Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia
2014; Elsevier BV; Volume: 135; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2014.08.031
ISSN1097-6825
AutoresMahboobeh Mahdavinia, Lydia Suh, Roderick G. Carter, Whitney W. Stevens, James E. Norton, Atsushi Kato, Bruce K. Tan, Robert C. Kern, David B. Conley, Rakesh K. Chandra, Jennifer Lavin, Anju T. Peters, Leslie C. Grammer, Robert P. Schleimer,
Tópico(s)Asthma and respiratory diseases
ResumoChronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is an inflammatory disease with a high impact on quality of life and is characterized by the presence of polyps in an individual with diagnosis of CRS. Although most of the nasal polyps (NPs) in patients with CRSwNP seen in Western countries are eosinophilic,1Jankowski R. Bouchoua F. Coffinet L. Vignaud J.M. Clinical factors influencing the eosinophil infiltration of nasal polyps.Rhinology. 2002; 40: 173-178PubMed Google Scholar, 2Mahdavinia M. Carter R.G. Ocampo C.J. Stevens W. Kato A. Tan B.K. et al.Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity.J Allergy Clin Immunol. 2014; 133: 1759-1763Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar noneosinophilic NPs comprise a significant percentage of CRSwNP seen in East Asian countries including China, Korea, Japan, and Malaysia.3Bachert C. Zhang N. Holtappels G. De Lobel L. van Cauwenberge P. Liu S. et al.Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma.J Allergy Clin Immunol. 2010; 126 (968.e1-6): 962-968Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 4Cao P.P. Li H.B. Wang B.F. Wang S.B. You X.J. Cui Y.H. et al.Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese.J Allergy Clin Immunol. 2009; 124 (484.e1-2): 478-484Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 5Kim S.J. Lee K.H. Kim S.W. Cho J.S. Park Y.K. Shin S.Y. Changes in histological features of nasal polyps in a Korean population over a 17-year period.Otolaryngol Head Neck Surg. 2013; 149: 431-437Crossref PubMed Scopus (63) Google Scholar, 6Nakayama T. Yoshikawa M. Asaka D. Okushi T. Matsuwaki Y. Otori N. et al.Mucosal eosinophilia and recurrence of nasal polyps—new classification of chronic rhinosinusitis.Rhinology. 2011; 49: 392-396PubMed Google Scholar, 7Tikaram A. Prepageran N. Asian nasal polyps: a separate entity?.Med J Malaysia. 2013; 68: 445-447PubMed Google Scholar, 8Hu Y. Cao P.P. Liang G.T. Cui Y.H. Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults.Laryngoscope. 2012; 122: 498-503Crossref PubMed Scopus (102) Google Scholar Studies comparing polyps in Chinese and Belgian patients have shown significantly lower eosinophil numbers3Bachert C. Zhang N. Holtappels G. De Lobel L. van Cauwenberge P. Liu S. et al.Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma.J Allergy Clin Immunol. 2010; 126 (968.e1-6): 962-968Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 9Zhang N. Van Zele T. Perez-Novo C. Van Bruaene N. Holtappels G. DeRuyck N. et al.Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008; 122: 961-968Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar and lower eosinophil cationic protein (ECP) levels9Zhang N. Van Zele T. Perez-Novo C. Van Bruaene N. Holtappels G. DeRuyck N. et al.Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008; 122: 961-968Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar in NPs in Chinese patients.In the last decade, there has been a trend toward increasing eosinophilic nasal polyposis in Asian populations.5Kim S.J. Lee K.H. Kim S.W. Cho J.S. Park Y.K. Shin S.Y. Changes in histological features of nasal polyps in a Korean population over a 17-year period.Otolaryngol Head Neck Surg. 2013; 149: 431-437Crossref PubMed Scopus (63) Google Scholar, 10Katotomichelakis M. Tantilipikorn P. Holtappels G. De Ruyck N. Feng L. Van Zele T. et al.Inflammatory patterns in upper airway disease in the same geographical area may change over time.Am J Rhinol Allergy. 2013; 27: 354-360Crossref PubMed Scopus (66) Google Scholar A Korean study has shown that eosinophilic NPs have increased from 24% of the total NPs resected in 1993-1994 to 50.9% in 2010-2012.5Kim S.J. Lee K.H. Kim S.W. Cho J.S. Park Y.K. Shin S.Y. Changes in histological features of nasal polyps in a Korean population over a 17-year period.Otolaryngol Head Neck Surg. 2013; 149: 431-437Crossref PubMed Scopus (63) Google Scholar However, recent studies still show that about half of the CRSwNP cases in East Asian countries have a noneosinophilic pathology.4Cao P.P. Li H.B. Wang B.F. Wang S.B. You X.J. Cui Y.H. et al.Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese.J Allergy Clin Immunol. 2009; 124 (484.e1-2): 478-484Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 5Kim S.J. Lee K.H. Kim S.W. Cho J.S. Park Y.K. Shin S.Y. Changes in histological features of nasal polyps in a Korean population over a 17-year period.Otolaryngol Head Neck Surg. 2013; 149: 431-437Crossref PubMed Scopus (63) Google Scholar, 6Nakayama T. Yoshikawa M. Asaka D. Okushi T. Matsuwaki Y. Otori N. et al.Mucosal eosinophilia and recurrence of nasal polyps—new classification of chronic rhinosinusitis.Rhinology. 2011; 49: 392-396PubMed Google Scholar, 7Tikaram A. Prepageran N. Asian nasal polyps: a separate entity?.Med J Malaysia. 2013; 68: 445-447PubMed Google Scholar, 8Hu Y. Cao P.P. Liang G.T. Cui Y.H. Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults.Laryngoscope. 2012; 122: 498-503Crossref PubMed Scopus (102) Google Scholar This raises the possibility that this type of NPs are influenced by different pathogenesis elements that are more common in that area and/or that genetic factors play a role in the level of eosinophilia in NPs in Asian populations.In an attempt to test whether the propensity of Asian populations to manifest noneosinophilic polyps is due to genetic factors, we evaluated the eosinophilic marker ECP and evidence for eosinophilia in the pathology report of polyp and sinus tissue collected during functional endoscopic surgery in a group of second-generation Asian patients with CRS in Illinois and compared them with those in patients of other ethnicities in Illinois. We focused on study patients with both parents from Asian countries who were born and raised in the United States. Such patients come from the same genetic pool as their parents but have presumably been exposed to environmental factors present in the United States. Our findings demonstrated reduced eosinophilia in Asian patients with CRSwNP who were born and raised in the United States.A consecutive series of 296 patients with CRSwNP who underwent surgery at Northwestern University from 2005 to 2013 were included. Patients with self-reported Asian ancestry and born in the United States were identified as second-generation Asian. Twenty-three patients had identified themselves as Asian (including Chinese, Korean, Japanese, and Malaysian), out of which 11 were second generation and were included. The rest were excluded from the study. Original pathology reports of polyp and sinus tissue obtained during surgery were reviewed for reported eosinophilia. The tissue would have been reported as eosinophilic by the pathologists if eosinophils comprised more than 10% of inflammatory cells in the studied area. Furthermore, in 161 of the enrolled cases, tissue homogenates of polyp and/or uncinate tissue (UT) were available in a prospectively collected biorepository and were analyzed for ECP. UT was used as representative of sinus and upper nasal tissue. Previous studies have shown that NPs and UT of patients with CRSwNP from the United States have a significantly higher number of eosinophils than does control UT.2Mahdavinia M. Carter R.G. Ocampo C.J. Stevens W. Kato A. Tan B.K. et al.Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity.J Allergy Clin Immunol. 2014; 133: 1759-1763Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar ECP levels were measured by ELISA using the Mesacup ECP Test Kit from MBL (Woburn, Mass). The ECP concentration was measured as ng/μL. The level was adjusted to total protein concentration in each sample, which was measured as mg/μL. All ECP levels were reported as ng/mg of total protein. Physician diagnosis of asthma and atopy was recorded as part of the study and was double-checked by using chart review. Atopy was defined by evidence of allergic sensitization to aeroallergens by using skin prick test or Immunocap testing. The study was approved by the Northwestern University institutional review board.Comparisons among groups in terms of ECP levels were assessed by using Kruskal-Wallis and Dunn's multiple comparisons tests. Comparisons between groups in terms of eosinophilic polyps, asthma, and atopy were done by using Fisher exact test. Adjusting for age and sex for the above analyses was performed by logistic regression. These statistical analyses were performed using IBM SPSS, version 22. A P value of less than .05 was considered statistically significant.Levels of ECP in polyp (mean, 179.4 vs 1256 ng/mg; P < .001) and UT samples (mean, 133.6 vs 838.6 ng/mg; P < .001) were significantly lower in tissue from second-generation Asian versus non-Asian patients (not shown). Further comparison of Asian patients with patients of European descent (white), blacks, and Hispanics showed that Asian patients had lower ECP levels in polyp extracts than did all these groups, but the difference reached statistical significance compared with only white patients (Fig 1, A). As with the polyp tissue, the ECP level in UT of Asian cases was significantly lower than the ECP level in UT extracts of white patients (Fig 1, B).Per pathology reports, 27% of polyp/sinus tissues from Asian patients were eosinophilic as opposed to 65% in white patients, 70% in Hispanics, and 62% in black patients (Fig 1, C; P < .05 for all comparisons). The ECP levels in both polyp and UT were significantly higher in cases reported to have eosinophilia in the pathology report (Fig 1, D).Moreover, Asian patients had a significantly lower prevalence of atopy (Fig 1, E) and a trend toward lower prevalence of asthma (Fig 1, F) than did white and black patients.Although the mean age of the Asian group was about 10 years lower than that of patients of other ethnicities, this difference was not statistically significant (mean age, 36.80 years in Asians vs 47.09, 47.10, and 43.12 years in white, black, and Hispanic patients, respectively). The male to female ratio was also slightly higher in Asians (72% in Asians, 59% in Hispanics, 53% in blacks, and 60% in whites), but this was not statistically different among various ethnicities.Age and sex were not associated with eosinophilic NPs in general or in the individual populations. After adjusting the analyses for age and sex by logistic regressions, the associations between ethnicity and ECP level, eosinophilia, and atopy remained significant (not shown).The difference between eosinophilic and noneosinophilic polyps seems to go beyond the presence or number of eosinophils. A study comparing the histopathology of polyps from Asian patients with polyps from white patients has shown significant differences not only in eosinophil numbers but also in terms of the T-helper cells involved in tissue inflammation.9Zhang N. Van Zele T. Perez-Novo C. Van Bruaene N. Holtappels G. DeRuyck N. et al.Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008; 122: 961-968Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Interestingly, observations within Asian populations have also shown different histologic characteristics and remodeling patterns in noneosinophilic versus eosinophilic polyps in Chinese patients with CRSwNP.4Cao P.P. Li H.B. Wang B.F. Wang S.B. You X.J. Cui Y.H. et al.Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese.J Allergy Clin Immunol. 2009; 124 (484.e1-2): 478-484Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 11Shi L.L. Xiong P. Zhang L. Cao P.P. Liao B. Lu X. et al.Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns.Allergy. 2013; 68: 101-109Crossref PubMed Scopus (97) Google ScholarThe infiltration of eosinophils in the mucosal membrane and polyps has also been linked to the clinical characteristics of the disease. Consistent with our results, other studies have shown that noneosinophilic polyps are less frequently associated with atopy and asthma.8Hu Y. Cao P.P. Liang G.T. Cui Y.H. Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults.Laryngoscope. 2012; 122: 498-503Crossref PubMed Scopus (102) Google Scholar, 9Zhang N. Van Zele T. Perez-Novo C. Van Bruaene N. Holtappels G. DeRuyck N. et al.Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008; 122: 961-968Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar, 12Sakuma Y. Ishitoya J. Komatsu M. Shiono O. Hirama M. Yamashita Y. et al.New clinical diagnostic criteria for eosinophilic chronic rhinosinusitis.Auris Nasus Larynx. 2011; 38: 583-588Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Furthermore, patients with noneosinophilic CRSwNP have a lower polyp recurrence rate6Nakayama T. Yoshikawa M. Asaka D. Okushi T. Matsuwaki Y. Otori N. et al.Mucosal eosinophilia and recurrence of nasal polyps—new classification of chronic rhinosinusitis.Rhinology. 2011; 49: 392-396PubMed Google Scholar and are associated with a lower blood eosinophil count.8Hu Y. Cao P.P. Liang G.T. Cui Y.H. Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults.Laryngoscope. 2012; 122: 498-503Crossref PubMed Scopus (102) Google Scholar, 12Sakuma Y. Ishitoya J. Komatsu M. Shiono O. Hirama M. Yamashita Y. et al.New clinical diagnostic criteria for eosinophilic chronic rhinosinusitis.Auris Nasus Larynx. 2011; 38: 583-588Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar It is noteworthy that the current practice in the management of noneosinophilic CRSwNP, which is primarily macrolide antibiotics, is different from the management of eosinophilic CRSwNP, in which corticosteroids are the mainstay of treatment.13Peric A. Vojvodic D. Matkovic-Jozin S. Effect of long-term, low-dose clarithromycin on T helper 2 cytokines, eosinophilic cationic protein and the 'regulated on activation, normal T cell expressed and secreted' chemokine in the nasal secretions of patients with nasal polyposis.J Laryngol Otol. 2012; 126: 495-502Crossref PubMed Scopus (22) Google ScholarThese differences in the phenotype and outcomes of disease suggest that it is worthwhile understanding the differences in pathogenesis of noneosinophilic and eosinophilic CRSwNP.There is evidence for the higher prevalence of noneosinophilic polyps in Asian patients enrolled in this study. Although the higher prevalence of noneosinophilic polyps in second-generation Asian patients is suggestive of a role of genetic factors that are present in Asian-descended subjects, environmental factors or genetic/environmental interaction effects cannot be excluded. Furthermore, different underlying causes could influence the formation of noneosinophilic polyps in Asians. Second-generation immigrant populations may maintain diet and lifestyle factors that influence the phenotype of disease or may have stable differences in the microbiome after immigration.The magnitude of the difference uncovered in the present study suggests that a prospective cohort of Asian immigrants with long-term follow-up is worthwhile and can potentially evaluate the true prevalence of both types of NPs in relation to lifestyle and genetic factors in this population. This could shed light on the pathogenesis and role of genetic and environmental risk factors influencing eosinophilia and CRSwNP in general and the relative paucity of eosinophilic polyps in Asians.In conclusion, our study showed a significantly lower eosinophilia in NPs surgically removed from second-generation Asian patients. This is in line with studies conducted on native-born patients in Asian countries that showed that up to half of the patients with nasal polyposis have a noneosinophilic histology. Although future studies are needed to further elucidate these findings, our results are suggestive of possible genetic factors or genetic/environment interactions playing a role in the pathogenesis of noneosinophilic NPs. Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is an inflammatory disease with a high impact on quality of life and is characterized by the presence of polyps in an individual with diagnosis of CRS. Although most of the nasal polyps (NPs) in patients with CRSwNP seen in Western countries are eosinophilic,1Jankowski R. Bouchoua F. Coffinet L. Vignaud J.M. Clinical factors influencing the eosinophil infiltration of nasal polyps.Rhinology. 2002; 40: 173-178PubMed Google Scholar, 2Mahdavinia M. Carter R.G. Ocampo C.J. Stevens W. Kato A. Tan B.K. et al.Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity.J Allergy Clin Immunol. 2014; 133: 1759-1763Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar noneosinophilic NPs comprise a significant percentage of CRSwNP seen in East Asian countries including China, Korea, Japan, and Malaysia.3Bachert C. Zhang N. Holtappels G. De Lobel L. van Cauwenberge P. Liu S. et al.Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma.J Allergy Clin Immunol. 2010; 126 (968.e1-6): 962-968Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 4Cao P.P. Li H.B. Wang B.F. Wang S.B. You X.J. Cui Y.H. et al.Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese.J Allergy Clin Immunol. 2009; 124 (484.e1-2): 478-484Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 5Kim S.J. Lee K.H. Kim S.W. Cho J.S. Park Y.K. Shin S.Y. Changes in histological features of nasal polyps in a Korean population over a 17-year period.Otolaryngol Head Neck Surg. 2013; 149: 431-437Crossref PubMed Scopus (63) Google Scholar, 6Nakayama T. Yoshikawa M. Asaka D. Okushi T. Matsuwaki Y. Otori N. et al.Mucosal eosinophilia and recurrence of nasal polyps—new classification of chronic rhinosinusitis.Rhinology. 2011; 49: 392-396PubMed Google Scholar, 7Tikaram A. Prepageran N. Asian nasal polyps: a separate entity?.Med J Malaysia. 2013; 68: 445-447PubMed Google Scholar, 8Hu Y. Cao P.P. Liang G.T. Cui Y.H. Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults.Laryngoscope. 2012; 122: 498-503Crossref PubMed Scopus (102) Google Scholar Studies comparing polyps in Chinese and Belgian patients have shown significantly lower eosinophil numbers3Bachert C. Zhang N. Holtappels G. De Lobel L. van Cauwenberge P. Liu S. et al.Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma.J Allergy Clin Immunol. 2010; 126 (968.e1-6): 962-968Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 9Zhang N. Van Zele T. Perez-Novo C. Van Bruaene N. Holtappels G. DeRuyck N. et al.Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008; 122: 961-968Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar and lower eosinophil cationic protein (ECP) levels9Zhang N. Van Zele T. Perez-Novo C. Van Bruaene N. Holtappels G. DeRuyck N. et al.Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008; 122: 961-968Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar in NPs in Chinese patients. In the last decade, there has been a trend toward increasing eosinophilic nasal polyposis in Asian populations.5Kim S.J. Lee K.H. Kim S.W. Cho J.S. Park Y.K. Shin S.Y. Changes in histological features of nasal polyps in a Korean population over a 17-year period.Otolaryngol Head Neck Surg. 2013; 149: 431-437Crossref PubMed Scopus (63) Google Scholar, 10Katotomichelakis M. Tantilipikorn P. Holtappels G. De Ruyck N. Feng L. Van Zele T. et al.Inflammatory patterns in upper airway disease in the same geographical area may change over time.Am J Rhinol Allergy. 2013; 27: 354-360Crossref PubMed Scopus (66) Google Scholar A Korean study has shown that eosinophilic NPs have increased from 24% of the total NPs resected in 1993-1994 to 50.9% in 2010-2012.5Kim S.J. Lee K.H. Kim S.W. Cho J.S. Park Y.K. Shin S.Y. Changes in histological features of nasal polyps in a Korean population over a 17-year period.Otolaryngol Head Neck Surg. 2013; 149: 431-437Crossref PubMed Scopus (63) Google Scholar However, recent studies still show that about half of the CRSwNP cases in East Asian countries have a noneosinophilic pathology.4Cao P.P. Li H.B. Wang B.F. Wang S.B. You X.J. Cui Y.H. et al.Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese.J Allergy Clin Immunol. 2009; 124 (484.e1-2): 478-484Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 5Kim S.J. Lee K.H. Kim S.W. Cho J.S. Park Y.K. Shin S.Y. Changes in histological features of nasal polyps in a Korean population over a 17-year period.Otolaryngol Head Neck Surg. 2013; 149: 431-437Crossref PubMed Scopus (63) Google Scholar, 6Nakayama T. Yoshikawa M. Asaka D. Okushi T. Matsuwaki Y. Otori N. et al.Mucosal eosinophilia and recurrence of nasal polyps—new classification of chronic rhinosinusitis.Rhinology. 2011; 49: 392-396PubMed Google Scholar, 7Tikaram A. Prepageran N. Asian nasal polyps: a separate entity?.Med J Malaysia. 2013; 68: 445-447PubMed Google Scholar, 8Hu Y. Cao P.P. Liang G.T. Cui Y.H. Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults.Laryngoscope. 2012; 122: 498-503Crossref PubMed Scopus (102) Google Scholar This raises the possibility that this type of NPs are influenced by different pathogenesis elements that are more common in that area and/or that genetic factors play a role in the level of eosinophilia in NPs in Asian populations. In an attempt to test whether the propensity of Asian populations to manifest noneosinophilic polyps is due to genetic factors, we evaluated the eosinophilic marker ECP and evidence for eosinophilia in the pathology report of polyp and sinus tissue collected during functional endoscopic surgery in a group of second-generation Asian patients with CRS in Illinois and compared them with those in patients of other ethnicities in Illinois. We focused on study patients with both parents from Asian countries who were born and raised in the United States. Such patients come from the same genetic pool as their parents but have presumably been exposed to environmental factors present in the United States. Our findings demonstrated reduced eosinophilia in Asian patients with CRSwNP who were born and raised in the United States. A consecutive series of 296 patients with CRSwNP who underwent surgery at Northwestern University from 2005 to 2013 were included. Patients with self-reported Asian ancestry and born in the United States were identified as second-generation Asian. Twenty-three patients had identified themselves as Asian (including Chinese, Korean, Japanese, and Malaysian), out of which 11 were second generation and were included. The rest were excluded from the study. Original pathology reports of polyp and sinus tissue obtained during surgery were reviewed for reported eosinophilia. The tissue would have been reported as eosinophilic by the pathologists if eosinophils comprised more than 10% of inflammatory cells in the studied area. Furthermore, in 161 of the enrolled cases, tissue homogenates of polyp and/or uncinate tissue (UT) were available in a prospectively collected biorepository and were analyzed for ECP. UT was used as representative of sinus and upper nasal tissue. Previous studies have shown that NPs and UT of patients with CRSwNP from the United States have a significantly higher number of eosinophils than does control UT.2Mahdavinia M. Carter R.G. Ocampo C.J. Stevens W. Kato A. Tan B.K. et al.Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity.J Allergy Clin Immunol. 2014; 133: 1759-1763Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar ECP levels were measured by ELISA using the Mesacup ECP Test Kit from MBL (Woburn, Mass). The ECP concentration was measured as ng/μL. The level was adjusted to total protein concentration in each sample, which was measured as mg/μL. All ECP levels were reported as ng/mg of total protein. Physician diagnosis of asthma and atopy was recorded as part of the study and was double-checked by using chart review. Atopy was defined by evidence of allergic sensitization to aeroallergens by using skin prick test or Immunocap testing. The study was approved by the Northwestern University institutional review board. Comparisons among groups in terms of ECP levels were assessed by using Kruskal-Wallis and Dunn's multiple comparisons tests. Comparisons between groups in terms of eosinophilic polyps, asthma, and atopy were done by using Fisher exact test. Adjusting for age and sex for the above analyses was performed by logistic regression. These statistical analyses were performed using IBM SPSS, version 22. A P value of less than .05 was considered statistically significant. Levels of ECP in polyp (mean, 179.4 vs 1256 ng/mg; P < .001) and UT samples (mean, 133.6 vs 838.6 ng/mg; P < .001) were significantly lower in tissue from second-generation Asian versus non-Asian patients (not shown). Further comparison of Asian patients with patients of European descent (white), blacks, and Hispanics showed that Asian patients had lower ECP levels in polyp extracts than did all these groups, but the difference reached statistical significance compared with only white patients (Fig 1, A). As with the polyp tissue, the ECP level in UT of Asian cases was significantly lower than the ECP level in UT extracts of white patients (Fig 1, B). Per pathology reports, 27% of polyp/sinus tissues from Asian patients were eosinophilic as opposed to 65% in white patients, 70% in Hispanics, and 62% in black patients (Fig 1, C; P < .05 for all comparisons). The ECP levels in both polyp and UT were significantly higher in cases reported to have eosinophilia in the pathology report (Fig 1, D). Moreover, Asian patients had a significantly lower prevalence of atopy (Fig 1, E) and a trend toward lower prevalence of asthma (Fig 1, F) than did white and black patients. Although the mean age of the Asian group was about 10 years lower than that of patients of other ethnicities, this difference was not statistically significant (mean age, 36.80 years in Asians vs 47.09, 47.10, and 43.12 years in white, black, and Hispanic patients, respectively). The male to female ratio was also slightly higher in Asians (72% in Asians, 59% in Hispanics, 53% in blacks, and 60% in whites), but this was not statistically different among various ethnicities. Age and sex were not associated with eosinophilic NPs in general or in the individual populations. After adjusting the analyses for age and sex by logistic regressions, the associations between ethnicity and ECP level, eosinophilia, and atopy remained significant (not shown). The difference between eosinophilic and noneosinophilic polyps seems to go beyond the presence or number of eosinophils. A study comparing the histopathology of polyps from Asian patients with polyps from white patients has shown significant differences not only in eosinophil numbers but also in terms of the T-helper cells involved in tissue inflammation.9Zhang N. Van Zele T. Perez-Novo C. Van Bruaene N. Holtappels G. DeRuyck N. et al.Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008; 122: 961-968Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Interestingly, observations within Asian populations have also shown different histologic characteristics and remodeling patterns in noneosinophilic versus eosinophilic polyps in Chinese patients with CRSwNP.4Cao P.P. Li H.B. Wang B.F. Wang S.B. You X.J. Cui Y.H. et al.Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese.J Allergy Clin Immunol. 2009; 124 (484.e1-2): 478-484Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 11Shi L.L. Xiong P. Zhang L. Cao P.P. Liao B. Lu X. et al.Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns.Allergy. 2013; 68: 101-109Crossref PubMed Scopus (97) Google Scholar The infiltration of eosinophils in the mucosal membrane and polyps has also been linked to the clinical characteristics of the disease. Consistent with our results, other studies have shown that noneosinophilic polyps are less frequently associated with atopy and asthma.8Hu Y. Cao P.P. Liang G.T. Cui Y.H. Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults.Laryngoscope. 2012; 122: 498-503Crossref PubMed Scopus (102) Google Scholar, 9Zhang N. Van Zele T. Perez-Novo C. Van Bruaene N. Holtappels G. DeRuyck N. et al.Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008; 122: 961-968Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar, 12Sakuma Y. Ishitoya J. Komatsu M. Shiono O. Hirama M. Yamashita Y. et al.New clinical diagnostic criteria for eosinophilic chronic rhinosinusitis.Auris Nasus Larynx. 2011; 38: 583-588Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Furthermore, patients with noneosinophilic CRSwNP have a lower polyp recurrence rate6Nakayama T. Yoshikawa M. Asaka D. Okushi T. Matsuwaki Y. Otori N. et al.Mucosal eosinophilia and recurrence of nasal polyps—new classification of chronic rhinosinusitis.Rhinology. 2011; 49: 392-396PubMed Google Scholar and are associated with a lower blood eosinophil count.8Hu Y. Cao P.P. Liang G.T. Cui Y.H. Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults.Laryngoscope. 2012; 122: 498-503Crossref PubMed Scopus (102) Google Scholar, 12Sakuma Y. Ishitoya J. Komatsu M. Shiono O. Hirama M. Yamashita Y. et al.New clinical diagnostic criteria for eosinophilic chronic rhinosinusitis.Auris Nasus Larynx. 2011; 38: 583-588Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar It is noteworthy that the current practice in the management of noneosinophilic CRSwNP, which is primarily macrolide antibiotics, is different from the management of eosinophilic CRSwNP, in which corticosteroids are the mainstay of treatment.13Peric A. Vojvodic D. Matkovic-Jozin S. Effect of long-term, low-dose clarithromycin on T helper 2 cytokines, eosinophilic cationic protein and the 'regulated on activation, normal T cell expressed and secreted' chemokine in the nasal secretions of patients with nasal polyposis.J Laryngol Otol. 2012; 126: 495-502Crossref PubMed Scopus (22) Google Scholar These differences in the phenotype and outcomes of disease suggest that it is worthwhile understanding the differences in pathogenesis of noneosinophilic and eosinophilic CRSwNP. There is evidence for the higher prevalence of noneosinophilic polyps in Asian patients enrolled in this study. Although the higher prevalence of noneosinophilic polyps in second-generation Asian patients is suggestive of a role of genetic factors that are present in Asian-descended subjects, environmental factors or genetic/environmental interaction effects cannot be excluded. Furthermore, different underlying causes could influence the formation of noneosinophilic polyps in Asians. Second-generation immigrant populations may maintain diet and lifestyle factors that influence the phenotype of disease or may have stable differences in the microbiome after immigration. The magnitude of the difference uncovered in the present study suggests that a prospective cohort of Asian immigrants with long-term follow-up is worthwhile and can potentially evaluate the true prevalence of both types of NPs in relation to lifestyle and genetic factors in this population. This could shed light on the pathogenesis and role of genetic and environmental risk factors influencing eosinophilia and CRSwNP in general and the relative paucity of eosinophilic polyps in Asians. In conclusion, our study showed a significantly lower eosinophilia in NPs surgically removed from second-generation Asian patients. This is in line with studies conducted on native-born patients in Asian countries that showed that up to half of the patients with nasal polyposis have a noneosinophilic histology. Although future studies are needed to further elucidate these findings, our results are suggestive of possible genetic factors or genetic/environment interactions playing a role in the pathogenesis of noneosinophilic NPs.
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