Effect of Botulinum toxin type A on nasal symptoms on allergic rhinitis

Sukonta Intarawong, MD, Third Year Resident Department of otolaryngology, Faculty of Medicine Ramathibodi Hospital, Mahidol University

This research submitted in partial fulfillment of the requirement for the Certificate of Otolaryngology-Head and Neck Surgery of Medical Council 2010.

กตตกรรมประกาศ

ผวจยขอขอบคณ 1. ผชวยศาสตราจารยนายแพทย วชต ชวเรองโรจน

หวหนาภาควชาโสต ศอ นาสกวทยา คณะแพทยศาสตร โรงพยาบาลรามาธบด มหาวทยาลยมหดล ทอนญาตใหท าการวจย 2. ศาสตราจารยนายแพทยบญช กลประดษฐารมณ ผบกเบกการน าเลเซอรมาใชในการรกษาโรคทางโสต ศอ นาสกวทยา ในประเทศไทย 3. รองศาสตราจารยนายแพทย เฉลมชย ชนตระการ ทปรกษาโครงการและควบคมการวจย 4. อาจารยพรทพย ฉตรชยพนธ อาจารยประจ าส านกงานวจยคณะแพทยศาสตรโรงพยาบาลรามาธบด มหาวทยาลยมหดล ผใหค าแนะน าการวเคราะหทางสถต 5. ดร. ศศวมล รตนศร อาจารยประจ าส านกงานวจยคณะแพทยศาสตรโรงพยาบาลรามาธบด มหาวทยาลยมหดล ผใหค าแนะน าการวเคราะหทางสถต 6. นายแพทย ปวน น าธวช ผใหค าแนะน าการวเคราะหทางสถต

Table of Contents Abstract 4 Introduction 5 Objective 8 Material and methods 8 Result 9 Discussion 16 Conclusion 18 Reference 19

การศกษาผลของสาร Botulinum toxin type A ในการรกษาโรคเยอบโพรงจมกอกเสบจากภมแพ สคนธา อนทรวงศ พบ., เฉลมชย ชนตระการ พบ.* บทคดยอ เนองจากผ ปวยโรคเยอบโพรงจมกอกเสบจากภมแพทมอาการตลอดปทไดรบการวจยและการรกษาดวยวธตางๆ เชน การรกษาดวยยา การรกษาดวยการผาตด ยงมผลการรกษาไมดเทาทควรและมผลขางเคยงจากการรกษาอยบาง ในปจจบนไดมการน าเสนอวธการรกษารปแบบตางๆ อาท การใชเลเซอร, การคดคนยาทมผลชวยลดอาการทเกดจากการกระตนสารกอภมแพตางๆ สาร Botulinum toxin type A เปนสารสอประสาททมผลยบยงการหลงของสาร Acetylcholine ทจดเชอมตอของเซลลประสาทในเสนใยกลามเนอ (Neuromuscular junction), ส าหรบในการวจยนไดน าสารดงกลาวมาใชในการรกษาผ ปวยโรคเยอบโพรงจมกอกเสบจากภมแพ โดยเชอวาสารจะสามารถลดอาการภมแพทางจมกของผ ปวยได วตถประสงค : เพอศกษาประสทธภาพของสาร Botulinum toxin type A ในการรกษาผ ปวยโรคเยอบโพรงจมกอกเสบจากภมแพทมอาการตลอดป และท าการประเมนผลโดยการใช nasal symptom score วธการศกษา : เปนการศกษาแบบ Prospective randomized control trial โดยท าการเกบขอมลจากผ ปวยเยอบโพรงจมกอกเสบจากภมแพทมอาการตลอดป ซงมาตรวจทแผนกผ ปวยนอก ภาควชา โสต ศอ นาสกวทยา คณะแพทยศาสตรโรงพยาบาลรามาธบด ตงแต วนท 1 ตลาคม พ.ศ. 2551 ถง วนท 30 กนยายน พ.ศ. 2552 จ านวนทงสน 30 คน แบงเปนผชาย 11 คนและผหญง 19 คน โดยท าการสมผ ปวยเขารบการรกษาดวยสาร Botulinum toxin A 15 คนโดยการใชซองสมตวอยาง สวนอก 15 คน เปนกลมผ ปวยทไดรบการรกษาดวยน าเกลอบรสทธ ตดตามผลการรกษานาน 8 สปดาห ผลการศกษา : เมอท าการตดตามผลของการใชสาร Botulinum toxin A ในการรกษาผ ปวยเยอบโพรงจมกอกเสบจากภมแพทมอาการตลอดป จนถงสปดาหท 1, 2, 4, 6 และ 8 พบวา ไดผลดกวาในแงของการลดอาการน ามกไหลและคดจมกเมอเปรยบเทยบกบการรกษาในกลมทใชน าเกลอ บรสทธ อยางมนยส าคญทางสถต สรป : การใชสาร Botulinum toxin A ฉดในเยอบโพรงจมก เปนทางเลอกทดวธหนงในการรกษาผปวยเยอบโพรงจมกอกเสบจากภมแพทมอาการตลอดป โดยเฉพาะอยางยงในกลมผปวยทไมตอบสนองตอการรกษาดวยวธปกต

ค ำส ำคญ : Allergic Rhinitis, Botulinum toxin A *ภาควชาโสต ศอ นาสกวทยา คณะแพทยศาสตร โรงพยาบาลรามาธบด

Effect of Botulinum toxin type A on nasal symptoms in allergic rhinitis.

Sukonta Intarawong, MD, Chalermchai Chintrakarn, MD* ABSTRACT Backgroung: Allergic rhinitis is a common inflammatory disease characterized by nasal symptoms such as rhinorrhea, sneezing, nasal congestion and itching. The patency of nasal airway is regulated by the autonomic nervous system. Sympathetic activity decreases nasal airway resistance by constricting nasal vessels, and parasympathetic activity produces nasal mucus from submucosal seromucinous gland. Botulinum toxin A is a neurotoxin inhibits the release of acetylcholine from presynaptic neurons at the neuromuscular junctions thus it might be useful in blocking the cholinergic control of nasal symptoms on allergic rhinitis.

Objective: To study the effect of botulinum toxin type A on inhibiting of nasal symptoms in patients with Allergic Rhinitis (AR).

Material and methods: 30 patients were randomly divided into two subgroups. The study were conducted between 1st October 2008 – 30th September 2009 in out patient clinic Department of otolaryngology Faculty of Medicine, Ramathibodi hospital. BTX-A was diluted to a concentration of 10 units/0.5ml. In Group A, 10 units of BTX-A was injected into each nasal cavity at inferior turbinate (total 20 units). In Group B, 1 ml of isotonic saline was injected as placebo. The symptoms of AR (rhinorrhea, sneezing , nasal obstruction, itching) were scored by the patients on a five-point scale. The follow up period was 8 weeks.

Results: There was a statistical difference between BTX-A group and control group in rhinorrhea and nasal obstruction improvement rate (P<0.05). There was no statistical different between BTX-A group and control group in sneezing and itching improvement rate (P>0.05).

Conclusion: Intranasal injection of BTX-A is the one of the simple and safe therapeutic method to relief the symptoms of allergic rhinitis especially in patients whose symptoms are poor response to standard therapeutic regimens. Key word: Allergic Rhinitis, Botulinum toxin A *Department of otolaryngology, Faculty of Medicine Ramathibodi Hospital

Introduction Allergic rhinitis is a common inflammatory disease characterized by nasal symptoms such as rhinorrhea, sneezing, nasal congestion and itching. These symptoms disturbed diary life, working performance and also patients emotional.

The patency of nasal airway is regulated by the autonomic nervous system. Sympathetic activity decreases nasal airway resistance by constricting nasal vessels, and parasympathetic activity produces nasal mucus from submucosal seromucinous gland (1).

Botulinum toxin (BTX) is a neurotoxin purified from Clostridium botulinum. It has seven antigenically different serotypes (type A-G)(2),(3). It was widely used in a treatment of muscle dystonia and spasticity, sialorrhea and Frey syndrome. This neurotoxin inhibits the release of acetylcholine from presynaptic neurons at the neuromuscular junctions thus it might be useful in blocking the cholinergic control of nasal symptoms on allergic rhinitis.

Shaari et al (4) demonstrated a reduction of rhinorrhea in experimentally indued nasal hypersecretion in dogs after nasal application of BTX type A (BTX-A).

Kim et al (5), Rohrbach and Laskawi (6),(7) applied sponge soaked with BTX-A 40 U in each nostril to patients with intrinsic rhinitis and obtained satisfactory result. Murat Unal (8) et al injected different dosage BTX-A in 3 groups. 20 units BTX-A was injected in each nasal cavity in group A (total 40 units), 30 unit in each nasal cavity in group B (total 60 unit) and group C is a control group (saline injection 2 ml). When total symptom scores ( the symptoms of AR) were evaluate, the result for group A and B were similar but significantly better than those for group C.

Wang J et al (9) investigated the effect and mechanism of BTX-A on rhinitis. Twelve guinea pigs were randomly divided in 2 group; BTX-A group and control. Merocel sponge soaked with 10 units (0.2ml) BTA was put into left nasal cavity under GA for one hour in BTA group. Saline replaced BTA in control group. The inferior turbinate were harvested at 7, 14, 28 days after BTA treatment and was observed with HE staining and electron microscope. They concluded that BTA can induce degeneration of glandular cells in the nasal mucosa.

Wen WD et al (10) studied the effect of BTX-A on inhibiting rhinorrhea and morphological change of the nasal mucosa with an immunohistochemical and histological staining methods in rats allergic rhinitis. Animal were divided into control group, allergic group and allergic animal treated by BTX-A group. Hematoxylin and eosin staining demonstrated no edema, small vessels were found in the nasal mucosa after BTX-A treatment. They concluded that BTX-A treatment can reduce the sensory neuron sensitivity of the nasal mucosa and can alleviate nasal congestion, rhinorrhea and sneezing.

Tae Yong Yang et al (11) compared the effects of botulinum toxin type A with intranasal steroid injections on nasal symptoms in patients with allergic rhinitis. They injected 25 U of BTX-A at inferior turbinate in each nasal cavity in group A patients, and 20 mg/ml of triamcinolone injected into each inferior turbinate in group B patients. They found that BTX-A provided better AR symptoms relief in term of duration and degree than a steroid injection.

Objective To study the effect of botulinum toxin type A on inhibiting of nasal symptoms in patients

with perennial Allergic Rhinitis (AR).

Material and methods

The study was conducted between 1st October 2008 – 30th September 2009 in out patient Department of otolaryngology Faculty of Medicine, Ramathibodi hospital.

30 patients (male=11, female=19) with allergic rhinitis were included in the study. All patients gave their inform consent. No patient had withdrawn from the study between the period of studying.

Inclusion criteria 1. Patients with evidence of allergic rhinitis. AR was diagnosed by means of

a. history b. clinical examination c. skin prick test d. elevate absolute eosiophil count and total serum IgE

2. All patients were given their informed consent. 3. Patients agree to sign in the inform consent form.

Exclusion criteria 1. Patients were pregnancy or the possibility of pregnancy. 2. Patients with evidence of

a. gross nasal anatomical abnormality (polyp or septal deviation). b. acute rhinosinusitis. c. accompanying disease such as glaucoma or prostate hypertrophy

that might be aggravated by anticholinergic therapy and serious systemic disease.

3. The patients who have severe symptoms and need other drugs during the studied period.

4. Patient who refused to attend or withdraw from the research.

Anterior and posterior rhinoscopy were performed in all patients. Skin prick test and peripheral blood for IgE were taken from all patients.

All patients were randomly divided into two subgroups, Group A and Group B. BTX-A was diluted to a concentration of 10 units/0.5ml. In Group A, 10 units of BTX-A was injected into each nasal cavity (total 20 units). In Group B, 1 ml of isotonic saline was injected as placebo. BTX-A was injected to both inferior turbinates using an insulin syringe injector (1ml) under direct vision (anterior rhinoscopy) at equal dose.

The symptoms of AR (rhinorrhea, nasal obstruction, sneezing, itching) were score by the patients on a five-point scale (11),(14) (0=none,1=mild, 2=moderate,3=moderate to severe, 4=severe). The two groups of patients were received the same medical treatment between the period (oral nasal decongestant (pseudoephedrine 1x1), NSS irrigation). They were followed up at 1st, 2nd, 4th, 6th and 8th week; an anterior rhinoscopic examination was done and symptoms were recorded at each visit.

Statistic analysis 1. Chi-square and t-test were used to compare age and sex of patients between

the BTX and control groups. 2. Wilcoxon Rank-sum method and t-test were used to compare nasal symptoms

score at baseline between the two groups. 3. Kaplan-Meier was used to estimate probability of improvement and median time

to improvement after receiving treatment. 4. Log-rank test was used to compare median time to improvement after receiving

treatment between the two groups. 5. Log-rank test was used to compare median time to worse after receiving

treatment between the two groups.

Results All patients were randomly divided into two subgroups. Group A (BTX group) n= 15 (10

females, 5 males, mean age 33.8 years range 18-49 years). Group B (Control group) n=15 (9 females, 6 males, mean age 33.9 years , range 19-48 years), (Table 1.1).

Table 1.1 Characteristic of the patients in BTX-A and control group.

Group Total

patients Female Male Mean

age (yr) Range

(yr) BTX-A 15 10 5 33.8 18-49 Control 15 9 6 33.9 19-48

All of the participants have similar socioeconomic and environmental backgrounds. All

patients have perennial symptoms. No patients kept pets in their house. The results of skin prick test were as follows. 16 patients were sensitive to mite. 4 patients were sensitive to mite, American cockroach. 3 patients were sensitive to mite, American cockroach, cat. 3 patients were sensitive to mite, cat, dog. 2 patients were sensitive to mite, Bermuda grasses. 1 patient was sensitive to mite, mold. 1 patient was sensitive to cat, dog.

mite

American cockroach

mite, American

cockroach, cat

mite, cat, dog

mite, Bermuda grasses

mite, mold

cat, dog

16

Furthermore, there were elevated total serum IgE and absolute eosinophil count in all

patient. Absolute eosinophil count: range 115-2,060 cell/cu.m, , mean 438.55 cell/cu.m Total serum IgE: range 110-2840 IU/ml, mean 480.22 IU/ml

Evidences from anterior, posterior rhinoscopy and paranasal sinus radiograph confirmed there was no deviated nasal septum, nasal polyps and sinusitis in all patients.

There was no statistical difference between age and sex of patients among the two group of patients (table 1.2).

There was no statistical difference on severity of symptoms before treatment among the two groups (table 1.2).

These evidence confirm that no statistical difference for patients characteristic in the two groups.

Table 1.2 Comparison of nasal symptoms score before treatment between BTX group and control group

Botox Control P-value

Statistical method

Mean SD Mean SD

Rhinorrhea 1.8667 0.7432 1.4164 0.6399 0.226 (Wilcoxon Rank-

sum)

Sneeze 1.8667 0.3519 1.8667 0.5164 0.9525 (Wilcoxon Rank-sum)

Obstruct 1.8 0.7446 1.4667 0.6399 0.2174 (Wilcoxon Rank-sum)

Itching 1.8667 0.7432 1.2667 0.8837 0.0539 (t-test)

Total symptom

score

7.4 0.9856 7.0667 0.9864 0.525

(t-test)

Age 33.8 9.6821 33.9334 9.8522 0.9704 (t-test)

Male sex (%)

45.45% 54.55% 0.705

(Chi2 test)

All patients had completed the study and no patients complaints about side effects or

any complications (epistaxis, crusting, muscular palsy.) Nasal symptoms score of the BTX group were compared with the control group

regarded on each nasal symptoms score. Nasal symptoms score was sub-classified to 2 groups, score at 0,1,2= improvement

and score at 3,4= worsen. Improvement rate= Number of patients improvement/100 patients/week (%) Median time to improvement= the duration of time that 50% of total patients have symptom

improvement(week) Median time to worse= the duration of time that 50% of total patients have symptom

worsen(week)

Rhinorrhea improvement rate in the BTX group was statistical significantly better than the control group (88/12, P value= 0.0024). Median time to improvement of BTX group was at week 1. Median time to improvement of control group was at week 2 (Table 2.1).

Sneezing improvement rate in the BTX group and control group were not statistical significant difference (100/68, P value= 0.3173). Median time to improvement of BTX group and control group were at week 1 (Table 2.2).

Nasal obstruction improvement rate in the BTX group was statistical significantly better than the control group (83/50, P value= 0.0027). Median time to improvement of BTX and control group were at week 1(Table 2.3).

Itching improvement rate in the BTX group and control group were not statistical significant difference (83/88, P value= 0.63). Median time to improvement of BTX group and control group were at week 1 (Table 2.4).

Table 2.1 Median time to rhinorrhea improvement

Factors No.of

improvement total

patients

improvement rate/100 คน/

wk

Median time to

improvement (wk) P value

Treatment BTX 15 15 88 1 0.0024

Control 8 15 12 2 Table 2.2 Median time to sneezing improvement

Factors No.of

improvement total

patients

improvement rate/100 คน/

wk

Median time to

improvement (wk) P value

Treatment BTX 15 15 100 1 0.3173

Control 15 15 68 1

Table 2.3 Median time to nasal obstruction improvement

Factors No.of improvement

total patients

improvement rate/100 คน/wk

Median time to improvement (wk) P value

Treatment BTX 15 15 83 1 0.0027 Control 9 15 50 1

Table 2.4 Median time to itching improvement

Factors No.of improvement

total patients

improvement rate/100 คน/wk

Median time to improvement (wk) P value

Treatment BTX 15 15 83 1 0.63 Control 15 15 88 1

Median time to worse of rhinorrhea of BTX group was 7 weeks after treatment. Median time to worse of rhinorrhea of control group was 1 week after treatment. (P value= 0), Table 3.1

Median time to worse of sneezing of BTX group was 7 weeks after treatment. Median time to worse of sneezing of control group was 3 week after treatment. (P value= 0.0002), Table 3.2

Median time to worse of nasal obstruction of BTX group was 7 weeks after treatment. Median time to worse of nasal obstruction of control group was 3 week after treatment. (P value= 0.0269), Table 3.3

Median time to worse of itching of BTX group and control group were 3 weeks after treatment (P value= 0.1501), Table 3.4

Table 3.1 Median time to rhinorrhea worsen

Factors No. of

worsen Total

patients

Worsen rate/100 คน/wk

Median time to worse (wk) P value

Treatment BTX 15 15 14 7 0

Control 8 15 47 1 Table 3.2 Median time to sneezing worsen

Factors No. of

worsen Total

patients

Worsen rate/100 คน/wk

Median time to worse (wk) P value

Treatment BTX 12 15 12 7 0.0002

Control 13 15 27 3 Table 3.3 Median time to nasal obstruction worsen

Factors No. of

worsen Total

patients

Worsen rate/100 คน/wk

Median time to worse (wk) P value

Treatment BTX 14 15 13 7 0.0269

Control 12 15 24 3

Table 3.4 Median time to nasal obstruction worsen

Factors No. of

worsen Total

patients

Worsen rate/100 คน/wk

Median time to worse (wk) P value

Treatment BTX 0 15 0 3 0.1501

Control 2 15 2 3

Discussion Nasal symptoms in allergic rhinitis are caused by histamine and other inflammatory mediators. They increased vascular permeability and mucosal edema, dilate blood vessels to cause congestion and stimulate sensory nerves, resulted in sensation of itching and sneezing. Furthermore, they alter the balance of the autonomic nervous system (15).

Nasal patency and secretion are mainly controlled by the autonomic nervous system. Parasympathetic hyperactivity in nasal cavity caused nasal discharge from submucosal seromucinous gland while sympathetic hypoactivity can give rise to nasal blockage.

The effect of BTX-A on the nasal cavity have been postulated to occur via three mechanisms (5),(6).

1) Inhibit the release of acetylcholine from cholinergic nerve endings in the nasal mucosa.

2) Inhibit the release of acetylcholine from pre-ganglionic cholinergic nerve endings in sphenopalatine ganglion.

3) Induction of apoptosis of nasal glands There was reported about the potent anticholinergic effect of BTX-A on nasal mucosa

regarding the nasal symptoms such as nasal discharge, sneezing and nasal obstruction (4-11). We choose the method of injection instead of applying the toxin because of easying to

control the dosage exactly. According to these study, we found that BTX-A significantly reduced rhinorrhea, and

nasal obstruction symptom. The effect was significant seen for 7 weeks. The effect about rhinorrhea was obviously caused by the potent anticholinergic of the BTX-A. In addition, The

toxin can block vasoactive intestinal polypeptide, the potent vasodilator, thus it provide the effect of relief nasal congestion(12). Rorbach et al(6),(7) hypothesized that a reduction in glandular volume or a decreased in nasal fluid is responsible for the change in nasal obstruction.

Even the sneezing and itching were not significant different between the two groups, the patients showed improvement of their symptoms. According to Wen WD et al(10) BTX-A can reduce the sensory neuron sensitivity of the nasal mucosa and can alleviate nasal congestion, rhinorrhea, sneezing and itching.

Recently, there is no accepted therapeutic dose of BTX-A in allergic rhinitis. For the toxic dose, systemic weakness can occur with doses greater than 200 U. The lethal dose is approximately 40 U/kg.(13)

The duration of BTX-A effect was unknown exactly. Kim et al(5) reported the duration of effect in their study for 4 weeks while Murat et al(8) observed symptomatic relief lasts for at least 8 weeks.

In this study, we found the duration of BTX-A effect to reduce the nasal symptoms was last for 7 weeks. When compare to other literatures, we injected less unit of BTX-A but the effect can persist as long as them.

The duration of BTX-A effect on autonomic nervous system in other disease was longer (6 months for lacrimination and 11 months for salivation in salivary fistula(14).) The lower duration of BTX-A effect might be explained by rich blood vessels in nasal mucosa leading to more rapid absorption and clearing.

There were reports about transient or permanent visual loss after intraturbinal steroid injections. The incidence was approximated 0.006%. Embolization and vasospasm of retinal artery were the possible cause. Small particle drugs might minimize this complication. There was no reported visual loss complication after intraturbinal BTX-A injection.(14)

BTX-A treatment was a non-traumatic, simple and selective method to reduce the nasal symptoms of allergic rhinitis especially in patients whose symptoms uncontrolled with standard therapeutic regimens.

Conclusions Intranasal injection of BTX-A is the one of the simple and safe therapeutic method to relief the symptoms of allergic rhinitis especially in patients whose symptoms are poor response to standard therapeutic regimens.

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