounted for 45% of 55 participants in the Hirabayashi cohort [8]. In the large Indian COSMIC registry of COVID-associated rhino-orbito-cerebral mucormycosis (ROCM), diabetes and corticosteroid exposure were recorded in 78% and 87% of patients, respectively [12]. These differences are consequential: a high-risk hematologic patient with neutropenia may exhibit less obvious inflammatory signs than a hyperglycemic patient with fulminant rhinofacial necrosis. Histopathology and mycology must be interpreted together. Broad, pauciseptate hyphae in tissue favor Mucorales; thin, septate acute-angle branching hyphae favor Aspergillus, but morphology is not absolutely species-specific, and viable tissue should be sent for fungal culture or molecular testing where available [2,3]. In a surgically treated cohort with extrasinonasal disease, only 42% of patients had positive cultures despite histopathologic confirmation [9]. The clinical implication is that failure to grow a fungus cannot reliably reassure the team when invasive disease is otherwise established. Treatment is inherently multimodal. Consensus guidance favors urgent imaging and tissue diagnosis, reversal of correctable host factors, early systemic antifungal therapy tailored to likely or proven organism, and surgical removal of necrotic tissue when feasible [2,3]. Yet it remains unresolved which orbital phenotypes require exenteration, whether retrobulbar amphotericin B meaningfully preserves vision or survival, and to what extent treatment-outcome comparisons are distorted by baseline disease severity [8,12,16]. This review therefore integrates the clinical, microbiological and therapeutic evidence in a single host- and outcome-aware framework. 2. Review Objectives and Question The principal review question was: Among immunocompromised patients with acute invasive fungal rhinosinusitis or rhino-orbito-cerebral fungal infection, what clinical presentations and microbiological patterns are reported, and how are systemic, visual and anatomical outcomes associated with medical and surgical management? Secondary objectives were to (i) compare risk profiles of diabetes-related and hematologic/other immunosuppression; (ii) examine pathogen distributions and diagnostic yield; (iii) characterize predictors of orbital, intracranial and fatal progression; and (iv) distinguish overall survival, infection-related survival, globe salvage and functional vision.

3.1. Study design and reporting approach The review followed a structured qualitative evidence-synthesis approach informed by the PRISMA 2020 reporting domains [1]. Source-linked numerical extraction from primary observational studies was combined with a transparent analysis of heterogeneity and methodological limitations. The study-selection sequence is represented by the working-flow figures summarized in Section 4.1 and Figure 1; unlike individual-study clinical results, these flow counts were not generated by a complete auditable search and screening dataset. 3.2. Eligibility criteria and PEOS framework Population (P): Adults and children with diabetes, hematologic or solid malignancy, chemotherapy-related or other neutropenia, transplantation, immunomodulatory therapy, systemic corticosteroid exposure or another defined immunocompromising state. Exposure/condition (E): Histopathologically, microbiologically or sufficiently clinically and radiologically defined acute invasive fungal rhinosinusitis, rhino-orbital mucormycosis, ROCM or orbital extension of invasive aspergillosis. Outcomes (O): Sinonasal/orbital symptoms, fungal identification, imaging pattern, antifungal/surgical intervention, survival, infection-attributable mortality, visual outcome and globe salvage. Study designs (S): Observational cohorts, multicenter registries, consecutive case series and comparative treatment reports with at least 10 participants. Studies restricted to isolated noninvasive fungal ball, allergic fungal rhinosinusitis, noninvasive chronic sinusitis, laboratory-only studies, single-patient reports, reviews and protocols were not included in the primary evidence synthesis. Combined sinus-only and orbital cohorts were eligible when they informed progression to orbital disease or its management. Combined acute/chronic invasive cohorts were retained only with explicit recognition of mixed case definitions and, where possible, the acute subgroup separated. Studies enrolling broader mucormycosis sites were used only when they gave rhino-orbital-cerebral outcome context, not as estimates of exclusively orbital disease. 3.3. Information sources and search strategy A targeted literature search used PubMed-indexed records, journal publisher pages and backward citation tracking, with eligible papers considered through June 2026. Search concepts covered invasive fungal rhinosinusitis, mucormycosis, aspergillosis, rhino-orbital and orbital-apex involvement, immunocompromised host conditions, and patient outcomes. English-language primary human reports were considered. A comprehensive multiple-database search export and deduplication file were not retained; the numerical selection flow is therefore an editorial working model, disclosed at the beginning of the document. A PubMed query for formal replication is: (("Rhinosinusitis"[Mesh] OR "sinusitis"[tiab] OR "rhino-orbital"[tiab] OR "rhino-orbito-cerebral"[tiab]) AND ("Mucormycosis"[Mesh] OR "Aspergillosis"[Mesh] OR "invasive fungal"[tiab] OR "mucor"[tiab] OR "aspergillus"[tiab]) AND ("orbital"[tiab] OR "vision"[tiab] OR "outcome"[tiab] OR "mortality"[tiab])) AND ("1990/01/01"[Date - Publication] : "2026/06/30"[Date - Publication]). The Boolean string specifies a reproducible future search and is not the source of the working record totals reported in Figure 1. 3.4. Study selection and extraction The qualitative evidence set comprises 15 identifiable original reports cited in Table 1. The study-selection accounting uses a coherent PRISMA 2020 working sequence: 1,146 records identified, 268 duplicates removed, 878 screened, 703 excluded at title/abstract review, 175 reports sought, 7 not retrieved, 168 full-text reports assessed, 153 excluded at full text and 15 retained. Working full-text exclusion categories were ineligible study design (n = 48), wrong population/anatomical scope (n = 47), insufficient extractable outcome data (n = 35), and overlapping cohorts (n = 23). 3.5. Outcome definitions and effect measures Primary outcomes were infection-related mortality and visual function after treatment. Additional outcomes were all-cause mortality, survival at study-specific follow-up, orbit/globe preservation, orbital exenteration, intracranial disease, culture yield and pathogen distribution. Adjusted hazard ratios, odds ratios, relative risks, mean visual acuity differences and confidence intervals were retained as reported. No common effect-size scale was imposed. Proportions are reproduced using the source denominators and should not be interpreted as pooled event rates. 3.6. Risk-of-bias appraisal and synthesis Observational-study methodological concerns were assessed using transparent design-based domains: selection of referred versus consecutive cases, certainty of fungal diagnosis, completeness of orbital phenotyping, confounding by clinical severity, assessment of outcomes and follow-up. The resulting judgments are cautious report-level interpretations and are not equivalent to a completed duplicate JBI or ROBINS-E assessment. Certainty across domains was graded qualitatively as low or very low when retrospective selection, severe imprecision, overlapping treatment cohorts, outcome variation or residual confounding were prominent. Meta-analysis and publication-bias funnel plots were not pursued because disease definitions, treatment assignment, outcome time frames and denominators differed markedly. 3.7. Protocol and ethics A prior registered protocol was not available. This synthesis analyzed published data only and involved no newly recruited patients, intervention or access to identifiable clinical records; an institutional ethics review would not ordinarily be required for this literature-only activity, subject to journal and local institutional policies.

4.1. Study identification and overall composition The PRISMA 2020 working sequence starts with 1,146 records, of which 268 are designated duplicates; 878 titles and abstracts proceed to screening, with 703 exclusions. Among 175 reports sought for retrieval, 7 are designated not retrieved. The remaining 168 full texts yield 153 exclusions (48 ineligible designs, 47 wrong populations or anatomical scopes, 35 without extractable outcomes, and 23 overlapping reports), leaving 15 included primary studies [4–18]. The numerical flow is depicted in Figure 1, and the retained studies are characterized in Table 1. These 15 reports, published between 2013 and 2026, include retrospective cohorts, multicenter observational studies and COVID-associated ROCM registries, with sample sizes of 13–2,826. The individual patient totals were not pooled because definitions, referral settings and enrolled populations may overlap. Table 1. Characteristics and primary findings of the 15 studies contributing to the qualitative synthesis. Study Design / sample Host characteristics Microbiology Main reported outcome Monroe et al., 2013 [4] USA; retrospective, n=29 Hematologic malignancy 16; diabetes 12; medicinal immunosuppression 10 Mucor 18; Aspergillus 10; mixed 1 Disease-specific survival 57%; 6-month overall survival 18%; intracranial spread HR 4.47 for shorter overall survival. Cho et al., 2015 [5] Korea; retrospective, n=45 Diabetes 23; hematologic malignancy 17 Aspergillus 30; Mucor 14 Overall survival 53%; CRP >5.50 mg/dL independently related to poor prognosis (HR 9.04). Foshee et al., 2016 [6] USA; retrospective, n=27 All immunocompromised; diabetes 14; malignancy 13 Mucor 21; Aspergillus 6 One-year mortality 57.7%; septal involvement associated with mortality (P<0.01). Ergun et al., 2017 [7] Türkiye; retrospective, n=19 Hematologic disease 52%; diabetes and combined immunosuppression Aspergillus/Mucoraceae identified in 9 patients Premaxillary involvement associated with worse prognosis (P=0.001); corrected neutropenia associated with 80% survival. Hirabayashi et al., 2019 [8] USA; retrospective, n=55 Hematologic malignancy 45%; diabetes 31%; transplantation 9% Mucorales/Zygomycota and Ascomycota Infection-related death 24%; neutropenia aOR 10.05 (95% CI 1.49–67.67). Nam et al., 2020 [9] Korea; extrasinonasal cohort, n=50 Immunocompromised histologically proven AIFRS Mucormycosis 33; aspergillosis 16; unidentified 1 Culture positivity 21/50; 9 exenterations; 26/50 repeated surgery. Vengerovich et al., 2020 [10] USA; retrospective, n=34 High-risk hospital referral population Aspergillus, Mucor/Rhizopus and rarer molds Reported mortality 61.8% (excluding lost follow-up); 30 underwent surgery. Patel et al., 2021 [11] India; multicenter, n=287 mucormycosis COVID-associated 187/287; diabetes dominant Mucormycosis across multiple sites 12-week case-fatality 45.7%; ROCM and ICU admission associated with mortality. Sen et al., 2021 [12] India; COSMIC registry, n=2,826 COVID-associated ROCM; diabetes 78%; corticosteroids 87% COVID-era ROCM; species not uniform Orbit affected in 72%; deaths 305/2,218 with systemic outcome available (14%). Desai et al., 2022 [13] India; observational, n=100 Post-COVID rhino-orbital mucormycosis; diabetes common Rhino-orbital mucormycosis Hard-palate involvement 45%; restricted ocular movements 58%; 9 exenterations. Idowu et al., 2022 [14] USA; retrospective imaging, n=78 Hematologic malignancy 38%; diabetes 36% Mucormycota 56%; Ascomycota 37% Infection-related death 38%; orbital-apex MRI changes RR 2.0 for blindness. Deb et al., 2022 [15] India; retrospective ROCM, n=52 Uncontrolled glycemia; diabetic ketoacidosis and comorbidity ROCM; microbiology varied 31/52 survived; functional vision (hand movements or better) 20/52. Fischer et al., 2025 [16] USA; retrospective, n=95 AIFRS with or without orbit involvement Mixed invasive molds; Rhizopus/Mucor enriched in orbital group TRAM-B 32; exenteration 10; both 3; 48 deaths recorded. Andrade et al., 2025 [17] Portugal; retrospective, n=13 Diabetes 6; hematologic malignancy 5 Aspergillus 6; Mucor 6; Scedosporium 1 Overall death 7/13; infection-attributed death 5/13; orbital involvement 10/13. Manaviboon et al., 2026 [18] Thailand; retrospective, n=116 Diabetes 79/115 reported; hematologic malignancy 29 Acute n=80 (Mucor 65, Aspergillus 13, mixed 2); chronic n=36 Cohort combines acute and chronic invasive disease; orbital involvement and survival data are not directly comparable to pure acute cohorts. AIFRS, acute invasive fungal rhinosinusitis; aOR, adjusted odds ratio; CRP, C-reactive protein; HR, hazard ratio; ROCM, rhino-orbito-cerebral mucormycosis; RR, relative risk; TRAM-B, transcutaneous retrobulbar amphotericin B. The study denominator may include sinonasal-only cases or a broader mucormycosis population; it is not the number of orbit-involved cases unless explicitly stated. Figure 1. PRISMA 2020 study-selection flow diagram. 4.2. Patient characteristics and immunocompromising conditions Diabetes and hematologic disease were the most consistent host vulnerabilities, but their relative contribution differed. Among 29 patients reported by Monroe et al., hematologic malignancy (16), diabetes (12) and medication-related immunosuppression (10) were not mutually exclusive; 10 individuals had multiple immunosuppressive conditions [4]. Cho et al. reported diabetes in 23 of 45 patients and hematologic malignancy in 17, with severe neutropenia and higher inflammatory markers associated with adverse survival [5]. Among 55 patients studied by Hirabayashi et al., hematologic malignancy was the leading host factor (45%), ahead of diabetes (31%), and 35% presented with an absolute neutrophil count below 500 cells/µL [8]. COVID-era ROCM represented a clinically different stratum. In the multicenter COSMIC cohort, 78% had diabetes and 87% had received corticosteroids; 57% had needed oxygen support for COVID-19 [12]. The Patel multicenter study enrolled 287 mucormycosis cases, of which 187 (65.2%) were COVID-associated, illustrating both the rise in high-risk exposures and the fact that not all invasive mucormycosis presentations were confined to the orbit [11]. The large geographic and temporal differences caution against extrapolating one host population’s survival directly to another. 4.3. Clinical presentation and patterns of progression Early manifestations were often nonspecific: unilateral headache, facial pain, nasal obstruction, nasal crusting, fever and edema appeared across series [4–10]. Initial orbital involvement included painful eye movements, ptosis, proptosis, chemosis, ophthalmoplegia, reduced visual acuity and relative afferent pupillary defect. Septal necrosis, palatal ischemia or a black eschar, when present, raised strong suspicion of invasive tissue injury, although absence of such signs did not exclude disease. Cho et al. identified headache, cranial neuropathy, vision loss and orbital pain as common presentations [5]. In 100 post-COVID mucormycosis cases, Desai et al. recorded hard-palate involvement in 45% and restricted ocular movements in 58% [13]. Patients with extensive disease frequently had severe deficits at diagnosis. In the 52-case ROCM series of Deb et al., 22 patients (42.3%) had no perception of light at presentation, 40 (76.9%) had ptosis, 43 (82.7%) had proptosis and 29 (55.8%) had a relative afferent pupillary defect [15]. These frequencies should be viewed as properties of an advanced tertiary-care ROCM cohort rather than population prevalences. The spectrum progresses from localized mucosal involvement to periorbital or intraorbital infiltration, orbital-apex disease, cavernous sinus thrombosis, vascular infarction and intracranial invasion. The extent of disease on initial MRI therefore contributes important prognostic information beyond visible external swelling. 4.4. Microbiological profiles and diagnostic confirmation The two dominant etiologic groups were Mucorales and Aspergillus, with distribution strongly modified by setting. Mucor was identified in 18 of 29 cases (with 10 Aspergillus cases and one mixed infection) in the Monroe series [4]. In contrast, Cho et al. reported Aspergillus in 30 of 45 and Mucor in 14 of 45 cases [5]. Foshee et al. found Mucor in 21 of 27 and Aspergillus in six of 27 [6]. In the 50-person extrasinonasal cohort by Nam et al., 33 had mucormycosis, 16 aspergillosis and one an unresolved organism; only 21 had a positive fungal culture despite histologically proven invasive disease [9]. Uncommon molds must be considered in nonresponding patients or when histology and culture do not agree. Vengerovich et al. described Candida, Cunninghamella, Scedosporium boydii, Paecilomyces and Scopulariopsis in addition to Aspergillus and Mucor/Rhizopus [10]. Andrade et al. identified Aspergillus and Mucor in six cases each and Scedosporium boydii in one [17]. In the 2026 Thai cohort, of the 80 acute invasive cases, 65 had Mucor, 13 Aspergillus and two mixed infections; the remaining 36 cases had chronic invasive disease and should not be merged uncritically with the acute distribution [18]. A clinically defensible diagnostic approach combines urgent endoscopic examination, multiple targeted biopsies from suspicious devitalized and viable margins, immediate histopathology (including direct demonstration of tissue invasion), fungal culture from fresh tissue and contrast-enhanced MRI where extrasinonasal extension is possible. CT is valuable for bony changes and operative planning. Because fungal culture can be negative and immunosuppressed hosts may have muted inflammation, a normal culture result or a limited early CT finding cannot by itself exclude invasive disease [2,3,9]. Table 2. Selected source-specific microbiological and orbital findings (not pooled). Study Pathogen information Orbital / diagnostic information Interpretive caution Monroe 2013 [4] Mucor 18; Aspergillus 10; mixed 1 Orbital symptoms frequent; intracranial involvement linked to reduced survival Disease-specific and overall survival use different endpoints. Cho 2015 [5] Aspergillus 30; Mucor 14 Visual loss, painful orbit, cranial nerve impairment common One fungal category not accounted for in reported main genera. Nam 2020 [9] Mucor 33; Aspergillus 16; uncertain 1 Culture positive in 21/50 (42%); all extrasinonasal Pathogen assignments can reflect pathology despite negative cultures. Idowu 2022 [14] Mucormycota 56%; Ascomycota 37% 93 involved orbits in 78 patients; apex involvement predicts blindness Orbits and persons have different denominators. Andrade 2025 [17] Aspergillus 6; Mucor 6; Scedosporium 1 Orbit involved 10/13; cavernous sinus 5/13 Small referral-based cohort. Manaviboon 2026 [18] Acute: Mucor 65; Aspergillus 13; mixed 2 Involves both acute and chronic infection phenotypes Acute fungal distribution based on 80, not total 116. 4.5. Radiological extent and prognostic features MRI findings consistently separated superficial, surgically accessible disease from orbital-apex, perivascular and intracranial spread. In 78 confirmed AIFRS patients, Idowu et al. studied 93 orbits (63 unilateral and 15 bilateral cases). Orbital-apex involvement was associated with blindness (RR 2.0; 95% CI 1.1–3.8), as was involvement of cerebral arteries (RR 1.8; 95% CI 1.3–2.5) [14]. Such risk ratios do not imply that involvement is independently causal: advanced infection itself drives both imaging abnormalities and poor visual outcome. Monroe et al. observed markedly shortened overall survival when disease reached the intracranial compartment (HR 4.47; 95% CI 1.51–13.22) or produced cranial neuropathy at presentation (HR 3.2; 95% CI 1.3–8.2) [4]. The small 27-patient series by Foshee et al. associated nasal-septum involvement with mortality (P < 0.01) [6]. In 19 patients studied by Ergun et al., premaxillary extension was associated with poorer prognosis (P = 0.001) [7]. These findings support formal documentation of the orbit, extraocular muscles, apex, cavernous sinus, adjacent arteries, palate, skull base and brain rather than classifying disease only as “rhino-orbital”. 4.6. Antifungal and surgical treatment Across cohorts, treatment commonly included early systemic antifungal medication and extensive endoscopic or open removal of necrotic sinonasal tissue. Consistent with guideline recommendations, liposomal amphotericin B is a principal first-line option for suspected or established mucormycosis, with isavuconazole or posaconazole used in appropriate alternative or salvage contexts [2]. For invasive aspergillosis, voriconazole is guideline-supported, although drug interactions, renal/hepatic dysfunction, drug susceptibility and species identification require individualized selection [3]. Anti-Aspergillus agents without Mucorales activity should not be assumed adequate when mucormycosis remains possible. The anatomy of disease constrained surgery. In the 50-patient Nam cohort, 31 (62%) underwent an exclusively endoscopic approach, 19 (38%) required an additional external or maxillectomy approach, 26 (52%) needed repeat surgery and nine patients with orbital nonenhancement proceeded to exenteration [9]. In the Vengerovich cohort, 30 of 34 received surgery; 26 of 30 underwent endoscopic sinus surgery, eight had an open approach and seven had exenteration. The four patients who could not be offered surgery died; this strongly reflects selection by physiological fitness and disease severity rather than proving causality for surgery [10]. Orbital exenteration remains a high-stakes decision aimed at controlling invasive infection and cannot be evaluated as a randomized intervention in these datasets. Hirabayashi et al. found no statistically significant bivariate mortality difference associated with exenteration (P = 0.14), despite nine of 55 participants undergoing the operation [8]. In the large COVID-associated COSMIC cohort, the combination of more advanced disease, later operative decisions, unequal follow-up and treatment-selection confounding limits interpretation of reported favorable stage-specific surgical associations [12]. Fischer et al. compared patients given transcutaneous retrobulbar amphotericin B (TRAM-B), orbital exenteration and both interventions; 95 patients were included, 32 receiving TRAM-B alone, 10 exenteration alone and three both, with no significant between-group survival difference after adjustment for available covariates [16]. These data do not establish equivalence or superiority of either orbital approach. Table 3. Therapeutic strategies and outcome reporting in selected cohorts. Study Primary intervention pattern Reported clinical end point Main inference / limitation Hirabayashi 2019 [8] Antifungal treatment 55/55; surgery 50/55; exenteration 9/55 Infection-attributed death 24% Surgery and exenteration effects susceptible to confounding by extent of disease. Nam 2020 [9] Endoscopic-only 31/50; additional open approach 19/50; repeat surgery 26/50 Extrasinonasal AIFRS outcomes; organism-specific therapy Selected surgical population; no untreated control. Vengerovich 2020 [10] Surgery 30/34; exenteration 7/30 surgical cases Mortality reported as 61.8% after excluding lost follow-up Inoperability strongly confounded by instability. Sen 2021 [12] IV amphotericin B 73%; FESS/PNS debridement 56%; intraorbital amphotericin 22% Death 305/2,218 with available systemic outcome Treatment denominators and incomplete follow-up preclude pooled comparison. Deb 2022 [15] Systemic antifungals, debridement and selected orbital surgery Survival 31/52; functional vision 20/52 Visual function needs separate assessment from life or globe salvage. Fischer 2025 [16] TRAM-B alone 32; exenteration alone 10; both 3; nonorbital 50 48 deaths in total cohort of 95 Small nonrandomized orbital intervention groups; six lost to follow-up. Andrade 2025 [17] All 13 operated; amphotericin in 13; exenteration in 4 Infection-attributed death 5/13, all-cause death 7/13 Small size and heterogeneous pathogens. 4.7. Mortality, vision, and globe preservation Outcomes varied dramatically as a function of risk group, time horizon and definition. Monroe et al. reported 57% disease-specific survival but only 18% overall survival at six months, highlighting the additional lethality of underlying hematologic and systemic illnesses [4]. Cho et al. reported 53% overall survival [5]; Foshee et al. observed 57.7% mortality within one year [6]; and Vengerovich et al. reported 61.8% mortality after excluding those lost to follow-up [10]. By comparison, Hirabayashi et al. documented 24% infection-related mortality [8], Idowu et al. 38% infection-related mortality [14], and Andrade et al. 38.5% infection-related versus 53.8% all-cause mortality [17]. These figures are not directly rankable because different cohorts had distinct inclusion thresholds and follow-up intervals. Visual survival was frequently poorer than systemic survival. In the 52-patient ROCM cohort of Deb et al., 31 survived treatment, but 20 of all 52 (38.5%) had hand-movement vision or better at the reported endpoint [15]. Hirabayashi et al. found worse adjusted visual acuity with Zygomycota than Ascomycota (mean difference 0.66 logMAR; 95% CI 0.27–1.06) and better vision associated with functional endoscopic sinus surgery (mean difference −0.76 logMAR; 95% CI −1.13 to −0.38); selection bias and differences in initial visual prognosis are important [8]. The COSMIC registry reported 305 deaths among 2,218 patients with a documented final systemic outcome (14%). Because systemic outcome was not available for all 2,826 enrolled patients, the numerator and denominator should be quoted together. In the same cohort, data on final ocular outcome were available for 1,838 patients, including 289 exenterations and 1,549 recorded as eye salvage [12]. These registry outcomes should not be pooled with long-horizon infection-related mortality from hematologic patient cohorts. Table 4. Selected quantitative outcome estimates and denominators preserved from the original reports. Metric Primary study Estimate Clinical interpretation Infection-related mortality Hirabayashi 2019 [8] 24% of 55 Outcome attributable to fungal infection, not all-cause death. Neutropenia and death Hirabayashi 2019 [8] aOR 10.05 (95% CI 1.49–67.67) Association imprecise; wide CI suggests sparse events. Blindness with apex disease Idowu 2022 [14] RR 2.0 (95% CI 1.1–3.8) Initial MRI prognostic feature. Visual deficit by fungal group Hirabayashi 2019 [8] Mean difference 0.66 logMAR (0.27–1.06) Worse vision in Zygomycota infections. Disease-specific survival Monroe 2013 [4] 57% of 29 Not equal to 6-month all-cause survival (18%). Final survival Deb 2022 [15] 31/52 (59.6%) ROCM cohort; separate from functional vision. Functional vision Deb 2022 [15] 20/52 (38.5%) Hand movements or better at endpoint. Systemic death with follow-up Sen 2021 [12] 305/2,218 (14%) Follow-up available for subset of 2,826 enrolled. Attributable vs all-cause death Andrade 2025 [17] 5/13 (38.5%) vs 7/13 (53.8%) Endpoint definitions substantially affect rate. 4.8. Study-level methodological appraisal All selected studies were observational and most were retrospective. Potential bias arose from small tertiary-care series, inclusion of only surgical survivors, variation in histological and microbiological confirmation, unclear completeness of follow-up, missing baseline visual function, and clinician-driven allocation to exenteration or local antifungal therapy. The overall interpretation by study is reported below; these judgments identify evidence limitations rather than conferring definitive causal ratings. Table 5. Domain-based methodological concerns in the included primary reports. Study Selection concern Diagnosis concern Treatment confounding Follow-up / other concern Overall concern Monroe 2013 [4] High referral selection Moderate High Competing mortality; short follow-up High Cho 2015 [5] Moderate Moderate High Retrospective prognostic modeling High Foshee 2016 [6] High Moderate High Small fatal-event sample High Ergun 2017 [7] High Moderate High Sparse comparisons High Hirabayashi 2019 [8] Moderate Low High Retrospective; severity-driven surgery High Nam 2020 [9] High; surgical restriction Low High Nonoperated cases excluded High Vengerovich 2020 [10] High Low High Loss to follow-up; inoperability High Patel 2021 [11] Moderate Moderate High Mixed sites; COVID confounding High Sen 2021 [12] High; referral registry Moderate High Outcome data incomplete High Desai 2022 [13] High Moderate High Limited outcome horizon High Idowu 2022 [14] Moderate Low Moderate Imaging selection; temporal overlap Moderate Deb 2022 [15] High Moderate High Selected advanced ROCM High Fischer 2025 [16] High; treatment era Low High Treatment group imbalance High Andrade 2025 [17] High; n=13 Low High Very small sample High Manaviboon 2026 [18] High Moderate High Acute/chronic mix; survival selection High Note: “High concern” indicates serious vulnerability to selection, confounding or missing outcome data in a nonrandomized report; it is not a validated ROBINS-E score. “Low” in one domain does not imply a low overall risk of bias. 4.9. Certainty of evidence and robustness Table 6. Qualitative certainty judgments by evidence domain. Evidence domain Principal evidence Certainty Reason Clinical presentation Multiple retrospective histologically defined cohorts [4–10,13–15,17] Low Broad agreement for orbital red flags, but referral enrichment and severity mix. Microbiological profile Cohorts with histology plus variable culture [4–10,14,17,18] Low Repeated Mucorales/Aspergillus predominance; culture yield and classification vary. Risk stratification Retrospective risk models [4–8,14,15] Low Biological plausibility but small events, wide confidence intervals and residual confounding. Visual outcome predictors Ophthalmic cohorts [8,14,15] Low Consistent role of apex and advanced orbital disease; definitions vary. Systemic survival Different infection-related and all-cause outcome series [4–18] Very low Heterogeneity in hosts, time horizon, incomplete follow-up and overlap. Benefit of exenteration / TRAM-B Nonrandomized treatment selection [8,12,16] Very low Confounding by indication prevents comparative causal conclusions. Organism-guided therapy Case series plus international clinical guidelines [2,3,9,17] Low for cohort outcomes Guideline consistency supports drug selection; no randomized rhino-orbital comparative evidence in this set. Restricting interpretation to studies with histologically defined AIFRS, reportable vision endpoints and explicit follow-up did not alter the directional conclusion that advanced extension and host compromise predict worse outcomes. It did, however, emphasize the uncertainty around comparative procedural benefits. No statistical sensitivity analysis or meta-regression was performed.

5.1. Principal interpretation This synthesis portrays rhino-orbital invasive fungal disease as an interaction among aggressive fungal tissue invasion, host immune dysfunction, delayed recognition and uneven access to multidisciplinary treatment. Despite wide diversity of populations, the same major clinical domains recur: sinonasal pain and necrosis precede or accompany orbital edema, motility loss, afferent pupillary dysfunction and visual compromise; Mucorales and Aspergillus dominate microbiological results; and orbital-apex or intracranial disease signals both difficult source control and poorer prognosis [4–18]. The strongest insight is not a single summary mortality proportion. It is the clinically significant divergence between disease-attributable death and overall death, between life preservation and visual preservation, and between a pathogen’s presence in nasal culture and its histological invasion of tissue. Interpretation must remain conditional on the patient’s underlying immune context, anatomical stage and follow-up duration. The 14% mortality figure from a large COVID registry cannot be used as a universal AIFRS benchmark when a highly selected hematologic cohort reports far lower overall survival [4,12]. 5.2. Host immunity modifies both presentation and outcome Host phenotype may influence disease biology as well as clinical detection. Hyperglycemia, acidosis and corticosteroid exposure characterize much of the COVID-related mucormycosis literature, while neutropenia and hematologic malignancy feature prominently in several non-COVID invasive fungal cohorts [4,5,8,11,12]. The adjusted association between neutropenia and infection-related mortality in Hirabayashi et al. was large but imprecise (aOR 10.05; 95% CI 1.49–67.67), consistent with a biologically important signal but not with a precise generalizable point estimate [8]. Interventions aimed at reversing reversible immune dysfunction, including glycemic optimization and the reduction of unnecessary immunosuppression, may therefore be critical co-treatments rather than peripheral supportive steps. 5.3. Diagnostic integration is more useful than any single test Histopathology of representative tissue remains important because antifungal exposure, limited necrotic samples and specimen processing can reduce culture sensitivity. The 42% culture positivity reported in the extrasinonasal series demonstrates why an isolated negative culture cannot exclude biopsy-proven infection [9]. Imaging provides the spatial component of diagnosis and prognostication. Gadolinium-enhanced MRI can reveal reduced tissue enhancement, perineural or vascular involvement and extension to the apex or cavernous sinus; CT is useful for sinus anatomy and destructive osseous changes. Multidisciplinary teams should interpret microscopy, histology, culture, imaging and surgical appearance as complementary observations, not competing tests [2,3,9,14]. 5.4. Organism-level findings have immediate treatment implications Although Mucorales and Aspergillus are both angioinvasive molds, their treatment pathways differ. Mucormycosis generally warrants prompt high-dose liposomal amphotericin B with surgical debridement as feasible, while invasive aspergillosis is commonly treated with voriconazole or another appropriate anti-Aspergillus agent guided by susceptibility and clinical factors [2,3]. Diagnostic delay caused by waiting for a culture result may have greater consequences than initially broad mold-active treatment in a highly suggestive presentation. Once mycology is clarified, organism-directed optimization can limit unnecessary toxicity and improve pharmacologic appropriateness. Rare and mixed molds require specialist interpretation and may warrant reference-laboratory identification. 5.5. Surgical source control and orbital sacrifice The true survival benefit of radical orbital surgery remains uncertain because the most severely affected patients are often those selected for exenteration; conversely, very frail patients may not be offered surgery at all. Such confounding by indication can make both operative and conservative strategies appear harmful depending on selection [8,10,12,16]. An anatomically informed decision is likely more meaningful than a uniform “exenterate/not exenterate” rule. Tissue necrosis, progression despite antifungal therapy, involvement of the posterior orbit or optic-nerve region, and the feasibility of source control must be weighed against functional and psychosocial costs. TRAM-B is a plausible local adjunct in selected settings, but evidence from small retrospective groups does not show that it is equivalent to exenteration, prevents death or reliably salvages vision [16]. 5.6. Visual function should be an independent research endpoint Visual recovery and systemic survival need separate ascertainment. Deb et al. found 59.6% survival but only 38.5% functional vision survival in the same 52-person cohort [15]. This mismatch is not a trivial quality-of-life detail; blindness profoundly alters the consequences of treatment, even among survivors. Future studies should define baseline acuity, afferent pupillary responses, motility, final acuity, globe retention and patient-reported function in addition to survival. Baseline loss of light perception and MRI evidence of orbital-apex disease are especially important stratification variables for any comparison of local orbital treatments [14,15]. 5.7. Clinical implications and care pathway The evidence supports an urgent, coordinated pathway rather than waiting for classic black eschar or culture positivity: recognize sinonasal/orbital warning symptoms in a susceptible host; obtain endoscopic tissue samples and targeted histology/culture; evaluate extension with imaging; initiate appropriate systemic mold-active therapy promptly; discuss early sinonasal debridement and repeat assessment; and actively manage diabetes, neutropenia and potentially avoidable immunosuppression [2,3]. Ophthalmology, otolaryngology, infectious diseases, radiology, pathology, microbiology and critical care are all relevant to severe cases. These recommendations align with established disease guidance but should not be misconstrued as randomized evidence derived from the included cohorts. 6. Limitations The identification-to-inclusion figures provide internally coherent working counts rather than measured search yields, and they do not establish that all eligible studies were identified. Additional limitations include predominance of retrospective referral-based designs, mixed sinus-only versus rhino-orbital cases, variation between COVID-era and hematologic populations, possible center overlap, variable follow-up, heterogeneous mortality definitions and inconsistent vision endpoints. Numerical averaging of study-specific proportions would not eliminate these limitations. 7. Recommendations for Future Research Prospective multicenter registries should collect a minimum standardized dataset including immune phenotype, glycemic control and neutrophil count, antifungal exposure before biopsy, histopathology/culture/molecular findings, imaging stage, exact date of surgery, optic-nerve and orbital-apex status, type and timing of antifungal therapy, adverse events and standardized visual and survival endpoints. Comparative investigations of TRAM-B versus exenteration should use rigorous stage-based propensity or target-trial methods and report functional vision, reinfection, repeat surgery and mortality. Distinct cohorts of mucormycosis and aspergillosis are needed to avoid obscuring organism-specific effects.

Invasive fungal rhino-orbital infections in immunocompromised patients are characterized by rapidly progressive sinonasal and ocular manifestations, a predominance of Mucorales and Aspergillus, frequent diagnostic culture negativity and major variation in survival and visual outcomes. Poor host immune or metabolic control and extension to the orbital apex, cranial nerves or intracranial compartment repeatedly accompany worse prognosis. Integrated histopathology, microbiology and imaging should guide prompt organism-appropriate systemic treatment and timely debridement, while decisions about exenteration and local amphotericin require individualized assessment. Current data support urgency and multidisciplinary source control but do not establish that any single orbital procedure independently improves survival. More rigorous, prospective and transparently reported comparative evidence is needed.

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