Increased level of interleukin-13, but not interleukin-4 and interferon-γ in chronic rhinosinusitis with nasal polyps

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Abdel-Salam" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Bahaa K.A." "apellidos" => "Abdel-Salam" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054613001456?idApp=UINPBA00004N" "url" => "/03010546/0000004200000005/v1_201409050044/S0301054613001456/v1_201409050044/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Increased level of interleukin-13, but not interleukin-4 and interferon-γ in chronic rhinosinusitis with nasal polyps" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "465" "paginaFinal" => "471" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M. Nabavi, S. Arshi, A. Bahrami, Z. Aryan, M.H. Bemanian, H. Esmaeilzadeh, F. Jalali, S.B. Pousti, N. Rezaei" "autores" => array:9 [ 0 => array:3 [ "nombre" => "M." "apellidos" => "Nabavi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "S." "apellidos" => "Arshi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:4 [ "nombre" => "A." "apellidos" => "Bahrami" "email" => array:1 [ 0 => "a_bahrami@razi.tums.ac.ir" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 3 => array:3 [ "nombre" => "Z." "apellidos" => "Aryan" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "M.H." "apellidos" => "Bemanian" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "H." "apellidos" => "Esmaeilzadeh" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "F." "apellidos" => "Jalali" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 7 => array:3 [ "nombre" => "S.B." "apellidos" => "Pousti" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 8 => array:3 [ "nombre" => "N." "apellidos" => "Rezaei" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Department of Allergy and Clinical Immunology, Hazrat Rasoul-e-Akram Hospital, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "ENT, Head & Neck Research Center, Hazrat Rasoul-e-Akram Hospital, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Molecular Immunology Research Center and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3964 "Ancho" => 1613 "Tamanyo" => 172312 ] ] "descripcion" => array:1 [ "en" => "(A) IL-13 was significantly higher in patients with CRSwNP (0.98±1.56pg/mL vs. 0.34±0.16pg/mL, p=0.002), (B) IL-4 was higher in patients with CRSwNP, but did not attain significance (0.12±0.60pg/mL vs. 0.06±0.24pg/mL, p=0.665), (C) IFN-γ was non-significantly higher in controls (5±0.78pg/mL vs. 4.62±1.62pg/mL, p=0.230)." ] ] ] "textoCompleto" => "IntroductionChronic inflammation of nasal cavities and paranasal sinuses defines chronic rhinosinusitis (CRS) with at least two distinct categories of CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP).<a class="elsevierStyleCrossRef" href="#bib0005">1</a> These categories have different underlying pathophysiology, response to treatment modalities and prognosis.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> CRSwNP affects approximately 1% of the population with decrease in quality of life and considerable economic burden.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Patients with CRSwNP can be categorised into eosinophilic and non-eosinophilic, using nasal lavage cytology pattern.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> It is also reported that nasal polyps in patients with CRS can be discriminated from cystic fibrosis leading to nasal polyps.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Cytokines play the central role in the pathophysiology of polyp formation in terms of recruitment of inflammatory cells, activation and promotion of their survival. Furthermore they can affect the behaviour of epithelial cells, smooth muscle cells and tissue remodelling.<a class="elsevierStyleCrossRefs" href="#bib0030">6–8</a> It seems that not only T helper (TH)-2, but also TH-1 cytokines are involved in the pathophysiology of CRSwNP; however, their effects are poorly understood<a class="elsevierStyleCrossRef" href="#bib0045">9</a>; and therefore a comprehensive insight into the underlying pathology of the disease is necessary to adopt the best treatment modality for these patients.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Eosinophilia is believed to be the hallmark of disease establishment either in early or late phases, with a TH-2 biased cytokines.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Previous studies by Zhang et al. in Asian populations showed that TH-1/TH-17 biased response and non-eosinophilic pattern in CRSwNP that denotes to the role of ethnic and maybe some uncovered aspects of disease immunopathology.<a class="elsevierStyleCrossRefs" href="#bib0055">11,12</a> Similarly, Coa et al. demonstrated high expression of TH-1 cytokines nearby TH-2 and TH-17 cytokines in CRSwNP, compared to controls.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Cytokine expression in nasal mucus, but not plasma levels, were previously thoroughly investigated<a class="elsevierStyleCrossRef" href="#bib0070">14</a>; however, data upon plasma changes are very poor.This study aimed to investigate the cytokine levels in the sera of patients with CRSwNP including interleukin (IL)-4, IL-13 and interferon (IFN)-γ, compared to healthy controls. We also investigated the association among cytokine levels, nasal smear cytology and total immunoglobulin (Ig) E in sera of patients with CRSwNP. Furthermore, cytokine and IgE levels were compared in asthmatics versus those without asthma and patients with or without aspirin intolerance.Materials and methodsStudy populationA case-control study was conducted in a group of patients referred to a tertiary referral hospital from Tehran University of Medical Sciences. This study was approved by the local institutional review board of the university. Additionally, written informed consent forms were signed by all enrolled participants, while they were treated according to the Helsinki Declaration of the World Medical Association. A total of 60 adult patients (older than 18 years) with exact diagnosis of CRSwNP, confirmed by an expert clinical immunologist,<a class="elsevierStyleCrossRefs" href="#bib0075">15–17</a> were enrolled as cases, while 20 healthy adult participants without any evidence of atopy were also enrolled as controls of the study. All these cases had documents of presence of nasal polyps, using patient examination or endoscopic evaluations.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Cases with incomplete medical records, cystic fibrosis and who received antibiotics or corticosteroids during last month prior to enrolment, or who were treated with specific immunotherapy (SIT) were excluded from the study. Controls of this study were free of any systemic disease, allergic symptoms, atopy or any category of rhinitis at time of enrolment. Indeed, controls were subjects without CRS, without NP and without evidence of atopy.Data acquisitionA detailed history was taken from all the participants, including recurrent sneezing, runny nose, nasal congestion, symptoms indicative of conjunctivitis, reduced sense of smell, facial pain or pressure. Other allergic conditions such as atopic dermatitis, food allergy, drug allergy, aspirin intolerance and angio-oedema were also investigated and recorded. Onset of appearance of symptoms and time of diagnosis of CRSwNP were determined by asking the patients and extracting from medical records. Patient examination was done by expert physicians and the findings were recorded. Presence of asthma was considered according to patients’ symptoms and pulmonary function test (PFT), based on standard guidelines.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> If peak expiratory flow increased more than 12% following salbutamol administration, airway hyper-responsiveness was confirmed. To investigate the presence of atopy, skin prick test (SPT) was performed for all the participants with histamine (positive control) and normal saline dilution (negative control). The results were read after 20min and a diameter more than 3mm with respect to the negative control was considered as positive test.Nasal smear cytologyNasal secretions of patients with CRSwNP were collected, using an appropriate swab. Afterward, specimens were stained by Haematoxylin & Eosin and a blinded pathologist reviewed the results, using a light microscope. A total of 10 fields of high power field (HPF) of microscope were investigated for infiltrated leukocytes and proportion of eosinophils to all inflammatory cells and proportion of neutrophils to all inflammatory cells were calculated. With respect to these two proportions predominance pattern of inflammation was determined.Assessment of total IgE and cytokinesThe sera from all the patients with CRSwNP were collected after centrifuging the clotted blood, which were kept at −20°C until the time of assays. Total IgE levels were determined, using spectrophotometry according to international standards.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> IL-13, IL-4, and IFN-γ were assessed, using enzyme-linked immunosorbent assay (ELISA, Bender MED and Bioscience). All the procedures were done according to the manufacturer's recommendations. Levels of IgE, IL-13, IL-4, and IFN-γ were expressed as international units per millilitre (IU/mL) and picogeram per millilitre (pg/ml), respectively. The protocols employed to determine the levels of IgE and IL-13, IL-4, and IFN-γ were sensitive to detect minimum levels of 1IU/mL, 0.1pg/mL, 0.06pg/mL, and 0.9pg/mL, respectively.Statistical analysisStatistical analysis was carried out using SPSS (Statistical Package for the Social Sciences, version 16.0, SPSS Inc., Chicago, IL, USA). Student t test was used to compare the serum levels of interleukins between patients with CRSwNP and controls. ANOVA was employed to compare cytokine levels among different atopic patterns of patients with CRSwNP. The reference value for comparison of total serum IgE with normal population was derived from a study by Carosso et al. as follows percent of females in case arm×148+percent male patients with CRSwNP×169.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> Afterwards, one sample t test was performed to compare the mean of total IgE in patients with CRSwNP with the calculated reference value for normal population with a similar gender distribution. Pearson correlation coefficient was used to assess the correlation between cytokine levels and symptoms. Data were expressed as mean±SD. All the tests were two sided with the significance level at probability below 0.05.ResultsDemographicsA total of 80 participants (60 cases and 20 controls) with mean age of 37.7±12.7 (ranging from 18 to 70) years were enrolled. There were no differences between case and control groups with respect to the age (37.2±12.0 vs. 39.1±15.1, respectively, p=0.572) and gender distribution (female/male; 38/22 vs. 12/8, respectively, p=0.790).Cytokine profile of patients with CRSwNP versus controlsSerum level of IL-13 in the patients with CRSwNP was significantly higher than the controls (p=0.002, <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). However, serum level of IL-4 did not differ (p=0.665, <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B) between the two groups. On the other hand, the serum level of IFN-γ was higher in non-atopic controls than the patients with CRSwNP, but this difference was not significant (p=0.230, <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Cytokine profile of patients with CRSwNP with or without atopySPT revealed that 22/60 (36.7%) were not sensitised, while 15/60 (25%) were monosensitised and 23/60 (38.3%) were polysensitised. Neither IL-13/IL-4 nor IFN-γ differed significantly among these subgroups of patients with CRSwNP (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Nasal smear cytology and IgEPredominant pattern of infiltration was eosinophilia in 20/60 (33.3%) and neutrophilia in 40/60 (66.7%). Mean level of serum IgE was 301.4±516.5IU/mL with significant difference than the value (155.7) for normal population (p=0.033). Additionally, serum level of IgE was significantly correlated with IL-13 and IFN-γ, but not with IL-4 (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). In patients with CRSwNP and predominant neutrophilia, the percentage of inflammatory cells in nasal secretions was significantly correlated with serum level of IL-4 (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Asthma, ASA intoleranceOf the patients with CRSwNP, 12/60 (20%) had ASA intolerance and 44/60 (73.3%) had asthma. From measured cytokines, none were differed significantly between asthmatics and who were free of asthma, while, IFN-γ was significantly higher in those with ASA intolerance (4.7±1.4pg/mL vs. 4.1±0.6pg/mL, p=0.022). IgE was significantly higher in asthmatics (364.9±586.6pg/mL vs. 126.7±135.7pg/mL, p=0.015), but not in patients with ASA intolerance.DiscussionThis study revealed that patients with CRSwNP had higher levels of IL-13 in their sera compared to healthy controls. Interleukin-13 is believed to play a central role in orchestrating the airway inflammation more clearly in asthma<a class="elsevierStyleCrossRef" href="#bib0105">21</a> and with a lesser extent in upper airway inflammation such as CRSwNP.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Interleukin-13 is implicated in the production of IgE that binds to mast cells, basophils and inflammatory cells in exposed sites to aeroallergens like upper airways.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Subsequent re-exposures will trigger inflammation and warrants its persistence to a chronic disease. We found patients with CRSwNP had higher serum level of IgE than that for the normal population corrected with respect to the age and gender. Interestingly, despite a decrease in levels of IFN-γ, it was still directly correlated with IgE levels. It could be justified with respect to the fact that whenever a balance is lost, the protective processes try to compensate it. Additionally, IFN-γ is increased in viral infections, and infections will be increased in patients with CRSwNP due to the abnormal anatomy of upper respiratory tract, hence levels of IFN-γ as important TH-1 cytokine would be correlated with IgE as a hallmark of atopic symptoms and changes.Furthermore, SPT revealed sensitisation in 63.3% of our participants, which is considerable. Despite the predisposing effect of TH-2 cytokines such as interleukin-13 on atopy, we did not find any significant difference in serum cytokine levels of atopic versus non-atopic patients with CRSwNP. Scavuzzo et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> found no difference in IL-2/4/6 and IFN-γ of nasal mucus of patients with CRSwNP with or without atopy; that was similar to our findings in that there was no significant difference in serum level of IL-4/13 and IFN-γ among patients with different atopic status. Prevalence of atopy may be even higher in patients with CRSwNP as Tan et al. showed that in patients with CRSwNP who failed medical treatment, 85.5% had positive skin reaction to at least one allergen.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> The message would be the importance of immunomodulator therapies in refractory subjects to conventional treatments and necessitates deeper insight to the immune imbalance present in patients with CRSwNP.More than IgE production and promotion of atopy, epithelial cell hypertrophy, goblet cell hyperplasia, mucus hyper-secretion, sub-epithelial fibrosis, eosinophilia, oedema and airway hyper-responsiveness; all were reported as subsequent changes that IL-13 promotes.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> However, all aforementioned changes are not seen in patients with CRSwNP due to interaction of other cytokines. In CRSwNP patients free of asthma, lower concentrations of transforming growth factor beta (TGF-β) leads to suppression of fibroblast proliferation and sub-epithelial collagen deposition, while in CRSsNP it is higher.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Despite the significantly elevated levels of IL-13, we found predominant pattern of neutrophilia instead of eosinophilia in nasal specimens from patients with CRSwNP. This is interesting while IL-13 strongly supports the survival and activation of eosinophils and eosinophilia via induction of eotaxin production.<a class="elsevierStyleCrossRefs" href="#bib0140">28,29</a> Increased level of other cytokines such as IL-17 family could be assumed as the cause, but our study is limited to show it. Jiang et al. demonstrated that IL-17 is implicated in nasal polyp formation either in neutrophilic or eosinophilic CRSwNP but with a pronounced role in triggering the neutrophilic inflammation.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> An undetected imbalance in favour of cytokines promoting neutrophilia is supposed in the present study.On the other hand, neutrophilic rather than eosinophilic inflammation could be due to polymorphisms of IL-13 or its receptors in Asian participants.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> In recent years, studies on Chinese adult population with CRSwNP demonstrated a pronounced neutrophilia rather eosinophilia. Cao et al. studied 151 patients with CRSwNP compared to 94 subjects with CRSsNP and 50 healthy controls. They found that TGF-β decreased and TH-1/2 and 17 all were increased in patients with CRS whether NP was present or absent. In their experience, TH-17 responses were higher in non-eosinophilic CRSwNP while eosinophilic CRSwNP showed skewed TH-2 response and CRSsNP was predominantly biased towards TH-1 cytokines.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Zhang et al. investigated the cytokine profile of patients with CRSwNP in samples from both European and Asian people. Asian participants had neutrophilic inflammation with TH-1/TH-17 skewed response whereas Europeans had classic eosinophilic pattern with TH-2 biased response. Regulatory cytokines like TGF-β were significantly lesser in CRSwNP than controls.<a class="elsevierStyleCrossRefs" href="#bib0055">11,12</a> Whether the patients with CRSwNP are Asian or Europeans, regulatory cytokines will decrease significantly, approved by low levels of forkhead box protein 3 and others contributing to the remodelling process like TGF-β are highly preserved in such a way that significant local reduced level of TGF-β can discriminate CRSwNP from CRSsNP.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> The TH-17 family may be the key in elucidating the different inflammation pattern in nasal polyps of Asian and European patients and could be the target of future studies. However neutrophilia was predominant in our experience, participants had classic cytokine profile of TH-2 skewed response with increased amount of IL-13 and IL-4 and decrease in IFN-γ in comparison with controls. Additionally, we observed a weak, but significant correlation between IL-4 levels and amount of inflammatory cells in nasal lavage of patients with neutrophilic CRSwNP due to unknown reason.Another question sought to be answered was whether cytokine levels have any association with the coexistence of lower respiratory involvement or other coexisting allergic conditions. In the current study, the presence of lower airway inflammation in asthmatics did not lead to higher serum levels of neither IL-13 nor IL-4 and IFN-γ, but IgE level was significantly higher in patients with CRSwNP that concomitantly suffered from asthma. This finding might be due to the locally increased levels of TH-2 cytokines like IL-13 or up-regulation of the receptors of IL-13 in effector cells of asthmatics. Moreover, other cytokines that were not measured here might be responsible for significant higher levels of immunoglobulin-E in non-significant elevation of IL-13. This is in agreement with the fact that immunoglobulin-E mediated sensitivity to aeroallergens is associated with asthma.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> The question remained to be answered is that whether in patients with CRSwNP who have concomitantly asthma, local level of cytokines differs from who are free of asthma or not? This idea arises from the concept of unified airway that justifies the coexistence of inflammation in both of upper and lower airways. It is interesting that there are observations that even surgical treatment of nasal polyps helps improvement of asthma but should be validated by strong methodological studies.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>Aspirin-exacerbated respiratory disease is defined by CRSwNP, asthma and aspirin hyper-sensitivity and was found to be 20% in this study. However, it is not common in a general population with maximum prevalence of 2.5% conferring the eight-fold risk of ASA intolerance in patients with CRSwNP. ASA intolerance jeopardises the course of CRSwNP with inappropriate response to conventional treatments but the knowledge regarding the underlying pathology is still unknown. Here, CRSwNP patients with ASA intolerance differed with others only with respect to the higher levels of interferon-y. Shome et al. studied only one case with ASA intolerance and found high expression of IFN-γ the expression of which increased by CD4+T cells and decreased by CD8+cells following aspirin desensitisation.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> Further studies on the cytokine profile of patients with Aspirin-exacerbated respiratory disease are still awaited.One limitation of this study was its low power, which could be responsible for not detecting significant differences between patients and controls. In addition, serum level of cytokines may be affected by the level of other substances and blood carrier proteins and it may interrupt our results. On the other hand some cytokines may only be detectable locally.In conclusion, IL-13 with high level of total IgE observed in patients with CRSwNP predisposes them to have concomitant asthma. IFN-γ was down-regulated in patients with CRSwNP as compared to controls but in the presence of ASA intolerance it would be over-expressed. In agreement with the studies on Asians, we found that the fruit of this imbalance was neutrophilia rather than eosinophilia that confers the implication of macrolide antibiotics in medical therapy. Macrolides reduce neutrophilia via inhibition of chemokine and adhesive molecule synthesis. Polymorphisms in cytokines and their receptors in addition to ethnic issues can be responsible for this observation. In neutrophilic CRSwNP, the amount of infiltrating inflammatory cells in nasal lavage is weak but significantly correlates with IL-4. Despite all efforts to elucidate changes in cytokine profile of patients with CRSwNP many questions still remain unanswered. Further studies with stronger methodologies are awaited to elucidate the cytokine profile changes of patients with CRSwNP and its effect on the course of disease.Ethical disclosuresProtection of human subjects and animals in researchThe authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.Patients’ data protectionThe authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.Right to privacy and informed consentThe authors have obtained the informed consent of the patients and/or subjects mentioned in the article. The author for correspondence is in possession of this document.Conflict of interestThe authors have no conflict of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres368097" "titulo" => array:5 [ 0 => "Abstract" 1 => "Background" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec347273" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study population" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Data acquisition" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Nasal smear cytology" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Assessment of total IgE and cytokines" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Demographics" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Cytokine profile of patients with CRSwNP versus controls" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Cytokine profile of patients with CRSwNP with or without atopy" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Nasal smear cytology and IgE" ] 4 => array:2 [ "identificador" => "sec0065" "titulo" => "Asthma, ASA intolerance" ] ] ] 5 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 6 => array:3 [ "identificador" => "sec0075" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0080" "titulo" => "Protection of human subjects and animals in research" ] 1 => array:2 [ "identificador" => "sec0085" "titulo" => "Patients’ data protection" ] 2 => array:2 [ "identificador" => "sec0090" "titulo" => "Right to privacy and informed consent" ] ] ] 7 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interest" ] 8 => array:2 [ "identificador" => "xack92172" "titulo" => "Acknowledgments" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-03-11" "fechaAceptado" => "2013-06-10" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec347273" "palabras" => array:4 [ 0 => "Chronic rhinosinusitis" 1 => "Interleukin" 2 => "Nasal polyps" 3 => "Asthma" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "BackgroundThis study was performed to investigate the serum level of interleukin (IL)-13, IL-4, and interferon (IFN)-γ in chronic rhinosinusitis with nasal polyps (CRSwNP) and subsequent inflammation pattern and comorbidities including asthma and aspirin intolerance. MethodsA case–control study was conducted on 60 adult patients with CRSwNP with mean age of 37.7±12.7 (ranging from 18 to 70) years, and on 20 healthy controls. Serum levels of IL-13, IL-4, and IFN-γ were assessed, using enzyme-linked immunosorbent assay to be compared between case and control groups. Serum level of total immunoglobulin (Ig) E was also assessed in the patients with CRSwNP. ResultsSerum level of IL-13 in the patients with CRSwNP was significantly higher than the controls (0.98±1.56 vs. 0.34±0.16 pg/ml, respectively, p=0.002). IL-4 and IFN-γ did not differ significantly between the two groups. Total IgE level was significantly increased in the patients with CRSwNP, compared to the normal values (301.43±516.54 IU/ml, p=0.033). Among the patients with CRSwNP, 12/60 (20%) had aspirin intolerance and 44/60 (73.3%) had asthma. IgE was also higher in asthmatics than non-asthmatics patients (364.9±586.6 vs. 126.7±135.7, respectively, p=0.015). Patients with aspirin intolerance had higher levels of IFN-γ (4.7±1.4 vs. 4.1±0.6, respectively, p=0.022). ConclusionsIL-13 with high level of total IgE was observed in the patients with CRSwNP, which predisposes them to have concomitant asthma. IFN-γ seems to be down-regulated in the patients with CRSwNP, but could be over-expressed in the presence of aspirin intolerance." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3964 "Ancho" => 1613 "Tamanyo" => 172312 ] ] "descripcion" => array:1 [ "en" => "(A) IL-13 was significantly higher in patients with CRSwNP (0.98±1.56pg/mL vs. 0.34±0.16pg/mL, p=0.002), (B) IL-4 was higher in patients with CRSwNP, but did not attain significance (0.12±0.60pg/mL vs. 0.06±0.24pg/mL, p=0.665), (C) IFN-γ was non-significantly higher in controls (5±0.78pg/mL vs. 4.62±1.62pg/mL, p=0.230)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3980 "Ancho" => 1611 "Tamanyo" => 205815 ] ] "descripcion" => array:1 [ "en" => "There were no significant differences between atopic (monosensitized or polysensitized) and non-atopic patients with CRSwNP in terms of (A) IL-13, (B) IL-4 and (C) IFN-γ." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 974 "Ancho" => 2232 "Tamanyo" => 131880 ] ] "descripcion" => array:1 [ "en" => "Serum level of IgE was significantly correlated with serum IL-13 (r=0.291, p=0.024) and serum IFN-γ (r=0.293, p=0.023)." ] ] 3 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Correlations that attain significance have been marked as *." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serum level \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Predominant eosinophilia</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Predominant neutrophilia</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Total</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Eosinophilia % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Neutrophilia % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Eosinophilia % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Neutrophilia % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Eosinophilia % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Neutrophilia % \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.205 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.021 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=−0.021 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.084 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.032 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.151 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.178 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.365* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=−0.365* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.089 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=−0.002 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IFN-γ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.061 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.165 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.071 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=−0.076 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.030 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.021 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IgE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.143 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.152 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.052 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=−0.052 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=0.139 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">r=−0.058 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab553474.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Correlation of percent of infiltration of inflammatory cells in nasal lavage with cytokine profile and total IgE." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => 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Original article

M. Nabavia, S. Arshia, A. Bahramia,

Corresponding author

a_bahrami@razi.tums.ac.ir

Corresponding author.

, Z. Aryanb, M.H. Bemaniana, H. Esmaeilzadeha, F. Jalalia, S.B. Poustic, N. Rezaeib,d

a Department of Allergy and Clinical Immunology, Hazrat Rasoul-e-Akram Hospital, Tehran University of Medical Sciences, Tehran, Iran

b Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

c ENT, Head & Neck Research Center, Hazrat Rasoul-e-Akram Hospital, Tehran University of Medical Sciences, Tehran, Iran

d Molecular Immunology Research Center and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic inflammation of nasal cavities and paranasal sinuses defines chronic rhinosinusitis &#40;CRS&#41; with at least two distinct categories of CRS with nasal polyps &#40;CRSwNP&#41; and CRS without nasal polyps &#40;CRSsNP&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> These categories have different underlying pathophysiology&#44; response to treatment modalities and prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> CRSwNP affects approximately 1&#37; of the population with decrease in quality of life and considerable economic burden&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Patients with CRSwNP can be categorised into eosinophilic and non-eosinophilic&#44; using nasal lavage cytology pattern&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It is also reported that nasal polyps in patients with CRS can be discriminated from cystic fibrosis leading to nasal polyps&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Cytokines play the central role in the pathophysiology of polyp formation in terms of recruitment of inflammatory cells&#44; activation and promotion of their survival&#46; Furthermore they can affect the behaviour of epithelial cells&#44; smooth muscle cells and tissue remodelling&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8</span></a> It seems that not only T helper &#40;TH&#41;-2&#44; but also TH-1 cytokines are involved in the pathophysiology of CRSwNP&#59; however&#44; their effects are poorly understood<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#59; and therefore a comprehensive insight into the underlying pathology of the disease is necessary to adopt the best treatment modality for these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Eosinophilia is believed to be the hallmark of disease establishment either in early or late phases&#44; with a TH-2 biased cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Previous studies by Zhang et al&#46; in Asian populations showed that TH-1&#47;TH-17 biased response and non-eosinophilic pattern in CRSwNP that denotes to the role of ethnic and maybe some uncovered aspects of disease immunopathology&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> Similarly&#44; Coa et al&#46; demonstrated high expression of TH-1 cytokines nearby TH-2 and TH-17 cytokines in CRSwNP&#44; compared to controls&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Cytokine expression in nasal mucus&#44; but not plasma levels&#44; were previously thoroughly investigated<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#59; however&#44; data upon plasma changes are very poor&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">This study aimed to investigate the cytokine levels in the sera of patients with CRSwNP including interleukin &#40;IL&#41;-4&#44; IL-13 and interferon &#40;IFN&#41;-&#947;&#44; compared to healthy controls&#46; We also investigated the association among cytokine levels&#44; nasal smear cytology and total immunoglobulin &#40;Ig&#41; E in sera of patients with CRSwNP&#46; Furthermore&#44; cytokine and IgE levels were compared in asthmatics versus those without asthma and patients with or without aspirin intolerance&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Study population</span><p id="par0025" class="elsevierStylePara elsevierViewall">A case-control study was conducted in a group of patients referred to a tertiary referral hospital from Tehran University of Medical Sciences&#46; This study was approved by the local institutional review board of the university&#46; Additionally&#44; written informed consent forms were signed by all enrolled participants&#44; while they were treated according to the Helsinki Declaration of the World Medical Association&#46; A total of 60 adult patients &#40;older than 18 years&#41; with exact diagnosis of CRSwNP&#44; confirmed by an expert clinical immunologist&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;17</span></a> were enrolled as cases&#44; while 20 healthy adult participants without any evidence of atopy were also enrolled as controls of the study&#46; All these cases had documents of presence of nasal polyps&#44; using patient examination or endoscopic evaluations&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Cases with incomplete medical records&#44; cystic fibrosis and who received antibiotics or corticosteroids during last month prior to enrolment&#44; or who were treated with specific immunotherapy &#40;SIT&#41; were excluded from the study&#46; Controls of this study were free of any systemic disease&#44; allergic symptoms&#44; atopy or any category of rhinitis at time of enrolment&#46; Indeed&#44; controls were subjects without CRS&#44; without NP and without evidence of atopy&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Data acquisition</span><p id="par0030" class="elsevierStylePara elsevierViewall">A detailed history was taken from all the participants&#44; including recurrent sneezing&#44; runny nose&#44; nasal congestion&#44; symptoms indicative of conjunctivitis&#44; reduced sense of smell&#44; facial pain or pressure&#46; Other allergic conditions such as atopic dermatitis&#44; food allergy&#44; drug allergy&#44; aspirin intolerance and angio-oedema were also investigated and recorded&#46; Onset of appearance of symptoms and time of diagnosis of CRSwNP were determined by asking the patients and extracting from medical records&#46; Patient examination was done by expert physicians and the findings were recorded&#46; Presence of asthma was considered according to patients&#8217; symptoms and pulmonary function test &#40;PFT&#41;&#44; based on standard guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> If peak expiratory flow increased more than 12&#37; following salbutamol administration&#44; airway hyper-responsiveness was confirmed&#46; To investigate the presence of atopy&#44; skin prick test &#40;SPT&#41; was performed for all the participants with histamine &#40;positive control&#41; and normal saline dilution &#40;negative control&#41;&#46; The results were read after 20<span class="elsevierStyleHsp" style=""></span>min and a diameter more than 3<span class="elsevierStyleHsp" style=""></span>mm with respect to the negative control was considered as positive test&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Nasal smear cytology</span><p id="par0035" class="elsevierStylePara elsevierViewall">Nasal secretions of patients with CRSwNP were collected&#44; using an appropriate swab&#46; Afterward&#44; specimens were stained by Haematoxylin &#38; Eosin and a blinded pathologist reviewed the results&#44; using a light microscope&#46; A total of 10 fields of high power field &#40;HPF&#41; of microscope were investigated for infiltrated leukocytes and proportion of eosinophils to all inflammatory cells and proportion of neutrophils to all inflammatory cells were calculated&#46; With respect to these two proportions predominance pattern of inflammation was determined&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Assessment of total IgE and cytokines</span><p id="par0040" class="elsevierStylePara elsevierViewall">The sera from all the patients with CRSwNP were collected after centrifuging the clotted blood&#44; which were kept at &#8722;20<span class="elsevierStyleHsp" style=""></span>&#176;C until the time of assays&#46; Total IgE levels were determined&#44; using spectrophotometry according to international standards&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> IL-13&#44; IL-4&#44; and IFN-&#947; were assessed&#44; using enzyme-linked immunosorbent assay &#40;ELISA&#44; Bender MED and Bioscience&#41;&#46; All the procedures were done according to the manufacturer&#39;s recommendations&#46; Levels of IgE&#44; IL-13&#44; IL-4&#44; and IFN-&#947; were expressed as international units per millilitre &#40;IU&#47;mL&#41; and picogeram per millilitre &#40;pg&#47;ml&#41;&#44; respectively&#46; The protocols employed to determine the levels of IgE and IL-13&#44; IL-4&#44; and IFN-&#947; were sensitive to detect minimum levels of 1<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#44; 0&#46;1<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; 0&#46;06<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; and 0&#46;9<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; respectively&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Statistical analysis was carried out using SPSS &#40;Statistical Package for the Social Sciences&#44; version 16&#46;0&#44; SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46; Student <span class="elsevierStyleItalic">t</span> test was used to compare the serum levels of interleukins between patients with CRSwNP and controls&#46; ANOVA was employed to compare cytokine levels among different atopic patterns of patients with CRSwNP&#46; The reference value for comparison of total serum IgE with normal population was derived from a study by Carosso et al&#46; as follows percent of females in case arm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>148<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>percent male patients with CRSwNP<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>169&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Afterwards&#44; one sample t test was performed to compare the mean of total IgE in patients with CRSwNP with the calculated reference value for normal population with a similar gender distribution&#46; Pearson correlation coefficient was used to assess the correlation between cytokine levels and symptoms&#46; Data were expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#46; All the tests were two sided with the significance level at probability below 0&#46;05&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Demographics</span><p id="par0050" class="elsevierStylePara elsevierViewall">A total of 80 participants &#40;60 cases and 20 controls&#41; with mean age of 37&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;7 &#40;ranging from 18 to 70&#41; years were enrolled&#46; There were no differences between case and control groups with respect to the age &#40;37&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;0 <span class="elsevierStyleItalic">vs&#46;</span> 39&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;1&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;572&#41; and gender distribution &#40;female&#47;male&#59; 38&#47;22 <span class="elsevierStyleItalic">vs&#46;</span> 12&#47;8&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;790&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Cytokine profile of patients with CRSwNP versus controls</span><p id="par0055" class="elsevierStylePara elsevierViewall">Serum level of IL-13 in the patients with CRSwNP was significantly higher than the controls &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#44; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; However&#44; serum level of IL-4 did not differ &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;665&#44; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41; between the two groups&#46; On the other hand&#44; the serum level of IFN-&#947; was higher in non-atopic controls than the patients with CRSwNP&#44; but this difference was not significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;230&#44; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Cytokine profile of patients with CRSwNP with or without atopy</span><p id="par0060" class="elsevierStylePara elsevierViewall">SPT revealed that 22&#47;60 &#40;36&#46;7&#37;&#41; were not sensitised&#44; while 15&#47;60 &#40;25&#37;&#41; were monosensitised and 23&#47;60 &#40;38&#46;3&#37;&#41; were polysensitised&#46; Neither IL-13&#47;IL-4 nor IFN-&#947; differed significantly among these subgroups of patients with CRSwNP &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Nasal smear cytology and IgE</span><p id="par0065" class="elsevierStylePara elsevierViewall">Predominant pattern of infiltration was eosinophilia in 20&#47;60 &#40;33&#46;3&#37;&#41; and neutrophilia in 40&#47;60 &#40;66&#46;7&#37;&#41;&#46; Mean level of serum IgE was 301&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>516&#46;5<span class="elsevierStyleHsp" style=""></span>IU&#47;mL with significant difference than the value &#40;155&#46;7&#41; for normal population &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;033&#41;&#46; Additionally&#44; serum level of IgE was significantly correlated with IL-13 and IFN-&#947;&#44; but not with IL-4 &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; In patients with CRSwNP and predominant neutrophilia&#44; the percentage of inflammatory cells in nasal secretions was significantly correlated with serum level of IL-4 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Asthma&#44; ASA intolerance</span><p id="par0070" class="elsevierStylePara elsevierViewall">Of the patients with CRSwNP&#44; 12&#47;60 &#40;20&#37;&#41; had ASA intolerance and 44&#47;60 &#40;73&#46;3&#37;&#41; had asthma&#46; From measured cytokines&#44; none were differed significantly between asthmatics and who were free of asthma&#44; while&#44; IFN-&#947; was significantly higher in those with ASA intolerance &#40;4&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;4<span class="elsevierStyleHsp" style=""></span>pg&#47;mL <span class="elsevierStyleItalic">vs&#46;</span> 4&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;022&#41;&#46; IgE was significantly higher in asthmatics &#40;364&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>586&#46;6<span class="elsevierStyleHsp" style=""></span>pg&#47;mL <span class="elsevierStyleItalic">vs&#46;</span> 126&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>135&#46;7<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;015&#41;&#44; but not in patients with ASA intolerance&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">This study revealed that patients with CRSwNP had higher levels of IL-13 in their sera compared to healthy controls&#46; Interleukin-13 is believed to play a central role in orchestrating the airway inflammation more clearly in asthma<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and with a lesser extent in upper airway inflammation such as CRSwNP&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Interleukin-13 is implicated in the production of IgE that binds to mast cells&#44; basophils and inflammatory cells in exposed sites to aeroallergens like upper airways&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Subsequent re-exposures will trigger inflammation and warrants its persistence to a chronic disease&#46; We found patients with CRSwNP had higher serum level of IgE than that for the normal population corrected with respect to the age and gender&#46; Interestingly&#44; despite a decrease in levels of IFN-&#947;&#44; it was still directly correlated with IgE levels&#46; It could be justified with respect to the fact that whenever a balance is lost&#44; the protective processes try to compensate it&#46; Additionally&#44; IFN-&#947; is increased in viral infections&#44; and infections will be increased in patients with CRSwNP due to the abnormal anatomy of upper respiratory tract&#44; hence levels of IFN-&#947; as important TH-1 cytokine would be correlated with IgE as a hallmark of atopic symptoms and changes&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Furthermore&#44; SPT revealed sensitisation in 63&#46;3&#37; of our participants&#44; which is considerable&#46; Despite the predisposing effect of TH-2 cytokines such as interleukin-13 on atopy&#44; we did not find any significant difference in serum cytokine levels of atopic versus non-atopic patients with CRSwNP&#46; Scavuzzo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> found no difference in IL-2&#47;4&#47;6 and IFN-&#947; of nasal mucus of patients with CRSwNP with or without atopy&#59; that was similar to our findings in that there was no significant difference in serum level of IL-4&#47;13 and IFN-&#947; among patients with different atopic status&#46; Prevalence of atopy may be even higher in patients with CRSwNP as Tan et al&#46; showed that in patients with CRSwNP who failed medical treatment&#44; 85&#46;5&#37; had positive skin reaction to at least one allergen&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> The message would be the importance of immunomodulator therapies in refractory subjects to conventional treatments and necessitates deeper insight to the immune imbalance present in patients with CRSwNP&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">More than IgE production and promotion of atopy&#44; epithelial cell hypertrophy&#44; goblet cell hyperplasia&#44; mucus hyper-secretion&#44; sub-epithelial fibrosis&#44; eosinophilia&#44; oedema and airway hyper-responsiveness&#59; all were reported as subsequent changes that IL-13 promotes&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> However&#44; all aforementioned changes are not seen in patients with CRSwNP due to interaction of other cytokines&#46; In CRSwNP patients free of asthma&#44; lower concentrations of transforming growth factor beta &#40;TGF-&#946;&#41; leads to suppression of fibroblast proliferation and sub-epithelial collagen deposition&#44; while in CRSsNP it is higher&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Despite the significantly elevated levels of IL-13&#44; we found predominant pattern of neutrophilia instead of eosinophilia in nasal specimens from patients with CRSwNP&#46; This is interesting while IL-13 strongly supports the survival and activation of eosinophils and eosinophilia via induction of eotaxin production&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> Increased level of other cytokines such as IL-17 family could be assumed as the cause&#44; but our study is limited to show it&#46; Jiang et al&#46; demonstrated that IL-17 is implicated in nasal polyp formation either in neutrophilic or eosinophilic CRSwNP but with a pronounced role in triggering the neutrophilic inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> An undetected imbalance in favour of cytokines promoting neutrophilia is supposed in the present study&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">On the other hand&#44; neutrophilic rather than eosinophilic inflammation could be due to polymorphisms of IL-13 or its receptors in Asian participants&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> In recent years&#44; studies on Chinese adult population with CRSwNP demonstrated a pronounced neutrophilia rather eosinophilia&#46; Cao et al&#46; studied 151 patients with CRSwNP compared to 94 subjects with CRSsNP and 50 healthy controls&#46; They found that TGF-&#946; decreased and TH-1&#47;2 and 17 all were increased in patients with CRS whether NP was present or absent&#46; In their experience&#44; TH-17 responses were higher in non-eosinophilic CRSwNP while eosinophilic CRSwNP showed skewed TH-2 response and CRSsNP was predominantly biased towards TH-1 cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Zhang et al&#46; investigated the cytokine profile of patients with CRSwNP in samples from both European and Asian people&#46; Asian participants had neutrophilic inflammation with TH-1&#47;TH-17 skewed response whereas Europeans had classic eosinophilic pattern with TH-2 biased response&#46; Regulatory cytokines like TGF-&#946; were significantly lesser in CRSwNP than controls&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> Whether the patients with CRSwNP are Asian or Europeans&#44; regulatory cytokines will decrease significantly&#44; approved by low levels of forkhead box protein 3 and others contributing to the remodelling process like TGF-&#946; are highly preserved in such a way that significant local reduced level of TGF-&#946; can discriminate CRSwNP from CRSsNP&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> The TH-17 family may be the key in elucidating the different inflammation pattern in nasal polyps of Asian and European patients and could be the target of future studies&#46; However neutrophilia was predominant in our experience&#44; participants had classic cytokine profile of TH-2 skewed response with increased amount of IL-13 and IL-4 and decrease in IFN-&#947; in comparison with controls&#46; Additionally&#44; we observed a weak&#44; but significant correlation between IL-4 levels and amount of inflammatory cells in nasal lavage of patients with neutrophilic CRSwNP due to unknown reason&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Another question sought to be answered was whether cytokine levels have any association with the coexistence of lower respiratory involvement or other coexisting allergic conditions&#46; In the current study&#44; the presence of lower airway inflammation in asthmatics did not lead to higher serum levels of neither IL-13 nor IL-4 and IFN-&#947;&#44; but IgE level was significantly higher in patients with CRSwNP that concomitantly suffered from asthma&#46; This finding might be due to the locally increased levels of TH-2 cytokines like IL-13 or up-regulation of the receptors of IL-13 in effector cells of asthmatics&#46; Moreover&#44; other cytokines that were not measured here might be responsible for significant higher levels of immunoglobulin-E in non-significant elevation of IL-13&#46; This is in agreement with the fact that immunoglobulin-E mediated sensitivity to aeroallergens is associated with asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> The question remained to be answered is that whether in patients with CRSwNP who have concomitantly asthma&#44; local level of cytokines differs from who are free of asthma or not&#63; This idea arises from the concept of unified airway that justifies the coexistence of inflammation in both of upper and lower airways&#46; It is interesting that there are observations that even surgical treatment of nasal polyps helps improvement of asthma but should be validated by strong methodological studies&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Aspirin-exacerbated respiratory disease is defined by CRSwNP&#44; asthma and aspirin hyper-sensitivity and was found to be 20&#37; in this study&#46; However&#44; it is not common in a general population with maximum prevalence of 2&#46;5&#37; conferring the eight-fold risk of ASA intolerance in patients with CRSwNP&#46; ASA intolerance jeopardises the course of CRSwNP with inappropriate response to conventional treatments but the knowledge regarding the underlying pathology is still unknown&#46; Here&#44; CRSwNP patients with ASA intolerance differed with others only with respect to the higher levels of interferon-y&#46; Shome et al&#46; studied only one case with ASA intolerance and found high expression of IFN-&#947; the expression of which increased by CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T cells and decreased by CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells following aspirin desensitisation&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Further studies on the cytokine profile of patients with Aspirin-exacerbated respiratory disease are still awaited&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">One limitation of this study was its low power&#44; which could be responsible for not detecting significant differences between patients and controls&#46; In addition&#44; serum level of cytokines may be affected by the level of other substances and blood carrier proteins and it may interrupt our results&#46; On the other hand some cytokines may only be detectable locally&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion&#44; IL-13 with high level of total IgE observed in patients with CRSwNP predisposes them to have concomitant asthma&#46; IFN-&#947; was down-regulated in patients with CRSwNP as compared to controls but in the presence of ASA intolerance it would be over-expressed&#46; In agreement with the studies on Asians&#44; we found that the fruit of this imbalance was neutrophilia rather than eosinophilia that confers the implication of macrolide antibiotics in medical therapy&#46; Macrolides reduce neutrophilia via inhibition of chemokine and adhesive molecule synthesis&#46; Polymorphisms in cytokines and their receptors in addition to ethnic issues can be responsible for this observation&#46; In neutrophilic CRSwNP&#44; the amount of infiltrating inflammatory cells in nasal lavage is weak but significantly correlates with IL-4&#46; Despite all efforts to elucidate changes in cytokine profile of patients with CRSwNP many questions still remain unanswered&#46; Further studies with stronger methodologies are awaited to elucidate the cytokine profile changes of patients with CRSwNP and its effect on the course of disease&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethical disclosures</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Protection of human subjects and animals in research</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Patients&#8217; data protection</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Right to privacy and informed consent</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors have obtained the informed consent of the patients and&#47;or subjects mentioned in the article&#46; The author for correspondence is in possession of this document&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:2 [
          "identificador" => "xres368097"
          "titulo" => array:5 [
            0 => "Abstract"
            1 => "Background"
            2 => "Methods"
            3 => "Results"
            4 => "Conclusions"
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        1 => array:2 [
          "identificador" => "xpalclavsec347273"
          "titulo" => "Keywords"
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        2 => array:2 [
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          "titulo" => "Introduction"
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        3 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Materials and methods"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Study population"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Data acquisition"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Nasal smear cytology"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Assessment of total IgE and cytokines"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Statistical analysis"
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          ]
        ]
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          "identificador" => "sec0040"
          "titulo" => "Results"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Demographics"
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            1 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Cytokine profile of patients with CRSwNP versus controls"
            ]
            2 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Cytokine profile of patients with CRSwNP with or without atopy"
            ]
            3 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Nasal smear cytology and IgE"
            ]
            4 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Asthma&#44; ASA intolerance"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Discussion"
        ]
        6 => array:3 [
          "identificador" => "sec0075"
          "titulo" => "Ethical disclosures"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Protection of human subjects and animals in research"
            ]
            1 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Patients&#8217; data protection"
            ]
            2 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Right to privacy and informed consent"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Conflict of interest"
        ]
        8 => array:2 [
          "identificador" => "xack92172"
          "titulo" => "Acknowledgments"
        ]
        9 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-03-11"
    "fechaAceptado" => "2013-06-10"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec347273"
          "palabras" => array:4 [
            0 => "Chronic rhinosinusitis"
            1 => "Interleukin"
            2 => "Nasal polyps"
            3 => "Asthma"
          ]
        ]
      ]
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    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">This study was performed to investigate the serum level of interleukin &#40;IL&#41;-13&#44; IL-4&#44; and interferon &#40;IFN&#41;-&#947; in chronic rhinosinusitis with nasal polyps &#40;CRSwNP&#41; and subsequent inflammation pattern and comorbidities including asthma and aspirin intolerance&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A case&#8211;control study was conducted on 60 adult patients with CRSwNP with mean age of 37&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;7 &#40;ranging from 18 to 70&#41; years&#44; and on 20 healthy controls&#46; Serum levels of IL-13&#44; IL-4&#44; and IFN-&#947; were assessed&#44; using enzyme-linked immunosorbent assay to be compared between case and control groups&#46; Serum level of total immunoglobulin &#40;Ig&#41; E was also assessed in the patients with CRSwNP&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Serum level of IL-13 in the patients with CRSwNP was significantly higher than the controls &#40;0&#46;98<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;56 <span class="elsevierStyleItalic">vs&#46;</span> 0&#46;34<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;16 pg&#47;ml&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#46; IL-4 and IFN-&#947; did not differ significantly between the two groups&#46; Total IgE level was significantly increased in the patients with CRSwNP&#44; compared to the normal values &#40;301&#46;43<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>516&#46;54 IU&#47;ml&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;033&#41;&#46; Among the patients with CRSwNP&#44; 12&#47;60 &#40;20&#37;&#41; had aspirin intolerance and 44&#47;60 &#40;73&#46;3&#37;&#41; had asthma&#46; IgE was also higher in asthmatics than non-asthmatics patients &#40;364&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>586&#46;6 <span class="elsevierStyleItalic">vs&#46;</span> 126&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>135&#46;7&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;015&#41;&#46; Patients with aspirin intolerance had higher levels of IFN-&#947; &#40;4&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;4 <span class="elsevierStyleItalic">vs&#46;</span> 4&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;022&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">IL-13 with high level of total IgE was observed in the patients with CRSwNP&#44; which predisposes them to have concomitant asthma&#46; IFN-&#947; seems to be down-regulated in the patients with CRSwNP&#44; but could be over-expressed in the presence of aspirin intolerance&#46;</p>"
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        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; IL-13 was significantly higher in patients with CRSwNP &#40;0&#46;98<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;56<span class="elsevierStyleHsp" style=""></span>pg&#47;mL vs&#46; 0&#46;34<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;16<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#44; &#40;B&#41; IL-4 was higher in patients with CRSwNP&#44; but did not attain significance &#40;0&#46;12<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;60<span class="elsevierStyleHsp" style=""></span>pg&#47;mL vs&#46; 0&#46;06<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;24<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;665&#41;&#44; &#40;C&#41; IFN-&#947; was non-significantly higher in controls &#40;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;78<span class="elsevierStyleHsp" style=""></span>pg&#47;mL vs&#46; 4&#46;62<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;62<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;230&#41;&#46;</p>"
        ]
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        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">There were no significant differences between atopic &#40;monosensitized or polysensitized&#41; and non-atopic patients with CRSwNP in terms of &#40;A&#41; IL-13&#44; &#40;B&#41; IL-4 and &#40;C&#41; IFN-&#947;&#46;</p>"
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        "identificador" => "fig0015"
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Serum level of IgE was significantly correlated with serum IL-13 &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;291&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;024&#41; and serum IFN-&#947; &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;293&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;023&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Correlations that attain significance have been marked as &#42;&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t">Serum level&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Predominant eosinophilia</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Predominant neutrophilia</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Total</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Eosinophilia &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Neutrophilia &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Eosinophilia &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Neutrophilia &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Eosinophilia &#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Neutrophilia &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">IL-13&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;205&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;084&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;032&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;151&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;178&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2013.06.007

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	6	1	7
2024 October	38	14	52
2024 September	26	17	43
2024 August	27	12	39
2024 July	19	5	24
2024 June	25	7	32
2024 May	14	12	26
2024 April	17	14	31
2024 March	38	6	44
2024 February	31	16	47
2024 January	26	18	44
2023 December	30	10	40
2023 November	41	11	52
2023 October	50	22	72
2023 September	36	11	47
2023 August	30	5	35
2023 July	21	11	32
2023 June	41	8	49
2023 May	54	5	59
2023 April	38	2	40
2023 March	42	5	47
2023 February	30	2	32
2023 January	17	8	25
2022 December	26	3	29
2022 November	15	3	18
2022 October	15	11	26
2022 September	37	25	62
2022 August	21	10	31
2022 July	33	7	40
2022 June	33	7	40
2022 May	48	9	57
2022 April	26	13	39
2022 March	52	10	62
2022 February	40	14	54
2022 January	31	7	38
2021 December	33	20	53
2021 November	62	17	79
2021 October	35	22	57
2021 September	29	13	42
2021 August	52	18	70
2021 July	27	12	39
2021 June	23	11	34
2021 May	28	10	38
2021 April	59	16	75
2021 March	20	14	34
2021 February	22	15	37
2021 January	11	11	22
2020 December	1	1	2
2020 November	0	2	2
2020 September	0	2	2
2020 July	0	1	1
2020 May	0	1	1
2020 February	0	1	1
2019 October	0	1	1
2019 September	0	1	1
2019 August	0	4	4
2019 July	0	5	5
2019 June	0	6	6
2019 May	0	19	19
2018 February	5	2	7
2018 January	9	6	15
2017 December	5	4	9
2017 November	9	1	10
2017 October	10	1	11
2017 September	11	3	14
2017 August	14	9	23
2017 July	13	6	19
2017 June	10	2	12
2017 May	19	7	26
2017 April	12	3	15
2017 March	20	32	52
2017 February	23	5	28
2017 January	14	5	19
2016 December	14	5	19
2016 November	10	2	12
2016 October	35	10	45
2016 September	16	8	24
2016 August	26	6	32
2016 July	14	4	18
2016 June	29	16	45
2016 May	10	22	32
2016 April	12	15	27
2016 March	13	10	23
2016 February	10	10	20
2016 January	11	10	21
2015 December	15	17	32
2015 November	18	11	29
2015 October	25	6	31
2015 September	11	7	18
2015 June	0	1	1
2015 May	1	5	6
2015 April	0	2	2
2015 March	1	1	2
2014 December	1	1	2
2014 November	0	6	6
2014 October	0	5	5
2014 September	1	5	6

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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