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Active smoking effect in allergic rhinitis

Open AccessPublished:January 17, 2021DOI:https://doi.org/10.1016/j.waojou.2020.100504

      Abstract

      Background

      Tobacco smoke has been described as causing increased prevalence of rhinitis symptoms and decreased atopy. Furthermore, these nasal symptoms and quality of life in smokers with Allergic Rhinitis (AR) were not significantly different to non-smokers. As a result of this duality, a comparison study between the quality of life and inflammatory markers of atopy among active smokers and non-smokers having AR was put forward.

      Material and methods

      Cross-sectional study in adult smokers and non-smokers, with a clinical diagnosis of AR and positive Skin Prick Test (SPT). Smoking status was confirmed by salivary cotinine measurements. Functional respiratory evaluation was performed, and quality of life between groups was compared using Mini-RQLQ questionnaire. Immunological markers in serum and nasal washes (IgE, IL-4, IL 5, IL 13, IL 17, IL 33) were evaluated, while samples from a third group of passive smokers was incorporated for serological comparison exclusively. The statistical analysis included Student T test, x2, Mann Whitney U (Anova 2-way), and Kruskal Wallis for 3 groups analysis. Values of P < 0.05 were considered significant.

      Results

      Twenty-two patients per group with similar demographics and allergen sensitivity were studied. Regarding inflammatory markers, a reduction of IL 33 in the serum of smokers (P < 0.001) was the only statistically significant different parameter revealed, showing a remarkable trend in nasal lavage. Salivary cotinine levels were absolutely different (P < 0.0001), but pulmonary function evaluations were not statistically significant after multiple adjusting. There were no significant differences in quality of life parameters.

      Conclusions

      In our study of AR, active smokers do not demonstrate impaired nasal related quality of life or impact on atopic inflammatory parameters, compared to non-smokers. Reduced levels of IL33 could explain a lack of symptoms alerting smokers of the harmful consequences of smoking.

      Keywords

      Background

      Allergic Rhinitis (AR) is a chronic disease of the upper airways, being the most prevalent allergic disease globally. The affected population varies by region from 12% to 40%, with rates close to 20% in our country.
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      Were these findings replicated in humans, it would suggest that smokers would show less allergy compared to non-smokers. A diminished prevalence of allergic sensitization was reported in a group of either second-hand or active smokers,
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      • Baena-Cagnani C.E.
      Adolescent smokers are at greater risk for current asthma and rhinitis.
      With the conflicting evidence currently available, we investigated the real-life effect of tobacco use in AR patients with objective evaluations of immuno-inflammatory parameters, lung function and quality of life.

      Material and methods

      Population-study

      A cross-sectional, comparative study of two groups of consecutive adult patients with clinical diagnosis of AR with positive SPT, case (Smokers) – control (Non-Smokers) 1:1.
      For serological evaluations only, a three-group comparison was performed between active smokers, passive smokers, and non-smokers. Passive smoker serum samples were obtained from a previously identified group of patients not having AR and being passive smokers, who had previously given consent for samples to be used in subsequent studies.
      Patients having at least 1 year of clinical history of AR, with no respiratory infection in previous month, were included. Patients with diagnosis of local AR, having received systemic steroids in last 6 months, allergen immunotherapy in previous 3 years, or anti-histamines in previous month were excluded. Participants' smoking status was based on self-report.
      • Connor Gorber S.
      • Schofield-Hurwitz S.
      • Hardt J.
      • Levasseur G.
      • Tremblay M.
      The accuracy of self-reported smoking: a systematic review of the relationship between self-reported and cotinine-assessed smoking status.
      Prior to any procedure, informed consent was obtained from each participant. The research study was approved by a local Ethics Committee where evaluations were carried out.

      Evaluations performed

      Demographic data of age and sex, weight and height

      Self-reported cigarette consumption was determined by packages per year.

      Saliva sample for cotinine quantification
      • Langone J.J.
      • Cook G.
      • Biercke R.J.
      • Lifschitz M.H.
      Monoclonal antibody ELISA for cotinine in saliva and urine of active and passive smokers.
      ,
      • van Vunakis H.
      • Tashkin D.P.
      • Rigas B.
      • Simmons M.
      • Gjika H.B.
      • Clark V.A.
      Relative sensitivity and specificity of salivary and serum cotinine in identifying tobacco-smoking status of self-reported nonsmokers and smokers of tobacco and/or marijuana.

      Taken spontaneously with disposable Pasteur plastic pipettes from the sublingual area 5 ml, with minimum requirements of the patient not having consumed drinks or meals for at least the previous 1 h before sampling, without rinsing or restricting previous smoking. Stored in Eppendorf tubes in refrigeration 0–2 °C, on average 1 h, prior to storage at −20 °C until analysis, using Elisa technique for cotinine determinations following strict supplier indications (www.salimetrics.com).

      Nasal lavage

      Technique reported by Bouloukaki and collaborators
      • Bouloukaki I.
      • Tsiligianni I.G.
      • Tsoumakidou M.
      • et al.
      Sputum and nasal lavage lung-specific biomarkers before and after smoking cessation.
      was followed to obtain the samples, with minimal modifications. The patients, in a sitting position, were instructed to flex the neck approximately 60° from the top, and not to breathe through the nose but through the mouth during the procedure. 5 ml of normal saline solution was applied at room temperature, gently instilled in each nostril using a disposable Pasteur pipette, with waiting time of about 5 s and a gentle massage to allow impregnation in the nostril. Next, the wash fluid was collected by repeated aspiration from both nasal cavities, using the same pipette, and placed in Eppendorf tubes. It was kept under refrigeration 0–2 °C for 1 h on average, prior to storage at −20 °C until analysis of IgE and cytokines.

      Venous blood sample

      Immediately after obtaining the above samples from each participant; centrifugation and serum collection were performed, and stored at −20 °C until analysis of IgE and cytokines could be performed. The third group of serum samples belonged to 13 well identified passive smokers having no personal background or current signs of any atopic disease, who had participated in an unrelated study (Chagas’ positive) and whose samples were ready to be discarded, with their previous consent for additional evaluations to their original purpose.
      • Gómez R.M.
      • Sánchez Negrette O.
      Presence of atopic diseases in Chagas' infected children.

      Functional respiratory tests

      Performed with a MIR Spirobank II spirometer with calibrated disposable turbine for the evaluation of all patients, with additional calibration control with a 3-l syringe. Measurements were made following American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations,
      • Miller M.R.
      • Crapo R.
      • Hankinson J.
      • et al.
      ATS/ERS Task Force
      General considerations for lung function testing.
      avoiding smoking in previous hour (smokers). The 3 best reproducible maneuvers were selected, and the best values of FEV1, FVC, and FEV1/FVC% were taken for analysis.

      Sensitivity to inhalant allergens by SPT

      Assessed according to References.
      • Bousquet J.
      • Heinzerling L.
      • Bachert C.
      • et al.
      Practical guide to skin prick tests in allergy to aeroallergens.
      ,
      • Carr T.F.
      • Saltoun C.A.
      Chapter 2: skin testing in allergy.
      The sum of maximum and perpendicular diameters divided by 2 from the papules, resulting equal to or greater than 3 mm compared to the negative control were considered positive.
      Allergens used were: Dermatophagoides pteronyssinusDermatophagoides farinae, Blomia tropicalis, Dog epithelium, Cat epithelium, Cockroach mix, Grass mix, Weeds mix, Trees mix, Alternaria sp, Aspergillus sp; glycerinated negative control and 10 mg/ml histamine positive control from Greer Labs through a local vendor. Lancets used were disposable metal tips 1 mm ALK type, also from local vendor.
      In order to be considered atopic for inclusion, the patient had to demonstrate a positive test to at least 1 of the allergens listed, plus the positive histamine control.

      Total IgE and cytokines

      Levels of total IgE (kU/L) and IL 4, IL 5, IL 13, IL 17, and IL 33 (pg/ml) were obtained by Elisa strictly following instructions from provider (Peprotech USA, www.peprotech.com). All techniques were standardized accordingly.

      Quality of life evaluation (Mini RQLQ)

      Permission was obtained to use the abbreviated (and Spanish validated) Juniper's questionnaire, being more efficient for cross-sectional studies,
      • Juniper E.F.
      • Thompson A.K.
      • Ferrie P.J.
      • Roberts J.N.
      Development and validation of the mini rhinoconjunctivitis quality of life questionnaire.
      wich was self administered.

      Statistical analysis

      The calculation of sample size considered total population of city, with a prevalence of AR of 17% (16.9% of allergic rhinoconjunctivitis reported in Ait-Khaled et al
      • Ait-Khaled N.
      • Pearce N.
      • Anderson H.R.
      • Ellwood P.
      • Montefort S.
      • Shah J.
      the ISAAC Phase Three Study Group
      Global map of the prevalence of symptoms of rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC) phase three.
      ) and 25% of them as smokers, resulting in a 1:1 comparison in 20 patients per group.
      Average and Confidence Interval 95% plus Standard Deviation were obtained in the results with homogeneous samples without dispersion, and Median in the evaluations with evident dispersion or low level of detection.
      Statistical analysis for continuous variables was performed with Anova and Student's T-Test for homogeneous unpaired data, and Mann Whitney U for non-parametric samples due to the heterogeneity of the variances, plus Anova 2-way.
      • Fay M.P.
      • Proschan M.A.
      Wilcoxon-Mann-Whitney or t-test? On assumptions for hypothesis tests and multiple interpretations of decision rules.
      Also Chi square was applied for comparison of proportions.
      For the evaluation of serum samples from 3 groups, Kruskal Wallis (including Dunn's post test) was used.
      All results with P < 0.05 were accepted as significant.

      Results

      Among the 49 patients invited to participate, 5 patients declined (3 smokers and 2 non-smokers), with 89.8% participation rate from patients meeting the necessary criteria. Thus, 44 patients were included in all, 22 smokers (case) and 22 non-smokers (control). Table 1.
      Table 1Comparative demographic data.
      Patients having ARSmokers (n = 22)Non Smokers (n = 22)Statistical difference (P)
      Median age in years ± SD37.3 ± 14.330.4 ± 10.1P = 0.097 (NS)
      Mann Whitney T test.
      Female sex, in % ± SD63.63 ± 0.3659.09 ± 0.50P = 0.789 (NS)
      Chi-square.
      BMI kg/m2, mean ± SD25,53 ± 5,3924,45 ± 4,38P = 0.482 (NS)
      Anova
      Pack/years, mean ± SD12,85 ± 10,23
      Cotinine in Saliva, in ng/ml. Mean ± SD340,59 ± 216,892,2 ± 3,35P = 0.0001
      Mann Whitney T test.
      Asthma Diagnosis, in % ± 95% CI9,09 (2,5–27,8)4,54 (0,8–21,8)P = 0.554 (NS)
      Chi-square.
      COPD Diagnosis, in % ± 95% CI9,09 (2,5–27,8)0 (0–14,9)P = 0.152 (NS)
      Chi-square.
      Sensitivity to mites, in % ± 95% CI59,1 (38,7–76,7)77,3 (56,6–89,9)P = 0.200 (NS)
      Chi-square.
      Sensitivity to pollens, in % ± 95% CI36,4 (19,7–57)13,6 (4,7–33,3)P = 0.084 (NS)
      Chi-square.
      Sensitivity to pets, in % ± 95% CI31,8 (16,4–52,7)36,4 (19,7–57)P = 0.750 (NS)
      Chi-square.
      Sensitivity to molds, in % ± 95% CI0 (0–14,9)4,54 (0,8–21,8)P = 0.317 (NS)
      Chi-square.
      FEV1% predicted, mean ± SD95 ± 16,63100 ± 13,12P = 0.284 (NS)
      Anova
      FEV1/FVC %, mean ± SD81,53 ± 7,6785,76 ± 6,52P = 0.060 (NS)
      Anova
      Mini RQLQ scores, mean ± SD3,39 ± 1,013,71 ± 0,75P = 0.250 (NS)
      Mann Whitney T test.
      P<0.05 is considered statistically significant.
      a Mann Whitney T test.
      b Chi-square.
      c Anova
      There were no serious events associated with procedures performed. Local, mild, and self-limited symptoms in minutes (without the need for any treatment) were experienced in 6 samples of nasal washes (pruritus), 4 skin tests with allergens (pruritus), and 3 venous punctures for blood collection (pain).
      There were no differences between groups in sensitivity to allergens (Table 1). More than half were mono-sensitized (n = 28); from these only 5 did not test positive to mites (2 to cat epithelium, 1 to dog epithelium, 1 to grass pool and 1 to Alternaria sp).
      In the Non-smoking group there was 1 case with intermittent asthma as co-morbidity; in the Smoking group there were 2 cases of asthma and 2 cases with a diagnosis of COPD (Chronic Obstructive Pulmonary Disease). Table 1. No one received neither systemic steroids according to exclusion criteria nor inhaled cortico-steroids at the time of evaluation; the use of SABA on demand was permitted. No other active and treatment co-morbidities were registered at the time of the study.
      Initial pulmonary function analysis, demonstrated statistically significant differences in FEV1% and FEV1/FVC% correlation. However, when excluding the 2 patients with previous COPD diagnosis and adjusting for age-sex and BMI, these became non-significant. Table 1.
      The impact of these results on quality of life parameters, measured by Mini RQLQ, showed no statistically significant differences in the comparison between patients with smoking and non-smoking AR. Table 1.
      One patient from the Smoking group refused to undergo blood sampling. Thus, 21 serum samples were available from this group for all evaluations.
      From serum samples, we obtained isolated positive results in the determinations of IL 4 (just one) and IL 5 (one detectable), and only 3 for IL17 in serum. The determinations of IL 5 and IL 13 were negative in all cases of Nasal Wash and only one detected for IL 4, even having been tested twice for this reason.
      The cytokines most commonly identified besides IgE were IL 33 in serum and nasal lavage, and IL17 in nasal lavage. Statistical significant differences on systemic IL 33 levels are displayed in Fig. 1.
      Fig. 1
      Fig. 1Serum IL 33 levels in Allergic Rhinitis’ patients Smokers and Non Smokers, plus a third Control group of Non Atopic, Passive Smokers (in pg/ml). For the present box plot, one outlier result of over 1100 pg/ml was ommited. Mann Whitney T test grouped AR vs Controls p = 0.0028; AR Smk vs AR Non Smk p = 0.0236.
      Relevant results are displayed in Table 2, with 3 groups in serum evaluations and 2 (smokers and non smokers) for the remaining procedures. Significant high IL 13 in control group was found.
      Table 2Levels of IgE and cytokines on biological samples. For serological comparisons, a third group of non atopic, passive smokers is included.
      Allergic Rhinitis, Smokers (n = 21)
      Serological samples were obtained in 21 out of 22 Smoker AR patients, and nasal lavage and saliva in 22 of them.
      Allergic Rhinitis, Non Smokers (n = 22)Statistical difference (P)Non Atopic, Passive Smokers (n = 13)Statistical difference (P)
      Serum IgE, in kU/L mean ± SD203,94 ± 163,45150,92 ± 85,96P = 0.742
      Mann Whitney T test.
      215,77 ± 118,25P = 0.643
      Anova Kruskal Wallis.
      Nasal Lavage IgE, in kU/L. Mean ± SD2,94 ± 6,143,92 ± 7,29P = 0.088
      Mann Whitney T test.
      Not available.
      Serum IL 33, in pg/ml. Mean ± SD181,94 ± 137,25609,58 ± 1080,56P = 0.0028
      Mann Whitney T test.
      127,31 ± 113,99P = 0.0006
      Anova Kruskal Wallis.
      Nasal Lavage IL 33, in pg/ml. Mean ± SD16,18 ± 34,6221,67 ± 43,92P = 0.088
      Mann Whitney T test.
      NS
      Not available.
      Nasal Lavage IL 17, in pg/ml. Mean ± SD26,75 ± 26,2229,3 ± 97,16P = 0.455
      Mann Whitney T test.
      Not available.
      Serum IL 4, in pg/ml. Mean ± SD50,26 ± 25.8513.91 ± 12.24P = 0.396
      Mann Whitney T test.
      6.61 ± 0.41P = 0.481
      Anova Kruskal Wallis.
      Serum IL 13, in pg/ml. Mean ± SD22.19 ± 6.0616.543 ± 6.18P = 0.370
      Mann Whitney T test.
      41.46 ± 0.87P = 0.032
      Anova Kruskal Wallis.
      P<0.05 is considered statistically significant.
      NS Non-Significant.
      a Serological samples were obtained in 21 out of 22 Smoker AR patients, and nasal lavage and saliva in 22 of them.
      b Not available.
      c Anova Kruskal Wallis.
      d Mann Whitney T test.

      Discussion

      As described in the results, there were no differences between groups in terms of demographic parameters or allergen sensitivity. There were also no differences in serum or nasal lavage concerning IgE. The true value of IgE as a marker of atopy has been debated, but has been re-evaluated following a demonstration of the effectiveness of the Anti-IgE treatment Omalizumab.
      • Sarinho E.
      • Cruz A.A.
      Anti-IgE monoclonal antibody for the treatment of the asthma and other manifestations related to allergic diseases.
      ,
      • Baena-Cagnani C.E.
      • Gómez R.M.
      Current status of therapy with omalizumab in children.
      At the time of this report, no reference of IgE levels in Nasal Lavage from AR patients have been found. The mean nasal IgE levels (in our smoker and non smoker patientes) of 2,94 and 3,92 kU/L were not statistically different.
      With regards to smoking status, there was a significant difference found in salivary cotinine measurements, with almost no detectable values n non-smokers (Table 1). Statistically significant differences were initially found in pulmonary function comparison, but after multiple logistic regression excluding 2 patients having COPD, it became non-significant. However, this tendency should be strongly remarked, as an anticipation of the increased incidence of asthma in patients with AR who smoke, in a dose-dependent way.
      • Polosa R.
      • Knoke J.D.
      • Russo C.
      • et al.
      Cigarette smoking is associated with a greater risk of incident asthma in allergic rhinitis.
      We faced the inability to detect certain cytokines; postulated reasons are: a) serum and nasal washes obtained were analyzed without stimulation or culture; b) patients were not required to be symptomatic at the time of sampling; c) ability to detect very low concentrations of these cytokines was limited by the performance of the testing kits, such as our IL 5 set with lower limit of 46 pg/ml, while detection limits of 2 pg/ml were reported in atopic subjects.
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      ,
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      • Joseph M.
      Serum interleukin-5 levels are elevated in mild and moderate persistent asthma irrespective of regular inhaled glucocorticoid therapy.
      Despite this situation, it has been possible to obtain relevant findings, such as the case of IL 17 in nasal washes, an indicator of active inflammatory phenomenon, being described in different situations of AR at local level regarding symptoms and seasonality,
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      • et al.
      Serum interleukin-17 levels are related to clinical severity in allergic rhinitis.
      and in nasal biopsies of patients with asthma.
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      • et al.
      Nasal IL-17F is related to bronchial IL-17F/neutrophilia and exacerbations in stable atopic severe asthma.
      IL 13 could not be detected in nasal washes but was positive in serum samples with no differences between groups; this cytokine is synthesized by mast cells (and other cellular sources) and stimulates the production of type I collagen by airway fibroblasts in an MMP-2 and TGFβ1-dependent manner in asthma.
      • Firszt R.
      • Francisco D.
      • Church T.D.
      • Thomas J.M.
      • Ingram J.L.
      • Kraft M.
      Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-β1 in airway fibroblasts in asthma.
      In AR (our study population) the presence of mast cells and an increase in type I and III collagen have also been identified in nasal biopsies, but remodeling in nasal mucosa is limited while in asthma it is extensive.
      • Watelet J.B.
      • Van Zele T.
      • Gjomarkaj M.
      • et al.
      GA(2)LEN Workpackage Members 2.7
      Tissue remodelling in upper airways: where is the link with lower airway remodelling?.
      The most relevant finding of this work is evidenced by nasal and serum level of IL 33 in AR.
      • Rogala B.
      • Glück J.
      The role of interleukin-33 in rhinitis.
      Conflicting data on the correlation between serum and nasal levels have previously been reported, including being undetectable in serum but present in nasal specimens.
      • Scadding G.
      Cytokine profiles in allergic rhinitis.
      ,
      • Asaka D.
      • Yoshikawa M.
      • Nakayama T.
      • Yoshimura T.
      • Moriyama H.
      • Otori N.
      Elevated levels of interleukin-33 in the nasal secretions of patients with allergic rhinitis.
      Nevertheless, IL 33 in nasal secretions expresses an inflammation directed towards a Th2 profile, alongside with IL 25 and TSLP, being released by tissue damage induced by a pathogen, an irritant or by allergen exposure. A murine experimental study demonstrated the fundamental role of IL 33 in comparison with IL 25 for the induction of AR sensitized to dust mites.
      • Nakanishi W.
      • Yamaguchi S.
      • Matsuda A.
      • et al.
      IL-33, but not IL-25, is crucial for the development of house dust mite antigen-induced allergic rhinitis.
      This alarmin, IL 33, is a key factor to start defense mechanisms against infectious aggressors and allergens, in the epithelial - mesenchymal interaction, fundamentally collaborating with the IgE mediated phenomenon but also with the Th 17 inflammatory mechanism, also corroborated in our results.
      • Saluja R.
      • Khan M.
      • Church M.K.
      • Maurer M.
      The role of IL-33 and mast cells in allergy and inflammation.
      It has been previously reported that tobacco nicotine attenuates Th1 and Th17 responses, favoring a deviation towards Th2 in the neuro-inflammatory response.
      • Nizri E.
      • Ironytursinai M.
      • Lory O.
      • Orrurtreger A.
      • Lavi E.
      • Brenner T.
      Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses.
      Furthermore, acrolein might also provoke an immunosuppressive response, with the remarkable finding of regulatory T cells (Foxp3+, CD4+ CD25+) both in tissue and bronchoalveolar lavage.
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      • Bergmayr C.
      • Meitz S.
      • et al.
      Janus-faced acrolein prevents allergy but accelerates tumor growth by promoting immunoregulatory Foxp3+ cells: mouse model for passive respiratory exposure.
      Our evaluations found that tobacco causes a decrease in IL 33, necessary to initiate these natural defense mechanisms, and attenuates the IgE mediated mechanism. In an experimental murine model, tobacco smoke did not generate active secretion of IL 33, and even demonstrated a decrease in the expression of its ST2 receptor in ILC2 cells.
      • Kearley J.
      • Silver J.S.
      • Sanden C.
      • et al.
      Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.
      Amazingly, levels of serum IL33 on the third group of passive smokers were comparable to smokers (and also IgE); unfortunately we do not have quantification on the exposure load in this group. Their elevated mean level of IgE could be explained both by the passive exposure to tobacco
      • Ahmed N.J.
      • Husen A.Z.
      • Khoshnaw N.
      • et al.
      The effects of smoking on IgE, oxidative stress and haemoglobin concentration.
      and/or by Chagas’ infection condition.
      • Gómez R.M.
      • Sánchez Negrette O.
      Presence of atopic diseases in Chagas' infected children.
      ,
      • Georg I.
      • Hasslocher-Moreno A.M.
      • Xavier S.S.
      • Holanda M.T.
      • Roma E.H.
      • Bonecini-Almeida M.D.G.
      Evolution of anti-Trypanosoma cruzi antibody production in patients with chronic Chagas disease: correlation between antibody titers and development of cardiac disease severity.
      Also in the Chagas’ passive smoker group, significantly elevated IL 13 levels were found. Even sharing many biological activities with IL 4, this last one was not increased in the same way as the former, a dissociation that was precisely described over 2 decades ago.
      • Dutra W.O.
      • Gollob K.J.
      • Pinto-Dias J.C.
      • et al.
      Cytokine mRNA profile of peripheral blood mononuclear cells isolated from individuals with Trypanosoma cruzi chronic infection.
      In order to demonstrate the clinical relevance of inflammatory markers in real life and to quantify this impact, we searched for a validated instrument both in clinical research and in daily practice.
      • Juniper E.F.
      • Thompson A.K.
      • Ferrie P.J.
      • Roberts J.N.
      Development and validation of the mini rhinoconjunctivitis quality of life questionnaire.
      ,
      • Juniper E.F.
      • Thompson A.K.
      • Ferrie P.J.
      • Roberts J.N.
      Validation of the standardized version of the rhinoconjunctivitis quality of life questionnaire.
      The Mini RQLQ developed by Prof. E. Juniper was implemented (under authorization) and no statistical difference was found between smokers and non-smokers. Similar evidence and also reduced allergic symptoms on tobacco smoke exposed individuals was previously mentioned.

      Conclusions

      Our group of patients with AR who smoke do not show a worsening in their quality of life or an increase in measured inflammatory parameters. Both groups of patients showed evidence of allergic inflammation at the nasal level with the presence of IgE and IL 17. However, smokers evidenced a significant decrease of IL 33 systemically and a remarkable reduced tendency at local level.
      This reduction of the alarmin signalling fails to alert smokers of the damaging effects of smoking; thus patients are less likely to be persuaded to quit smoking, with subsequent increase in incident asthma and COPD.

      Abbreviations

      ALK: Company's brand name; AR: Allergic Rhinitis; ARC: Allergic Rhino-Conjunctivitis; ATS: American Thoracic Society; BMI: Body Mass Index; °C: Celsius centigrades; CD4: Cluster of Differentiation 4 (Lymphocyte); COPD: Chronic Obstructive Pulmonary Disease; ERS: European Respiratory Society; FEV1: Forced Expiratory Volume in 1 (first) second; FVC%: Forced Vital Capacity in average (%); IgE: Immunoglobulin E; IL: Interleukin; ILC2: Innate Lymphoid Cells – type 2; MIR: Spirometer brand's name; MMP-2: Matrix Metalloproteinase 2; P (as P-value): Probability of test result; Pg: picograms; RQLQ: Rhinitis’ Quality of Life Questionnaire; SABA: Short Acting Beta Agonist; SD: Standard Deviation; SPT: Skin Prick Test; ST2: IL33 receptor; TGFβ1: Transforming Growth Factor Beta 1; Th: T helper (Lymphocyte); TSLP: Thymic Stromal Lymphopoietin.

      Funded

      The present study was completely funded by Fundación Ayre.

      Consent for publication

      RM Gómez, VH Croce, ME Zernotti and JC Muiño give their consent for the publication of this work in the World Allergy Organization Journal.

      Author's contribution

      RMG contributed on the design of study, execution of protocol, interpretation of results, discussion and writing of manuscript.
      VHC contributed on evaluation of study's design, checking of protocol procedures, interpretation and discussion of results.
      MEZ contributed on evaluation of study's design, checking of protocol procedures, interpretation and discussion of results.
      JCM contributed on evaluation of study's design, statistical analysis of data, interpretation and discussion of results.

      Availability of data and materials

      All material used on study's procedures were obtained through Fundación Ayre specific and personal grant to RMG, except spirometer which belongs to RMG.

      Ethics approval

      The protocol for this study was approved by Bioethics Committee of the Medical Association of Salta (Argentina), where all subjects' procedures were performed.

      Declaration of competing interest

      RM Gómez, VH Croce, ME Zernotti and JC Muiño declare to have no conflict of interest regarding present study.

      Acknowledgements

      To Prof Carlos E. Baena-Cagnani (ARG) in memoriam, for his guidance in life and work.
      To Prof Dermot Ryan (UK), for his critical review of content and edits.
      To Prof William Vollmer (USA), for his support on in-depth analysis of data and its interpretation.
      To Prof Olga Sánchez Negrette (ARG), for ELISA test performance.
      To Prof Dolores Fernández Aráoz for their editorial assistance.

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