Abstract
Background:
Prior studies have demonstrated associations between serum eosinophilia and chronic rhinosinusitis (CRS) pathogenesis. However, the association of serum eosinophilia with histopathology profiling in CRS has not been fully delineated and may help better characterize CRS disease burden prior to surgery.
Methods:
A structured histopathology report of 13 variables was utilized to analyze sinus tissue removed during functional endoscopic sinus surgery (FESS). Complete blood count (CBC) with differential was drawn within 4 weeks prior to FESS. Serum eosinophilia was defined as >6.0% (>0.60 th/μL). Histopathology variables were compared among patients.
Results:
A total of 177 CRS patients (37 with serum eosinophilia and 140 with normal serum eosinophilia) were analyzed. Compared to CRS patients with normal serum eosinophil counts, CRS patients with serum eosinophilia demonstrated increased polypoid disease (67.6% vs 35.0%, P < .001), eosinophil aggregates (45.9% vs 20.7%, P = .003), and eosinophils per high-power field (>5/HPF) (67.6% vs 40.7%, P = .003).
Conclusion:
CRS patients with serum eosinophilia demonstrated severe disease burden on histopathology with high levels of polypoid disease and tissue eosinophilia. However, a considerable number of patients without serum eosinophilia demonstrated eosinophilic disease on histopathology, indicating that preoperative serum eosinophilia alone could not be reliably used to predict eosinophilic CRS.
Level of evidence:
4
Introduction
Chronic rhinosinusitis (CRS) is an inflammatory disease characterized by sinonasal symptoms that last longer than 12 weeks with incomplete resolution and CT or nasal endoscopy showing sinonasal inflammation. 1 CRS is often divided into two subtypes, CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). However, recent studies of postoperative histopathologic profiles in CRS have emphasized the role of tissue eosinophilia in disease pathogenesis, noting that eosinophilic infiltration is associated with significantly increased disease burden. Kuhar et al demonstrated that the presence of eosinophilic aggregates on histopathology was associated with higher preoperative Lund-McKay CT scores. Bassiouni et al found that tissue eosinophilia was associated with postoperative refractory disease.2,3 Based on the growing body of literature correlating eosinophilic inflammation with disease pathogenesis, additional studies have proposed endotyping CRS into eosinophilic CRS (eCRS) and non-eosinophilic CRS (non-eCRS).4-6
A limitation for a practicing physician in assessing histopathologic disease burden and determining whether patient presentation is consistent with eCRS is that these assessments rely on analysis of tissue specimens performed postoperatively. Given the evidence that tissue eosinophilia may have a significant impact on CRS pathogenesis, there is a need for clinical tools that can more readily aid in making these assessments. One potential tool is a serum eosinophil count, which is typically obtained as part of routine preoperative evaluations. A 2017 study demonstrated that patients with serum eosinophilia were at significantly increased risk of CRSwNP recurrence. 7 Another study conducted by Aslan et al suggested that peripheral eosinophilia may be a useful marker in predicting the severity of nasal polyps. 8 This finding merits further investigation to better characterize the relationship between serum eosinophilia and postoperative histopathology. The goals of the current study are to explore the association between serum eosinophil counts and structured histopathology and to assess whether serum eosinophil counts can be used to predict eCRS.
Materials and Methods
A retrospective review was conducted on patients who presented to a tertiary academic center for surgical management of medically recalcitrant CRS. Patients were included in the study cohort if they met the following criteria: age 18 or older, CRS diagnosis based on 12 weeks of continuous sinonasal symptoms, positive findings for sinusitis on computed tomography (CT) scan and underwent FESS due to insufficient clinical improvement with appropriate medical management. Patients taking preoperative oral prednisone at the time of their CBC were excluded from the analysis; in addition, patients diagnosed with sinonasal malignancy or autoimmune disease were also excluded.
As part of their preoperative evaluation, all patients in the cohort obtained a complete blood count (CBC) with differential within 4 weeks prior to undergoing FESS. Serum eosinophilia was defined as an eosinophil percentage >6 or an eosinophil count >0.60 th/μL; this value was chosen because it represents the upper limit of a normal eosinophil count at our laboratory. Tissue specimens resected during FESS were analyzed by two dedicated head and neck pathologists at Rush University Medical Center who compiled structured reports consisting of 13 histopathologic variables (Table 1). The variables assessed by subspecialty pathologists included: tissue present (respiratory mucosa, mucoserous tissue, or bone), degree of inflammation (mild or moderate/severe), neutrophilic infiltrate (present or absent), basement membrane thickening (present or absent), mucosal ulceration (present or absent), sub-epithelial edema (present [focal, perivascular, or distortion of mucosal structure] or absent), hyperplastic or papillary changes (present or absent), squamous metaplasia (present or absent), fungal elements (present or absent), fibrosis (present or absent), Charcot–Leyden crystals (present or absent), eosinophil aggregates (present or absent), and number of eosinophils per high-power field (HPF) (<5/HPF or >5/HPF and <10/HPF or >10/HPF).
Chronic Rhinosinusitis Structured Histopathology Report.
Each of these histopathologic variables was subsequently compared between the subgroups of patients with and without serum eosinophilia. Statistical significance of parametric data associations was evaluated with a two-tailed student’s t-test. Means between more than two independent groups were compared using a one-way ANOVA test. All analyses were performed using SPSS Statistics software (IBM Corporation, Version 24, Armonk, NY). Significance was established as P < .05.
All patient identifiers were removed from the data prior to performing analysis. This study received prior approval from the Institutional Review Board (IRB) at Rush University Medical Center.
Results
A total of 177 CRS patients were included in this analysis. The average age of cohort was 51 ± 16 years. Females comprised 53% of the sample, and the cohort was predominantly white (61%). Seventy-four patients (42%) were diagnosed with CRSwNP while the remaining patients were diagnosed with CRSsNP.
Thirty-seven patients (20.9%) in the study cohort were found to have serum eosinophilia, while the remaining 140 had normal eosinophil counts (Table 2). Compared to CRS patients with normal serum eosinophil counts, CRS patients with serum eosinophilia demonstrated increased polypoid disease (67.6% vs 35.0%, P < .001), eosinophil aggregates (45.9% vs 20.7%, P = .003), eosinophils per high-power field (>5/HPF) (67.6% vs 40.7%, P = .003), and eosinophils per high-power field (>10/HPF) (51.4% vs 30.0%, P = .014). The remaining histopathologic variables analyzed did not differ significantly between the two groups.
The Association of Serum Eosinophilia with Histopathologic Characteristics.
Abbreviations:
Serum eosinophilia predicted the presence of eosinophilic aggregates with a sensitivity of 37.0% and specificity of 84.7%, corresponding to positive and negative likelihood ratios of 2.42 and 0.74, respectively. Serum eosinophilia predicted the presence of more than 10 eosinophils per HPF with a sensitivity of 31.2% and a specificity of 84.5%, corresponding to positive and negative likelihood ratios of 2.01 and 0.81, respectively.
Discussion
Structured histopathology has been investigated in prior studies as a tool that allows physicians to classify a patient’s CRS presentation into endotypes, thereby allowing for improved understanding of disease prognosis and appropriate management.2,3,9,10 However, given that these profiles can only be analyzed postoperatively, this study was conducted with the goal of the association of preoperative serum eosinophilia with structured histopathology in CRS. Our analysis suggests that preoperative serum eosinophilia is significantly associated with polyposis, eosinophilic aggregates (Figure 1), and tissue eosinophilia, defined as >10 eosinophils per HPF on postoperative histopathology.
Histopathologic image demonstrating an eosinophilic aggregate (yellow arrow) and basement membrane thickening (green arrow).
In terms of the immunologic pathogenesis of CRS, studies have suggested that particular endotypes of CRS demonstrate persistent Th2-associated cytokine activation that causes sinonasal eosinophilic infiltration. 4 As part of this inflammatory pathway, production of cytokines such as IL-5 stimulate the maturation of eosinophils in the bone marrow and their release into circulation; the eosinophils then accumulate in tissue, and excess activation and accumulation becomes evident on histopathology as tissue eosinophilia or tissue eosinophilic aggregates. Thus, chronic local eosinophilic activation may be associated with systemic findings that would facilitate assessment of disease pathogenesis. This is supported by several prior studies of serum eosinophilia: a 2017 study conducted by Aslan et al noted that Lund-MacKay CT scores and Lund-Kennedy endoscopic scores were significantly higher in patients with high peripheral eosinophil counts. 8 Two additional studies conducted by Newman et al and Gitomer et al similarly noted that the serum eosinophil count correlated with the severity of findings on sinonasal CT imaging.11,12 Thus, our study provides additional evidence for a systemic manifestation of local disease by showing that serum eosinophil counts are associated with certain features of inflammation evident on histopathology.
Several prior studies have correlated the aforementioned histopathologic features with increased disease burden as well as poorer long-term prognosis. A 2017 study of structured histopathology suggested that the presence of eosinophilic aggregates was associated with increased development of polyp disease. 2 Investigations of tissue eosinophilia have demonstrated its association with limited postoperative symptom improvement and increased need for revision surgeries.3,6 Thus, in conjunction with these prior studies, our findings suggest that preoperative serum eosinophilia may be associated with higher disease burden and poorer long-term prognosis. This assessment is supported by several investigations that directly evaluated the association between serum eosinophilia and postoperative prognosis. A study conducted by Zadeh et al demonstrated that CRS patients with serum eosinophilia have a significantly worse postoperative prognosis requiring additional courses of antibiotics or surgical revisions compared to patients with normal serum eosinophil counts. 13 Furthermore, a 2016 study by Honma et al found that surgical management of CRS was associated with a significant postoperative reduction in serum eosinophil counts. 14 Thus, our analysis of the postoperative histopathologic profile adds to the growing body of evidence that the presence of serum eosinophilia may be a useful clinical indicator of CRS disease burden.
The second goal of this study was to evaluate whether serum eosinophil counts could be utilized to identify eCRS. Although a precise diagnostic definition of eCRS has not yet been developed, potential histopathology markers of this sub-classification include the presence of eosinophil aggregates and >10 eosinophils counted per HPF. 6 Our analysis does not suggest that serum eosinophilia alone is sufficient to reliably predict the development of eCRS, based on either of these definitions. We found that the eosinophilia predicted the presence of eosinophilic aggregates with positive and negative likelihood ratios of 2.42 and 0.74, respectively, and it predicted the presence of tissue eosinophilia with positive and negative likelihood ratios of 2.01 and 0.81, respectively. Although the positive likelihood ratios raise the pretest probability of eCRS by approximately 15% to 20%, this relatively small increase does not justify the regular use of serum eosinophilia alone as a preoperative predictor. 15 A 2011 study that proposed diagnostic criteria for eCRS noted that in addition to a serum eosinophil count, scoring of the posterior ethmoid and olfactory cleft based on CT imaging should be performed; this method identified eCRS with high sensitivity and specificity. 5 Thus, the data available at present suggest that serum eosinophilia is useful as a preoperative indicator of increased histopathologic disease burden, but not as a diagnostic marker of eCRS.
A major limitation of our analysis is that the calculations of sensitivity, specificity, and positive and negative predictive values are based on a small subset of patients with serum eosinophilia. In addition, our analysis only included patients who were scheduled to undergo FESS and thereby excluded patients whose CRS was well managed medically without the need for surgical intervention. As a result, the conclusions from this study are based on a patient population with moderate to severe disease.
Conclusion
Serum eosinophilia may be clinically useful as a preoperative indicator of increased CRS disease burden on histopathology, particularly polypoid disease, eosinophil aggregates, and tissue eosinophilia. However, serum eosinophilia by itself is not as useful a diagnostic marker of eCRS as structured histopathology reporting.
Footnotes
Authors’ Note
These findings were presented orally on Friday, October 5, 2018 at the 64th American Rhinologic Society Annual Meeting in Atlanta, Georgia, USA.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MM: Cohn Scholarship Program from Rush University. PSB: Medtronic (research grant), Optinose, Regeneron (consultant), Springer (royalties).
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
