Original Article Randomized Controlled Study of Desloratadine Citrate and Loratadine in the Treatment of Allergic Rhinitis

Int J Clin Exp Med 2016;9(2):4388-4395 www.ijcem.com /ISSN:1940-5901/IJCEM0019483

Original Article Randomized controlled study of desloratadine citrate and loratadine in the treatment of allergic rhinitis

QingJia Gu, Gang He, Jiangang Fan, Jingxian Li, Debing Li, Libing Zhao, Li Huang

Department of Otorhinolaryngology, Affiliated Hospital of University of Electronic Science and Technology of China, Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China Received November 9, 2015; Accepted November 13, 2015; Epub February 15, 2016; Published February 29, 2016

Abstract: Objective: To observe the clinical efficacy and safety of desloratadine citrate disodium in the treatment of allergic rhinitis (AR). Methods: 200 patients with AR treated at otorhinolaryngology department of Sichuan Provincial People’s Hospital from January, 2012 to October, 2014 were selected for this study. They were randomly divided into therapeutic group and control group with 100 patients in each. And there was no obvious difference in general data between two groups. The therapeutic group was treated with desloratadine citrate disodium tablets with daily dosage of 8.8 mg by oral administration, while the control group was given loratadine with daily dosage of 10 mg by oral administration. The treatment course was one month. All the patients were not given corticosteroids and other antihistamines. Observe symptoms before and after the treatment, signs score and clinical efficacy in two groups. We intraperitoneal injected 100 µg of ovalbumin 2 times to build sensitized model in ICU mic and separated splenic lymphocyte; pretreated with 1.5 mol/L esloratadine citrate disodium and loratadine, and then added 200 mg/L ovalbumin for stimulation; the influence of esloratadine citrate disodium and loratadine on lymphocyte releasing prostaglandin E2, leukotrienes, interleukin-4, interleukin-5 and tumor necrosis factor were detected and compared by ELISA method. Results: In the 99 cases selected in therapeutic group, 58 cases were markedly effective, 34 cases were effective, 7 cases were ineffective, and the total effective rate was 92.9%. In the 98 cases selected in control group, 7 cases were markedly effective, 48 cases were effective, 23 cases were ineffective, and the total effective rate was 76.5%. There was statistically significant difference in the total effective rate between the two groups (P<0.05). In mouse sensitization model, compared with those in the loratadine group, desloratadine citrate disodium could significantly decrease the levels of lymphocytes releasing PGE2, LTB4, IL-4, IL-5, TNF-α. Conclusion: Compared with loratadine, the clinical efficacy of desloratadine citrate disodium tablets is better in the treatment of AR and with good safety.

Keywords: Desloratadine citrate disodium, loratadine, allergic rhinitis, efficacy

Introduction will not cause life risk, it seriously affects patients’ life quality and reduces work efficien- Allergic rhinitis (AR) is a disease seriously cy [5, 6]. If not treated in time, it may cause affecting patients’ quality of life; domestic many other complications, such as sinusitis, investigation [1] shows that AR patients secretory otitis media, asthma, stress and accounted for 1/5 of otorhinolaryngology out- anxiety. patient, and 1/3 of total nasal sinus disease outpatients, it has become one of the most H1-antihistamine is one of the main drugs to common diseases in otorhinolaryngology de- treat AR, it’s a kind of drug blocking histamine partment. AR and bronchial asthma belong to on H1 receptor levels (inverse agonist), and the IgE-mediated allergic airway inflammation, some of them also have anti-allergic inflamma- both of them are closely related and often coex- tion characteristics. It is mainly used in the ist in the same patient [2, 3]. 40% of AR patients early stage of AR, and can relieve sneezing, can be combined with bronchial asthma [4]. In itchy nose, runny nose, and even nasal obstruc- recent years, the incidence of the disease is tion symptoms [7, 8]. Loratadine is a new recep- increasing year by year. Although the disease tor antagonist antihistamine with no drowsi- generally does not need to be hospitalized and ness effect, it does not affect the patient’s Study of desloratadine citrate and loratadine in the treatment of AR

Table 1. The observation group and the control group of patients with the 2009 Wuyi Mountain clinical feature conference diagnostic cri- Clinical symptoms The observation group The control group teria which formulated by Sex Chinese Medical Associ- ation of Otorhinolaryngo- Male 43 45 logy, Head and Neck Sur- Female 57 55 gery branch. (2) age ≥18; Course of disease 3 months—6 years 5 months—9 years (3) history of rhinitis ≥2 With dogs or cats at home years. Exclusion criteria: (1) None 58 47 applied other antihista- Yes 42 53 mines and corticosteroids With asthma in 2 weeks; (2) combined Yes 23 27 use of imidazole antifungal None 77 73 drugs, macrolide antibiot- Parents with AR ics, sedatives, corticoste- Yes 18 14 roids, immunomodulatory None 82 86 drugs, anticholinergic age- nts, beta receptor agonist and other drugs; (3) allergic behavior, work and life quality, and has good to this medicine; (4) organic heart disease, treatment effect at early response; however, it arrhythmia, recently had chronic gastrointesti- has limited efficacy in nasal congestion [9]. nal, liver, kidney disease or other serious dis- Based on a single component of desloratadine eases; (5) the positive pregnancy or lactating compounds, desloratadine citrate is made from women, women at childbearing age who planed the reaction of desloratadine and disodium to reproduce in near future, driver, mechanical hydrogen citrate, it is the third-generation anti- workers and high-altitude operators; (6) urti- histamines with higher water solubility, rapid caria caused by physical stimulus (pressure, onset, superior bioavailability. The relationship cold, sunlight etc.), cholinergic urticaria, serum between desloratadine citrate and loratadine is disease urticaria, vasculitis urticaria, heredi- not a simple replacement of acid radical or salt tary vascular edema, other diseases (such as base. They are two completely different com- SLE, thyroiditis) induced urticaria; (7) people pounds with great difference in physical and can not complete the treatment program and chemical properties, to further evaluate clinical follow up according to the requirements. The efficacy and safety of desloratadine citrate in study was approved by the hospital ethics com- treatment of allergic rhinitis, from January, mittee and consent papers were signed and 2012 to October, 2014, our department applied obtained from all the patients. The basic infor- desloratadine citrate (trade name: Beixue, mation of patients is shown in Table 1. Yangtze River Pharmaceutical Group) and loratadine (trade name: Clarityne, Shanghai The method of treatment Schering-Plough Pharmaceutical Co., Ltd) in treating allergic rhinitis of 200 cases, and com- According to the random number table, we pared its efficacy, adverse reactions, and other divided 200 patients into observation group related issues. and control group with 100 in each group. The observation group consisted of 43 cases of Materials and methods male, 57 cases of female, and was given desloratadine citrate disodium tablets (Beixue Clinical data Yangtze River Pharmaceutical Group, Guang- 200 AR patients treated at otorhinolaryngology zhou Hairui Pharmaceutical Co., Ltd., specifica- department of Sichuan Provincial People’s tions: 8.8 mg per tablet, batch number: Hospital from January, 2012 to October, 2014 32110604) 8.8 mg, Po, qd, for 1 month. The were collected in this study, they were aged control group consisted of 45 cases of male, from 18 to 60 with a median age of (43.2±5.8), 55 cases of female, and was given loratadine in which 126 cases were male, 74 cases were (Clarityne, Shanghai Schering-plough Phar- female. Inclusion criteria: (1) a diagnosis of maceutical Co., Ltd, specifications: 10 mg per patients with allergic rhinitis in accordance with tablet, batch number: 10BRXF1007) 10 mg,

4389 Int J Clin Exp Med 2016;9(2):4388-4395 Study of desloratadine citrate and loratadine in the treatment of AR

Table 2. Symptoms and signs of scoring criteria Grading score Sneezing○ Runny noseΔ Rhinobyon Rhinocnesmus 1 point 3~5 ≤4 breathe consciously in feeling interruption 2 points 6~10 5~9 intermittent or interactive formication but tolerable 3 points ≥11 ≥10 mouth breathing all day formication but unbearable Attention: ○Number of continuous sneezing at one time, Δthe daily times to blow nose.

Table 3. Serum specific IgE levels Specific IgE content (kUA/L) Classification Specific IgE levels Clinical manifestation <0.35 0 none or no detection not allergic 0.35-0.69 1 low may or mild allergies 0.70-3.49 2 raise light allergy 3.50-17.49 3 significantly increase moderate allergic 17.50-49.9 4 higher moderate or severe allergies 50-100 5 high severe allergic >100 6 extremely high particularly severe allergic

Table 4. Comparison between observation group and control group Detection of serum specific Groups Cases Effective Valid Invalid Total efficiency IgE Observation group 99 58 34 7 92.9* The serum allergen specific Control group 98 27 48 23 76.5 IgE antibody content of *P<0.05 vs control group. patients in each group was detected quantitatively by Po, qd, for 3 months. No corticosteroids and Western blot method before treatment. Serum other antihistamine drugs were applied in both specific IgE grading criteria: the positive reac- groups. tion intensity was divided into 6 levels according to the content of specific IgE in serum, the Symptom and standards of signs score [10] grading levels can be used to predict patients The symptom score standard of rhinitis is with mild, moderate or severe allergic reaction shown in Table 2. Standards of signs score: the (grading criteria was provided by Mediwiss inferior turbinate was closely adjacent to basis company). See in Table 3. nasi and nasal septum, without seeing the middle turbinate, or middle turbinate mucosal pol- Adverse reactions ypoid, polyp formation, recorded 3 points; inferior turbinate was closely adjacent to nasal sep- Observe adverse reaction after patients using tum (or basis nasi), small gap between inferior the medicine, and take auxiliary examination of turbinate and basis nasi (or the nasal septum), ECG, urine routine, blood routine, and blood recorded 2 points; mild swelling of the turbi- pressure etc. nate, nasal septum and middle turbinate is vis- ible, recorded 1 point. To construct the sensitized mouse model and isolate the spleen lymphocytes Efficacy evaluation criteria [10]

Treatment efficacy was evaluated according to 0.2 ml saline containing 100 µg egg protein symptoms and signs score; the scoring (purity level of 98%) and 4 mg aluminum hydrox- method: ide was injected into ICR mice (provided by experimental animal center of Sichuan (pre-treatment score - post-treatment score)/ University, qualified certificate number: SCXK pre-treatment score × 100% (Sichuan) 2009-09) in abdominal cavity, repeat The outcome ≥66% was considered markedly the procedure 2 weeks later to construct oval- effective, 65% to 26% was effective, and ≤25% bumin sensitized mice model. After 24 h, the was invalid. mice were sacrificed, their spleens were

4390 Int J Clin Exp Med 2016;9(2):4388-4395 Study of desloratadine citrate and loratadine in the treatment of AR

Table 5. The symptom scores comparison of pretreatment, 1 month after treatment, and 3 months after treatment between two groups (x±s) Observation group Control group Symptom scores Before 1 month after 3 months after Before 1 month after 3 months after Integral treatment treatment treatment treatment treatment treatment (n =100) (n =99) (n =99) (n =100) (n =99) (n =99) Sneezing 2.32±0.59*,# 0.72±0.20*,# 0.42±0.10*,# 2.34±0.37*,# 1.23±0.45* 1.07±0.21* Runny nose 2.43±0.48*,# 0.79±0.20*,# 0.49±0.20*,# 2.56±0.53*,# 1.16±0.27* 1.04±0.07* Nasal congestion 2.27±0.42*,# 0.94±0.18*,# 0.41±0.13*,# 1.02±0.54*,# 1.27±0.23* 1.03±0.03* Nasal itching 2.42±0.72*,# 0.77±0.12*,# 0.32±0.08*,# 2.34±0.24*,# 1.25±0.28* 1.04±0.04* Inferior turbinate swelling 2.74±0.47*,# 0.91±0.23*,# 0.43±0.13*,# 2.60±0.72*,# 1.45±0.27* 1.05±0.23* Attention: compared with the pretreatment of it’s own group, *P<0.05; compared with the control group after treatment, #P<0.05.

Table 6. Comparison of adverse reactions in two groups Group Total cases Nausea Dizziness Headache Fatigue Drowsiness Erythra Rate Observation group 7 1 3 2 2 0 0 7% Control group 16 4 2 2 3 3 2 16% Attention: compared with the control group, P<0.05. removed out under aseptic operation and Statistical treatment digested by trypsin for 10 min at 37°C; use 200 mesh strainer to prepare the spleen lympho- All data were processed by SPSS12.0 software cytes suspensions. 1640 culture fluid was used package, and measurement data were repre- to subculture the lymphocytes in the 24 hole sented by mean ± standard deviation, compari- cell culture plate. The control group was intra- son between groups adopted single factor vari- peritoneal injected with the same dose of nor- ance, classification data were represented by mal saline. percentage, comparison between groups were examined by using χ2, P<0.05 was considered Detect the expression level of various inflam- statistically significant. matory factors in cell culture supernatant Result The spleen cell suspension was prepared, and the cells were adjusted to 2×106/ml with 1640 The levels of serum specific IgE classification culture fluid, and the suspension was added to in the two groups were similar before treat- 24 holes culture plate with 1.5 ml in each hole. ment Dilute desloratadine citrate disodium tablets and loratadine tablets with 1640 cell culture 99 effecive cases were collected at the end of fluid which containing 10% fetal bovine serum, the observation period in the observation sterilization by microporous membrane. The group, according to the grading criteria of final concentration of desloratadine citrate serum specific IgE before treatment, we classi- disodium and loratadine in each suspension fied 0-2 level of 14 cases, 3-4 level of 66 cases, was 1.5 µmol/L. After pharmacological precon- 5-6 level of 19 cases, and 1 dropout patients ditioned of desloratadine citrate clarityne and (missing follow-up on 9th day, result in incom- loratadine, the lymphocytes suspension was plete data). A total 98 effective cases were col- stimulated by directly adding egg protein (final lected in the control group, according to the concentration of 200 mg/L), put it in 5% CO2 same grading criteria, we classified 0-2 of 12 incubator for 2 h at 37°C. Culture supernatant cases, 3-4 of 67 cases, 5-6 level of 19 cases, was collected to detect the level of LTB-4 and and 2 dropout cases (1 case was lost during PGT-2 by ELISA method; detect the level of the observation period and 1 case was exclud- TFN-α after 9h incubation and level of IL-4, IL-5 ed due to unstandardized medicine taking). after 36 h incubation with the same method There was no significant difference between Each group has 5 complex holes. the two groups before treatment (P>0.05).

4391 Int J Clin Exp Med 2016;9(2):4388-4395 Study of desloratadine citrate and loratadine in the treatment of AR

Table 7. Levels of PGE2, LTB4, IL-4, IL-5 and TNF-α released by spleen lymphocytes of sensitized mice

Group PGE2 (ng/L) LTB4 (ng/L) IL-4 (ng/L) IL-5 (ng/L) TNF-α (ng/L) Control group 51.12±10.76 43.25±8.46 33.56±8.45 22.41±3.79 86.95±10.82 Model group 215.41±37.62* 179.94±42.11* 108.16±20.81* 62.51±9.63* 307.41±34.12* Attention: *compared with control group, P<0.05.

Table 8. Level comparison of PGE2, LTB4, IL-4, IL-5 and TNF-α released by spleen lymphocytes of sensitized mice after treated with two drugs

Group PGE2 (ng/L) LTB4 (ng/L) IL-4 (ng/L) IL-5 (ng/L) TNF-α (ng/L) Desloratadine citrate group 124.62±17.96 113.75±16.86 57.96±8.05 42.86±5.59 186.65±36.52 Clarityne group 183.41±17.92* 149.14±12.91* 77.66±10.21* 69.21±9.77* 265.32±44.82* Attention: *compared with control group, P<0.05.

The effective rate of observation group was egg protein again. In Table 7, it indicated the higher than that of control group model constructed successfully in mice.

The total effective rate of the observation group Levels of TNF-α, LTB4, IL-4, IL-5 and PGE2 in was 92.9% and the control group was 76.5%. spleen lymphocytes after drug treatment The difference was statistically significant (P< 0.05) in Table 4. Compared with Clarityne treatment group, lev-

els of PGE2, LTB4, IL-4, IL-5 and TNF-α released The symptom score of the observation group by allergic mice spleen lymphocytes decreased were lower than those of the control group significantly in desloratadine citrate treatment group, and the difference has statistical signifi- Compared the pre-treatment symptom scores cance. See in Table 8. on runny nose, nasal congestion, sneezing, itchy nose and inferior turbinate swelling Discussion between two groups, the difference was considered no statistical significance (P>0.05). AR is a chronic inflammatory reaction of nasal After treatment, the symptom scores of the two mucosa, which involves immunologically active groups were significantly lower than before, the cells and cytokines, etc. that released by IgE difference was statistically significant (P< media after the specific individual exposed to 0.05), and the observation group was lower allergens, it’s one of the common diseases in than the control group, the difference was sta- the department of otolaryngology. Epide- tistically significant (P<0.05). See in Table 5. miological surveys show that increasing preva- lence of AR is closely related to indoor air pollu- The incidence of adverse reactions in observation [11]. H1 receptor antagonists are impor- tion group was lower than that in control group tant drugs for the treatment of AR. The first generation of anti-histamine drugs easily leads We can see from Table 6, the incidence of to drowsiness, sedation and fatigue that may adverse reaction in patients taking deslorata- reduce the efficiency of learning and working, dine citrate was 7%, which was significantly and results in abnormal sleep [12, 13]. At pres- lower than the 16% of loratadine. In this study, ent, the second generation of H1 receptor adverse reactions included nausea, dizziness, antagonists, represented by Clarityne, is rec- headache, fatigue, drowsiness and erythra. ommended to treat adults and pediatric allergic rhinitis (AR) [14], it has good effect in relieving The expression level of LTB4, IL-4, PGE2, IL-5 and TNF-α were improved after egg protein histamine-mediated symptoms (runny nose, stimulated spleen lymphocytes in mice sneezing, itchy nose and eye symptoms) as well as nasal congestion [15, 16]. The past clinical Compared with the normal control group, the researches confirmed that Clarityne can relieve levels of PGE2, LTB4, IL-5, TNF-α, and IL-4 in seasonal AR symptoms quickly and continu- ovalbumin-sensitized model group were signifi- ously, and even efficient to moderate and cantly elevated (P<0.05) after stimulated by severe patients [18]. Some patients may have

4392 Int J Clin Exp Med 2016;9(2):4388-4395 Study of desloratadine citrate and loratadine in the treatment of AR temporary headache or dizziness, but no other tively; therefore it can antagonize peripheral H1 severe side effects. However, overdose treat- receptor selectively. In addition to the antihista- ment can cause adverse reactions in the cen- mine function, desloratadine also reveals anti- tral nervous system, digestive system and allergic and anti-inflammatory effects, and blood system of patients and even leads to shows inhibitory effect on many taches during drowsiness, dizziness, fatigue, abdominal pain, early and advanced periods of allergic inflam- heart palpitations and ECG abnormalities and mation in vitro experiments. Including: the other symptoms [17]. release of inflammatory cytokines (IL-4, IL-6 and IL-8 and IL-13), important chemokines in Desloratadine citrate disodium is a first an- inflammation, such as RANTES (activity regula- ti allergy medicine invented by Chinese, and it’s tion factor expressed and secreted by normal T the only ideal drug fully meets the requirements cell); Reactive oxygen species generated by of antihistamines currently. The pharmacologi- activating polymorphic neutrophilic cells; adhe- cal effects of desloratadine citrate is inhibit H1 sion and chemotactic activity of eosinophilic receptor and mast cells releasing histamine granulocyte; the expression of adhesion mole- and other allergic substances by selective com- cules like P-selectin; IgE-dependent release of petion, it can effectively inhibit inflammatory PGD2 and LTC4. Animal experiments have con- medium releasing in multiple taches during the firmed that desloratadine citrate disodium can early stage and advanced stage of inflamma- relieve nasal itching and runny nose symptoms tion, and has certain effect on IgE level control. significantly, reducing the expression of IL-4 to Compared with desloratadine, it has advantag- suppress the inflammatory response of the es of faster onset, better therapeutic effect, nasal mucosa by reducing the concentration of higher stability and smaller side effects, serum levels of IFN-γ and IL-12. Desloratadine Desloratadine citrate disodium have better citrate disodium can reduce AR symptoms by anti-inflammatory potential by comparing with regulating reaction of T cell, which is increasing the similar drugs of cetirizine hydrochloride and the level of Th1 cell and inhibiting the level of ebstine. The function features of desloratadine Th2 cells [20]. citrate disodium mainly are: 1. Strong anti-allergic effects: desloratadine citrate disodium In this study, the total effective rate of the combined H1 receptor specifically with high observation group was 92.9%, the control selectivity. In the currently known antihista- group was 76.5%, while the observation group mines, desloratadine citrate disodium has the having 7 (7%) adverse reaction cases and the strongest combination capability with H1 recep- control group having 15 cases (15%), which tor, possessing significant function of H1 recep- were nausea, headache, dizziness, fatigue, tor antagonist. It’s 4 times stronger than lorata- sleepiness and skin rash, etc. Obviously, com- dine in the inhibition of mice foot swelling pared with loratadine, desloratadine can induced by histamine. Desloratadine citrate improve the treatment efficiency and reduce disodium inhibits inflammatory cytokines from the incidence of adverse reactions of AR stimulated human mast cells and eosinophils patients (P<0.05). To discuss the differences in at nanomolar levels, the cytokines includs IL-3, the anti allergic effects between desloratadine IL-6, TNF, GM-CSF, etc. The effect is stronger citrate disodium and loratadine, this study con- than dexamethasone and cetirizine levocetiri- structed sensitized mouse model by intraperi- zine. 2. Rapid onset, sustained efficacy: deslo- toneal injection of ovalbumin (OVA) and alumi- ratadine citrate has water solubility, good num hydroxide, separated and cultured mice absorption, and the onset time is less than 30 spleen lymphocytes; We detected the influence minutes. Researching reports show that [19], of desloratadine citrate disodium on lympho- desloratadine citrate disodium is faster than cyte releasing PGE2, LTB4, IL-4, IL-5, and TNF-α the existing antihistamine drug in onset time, such inflammation related factors, and com- the average of which is 28.45 minutes, while 1 pared with loratadine. The experimental results hour for loratadine and mizolastine, 2 hours for indicated that desloratadine citrate disodium cetirizine. Half life time of desloratadine citrate can reduce the level of PGE2, LTB4, IL-4, IL-5, disodium is about 24 hours that sustained and TNF-α significantly and possess early anti- effect. After oral feeding, desloratadine is inflammatory potential. So, it provided an im- rejected by the central nervous system effec- portant experimental basis to demonstrate and

4393 Int J Clin Exp Med 2016;9(2):4388-4395 Study of desloratadine citrate and loratadine in the treatment of AR study desloratadine citrate disodium having Deleanu D, Denburg JA, Devillier P, Didi T, anti-inflammatory therapeutic effect further. Dokic D, Dolen WK, Douagui H, Dubakiene R, Durham SR, Dykewicz MS, El-Gamal Y, El- In summary, desloratadine citrate disodium Meziane A, Emuzyte R, Fiocchi A, Fletcher M, Fukuda T, Gamkrelidze A, Gereda JE, Gonzalez treats AR by reducing the level of PGE2, LTB4, IL-4, IL-5, and TNF-α, it can relieve the symp- Diaz S, Gotua M, Guzman MA, Hellings PW, toms and signs of runny nose, nasal conges- Hellquist-Dahl B, Horak F, Hourihane JO, tion, sneezing, nasal itching and inferior turbi- Howarth P, Humbert M, Ivancevich JC, Jackson nate swelling of patients. The clinical curative C, Just J, Kalayci O, Kaliner MA, Kalyoncu AF, Keil T, Keith PK, Khayat G, Kim YY, Koffi N’goran effect is better than loratadine, and has good B, Koppelman GH, Kowalski ML, Kull I, safety and strong anti-inflammatory effect. It is Kvedariene V, Larenas-Linnemann D, Le LT, also the only one in the full compliance with the Lemiere C, Li J, Lieberman P, Lipworth B, requirements of the antihistamine medicine; Mahboub B, Makela MJ, Martin F, Marshall with faster onset, better efficacy, less side GD, Martinez FD, Masjedi MR, Maurer M, effects, it is worthy of wide clinical application. Mavale-Manuel S, Mazon A, Melen E, Meltzer EO, Mendez NH, Merk H, Mihaltan F, Disclosure of conflict of interest Mohammad Y, Morais-Almeida M, Muraro A, Nafti S, Namazova-Baranova L, Nekam K, None. Neou A, Niggemann B, Nizankowska- Mogilnicka E, Nyembue TD, Okamoto Y, Okubo Address correspondence to: Gang He, Department K, Orru MP, Ouedraogo S, Ozdemir C, Panzner of Otorhinolaryngology, Affiliated Hospital of Uni- P, Pali-Scholl I, Park HS, Pigearias B, Pohl W, versity of Electronic Science and Technology of Popov TA, Postma DS, Potter P, Rabe KF, China, Sichuan Provincial People’s Hospital, Ratomaharo J, Reitamo S, Ring J, Roberts R, Chengdu, Sichuan, China. E-mail: hgsc12345@163. Rogala B, Romano A, Roman Rodriguez M, com Rosado-Pinto J, Rosenwasser L, Rottem M, Sanchez-Borges M, Scadding GK, Schmid- References Grendelmeier P, Sheikh A, Sisul JC, Sole D, Sooronbaev T, Spicak V, Spranger O, Stein RT, [1] Tian HQ, Chen XY, Lu Y, Lu WM, Wang ML, Zhao Stoloff SW, Sunyer J, Szczeklik A, Todo-Bom A, HL, Lu MP, Zhou H, Chen RX, Zhang ZD, Shen Toskala E, Tremblay Y, Valenta R, Valero AL, C, Cheng L. Association of VDR and CYP2R1 Valeyre D, Valiulis A, Valovirta E, Van Polymorphisms with Mite-Sensitized Persistent Cauwenberge P, Vandenplas O, van Weel C, Allergic Rhinitis in a Chinese Population. PLoS Vichyanond P, Viegi G, Wang DY, Wickman M, One 2015; 10: e0133162. Wohrl S, Wright J, Yawn BP, Yiallouros PK, Zar [2] Bousquet J, Schunemann HJ, Samolinski B, HJ, Zernotti ME, Zhong N, Zidarn M, Zuberbier Demoly P, Baena-Cagnani CE, Bachert C, T, Burney PG, Johnston SL, Warner JO. Allergic Bonini S, Boulet LP, Bousquet PJ, Brozek JL, Rhinitis and its Impact on Asthma (ARIA): Canonica GW, Casale TB, Cruz AA, Fokkens WJ, achievements in 10 years and future needs. J Fonseca JA, van Wijk RG, Grouse L, Haahtela T, Allergy Clin Immunol 2012; 130: 1049-62. Khaltaev N, Kuna P, Lockey RF, Lodrup Carlsen [3] Blaiss MS. Pediatric allergic rhinitis: physical KC, Mullol J, Naclerio R, O’Hehir RE, Ohta K, and mental complications. Allergy Asthma Palkonen S, Papadopoulos NG, Passalacqua Proc 2008; 29: 1-6. G, Pawankar R, Price D, Ryan D, Simons FE, Togias A, Williams D, Yorgancioglu A, Yusuf OM, [4] Greiner AN, Hellings PW, Rotiroti G, Scadding Aberer W, Adachi M, Agache I, Ait-Khaled N, GK. Allergic rhinitis. Lancet 2011; 378: 2112- Akdis CA, Andrianarisoa A, Annesi-Maesano I, 22. Ansotegui IJ, Baiardini I, Bateman ED, [5] Wheatley LM, Togias A. Clinical practice. Bedbrook A, Beghe B, Beji M, Bel EH, Ben Allergic rhinitis. N Engl J Med 2015; 372: 456- Kheder A, Bennoor KS, Bergmann KC, 63. Berrissoul F, Bieber T, Bindslev Jensen C, [6] Meltzer EO, Blaiss MS, Naclerio RM, Stoloff Blaiss MS, Boner AL, Bouchard J, Braido F, SW, Derebery MJ, Nelson HS, Boyle JM, Brightling CE, Bush A, Caballero F, Calderon Wingertzahn MA. Burden of allergic rhinitis: al- MA, Calvo MA, Camargos PA, Caraballo LR, lergies in America, Latin America, and Asia- Carlsen KH, Carr W, Cepeda AM, Cesario A, Pacific adult surveys. Allergy Asthma Proc Chavannes NH, Chen YZ, Chiriac AM, Chivato 2012; 33 Suppl 1: S113-41. Perez T, Chkhartishvili E, Ciprandi G, Costa DJ, [7] Wang L, Qu F, Zhang Y, Louise B, Weschlera Cox L, Custovic A, Dahl R, Darsow U, De Blay F, D, Jan S. Home environment in relation to al-

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