This cohort study identifies prognostically important factors in acute invasive fungal sinusitis and incorporates the factors into a comprehensive functional severity staging system and clinical severity staging system.
Key Points
Question
Is it possible to identify patients with acute invasive fungal sinusitis (AIFS) who are at higher risk for poor survival outcomes?
Findings
In this cohort study of 71 patients with AIFS, 6-month overall survival was 39%. A 3-stage composite clinical staging system was developed based on symptoms, comorbidity burden, and presence and duration of severe neutropenia.
Meaning
This study presents a staging system using presenting clinical factors that may prognosticate survival in patients with AIFS.
Abstract
Importance
Despite the aggressive progression of fulminant acute invasive fungal sinusitis (AIFS), data on prognostic factors have been disparate, hindering the development of a staging system. A composite staging system may improve prognostication for patient counseling and conduct of clinical research.
Objective
To identify prognostically important factors in AIFS and to incorporate the factors into a comprehensive Functional Severity Staging System and Clinical Severity Staging System.
Design, Setting, and Participants
This retrospective cohort study included adult patients diagnosed with pathology-proven AIFS from June 1, 1992, to December 31, 2022, at Washington University Medical Center and Barnes-Jewish Hospital, a tertiary care center in St Louis, Missouri. Data were analyzed from April to July 2023.
Main Outcome and Measures
Sequential sequestration and conjunctive consolidation was used to develop a composite staging system to predict 6-month overall survival.
Results
Of 71 patients with pathology-proven AIFS over the 30-year period, the median (range) age of the cohort was 56 (19-63) years, and there were 47 (66%) male patients. The median (range) follow-up time was 2 (0-251) months. There were 28 patients alive within 6 months, for a 39% survival rate. Symptoms, comorbidity burden, and presence and duration of severe neutropenia were associated with 6-month survival and were consolidated into a 3-category Clinical Severity Staging System with 6-month survival of 75% for stage A (n = 16), 41% for stage B (n = 27), and 18% for stage C (n = 28). The discriminative power of the composite staging system was moderate (C statistic, 0.63).
Conclusion and Relevance
This cohort study supports the clinical importance of symptomatology, comorbidity burden, and prolonged severe neutropenia at the time of AIFS presentation. The composite clinical staging system may be useful for clinicians when counseling patients with AIFS and conducting clinical research.
Introduction
Acute invasive fungal sinusitis (AIFS) is one of the most fatal infectious diseases of the head and neck. It is characterized by invasion into mucosal and submucosal structures of the nasal cavity, paranasal sinuses, and extension into neighboring structures.1 Patients most frequently reported with AIFS are those with hematological cancers, bone marrow transplant, and poorly controlled diabetes, and those who take immunosuppressive medications.2 AIFS can have variable and nondescript presentation that includes rapid onset fever, facial swelling, headache, diplopia, or nasal congestion. Treatment typically involves early systemic antifungal therapy and surgical debridement.3,4 Despite the aggressive progression of fulminant AIFS, prognostic data on survival have been limited.
Investigating important prognostic factors for AIFS has been challenging due to the rarity of the disease. To date, 1 AIFS staging system has been developed, which exclusively assessed anatomical extent of disease.4 A previous systematic review studied AIFS prognostic factors in terms of mortality.5 While symptom presentation is a fundamental characteristic of infectious diseases, to our knowledge, the prognostic relevance of symptoms has not been investigated in the context of AIFS. Limitations in the ability to predict survival have left patients and physicians unclear on best practices. Improved understanding of AIFS disease course will allow for evidence-based decision-making when considering the risks and benefits of aggressive therapies. This is especially important because patients with AIFS are at risk of the high costs of health care due to their immunocompromised status.
In this cohort study, we aimed to identify clinical factors among patients with AIFS that are associated with survival. Clinically important factors were incorporated into a model to predict survival.
Methods
Study Design
We conducted a retrospective cohort study of patients diagnosed with AIFS from June 1, 1992, to December 31, 2022, at Washington University Medical Center and Barnes-Jewish Hospital in St Louis, Missouri. Adult patients with pathology-proven disease were included. All data were gathered from medical records. Exclusion criteria included pathological findings inconsistent with AIFS. The study was given exempt status by the Washington University in St Louis Institutional Review Board because the study posed no more than minimal risk to privacy of information based on adequate plan to protect identifiers from improper use and plan to destroy identifiers. Patient informed consent was also waived because the study was retrospective and no contact with patients was needed. Study data were stored using REDCap hosted at Washington University in St Louis.6 This study fulfilled all Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines except that we did not have a statement on study size.
Study Population
Patient records were reviewed individually to abstract relevant demographic and clinical data. Variables of interest were identified based on institutional experience and literature review. Demographic data collected included sex, date of birth, and race and ethnicity. Clinical data collected included date of diagnosis, presenting symptoms, medical history, comorbidity severity, use of prophylactic antifungals, use of chronic immunosuppressive therapeutics, use of therapeutic antifungals, examination findings, laboratory values, imaging findings, surgical intervention, fungal species, extent of disease, and vital status. Symptoms included cough, nasal discharge, epistaxis, edema, headache, vision loss, dipoplia, ophthalmoplegia, fever, facial pain, altered mental status, or facial numbness. Unless otherwise indicated, lack of documentation of these symptoms was interpreted to signify their absence.
The date of proven AIFS diagnosis was designated as zero time for the purposes of identifying prognostic factors and developing the clinical staging systems. Proven AIFS was defined as criterion-standard pathology findings demonstrating evidence of tissue-invasive fungi with associated necrosis.
Data Classification
Because each person could have multiple symptoms, the sequential sequestration method was used to determine the individual contribution of each symptom to survival and to create stage categories of survival in a manner analogous to the TNM method.7 All presenting symptoms were identified, and the survival rate for patients with each symptom was calculated. The symptoms were then rank ordered by survival rate from lowest to highest. The patients with the symptom associated with the worst survival rate were then removed (ie, sequestered) from the cohort. The symptoms were then rank ordered by survival rate for the remaining patients. The patients with the symptom that had the worst survival were removed. This iterative process continued until all patients were removed. This sequential sequestration process resulted in classification of patients’ presenting symptoms based on their worst prognostic effect and presumed degree of fungal spread into 3 distinct groups: (1) local congestive, (2) perilocal/visual, and (3) sensory-perceptual changes. The local congestive category included symptoms attributed to sinonasal symptoms at the site of infection such as nasal discharge, epistaxis, and congestion. The perilocal/visual category included symptoms attributed to regional extension of disease, such as facial edema, or those associated with visual changes, such as diplopia. The sensory-perceptual changes category included symptoms attributed to distant extension of disease associated with alteration of senses, such as facial numbness, or altered mentation.
Laboratory measurement of neutrophil cells was used as a surrogate of immunosuppression severity at presentation. Severe neutropenia was defined by absolute neutrophil count (ANC) less than 500/μL (to convert to cells ×109/L, multiply by 0.001). ANC recovery was defined as 3 consecutive values of 500/μL or higher. The number of days between severe neutropenic levels and ANC recovery defined duration of severe neutropenia. The duration of severe neutropenia was classified into 3 distinct groups of 0, 1 to 30, and 31 or more days.
Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) severity index, which is a comorbidity scoring system that uses a set of criteria to rate the burden of comorbidity based on presence and severity of comorbidity of each organ system.8 The final ACE-27 is graded as none, mild, moderate, or severe, based on the highest severity comorbidity from all of the organ systems. In the case of 2 separate organ systems with moderate severity, the final ACE-27 score is defined as severe. Patients were classified into 2 distinct comorbidity severity groups: (1) not severe comorbidity (comprising comorbidity grades of none, mild, or moderate) or (2) severe comorbidity.
Therapeutic Nil Hypothesis and Primary Outcome
The prognostic data were collected and analyzed according to the nil hypothesis, which is different from the statistical null hypothesis and makes the assumption that therapy (eg, surgery) had no effect on a patient’s clinical outcome. Thus, all baseline features were analyzed for their association with outcome regardless of treatment.7 The primary outcome was vital status (alive or dead) at 6 months after the date of diagnosis.
Statistical Analysis
Descriptive statistics were used to explore distribution of patient characteristics. Continuous variables are reported as mean (SD) when normally distributed or median (range) when not normally distributed. Effect sizes with 95% CIs were reported. Categorical variables are summarized using frequencies and proportions. Effect sizes for categorical variables were reported using proportion difference with 95% CI. Univariate logistic regression was used to explore characteristics associated with 6-month survival. No a priori sample size calculation was performed. Instead, study sample size was determined by the number of patients available.
Multivariable composite staging systems were created to predict 6-month vital status based on presenting clinical factors. Clinical factors at presentation that were identified as having an association with survival were consolidated into groups using conjunctive consolidation, a cluster-type technique that involves cross-table analysis of independent predictor variables.7,9,10 The rate of outcome interest—6-month survival rate—was examined within each category of each predictor variable (univariate analysis). Then, the conjoined effect of 2 variables on the outcome was examined. Conjoined cells—cross-table cells demonstrating the combined effect of 2 clinical factors on survival rate—were consolidated into 3 prognostic groups based on similar rates of the outcome and biological coherence. Comorbidity severity and presenting symptoms were explored for association with survival rate. The prognostic groups created by consolidating comorbidity severity and presenting symptoms was the Functional Severity Staging System (FSSS). These conjoined cells were cross-tabulated with days of severe neutropenia and consolidated to create the Clinical Severity Staging System (CSSS). The prognostic performance of the FSSS and the CSSS were evaluated by the overall survival rate gradient (ie, the difference in the highest and lowest survival rate). A gradient that was greater than any predictor variable alone was deemed a successful consolidation. The performance of each staging system, and the variables that were identified as independent contributors to survival rates, were compared using monotonicity of survival, survival gradient, and log rank for linear trend. Discriminative power was evaluated using C statistic calculated from logistic regression analysis, with 6-month survival rate as the dependent variable and the clinical factors and new staging systems as the independent variables. Kaplan-Meier product-limit estimates were used to compare survival between categories of each staging system. Statistical analysis was conducted using SPSS Statistics for Macintosh, version 28 (IBM).
Results
Baseline Characteristics and 6-Month Survival
A total of 71 patients had pathology-proven AIFS over the 30-year study period. The median (range) age of the cohort was 56 (19-63) years, and there were 47 male patients (66%) and 24 female patients (34%). The median (range) follow-up time was 2 (0-251) months. There were 28 patients who were alive within 6 months for a 39% 6-month survival rate. Table 1 summarizes the baseline variables, the number and rate of survivors at 6 months, and the difference (or gradient) between the highest and lowest 6-month survival rate within each baseline category.
Table 1. Patient Characteristics and Association With Survival.
| Characteristic | No. (%) | Survival gradient (95% CI), %b | |
|---|---|---|---|
| Patients with AIFS (n = 71) | Survivors (n = 28)a | ||
| Age, y | |||
| 19-40 | 17 (24) | 4 (24) | 29 (3 to 57) |
| 41-60 | 24 (34) | 8 (33) | |
| ≥61 | 30 (42) | 16 (53) | |
| Sex | |||
| Female | 24 (34) | 8 (33) | 10 (−14 to 33) |
| Male | 47 (66) | 20 (43) | |
| Race and ethnicity | |||
| Black, non-Hispanic | 8 (11) | 3 (38) | 20 (−18 to 57) |
| White, non-Hispanic | 58 (82) | 23 (40) | |
| Otherc | 5 (7) | 1 (20) | |
| Primary disease | |||
| DKA/HHS | 7 (10) | 4 (57) | 31 (−10 to 72) |
| Hematologic cancer | 55 (77) | 19 (35) | |
| Bone marrow transplant | 23 (32) | 6 (26) | |
| Other immunosuppressed state | 6 (8) | 2 (33) | |
| Immunosuppressive therapy | |||
| Chemotherapy | 54 (76) | 19 (35) | 15 (−13 to 43) |
| Steroid | 19 (27) | 6 (32) | |
| Otherd | 10 (14) | 2 (20) | |
| Symptom stage | |||
| Local congestive | 19 (27) | 11 (58) | 29 (3 to 55) |
| Perilocal/visual | 14 (20) | 6 (43) | |
| Sensory-perceptual changes | 38 (53) | 11 (29) | |
| Days with severe neutropeniae | |||
| 0 | 32 (45) | 16 (50) | 32 (7 to 57) |
| 1-30 | 22 (31) | 9 (41) | |
| ≥31 | 17 (24) | 3 (18) | |
| Fungal species | |||
| Rhizopus | 12 (17) | 4 (33) | 4 (−31 to 40) |
| Aspergillus | 14 (20) | 4 (29) | |
| Otherf | 22 (31) | 7 (32) | |
| No growth | 18 (25) | 7 (39) | |
| Systemic antifungal | |||
| Amphotericin | 61 (86) | 22 (36) | 7 (−45 to 32) |
| Otherg | 7 (10) | 3 (43) | |
| ACE-27 comorbidity grade | |||
| Not severe | 30 (42) | 17 (57) | 29 (8 to 52) |
| Severe | 41 (58) | 11 (27) | |
Abbreviations: ACE-27, Adult Comorbidity Evaluation-27; AIFS, acute invasive fungal sinusitis; DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state.
Overall 6-month survival rate of 39%.
Difference between highest and lowest survival rate at 6 months.
Other includes patients who identified as Asian or Pacific Islander or who declined to report. This category was grouped together owing to small sample sizes.
Other includes antiretroviral therapy, disease-modifying antirheumatic drugs, and immunemodulators.
Consecutive number of days with absolute neutropenia count less than 500/μL.
Other includes Fusarium and Alternaria.
Other includes caspofungin, voriconazole, isavuconazole, and micafungin.
Survival rate was associated with older age. Patients older than 61 years had 29% greater survival rate compared with adults younger than 40 years (6-month survival rate difference, 29%; 95% CI, 3%-57%). Survival was also associated with symptom stage. There was a 29% survival gradient between least (local congestive) and most (sensory-perceptual changes) severe symptom stage (6-month survival rate difference, 29%; 95% CI, 3%-55%). Survival rate was associated with fewer days with severe neutropenia. Patients with 0 days of severe neutropenia had a 32% higher survival rate compared with those with more than 31 days of severe neutropenia (6-month survival rate difference, 32%; 95% CI, 7%-57%). Lower comorbidity severity was associated with survival. Patients without severe comorbidity had a 29% higher survival rate compared with those with severe comorbidity (6-month survival rate difference, 29%; 95% CI, 8%-52%). Primary disease, use of immunosuppressive therapy, fungal species, and use of systemic antifungals were not associated with survival (Table 1). The 3 presenting clinical characteristics (symptom severity, comorbidity, and neutropenia) that had a meaningful association with survival were later used to develop a composite clinical staging system.
Conjunctive Consolidation of Symptoms and Comorbidity Into the FSSS
The prognostic gradients of 6-month survival rate for symptoms and comorbidity are described in the marginal totals of the last row and column, respectively, in Figure 1. The survival gradient for symptoms extends from 58% to 29%, and the survival gradient for comorbidity extends from 57% to 27%. The distinct combined effects of symptoms and comorbidity are shown in each cell of Figure 1. Within each symptom category, comorbidity severity produces a distinctive prognostic gradient. For example, for local congestive symptoms, the survival prognosis based on severity of comorbidity extends from 78% to 40%. Similarly, within each comorbidity category, each symptom category produces a distinctive prognostic gradient. For example, for the not severe comorbidity category, the survival prognosis extends from 78% to 46% from local congestive symptoms to sensory-perceptual changes, and, correspondingly, within severe comorbidity from 40% to 20%. These distinctive prognostic gradients demonstrate the dual effect of symptomatology and comorbidity on survival. Categories of symptoms and comorbidity that were consolidated were clinically cogent and had reasonably similar survival rates to form a 3-stage FSSS.
Figure 1. Conjunctive Consolidation of Comorbidity and Symptoms Into the Functional Severity Staging System (FSSS).
Data are reported as number of patients alive at 6 months of the total number of patients in each category.
The 3 stages of the FSSS were defined as α, β, and γ. Stage α comprises local congestive symptoms and not severe comorbidity, stage β comprises not severe comorbidity with perilocal/visual symptoms or sensory-perceptual changes, and stage γ comprises severe comorbidity regardless of symptom category. The FSSS 6-month survival was 78% for stage α (n = 9), 48% for stage β (n = 21), and 27% for stage γ (n = 41).
Conjunction Consolidation of FSSS and Duration of Severe Neutropenia Into the CSSS
The combined effect of the FSSS and duration (in days) of severe neutropenia on 6-month survival rate is shown in Figure 2. The marginal totals demonstrate that the prognostic gradients for FSSS and duration of severe neutropenia range from 78% to 27% and 50% to 17%, respectively. Within each progressive increase in days in the severe neutropenia category, FSSS produces a distinctive prognostic gradient. Similarly, within each FSSS stage, duration of severe neutropenia produces a distinct prognostic gradient (excluding cells with small totals). The dual prognostic effect of FSSS and duration of severe neutropenia was consolidated to form a CSSS, summarized in Figure 2.
Figure 2. Conjunctive Consolidation of the Functional Severity Staging System (FSSS) and Days Immunosuppressed Into the Clinical Severity Staging System (CSSS).
Data are reported as number of patients alive at 6 months of the total number of patients in each category.
The 3-stage CSSS was defined as A, B, and C. Stage A comprises patients who did not have severe comorbidity and either local congestive symptoms regardless of duration of severe neutropenia or perilocal/visual or sensory-perceptual changes with 0 days of severe neutropenia. Stage B comprises patients who did not have severe comorbidity but had either perilocal/visual or sensory-perceptual changes with severe neutropenia not exceeding 30 days or severe comorbidity without severe neutropenia. Stage C comprises patients who did not have severe comorbidity and perilocal/visual or sensory-perceptual changes with severe neutropenia for 31 days or longer or severe comorbidity with at least 1 day of severe neutropenia. The CSSS had a 6-month survival of 75% for stage A (n = 16), 41% for stage B (n = 27), and 18% for stage C (n = 28). The CSSS survival gradient was 57%, a 6% increase from the 51% survival gradient observed in FSSS.
Quantitative Comparison of Staging Systems
The performance of each staging system is summarized in Table 2. Both FSSS and CSSS showed monotonicity of survival; improved survival gradients compared with symptoms, comorbidity severity, and days with severe neutropenia alone; higher values of the log-rank test; and improved discrimination power. The survival experience of the categories defined by the composite CSSS is shown in Kaplan-Meier curves in Figure 3. The survival experience of the entire cohort obscures the distinct survival gradients defined by the least and most severe clinical stage (57%). This effect persists beyond the primary 6-month end point.
Table 2. Quantitative Evaluation of Staging Systems.
| Category of evaluation | Symptom stage | Comorbidity severity | Days with severe neutropenia | Staging system | |
|---|---|---|---|---|---|
| FSSS | CSSS | ||||
| Monotonicity of survival gradient | Yes | Yes | Yes | Yes | Yes |
| Overall survival gradient, % | 29 | 29 | 32 | 51 | 57 |
| Log rank for linear trend | 3.0 | 6.0 | 3.1 | 7.5 | 10.1 |
| C statistic | 0.56 | 0.60 | 0.53 | 0.61 | 0.63 |
Abbreviations: CSSS, Clinical Severity Staging System; FSSS, Functional Severity Staging System.
Figure 3. Kaplan-Meier 6-Month Overall Survival Curves of the Clinical Severity Staging System.
Discussion
In this study of patients with AIFS, we identified presenting symptoms, comorbidity burden, and presence and duration of severe neutropenia as independent factors associated with survival outcomes at 6 months. We used sequential sequestration to separate overlapping symptoms within each patient and identified local congestive symptoms as the symptom category that contributed to the highest survival rate and sensory-perceptual changes as the symptom category with the lowest survival rate. Conjunctive consolidation of symptoms and comorbidity severity was used to develop the FSSS. The inclusion of duration of severe neutropenia allowed for the development of the composite CSSS. Applying these clinical factors into a multivariate model demonstrated patient groups with meaningfully different survival experiences. We found that patients without severe comorbidity burden and either local congestive symptoms or perilocal/visual or sensory-perceptual changes without severe neutropenia had better survival experience. Patients without severe comorbidity burden but with symptoms extending beyond local congestive symptoms and experiencing 31 days or more of severe neutropenia or patients with severe comorbidity burden and any duration of severe neutropenia had worse survival experience.
These data support previous findings that sensory-perceptual changes are associated with worse survival. In the systematic review of prognostic factors by Turner et al,5 the authors found that of all of the presenting symptoms, altered mental status was the strongest predictor of mortality. However, considering patients often present with more than 1 symptom, this finding was limited by the overlapping effect of other presenting symptoms. The process of sequential sequestration allows for the disentanglement of the overlapping prognostic effect of multiple symptoms within individual patients. Previously published work that evaluated presenting symptoms largely focused on time since symptom onset, and to our knowledge, no study to date has assessed the individual effect of presenting symptoms one by one. In regard to comorbidity, previous AIFS studies frequently reported the presence of comorbid conditions and primarily investigated the role of diabetes on survival.11 The effect of diabetes on survival has been inconclusive, but diabetic ketoacidosis is associated with better survival compared with other nonreversible immunocompromised states.3,5 The present findings on this population were inconclusive due to small number of patients presenting with diabetic ketoacidosis. Despite evidence on the influence of comorbidity severity on survival in many disease states,8 the prognostic role of overall comorbidity burden in AIFS has not been previously studied. The role of neutropenia was investigated; however, the prognostic value of ANC remains controversial.12,13,14 While several studies have demonstrated that neutropenia and prolonged neutropenia are associated with higher mortality rates, any degree of neutropenia is considered highly concerning in practice. The current evidence-based recommendation is that ANC be used as a diagnostic tool for workup and monitoring.3 The present findings provide additional insight on the use of ANC, particularly prolonged neutropenia at presentation, as a surrogate for long-standing immunosuppressive state in patients with AIFS.
This study demonstrated that there is heterogeneity in survival outcomes among patients with AIFS, and readily available clinical factors can be used to identify patients with unique prognostic outcomes. These readily available clinical factors—symptoms, comorbidity severity, presence and duration of severe neutropenia—present a low-cost tool for patient-centered risk assessment and use in clinical research. The current paradigm among affected patients and clinicians is that a diagnosis of AIFS is fatal in almost all patients. However, we show that in a group of patients with AIFS, unique prognostic subgroups exist and can be identified with simple clinical features. In the setting where therapeutic management of AIFS often involves aggressive surgical management, it is essential to consider which patient population is most likely to benefit from invasive therapies.
Limitations
This study had several limitations due to its retrospective design. This cohort spanned a 30-year period in which data collected under usual care evolved. There may be a bias in medical history obtained from patients suspected to have AIFS. This study was also biased by clinical practices at a single, high-volume tertiary medical center and a patient population with a majority affected by hematologic cancer. The primary outcome was limited to overall survival rather than disease-specific outcome. The sample size was also limited due to the rarity of AIFS, leading to imprecision in the estimations of effect, which are reflected in wide confidence intervals. The final composite staging model was limited to presenting variables, and surveillance data were not assessed. Future studies that assess multiple institutions and include more AIFS cases are warranted. Secondary external validation of the composite CSSS is needed to establish generalizability prior to clinical application. Despite these limitations, and unlike previous studies that conducted multivariable logistic regression of prognostic factors, this study is, to our knowledge, the first composite staging system for AIFS, contributes novel information on survival prognostication, and provides clinicians with the ability to risk stratify patients at initial presentation.
Conclusions
This cohort study supports the clinical importance of symptomatology, comorbidity burden, and prolonged neutropenia at the time of AIFS presentation for prognostication. The composite clinical staging system may be useful for clinicians when counseling patients with AIFS and in the conduct of clinical research.
Data Sharing Statement
References
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Supplementary Materials
Data Sharing Statement