Allergic Rhinitis and Asthma ---The-The Link

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Allergic Rhinitis and Asthma ---the-the link

Ruby Pawankar, MD, Ph.D Nippon Medical School, Tokyo, Japan rpawankar @gmail.com

Ruby Pawankar, NMS TheThe GlobalGlobal BurdenBurden ofof AsthmaAsthma

AsthmaAsthma isis oneone ofof thethe mostmost commoncommon chronicchronic diseasesdiseases inin thethe world,world, especiallyespecially inin childrenchildren AnAn estimatedestimated 300300 millionmillion peoplepeople areare affectedaffected worldwideworldwide AsthmaAsthma prevalenceprevalence increasesincreases asas communitiescommunities adoptadopt westernwestern lifestyleslifestyles andand becomebecome urbanisedurbanised AsthmaAsthma mortalitymortality isis alsoalso increasingincreasing andand isis alarminglyalarmingly highhigh Ruby Pawankar, NMS Allergic rhinitis

● Allergic rhinitis is a global health problem affecting 10 to 50 % of the population ● Its prevalence is increasing. ● Although it is not usually a severe disease, rhinitis alters social life and affects school performance and work productivity. ● Costs incurred by rhinitis are substantial. ● Most importantly, Allergic rhinitis is a risk factor for asthma.

Ruby Pawankar, NMS InternationalInternational StudyStudy ofof AsthmaAsthma && AllergiesAllergies inin ChildhoodChildhood (ISAAC(ISAAC III)III) Asthma Allergic Rhinoconjunctivitis

Ruby Pawankar, NMS ImpairmentImpairment DueDue toto AllergicAllergic Rhinitis:Rhinitis: workwork productivityproductivity andand activityactivity impairmentimpairment questionnquestionnaireaire

Ability to do daily activities 96

Work productivity 91

Classroom productivity 93

Any work time missed 23

Any classroom time missed 23

0 25 50 75 100 % of patients

AR markedly impairs the QOL of patients

Tanner LA et al. Am J Managed Care 1999;5(Suppl):S235 Ruby Pawankar, NMS ASIANASIAN SURVEYSURVEY :: ImpactImpact ofof ARAR onon AsthmaAsthma inin Child’sChild’s QualityQuality ofof LifeLife

A great deal and Quite a lot A little bit TotalTotal disrupted: disrupted:

Ability to get a good 85%85% night’s sleep 51% 35%

Participation in 82%82% leisure & sports . . . 44% 38%

Concentration at 83%83% work/ school 48% 33%

63% Ability to enjoy 22% 41% 63% social activities

0% 20% 40% 60% 80% 100%

Most patients (73%) had pre-existing AR when diagnosed with asthma. most troublesome symptom was wheezing (17%) and coughing (17%).

Erkka V and Pawankar R, 2007 Ruby Pawankar, NMS Asthma and Rhinitis

• Common Triggers

• Epidemiological Link

• Common inflammatory processes

• Pathophysiological links

• Treatment Outcomes

Ruby Pawankar, NMS AllergicAllergic RhinitisRhinitis IsIs aa RiskRisk FactorFactor forfor AsthmaAsthma 80% of asthmatics have rhinitis and 40% of rhinitis patients have asthma

12 p<0.002 10 10.5 % of 8 patients who 6 developed asthma 4

3.6 2

0 No allergic rhinitis Allergic rhinitis at baseline at baseline (n=528) (n=162) 23-year follow-up of college freshmen undergoing allergy testing; data based on 738 individuals (69% male) with average age of 40 years. Adapted from Settipane RJ et al Allergy Proc 1994;15:21-25. Ruby Pawankar, NMS Allergic Rhinitis: Risk Factor for Asthma Development Perennial rhinitis often preceeds asthma 10 year prognosis for childhood (3-17 years old) allergic rhinitis

% 70 60 seasonal AR 50 perennial AR 40

30 asthma 20 10 symptom -free 0 SAR n = 110 PAR n = 44 Type AR at the beginning of the study

Linna, et al. Acta Pediatr 1992 Ruby Pawankar, NMS Allergic rhinitis as a risk factor for the development of asthma Incidence of asthma over an 8-year period in the Copenhagen Allergy Study

% of subjects 15

0 pollen animal mite

no rhinitis rhinitis at baseline at baseline

Linneberg et al. Allergy 2002;57:1048 Ruby Pawankar, NMS RiskRisk factorfactor inin ChildrenChildren

Physician diagnosed allergic rhinitis in children - By 6 years of age 42% • Began in first year 77% • Began after first year 57% • Prick skin test positive * 20% Development of asthma by 6 years – When rhinitis began in first year 23% (p<.005) – When rhinitis began after first year 13%

* Only 50% of study children skin tested.Wright et al. Pediatrics. 1994; 94:895. Ruby Pawankar, NMS AllergicAllergic RhinitisRhinitis andand AsthmaAsthma HaveHave ComonComon TriggersTriggers

Outdoor allergens – Pollens – Molds

Indoor allergens – HouseHouse----dustdust mites – Animal dander – Insects (e.g., cockroach allergen)

Nonsteroidal AntiAnti---- inflammatory Drugs (NSAIDs) (e.g., aspirin)

Ruby Pawankar, NMS EarlyEarly andand LateLate PhasePhase ResponsesResponses inin AllergicAllergic RhinitisRhinitis andand AsthmaAsthma

Upper Score for nasal Immediate (early) phase Late phase Airways symptoms (Allergic Sneezing rhinitis) Nasal pruritus Congestion Rhinorrhea Antigen 1 3–4 8–12 24 challenge Time postchallenge (hours)

Lower 100 Airways (Asthma) FEV 1 50 (% change)

0 01 2 3 4 5 6 7 8 9 10 24 Time (hours)

Adapted from Varner AE, et al. Asthma and Rhinitis 2000 and Togias A. JACI 2000 Ruby Pawankar, NMS Common Inflammatory Cells and Mediators

Membrane-bound IgE Preformed Mediators Mast Cysteinyl leukotrienes Early-phase cell Prostaglandins response Platelet-activating factor

Allergen

Eosinophils

Inflammatory Late-phase T cells Cytokines mediators response

Adapted from Casale TB, et al. Clin Rev Allergy Immunol 2001 and Kay AB N Engl J Med 2001 Ruby Pawankar, NMS Bronchial biopsies in patients with SAR

60 CD4+ 50 CD8+

40 CD45RO+ EG1+ 30 connectivetissue 2 20

10 Cells/mm

0 out in pollen season Chakir et al, Allergy Clin Immunol 2000 Ruby Pawankar, NMS Eosinophilic inflammation in submucosa Controls Asthmatics 80 80 untreated CS-dependent 60 60

40 40

20 20 Eosinophils (/mm2) Eosinophils 0 0

nose bronchi nose bronchi Chanez et al, Am J Respir Crit Care Med 1999 Ruby Pawankar, NMS Nasal provocation results in bronchial inflammation

2 n = 14 p = 0.03

1.5

Sputum eosinophils (%) 1

0 baseline 24 hrs after nasal allergen challenge

Ruby Pawankar, NMS BronchialBronchial AllergenAllergen ChallengeChallenge ProducedProduced NasalNasal InflammationInflammation

Allergic Patients Control Patients

Blood Bronchial Nasal Lamina Propria (N = 16) Subepithelium (N = 16) (N = 16) ) 1600 † 2

600 ) ) 100

* 2 2 * † 500 1200 80

Cells/mm 400 6 60 300 800 40 200 400 20 100

Eosinophils (10 Eosinophils * Eosinophils (No. Cells/mm (No. Eosinophils 0 Cells/mm (No. Eosinophils 0 0

Unchallenged Allergen- T0 T24 T0 T0 T24 Left Lung Challenged Right Middle Lobe

T0 = before challenge; T 24 = 24-hr postchallenge. † T24 * P <.05 vs control (T 0); P <.01 vs allergic patients (T 0). Braunstahl et al. Am J Respir Crit Care Med . 2000;161:2051-2057. Ruby Pawankar, NMS18 Correlation between nasal and bronchial inflammation Gaga et al. Clin Exp Allergy 2000

40 (n= 17) 35 30 25 EOS in nasal mucosa 20 (asthmatics) 15 10 5 r= 0.851, p<0.001 0 0 5 10 15 20 25 30 EOS in bronchial mucosa (asthmatics) There exists nasal inflammation in asthma despite the pres ence of allergic rinitis in at opic individuals (20 to 66 yr old) Ruby Pawankar, NMS NasalNasal SteroidsSteroids ReducedReduced AsthmaAsthma SymptomsSymptoms inin PatientsPatients WithWith SeasonalSeasonal ARAR andand SeasonalSeasonal AsthmaAsthma

Placebo (n = 14) Cromolyn (n = 14)

Flunisolide (n = 19) BDP (n = 11) Treatment 1400

15 200

Daily 1000 Ragweed 10 Pollen 800 Count (Grain/ m 3 ) 5 600

400

Asthma Chest Symptom* Score Score Symptom* Asthma Chest 0 200 (Mean Weekly Difference From Baseline) From Difference Weekly (Mean

-5 PrepeakPeak Postpeak 0

7/11 7/17 7/24 7/31 8/7 8/14 8/21 8/28 9/4 9/11 9/18 *Chest tightness and wheezing.1984 Welsh et al. Mayo Clin Proc . 1987;62:125-134 Ruby Pawankar, NMS20 AntihistamineAntihistamine ImprovedImproved AsthmaAsthma SymptomsSymptoms inin PatientsPatients WithWith SeasonalSeasonal ARAR andand AsthmaAsthma

8 Placebo (n = 93) Cetirizine (10 mg/d) (n = 93) 7 6 5 4 * * * 3 * * Total Asthma Score Total 2 1 0 0 1 2 3 4 5 6 Week

* P <.05 vs placebo. Grant et al. J Allergy Clin Immunol . 1995;95:923-932. Ruby Pawankar, NMS21 Inhibition of the bronchial allergic reaction by an antileukotriene and an antihistamine

100 early N = 16 late 75 % inhibition of the allergen induced drop 50

in FEV 1

0 montelukast loratadine montelukast and loratadine

Ruby Pawankar, NMS PercentagePercentage ofof ChildrenChildren AfterAfter 33 YearsYears ofof SITSIT vs.vs. ControlControl WithWith oror WithoutWithout AsthmaAsthma

Möller C, et al. J Allergy Clin Immunol . 2002; 109:251-256. Ruby Pawankar, NMS Asthma and allergic rhinitis – Two related conditions linked by one common airway

Anatomy/Physiology Same mediators • Upper and lower airways are contiguous • IgE • Functional linkage - nose vs. mouth breathing •Cytokines • Similar histology • Histamine • Leukotrienes

Allergic Same cells Rhinitis • Mast cells Same drugs • Eosinophils • Anti-IgE • Th2 cells Asthma • Steroids (ICS/INS) • CD34 Stem cells + AR • Antihistamines (?) (the bone marrow • Antileukotrienes connection)

Asthma Ruby Pawankar, NMS Increased Risk of ER Visits for Asthma in AR Patients

4.0 p=0.029 3.5 3.6 3.0 2.5 % of patients 2.0 1.5 1.7 1.0 0.5 0 Patients Patients with asthma with asthma + allergic rhinitis (n=597) (n=893)

Patients with AR and asthma had an increased risk of ER visits

Bousquet J, et al. Poster presented at the (EAACI) 2004 (Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic rhinitis over 52 weeks) Ruby Pawankar, NMS Increased Risk of Hospitalization for Asthma in AR Patients

0.8 p<0.006 0.7 0.76 0.6 % of patients 0.5 hospitalized 0.4 0.45 annually 0.3 0.2 0.1 0 Patients Patients with asthma with asthma + allergic rhinitis (n=22,692) (n=4611)

Patients with AR and asthma had an increased risk of hospitalization

Price D, et al. Clin Exp Allergy 2005, in press.(Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in a general practice in the UK) Ruby Pawankar, NMS TreatingTreating AllergicAllergic RhinitisRhinitis DecreasedDecreased Asthma-RelatedAsthma-Related ResourceResource UtilizationUtilization

2.5 p<0.01

2.0 2.3

% of 1.5 patients 1.0 0.9

0.5

0 Patients untreated for Patients treated for allergic rhinitis (n=1357) allergic rhinitis (n=3587)

61% fewer hospitalizations in patients treated for AR

Retrospective cohort study of costs over a period of up to one year incurred by patients 12 to 60 years of age with both allergic rhinitis and asthma. Adapted from Crystal-Peters J et al J Allergy Clin Immunol 2002;109(1):57-62. Ruby Pawankar, NMS Asthma and Allergic Rhinitis – Two Related Conditions Linked by One Common Airway

Module 1: The underlying mechanisms of the United Airway concept Asthma and Allergic Rhinitis: WAO Online Lecture Series Ruby Pawankar, NMS Interactions Nose – Lower Airways :: Possible Mechanisms of Relationship

Mouth breathing Central sensitization and ↓↓↓ Air warming & nasopharyngo- humidification bronchial reflexes ↓↓↓ Particle/irritant trapping (↓↓↓ Nitric oxide) Drainage of inflammatory Systemic material propagation of (para)nasal inflammation

Adapted from Togias A. JACI 2003 Ruby Pawankar, NMS Link between Rhinitis and Asthma

CCR3 CCR4 CCR5 Bone marrow IL-4 Th2 E25 Mc Allergic Rhinitis IL-3 IL-5 IL-4, IL-5 GM-CSF Histamine IL-6, IL-13, CysLT 1 R Tryptase RANTES CysLT 2 R Allergen Cys LTs Eotaxin IL-5 R, IL-3 R PGs GM-CSF R IL-4, IL-5 Eo /Ba progenitor IL-6, IL-13, VCAM GM-CSF -1 VLA-4 TNF-α CCR3 Asthma CysLT 1 R Upregulated CysLT 2 R Adhesion Blood vessel Molecules & Eosinophil chemoattractacta nts Eosinophil

c Pawankar R 2006-.Clin Exp Allergy 36(1): 1-4, 2006. Ruby Pawankar, NMS Asthma and Rhinitis

OneOne Airway,Airway, OneOne Disease?Disease?

Togias: ‘Asthma and rhinitis are manifestations of one syndrome, the chronic allergic respiratory syndrome’ JACI 2003 Ruby Pawankar, NMS Ruby Pawankar, NMS Ruby Pawankar, NMS