EOSINOPHILIC RHINOSINUSITIS AND OTITIS MEDIA IN PATIENTS WITH ASTHMA – FOCUS ON EOSINOPHILIC NASAL POLYPOSIS

Masami Taniguchi, Noritaka Higashi, Toyota Ishii

Sagamihara National Hospital, Sagamihara, Kanagawa, Japan

Epidemiology and clinical features of eosinophilic otitis media (EOM) with asthma and eosinophilic nasal polyposis (ENP) in Japan

Eosinophilic nasal polyposis (ENP), in which there are prominent infiltration of eosinophils and submucosal edema, is linked to comorbidities such as non-atopic asthma, adult-onset asthma, aspirin intolerance, or may represent a part of a systemic disease such as Churg-Strauss syndrome.1,2,3 Eosinophilic otitis media (EOM) is an intractable otitis media characterized by the presence of a highly viscous yellow effusion containing eosinophils.4 It mainly occurs in patients with adult asthma.4,5 Table 1 shows the frequencies of severe asthma, ENP, and EOM in Japanese adult asthmatics obtained from our hospital database of 400 patients. The frequencies of severe asthma, ENP, and EOM are low in atopic asthmatics. In non-atopic asthmatics, the frequency of severe asthma is 31%, and that of ENP is 21%. The frequency of EOM is also low in non-atopic asthmatics. In aspirin-induced asthma (AIA) patients, the frequencies of severe asthma, ENP, and EOM are very high. Figure 1 shows the frequencies of ENP and EOM in patients with severe and non-severe aspirin-tolerant asthma (ATA) and AIA. Almost all patients with severe and non-severe AIA show ENP. The frequencies of ENP and EOM in non-severe ATA patients are very low, while the frequency of EOM in severe AIA patients is very high. These data indicate that EOM is very common in AIA patients, particularly in severe AIA patients, and is rare in non-severe ATA patients. Figure 2 shows the frequency of EOM in AIA patients with or without ENP. EOM is very rare in AIA patients without ENP, but very common in AIA patients with a history of ENP surgery. These data suggest that EOM is common particularly in AIA patients with severe ENP. Many AIA patients firstly manifest only ENP symptoms at a mean age of 36. A few years later, asthma symptoms appear,6,7 and five to ten years after the onset of asthma, EOM symptoms appear (Fig. 3).8

Table 1. Frequency of asthma, ENP and EOM in Japanese patients with adult asthma.

Severe asthma

ENP

EOM

Atopic asthma (n = 200)

9%

2%

3%

Non-atopic asthma

31%

21%

6%

without AIA (n = 100)

AIA (n =100)

56%

96%

66%

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Fig. 1. Frequency of ENP and EOM in patients with (severe and non-severe) ATA and AIA.

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Fig. 2. Frequency of EOM in AIA patients with and without history of ENP surgery.

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Fig. 3. The typical courses of onset of ENP, asthma, and EOM in Japanese AIA patients: Many AIA patients firstly manifest only ENP symptoms at a mean age of 36. A few years later, asthma symptoms appear, and lastly, five to ten years after the onset of asthma, EOM symptoms appear.

Figure 4 shows the annual changes in the number of hospitalizations due to asthma exacerbation and the frequency of EOM in our AIA patients. The number of hospitalizations due to asthma exacerbation has decreased to one-fourth over the last twelve years. On the other hand, the percentage of EOM patients with AIA has increased fourfold over the last twelve years. These findings suggest that stabilization of asthma may lead to EOM manifestation in Japanese asthmatics. We do not know the precise mechanism underlying this phenomenon, but many asthma specialists in Japan believe that the increased EOM frequency is due to the stabilization of bronchial inflammation by recent powerful inhaled corticosteroids (ICS). In Japan, old-type ICS such as beclomethasone were commonly used in the 1990s. However, the new-type powerful ICS, such as fluticasone (FP) and budesonide (BUD) have been widely used from 2000 to the present (Fig. 4).

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Fig. 4. The annual changes in the number of hospitalizations due to asthma exacerbation and the frequency of EOM in our AIA patients.

To summarize the epidemiology of EOM and ENP in Japanese asthmatics:

1.EOM is closely related to adult-onset asthma, ENP, and AIA.

2.EOM appears in almost all patients with both ENP and asthma, mainly at middle age.

3.EOM frequently develops in severe ENP with asthma, particularly in AIA with severe ENP.

4.AIA patients firstly manifest only ENP symptoms; a few years later, asthma symptoms appear, and lastly, EOM symptoms appear.

5.Over the last twelve years, the frequency of EOM has markedly increased in Japan. The reason for this increase is perhaps asthma stabilization by new-type ICS treatment.

Difference between chronic rhinosinusitis (CRS) with and without ENP

Inflammatory mechanisms of ENP1,2

Nasal polyps are edematous semi-translucent masses in the nasal and paranasal cavities, mostly originating from the mucosal linings of the sinuses and prolapsing into the nasal cavities. The results of immunohisto-chemical analysis in previous studies demonstrate that activated eosinophils and B cells increase in number in polyp-tissue samples from patients with CRS with ENP. Activated eosinophils, B cells, and plasma cells increase in number in polyp tissue in ENP, particularly in ENP with AIA. Increased levels of cytokines and chemokines, such as IL-5 and eotaxin, were also confirmed in ENP tissue. B cell-activating factor (BAFF) level also increases in ENP tissue. On the other hand, IL-1beta and IL-10 levels decrease in ENP tissue. Polyclonal production of local immunoglobulins, not only IgE but also IgG and IgA, increases in ENP, particularly in ENP with AIA. Iino et al. reported that EOM fluid show also increased IgE and ECP concentration.9

From these findings, we may ask, which factor plays the central role in these imbalances in ENP and EOM tissue? We hypothesized that these imbalances may be due to a decreased cyclo-oxygenase (COX) activity, particularly COX-2 activity.

Findings that support our hypothesis are:

1.Marked eosinophil infiltration and increased leukotriene production are observed in the lungs of COX-KO asthmatic mice10 or COX-2-antagonist-treated mice.11

2.Increased local immunoglobulin (IgE, IgG, and IgA) production is also observed in COX-KO asthmatic mice 10,12) or COX-2-antagonist-treated mice.11

3.Decreased COX-2 activity decreases production of strong anti-inflammatory mediators, such as PGE2 and lipoxin in both animal models and humans.13

4.A significant decrease in COX-2 activity is confirmed in ENP tissue, particularly in ENP tissue from AIA patients.14,15

5.There are significant positive correlations of COX activity with PGE2 and lipoxin concentrations in nasal polyp tissues. Moreover, there are significant negative correlations of COX activity with Il-5, IgE, and CysLT concentrations in ENP tissue.16,17

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Fig. 5. Differences among CRS, CRS+ENP, and CRS+ENP+AIA.

However, unfortunately, the mechanism underlying the decrease in COX activity in the airway is as yet unclarified.

Perez-Novo et al. reported that the IL-5 concentrations and the eosinophil cationic protein (ECP) concentrations in four groups, which are the normal control, CRS without nasal polyps,17 CRS with nasal polyps, and CRS with aspirin-sensitive nasal polyps. They reported that both IL-5 and ECP concentrations significantly increase in CRS with polyps in comparison with those in CRS without polyps. Moreover, aspirin-sensitive nasal polyp tissue shows a marked and significant increase in IL-5 concentration.17

Eicosanoid imbalance in nasal polyp tissue

Cysteinyl leukotrienes (CysLT: leukotrienes C4, D4, and E4) have long been implicated in the pathogenesis of asthma and several allergic diseases.18 CysLT are potent bronchoconstrictors that have the additional effects of edema, mucous secretion, and eosinophilic accumulation, and airway remodeling.18 Steinke et al. reported that the concentrations of CysLT significantly increase in ENP tissue compared with those in non-ENP tis-sue.19 Perez-Novo et al. reported that the CysLT concentrations and prostaglandin E2 (PGE2) concentrations in four groups, which are the normal control, CRS without nasal polyps, CRS with nasal polyps, and CRS with aspirin-sensitive nasal polyps.17 CysLT concentrations significantly increase in CRS with polyps in comparison with those in CRS without polyps. Moreover, aspirin-sensitive nasal polyp tissue shows marked and significant increases in CysLT concentrations. On the other hand, PGE2 concentration significantly decreases in CRS with aspirin-sensitive nasal polyps.17

Figure 6 shows a summary of the imbalance of eicosanoids in the nasal polyp tissue. Previous studies demonstrated that the concentration of the anti-inflammatory prostanoid PGE2 decreases in the nasal polyp tissue. The low concentration of PGE2 may be due to the decreased COX2 activity.14,15 On the other hand, the high concentrations of strong inflammatory mediators, namely, CysLT, are probably due to the upregula-tion of LTC4 synthase.19

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Fig. 6. The imbalance of eicosanoids in nasal polyp tissue.

Systemic leukotriene production in patients with nasal polyposis

LTE4 has been identified as a major metabolite of LTC4 and urinary LTE4 (U-LTE4) has been considered as the most reliable analytic parameter for monitoring the endogenous synthesis of CysLT.20 We have demonstrated that nasal polyposis is one of the most important factors indicating hyperleukotrienuria.21 Figure 7 shows U-LTE4 concentrations in adult asthmatics with and without ENP. U-LTE4 concentration is expressed on a log scale. The ATA patients with ENP showed higher U-LTE4 concentrations than the ATA patients without ENP.22 In contrast, because there were only eight patients without ENP in the AIA group, no significant correlations between AIA with ENP and AIA without ENP were found.

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Fig. 7. Urinary LTE4 concentrations in adult asthmatics with and without ENP.

From these observations, we hypothesized that the ENP tissue is an important source of CysLT. To confirm this hypothesis, we compared the concentrations of U-LTE4 before and after the surgical treatment of nasal polyps. Figure 8 shows a significant decrease in the concentrations of U-LTE4 after endoscopic surgery of the sinuses in both the ATA and AIA groups.22 Surprisingly, in a retrospective study, more than one-half of the patients with sinusitis showed normal U-LTE4 concentrations after endoscopic sinus surgery. In our prospective study carried out over the last six years, we have confirmed a significant decrease in U-LTE4 concentration after sinus surgery in AIA patients.

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Fig. 8. Significant decrease in the concentrations of U-LTE4 after endoscopic surgery of the sinuses in both the ATA and AIA groups.

If our hypothesis, that is, the nasal polyp tissue is a major source of CysLT, is correct, there may be a positive correlation between sinus CysLT concentration and urinary LTE4 concentration. We confirmed that there is a strong and significant correlation between sinus tissue and urinary concentrations of leukotrienes. From these findings, CRS tissue with nasal polyps is a major source of CysLT in adult asthmatics with both AIA and ATA.

Summary of EOM and ENP in Japanese asthmatics

1.EOM is closely related to adult-onset asthma, ENP, and AIA.

2.The frequency of EOM has markedly increased in Japan. The reason for this increase is perhaps asthma stabilization by new-type ICS treatment.

3.Marked eosinophil infiltration and increased IgE, CysLT, IL-5 concentrations in ENP tissue may be due to a decreased COX-2 activity.

4.ENP is a major cause of CysLT overproduction in stable asthmatics both with AIA and ATA patients.

5.ENP may play an important role in not only cysLT production, but also aspirin sensitivity in AIA patients.

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Address for correspondence: Masami Taniguchi MD PhD, Sagamihara National Hospital, 18–1 Sakuradai Minami-ku Sagamihara Kanagawa, 252–0315, Japan. m-taniguchi@sagamihara@hosp.gr.jp

Cholesteatoma and Ear Surgery – An Update, pp. 79–85

Edited by Haruo Takahashi

2013 © Kugler Publications, Amsterdam, The Netherlands