Abstract
Background:
Evidence for a relationship between allergy and chronic rhinosinusitus with nasal polyps (CRSwNP) is equivocal. Central compartment (CC) atopic disease is a nasal inflammatory condition related to inhalant allergy. CC involvement is common in aspirin-exacerbated respiratory disease (AERD), a subset of CRSwNP, and we hypothesize it is related to allergic status.
Methods:
This study was a retrospective analysis of a single-institution database for the January 2016 to February 2019 time period. Data regarding endoscopic CC findings, clinical allergy history, and results of allergy testing were collected. Statistical analysis was performed, with significance set at p < 0.05.
Results:
Seventy-two AERD patients met the inclusion criteria. Fifty-nine patients had CC involvement (53 bilateral, 6 unilateral). For patients with documented allergy status, 100% of patients with endoscopic CC disease had clinical allergic rhinitis (AR), and 45 of 48(93.8%) had positive allergy testing. Thirteen patients had no CC involvement (4 with clinical AR; 3 of 7 with positive allergy testing). CC endoscopic findings in AERD were significantly associated with clinical allergy (p < 0.0001, phi = 0.771). Overall, patients with CC involvement averaged 3.8 surgeries vs 3.2 for those without CC involvement (p = not statistically significant). However, patients with septal involvement averaged 4.2 surgeries vs 2.0 for those without septal involvement (p = 0.004). As the number of sinus surgeries increases, middle turbinate (MT) resection (r = 0.300, p = 0.022) and septal involvement (r = 0.372, p = 0.004) significantly increase. All patients with MT resection had septal disease, whereas none without CC disease had MT resection.
Conclusion:
Most AERD patients exhibit AR, and this correlates with CC disease. As the number of surgeries increases, MT resection may predispose to polyposis of the septum.
Keywords: allergy, allergic rhinitis, chronic rhinosinusitis, chronic sinusitis, aspirin-exacerbated respiratory disease, endoscopic sinus surgery, nasal polyp
Chronic rhinosinusitis (CRS) is a disease that may result from various etiologic factors but is often categorized into 2 broad phenotypes: CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP). Allergy has long been considered one of the risk factors for CRSwNP, although the studies evaluating this connection have been equivocal. Recent systematic reviews evaluating the relationship between allergy and CRSwNP showed a nearly even distribution of studies that demonstrate a relationship between these 2 entities and those that do not (aggregate level of evidence D).1–3
One of the concerns that has been raised regarding the studies that evaluated the allergy-CRSwNP connection is the consideration of CRSwNP as a single disease process, with the presence of nasal polyposis satisfying inclusion criteria for the CRSwNP group. However, CRSwNP is a broad phenotypic category, not a single disease process. CRSwNP-related disease states may be further divided into more discrete Categories based on underlying etiology. Inflammatory nasal polyp subsets include allergic fungal rhinosinusitis (AFRS), aspirin-exacerbated respiratory disease (AERD), central compartment atopic disease (CCAD), cystic fibrosis (CF), eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), and CRSwNP not otherwise specified (CRSwNP NOS). CF is usually excluded from studies on CRSwNP because it has a known genetic cause and neutrophilic predominance. Due to the various etiologies and endotypes of CRSwNP, we hypothesize that separating CRSwNP into these more discrete endotypes and etiologic categories can help elucidate a clearer association with inhalant allergy.
Recently, there have been some notable steps toward understanding the association between CRSwNP and allergy. The central compartment of the nasal cavity includes the area of the middle turbinate (MT), superior turbinate (ST), and superior nasal septum (SNS). This is the area where nasal airflow is greatest,4 and these structures are derived from the ethmoid complex.5 The association of isolated MT polypoid edema/polyps and inhalant allergy was first described in a 2014 case series by White et al.6 All patients with MT polypoid changes were found to have positive reactions on allergy testing. This finding was supported by a large retrospective study by Hamizan et al, who found that significant polypoid edema and discrete polyps on the MT had a strong association with positive allergy status.7 Furthermore, in 2017, Brunner et al reported that isolated MT polyp patients and diffuse sinonasal polyp patients were clinically distinct groups, with statistically significant differences in allergy status (83% vs 34%, respectively), presence of CRS (10% vs 100%, respectively), Lund-Mackay score, and NOSE score.8
CCAD is a recently defined phenotype of nasal inflammatory disease that is strongly associated with inhalant allergy. All patients described in the case series by DelGaudio et al9 had positive allergy testing. CCAD is a process similar to that with seen with isolated MT polyps but with more diffuse involvement, including the SNS with or without the MT and/or ST. This is a highly eosinophilic process correlated with inhalant allergy. The radiologic pattern on computed tomography (CT) shows central nasal soft tissue thickening, with more significant disease progressing to secondary obstruction of the sinuses. Typically, a pattern of medial nasal cavity and sinus opacification is seen, along with peripheral clearing along the lamina papyracea, ethmoid skull base, and lateral aspects of the maxillary sinuses. In addition, Hamizan et al described the central radiologic patterns on sinus CT that are associated with allergy status.10
AERD, formerly known as Samter’s triad, is a condition that involves the triad of asthma, nasal polyps, and sensitivity to salicylates, including aspirin and nonsteroidal anti-inflammatory medications (NSAIDs). A recent study showed that 83% of patients with AERD had respiratory reactions with alcohol ingestion. This is an important consideration in diagnosing this disease, as many patients do not take cyclooxygenase-1 inhibitors such as aspirin.11 It is estimated that up to 33% of CRSwNP patients have AERD. AERD patients have elevated levels of sinonasal mucosal eosinophilia and approximately 50% have peripheral eosinophilia. Elevated total serum immunoglobulin E (IgE) is common but does not correlate with disease severity, and up to 70% of AERD patients are atopic.12–17 The authors have noted for some time that patients with AERD, especially those with previous sinus surgery, have polypoid changes of the central compartment of the nasal cavity, most notably on the nasal septum. With the recent elucidation of the association between central compartment polyps and allergy, it is hypothesized that the septal and central compartment changes in AERD may be related to allergic status.
Patients and methods
This study was approved by the institutional review board of Emory University. A retrospective review was performed of all patients with AERD treated in the Division of Rhinology at Emory University in the past 3 years. Patients were identified from prospectively collected surgical case logs and the secondary analysis of an institutional AERD database. To be included in this analysis, patients must have undergone surgery and/or nasal endoscopy with clear documentation of the presence or absence of polypoid changes or polyps of the central compartment structures. Inclusion criteria were: diagnosis of AERD based on (1) presence of asthma, (2) presence of nasal polyps, and (3) respiratory reaction to aspirin or NSAIDs; and patients with airway symptoms with alcohol ingestion. Data collected included respiratory reactions related to aspirin or NSAIDs, aspirin challenge and desensitization, clinical history of allergic rhinitis (AR) symptoms, allergy testing and results, presence or absence of polyp involvement of the central compartment (MT, ST, SNS), and number of sinus surgeries. Data were collected from operative reports, office notes, laboratory reports, outside records (referring physician notes and outside allergy evaluations), and patient interviews. Patients were excluded if they did not meet the inclusion criteria for AERD, did not have endoscopic documentation of central compartment status, or had a negative aspirin challenge.
Statistical analysis was performed using Fisher’s exact test and phi correlation analysis to evaluate for associations between central compartment involvement and clinical allergy history. T-tests were used to evaluate for associations between central compartment involvement and number of surgeries. Point-by-serial correlation analysis was used to analyze the relationship between number of sinus surgeries and turbinate resection. Point-by-serial correlation analysis was also used to analyze the relationship between number of sinus surgeries and polypoid involvement of specific central compartment structures. Statistical significance was set at p < 0.05.
Results
Seventy-two AERD patients met the inclusion criteria. There were 36 males and 36 females; racial/ethnic breakdown was 41 white, 29 black, 1 Hispanic, and 1 Asian. Mean age was 48.9 (range, 20–82) years.
Fifty-nine (80.6%) AERD patients had central compartment polyps/polypoid disease (31 males, 28 females; mean age, 49.4 [range, 20–82] years). Fifty-three patients had bilateral central compartment polyps (28 males, 25 females; mean age, 50.5 [range, 20–82] years), and 6 patients had unilateral central compartment polyps (3 males, 3 females; mean age, 39.8 [range, 26–55] years). Of the 59 AERD patients with central compartment involvement, 58 had allergy data recorded. All 58 patients with available allergy data exhibited a clinical history of AR symptoms (100%); 48 of these underwent allergy testing, and 45 (93.8%) demonstrated positive reactivity to at least 1 allergen on testing. One AERD-bilateral central compartment patient had no allergy data recorded, and had AR symptoms, but allergy testing results could not be verified.
Thirteen (18.1%) AERD patients had no central compartment involvement (5 males, 8 females; mean age, 46.2 [range, 24–69] years). Eleven of these patients had allergy data recorded. In the AERD patient group without central compartment involvement, only 4 of 11 patients (36.4%) reported a clinical history of AR symptoms. Seven of the 11 patients with available allergy data underwent allergy testing, and only 3 of these (42.8%) demonstrated positive results.
Allergy analyses was performed for the 69 AERD patients with allergy history documented. Central compartment endoscopic findings in AERD are significantly associated with clinical AR (p < 0.0001, phi = 0.771). Statistical analysis could not be performed for an association between central compartment findings and positive allergy test results because the AERD patients without central compartment disease had too many data points missing (4 of 11 patients who did not undergo allergy testing, and 2 without identifiable allergy history) (Table 1).
TABLE 1.
Central compartment involvement and allergy status
| AERD patients | 72 (100%) | 59 of 72 (81.9%) | 53 of 59 (89.8%) | 6 of 59 (10.2%) | 13 of 72 (18.1%) | |
| No allergy recordb | 3 (4.2%) | 1 | 1 | 0 | 2 | |
| Clinical allergic rhinitis | 62 of 69 (89.9%) | 58 of 58 (100%) | 52 of 52 (100%) | 6 of 6 (100%) | 4 of 11 (36.4%) | p < 0.0001, phi = 0.771 |
| Allergy test available | 55 of 69 (79.7%) | 48 of 57 (84.2%) | 42 of 51 (82.4%) | 6 of 6 (100%) | 7 of 11 (63.6%) | |
| Positive allergy test | 48 of 55 (87.3%) | 45 of 48 (93.8%) | 39 of 42 (93.0%) | 6 of 6 (100%) | 3 of 7 (42.8%) |
Bilateral and unilateral CC reported as subsets of overall CC-involvement group.
No clinical allergy history or allergy test recorded in patient record.
AERD = aspirin-exacerbated respiratory disease; CC = central compartment.
Overall, there was no significant difference in number of surgeries between patients with CC involvement (mean, 3.8) and those without CC involvement (mean, 3.2). However, patients with CC involvement of the nasal septum (n = 47) had more surgeries than those without septal involvement (n = 12) (4.2 vs 2.0, p = 0.004). As the number of sinus surgeries increased, MT resection and septal involvement with polyposis significantly increased (p = 0.022, r = 0.300; and p = 0.004, r = 0.372, respectively). Comparison of ST status and surgery did not reach significance (Table 2, Figure 1 and Figure 2).
TABLE 2.
Central compartment involvement and surgical history
| No CC involvement | 13 | 3.2 | 1–6 | p = 0.396 |
| CC involvementa | 59 | 3.8 | 1–10 | |
| MT resected | 11 | 5.5 | 2–8 | r = 0.300 |
| MT retained | 48 | 3.4 | 1–10 | p = 0.022 |
| ST resected | 5 | 5.4 | 3–6 | r = 0.212 |
| ST retained | 53 | 3.5 | 1–10 | p = 0.106 |
| Septum with polypoid involvement | 47 | 4.2 | 1–10 | r = 0.372 |
| Septum without polypoid involvement | 12 | 2.0 | 1–4 | p = 0.004b |
| MT present, with polypoid involvement | 34 | 3.2 | 1–10 | r = 0.101 |
| MT present, without polypoid involvement | 14 | 3.7 | 1–10 | p = 0.496 |
| ST present, with polypoid involvement | 14 | 3.0 | 1–5 | r = 0.131 |
| ST present, without polypoid involvement | 39 | 3.7 | 1–10 | p = 0.351 |
Bilateral and unilateral CC reported as subsets of overall CC-involvement group.
As the number of sinus surgeries increased, septal involvement with polyposis significantly increased (r = 0.372, p = 0.004).
CC = central compartment; MT = middle turbinate; ST = superior turbinate.
FIGURE 1.
Right nasal cavity in allergic patient without previous sinus surgery. Polyps are seen medial to the middle turbinate, originating from the superior nasal septum.
FIGURE 2.
Three patients with nasal septal polyps and absent middle turbinates. (A) Right nasal septal polyps in a 79-year-old woman after multiple previous surgeries. (B) Left nasal septal polyps in a 20-year-old patient after multiple (10) previous sinus surgeries. The polyps are thick and fibrous in appearance. The maxillary ostium is noted in the lower right of the image. (C) Right nasal cavity of 45-year-old male with nasal septal polypoid changes/polyps of the superior nasal septum. Note the clear Lothrop cavity.
None of the AERD patients without CC involvement had previous MT resections. All 11 patients in the CC group who had undergone MT resection had septal polyp disease. Only 11 patients had a single sinus surgery, of whom 1 patient had no central involvement and 10 had central disease. Of these 10 patients with CC involvement, 5 had septal polyps.
Discussion
It is estimated that 10%–30% of the population has symptomatic AR.18 However, in the United States, it has been reported that 53.9% of people will demonstrate positive reactivity to inhalant allergens on skin testing, with 15.5% sensitized to a single allergen and 38.8% sensitized to multiple allergens.19 The discrepancy between positive allergy test results (>50% of the US population) and clinical AR (10%–30% worldwide) illustrates that many people are sensitive to allergens by skin testing but do not exhibit clinical symptoms. Therefore, in the evaluation of AR, it is important to elicit a clinical history of allergic triggers and confirm with allergy testing, as shown in our reported series. Conversely, allergy skin testing is the “gold standard” for confirming a diagnosis of AR, but some of these patients with classic AR symptoms and inhalant triggers will have negative allergy testing. Local allergy, or an allergic response confined to the nasal tissues, is presumed to be occurring in these patients. Unfortunately, testing for allergen-specific IgE in nasal tissues or secretions is not commercially available in the US and is typically performed only in research protocols.
Although the level of evidence for allergy as a cause for CRSwNP is low when CRSwNP is considered as an all-encompassing phenotypic group, there is evidence that an association between allergy and nasal polyposis exists for certain polyp disease endotypes, such as AFRS and CCAD.
The prevalence of AR in AERD patients in this study was much higher (89.9%) than would be expected in the general population (10%–30%). Although the prevalence of central compartment disease in the general population is not known, as CCAD was only first reported in 2017, it cannot approach the frequency found in our AERD patient population.
The unilateral CC patients deserve further mention. This is obviously less commonly seen than bilateral involvement, but is seen in other allergy-mediated disease processes, such as isolated MT polyps, CCAD, and AFRS. Unilateral involvement is thought to be due to preferential airflow through the more open side of the nose. In our patient series, analyses both including and excluding unilateral central compartment disease in AERD revealed a significant association with clinical AR symptoms.
AERD is a disease that is frequently diagnosed at a late stage, and patients may undergo multiple sinonasal surgeries before they are accurately diagnosed. Although the number of surgeries did not differ between the AERD patients with and without central compartment involvement, among the patients with central compartment involvement there was a significantly higher number of surgeries in patients with septal polypoid disease compared to those without septal polyposis (4.2 vs 2.0 surgeries, respectively). In addition, as the number of sinus surgeries increases, septal polypoid involvement significantly increases and MT resection significantly increases. The 11 patients with previous MT resection all had septal involvement (Figure 2). The decrease in MT tissue as a protective barrier in allergic patients may result in more allergen deposition along the superior nasal septal mucosa, resulting in the polypoid changes. This may reflect the loss of the protective filtering function of the MT. This is further supported by the finding that none of the 13 patients without CC involvement had undergone previous MT resection, despite undergoing an average of 3.2 surgeries (1–6). Two computational fluid dynamics studies looked at the effect of airflow after MT resection. Zhao et al showed that after partial MT resection there was a shift of airflow toward the area of MT resection.20 This resulted in decreased airflow velocity, decreased wall shear stress, and increased local air pressure. Lee et al showed that, although physiologic changes in 4 partial MT resection models were insignificant, changes in near-total resection were prominent.21 The conclusions of both of these studies seem to support a possible mechanism of increased allergen deposition on the nasal septum after MT resection.
One limitation of this study is its retrospective nature. Not all data were available for each patient (3 patients without documentation of allergy status), despite efforts to obtain all pertinent data. Also, due to the small number of patients included, the sample did not represent all AERD patients seen in our practice. Unfortunately, those patients who did not have distinct endoscopic documentation of the presence or absence of central compartment disease could not be included. Not all surgeons routinely list the status of the central compartment structures, or only started doing so recently. One reason for this is that it is such a frequent finding in our practice that it has become commonplace, and therefore it may not be mentioned specifically in operative reports or office endoscopy documentation.
We also recognize that there may be some regional influence on this data. It is known that the prevalence of AR varies by geographic location and climate, and some allergy-mediated diseases are regional, such as AFRS. Because our institution is in the southeastern US, we acknowledge that our patients may be exposed to more seasonal inhalant allergens over longer periods of the year than in other geographic areas. Therefore, these findings may be seen more frequently in our practice than in other geographic areas with less allergy.
As a result of the data presented in this study, we recommend the following clinical considerations. Because most AERD patients in our series have AR, we recommend considering allergy testing in these patients, and immunotherapy when appropriate. As the MT seems to be an important part of the nasal allergen filter, and likely involved in protection from allergens reaching the lower airway, we recommend conservative MT management when possible. MT sculpting can be utilized when polypoid changes are present, preserving a significant portion of the MT to continue to function in this protective role. Total MT resection reduces the available surface area for allergen filtration, and exposes the septal mucosa to more allergen. Regarding the extent of surgery in the presence of central compartment disease, it depends on the extent of septal involvement. If the septal polypoid disease extends anterior to the leading edge of the MT, then this tissue needs to be addressed. The leading edge of the MT can be trimmed and the septal tissue sculpted to allow postoperative topical steroid irrigations to more effectively reach the upper nasal septum. In severe cases, an endoscopic Lothrop procedure may be indicated. This can be effective as it resects the polyp-bearing mucosa in the upper nasal septum anterior to the MT, which, if not addressed adequately, may progress and cause postoperative frontal sinus obstruction. We do not advocate complete resection of the MT in AERD patients with AR when it can be avoided. Our data suggest that excessive MT resection may result in progression of polypoid changes of the nasal septum in this group of atopic patients.
Conclusion
The prevalence of AR in AERD patients is very high, and this correlated with central compartment involvement in this patient series. As the number of surgeries increases, the likelihood of nasal septal involvement increases. This is likely due to decreases in MT tissue with loss of its protective filtering function and increased deposition of allergens on the upper nasal septum.
Footnotes
Potential conflict of interest: J.M.D.: Spirox, grant support; Medtronic, consultant. S.K.W: OptiNose, scientific advisory board; SinopSys Surgical, scientific advisory board; Stryker, consultant; and NeurENT, consultant.
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