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MANAGEMENT OF THE PATIENT WITH RHINITIS AND ASTHMA Giovanni Passalacqua Allergy & Respiratory Diseases Dept.Internal Medicine- University of Genoa ITALY

Moderate-severe One or more:. No sleep disturbances daily activity limitations impaired work or school activity bothersome symptoms Persistent. > 4 days/week. AND > 4 weeks MILD All the following No sleep disturbance No daily activity limitations normal work/school Activity No bothersome symptom Intermittent. < 4 days/week. or < 4 weeks ARIA Classification ALTERNATIVE: VAS No symptoms Untolerable symptoms X

Diagnostic tools. The problem Differently from asthma, there is no reliable or Standardized objective measurement. No objective evaluation of severity No tool is capable to discriminate allergic and nonallergic rhinitis. No tool is capable to discriminate healthy and rhinitics

PERSPECTIVES: Phenotypes of rhinitis? PURE SEASONAL (hayfever) PERSISTENT LOCAL RESPONSE NON IgE POLYPS NARES NA-NI NARESMA VASOMOTOR HORMONAL OCCUPATIONAL IgE

Rhinitis: comorbidities RHINITIS ASTHMA RHINOSINUSITIS CONJUNCTIVITIS OTITIS SLEEP DISORDERS polyps

Allergic rhinobronchitis: the asthma-allergic rhinitis link. Simons FER J Allergy Clin Immunol Sep;104(3 Pt 1): United airways disease: therapeutic aspects. Passalacqua G, Ciprandi G, Canonica GW Thorax Oct;55 Suppl 2:S26-7. Linking upper and lower respiratory airways. Aubier M. J Allergy Clin Immunol 1999; 83:

UNITED AIRWAYS EPIDEMIOLOGY Comorbidity rhinitis asthma Natural history Rhinitis as risk factor for asthma

Pariente Leynaert Wright Settipane Sibbad France ECRHS Tucson Providence England adults children adolesc adults rhin no rhin. 3.8 rhin no rhin. 4 rhin. 32 no rhin. 5 rhin no rhin. 3.6 SAR. 23 PAR 26 both 43 STUDYLOCUSSUBJECTS% ASTHMA Leynaert et al. JACI % of asthmatics have concomitant rhinitis Kapsali T et al, JACI 1998

- 591 patients controls - allergic to pollens, mite, -epithelia % subjects contrmildseveremildsevere intermittent persistent % pazienti Prevalence of asthma (physician diagnosed) in rhinitis Bousquet, CEA 2005

Shaaban, Lancet 2008

Allergic rhinitis as a predictor for wheezing onset in school- aged children. Rochat et al, JACI 2010 Cohort of 1,314 children followed from birth to 13 yrs

UNITED AIRWAYS PATHOPHYSIOLOGY Naso-broncghial reflex Physical filter Nonspecific hyperresponsiveness IMMUNOLOGY Allergic inflammation Bone marrow response Neuroinflammation

Bronchial biopsioes after Specific provocation in patients with rhinitis or asthma Crimi E et al, JAP 2001 ASTHMA RHINITIS ALONE Same inflammation

Nasal allergen challenge Increases bronchial reactivity Induces bronchial inflammation Littell NT, Changes in airways resistance following nasal provocation. Am Rev Respir Dis 1990 Corren J Changes in bronchial responsiveness following nasal provocation with allergens. JACI 1992 Small P ET AL The effects of allergen-induced nasal provocation on pulmonary function in patients with perennial allergic rhinitis. Am J Rhinol 1989

Bronchial endoscopic challenge With allergen Induces nasal inflammation

The nose-lung interaction in allergic rhinitis and asthma: united airways disease G.Passalacqua, G.Ciprandi & G.W.Canonica 2004 Asthma and rhinitis as different Aspects of a sinlge disorder

Perennial rhinitis: independent factor for developing asthma Leynaert et al, J Allergy Clin Immunol % pazienti asmatici atopicnon-atopic controls rhnitis

Children with allergic and nonallergic rhinitis have a similar risk of asthma. Chawes et al JACI 2010

naso-bronchial reflex INFLAMMATION allergen cytokinesbone marrow nose bronchi bronchial hyperreactivity physical filter function adhesion molecules viral infection

PATIENTS WITH PERSISTENT RHINITIS MUST BE ASSESSED FOR THE POSSIBILITY OF ASTHMA HISTORY/EXAMINATION Spirometry IF POSITIVE obstruction normal Assess reversibility Nonspecific Bronchial provocation Do you have recurrent wheezing? Do you have dry cough? Do you experience cough after exercise? Do you have chest tightness?

THERAPY Immunotherapy Nasal steroids Antihistamines Combination therapy UNITED AIRWAYS

mild intermittent Mild persistent Moderate- severe intermittent Moderate- severe persistent Allergen avoidance Decongestant (<10 days) Nasal steroid 2nd Generation antihistamine Immunotherapy TREATMENT OF ALLERGIC RHINITIS ARIA -Allergic Rhinitis and its Impact on Asthma Cromones Antileukotrienes (if asthma)

Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. Journal of Allergy and Clinical Immunology 2010; 126: CLINICAL QUESTIONS ON THE TREATMENT RECOMMENDATION: CONDITIONAL/STRONG LEVEL OF EVIDENCE: HIGH/MODERATE/LOW/VERY LOW

Weak: 84% high moderate low Very low Strenght of recommendation Grade of evidence

BASIC QUESTIONS: Does the treatment of rhinitis affect comorbid asthma? Any effect on the natural history?

Cruz, Allergy 2008

Untreated rhinitis increases the risk of asthma attacks. Bousquet, Clin Exp Allergy 2005 asthma Asthma + rhinitis

Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion. Berger et al. Ann Allergy Asthma Immunol WKS 1-2WKS 1-4 Mean % reduction of AM instantaneous asthma score Mean % reduction of AM/PM asthma score * *

Taramarcaz, Cochrane 2008

Effects of mometasone furoate on the Quality of Life: a randomised placebo controlled trial in persistent allergic rhinitis and intermittent asthma using the Rhinasthma questionnaire Ilaria Baiardini 1, Elisa Villa 1, Anthi Rogkakou 1, Sara Pellegrini 1, Micaela Bacic 1, Enrico Compalati 1, Fulvio Braido 1, Cristina Le Grazie 2, Giorgio Walter Canonica 1, Giovanni Passalacqua 1 Clin Exp Allergy 2011

Run in 1 sett 52 MFNS N= 26 Placebo N= 26 V1V2V3

Primary outcome: Global Summary (GS) of Rhinasthma, Changes at 2 and 4 weeks versus baseline Secondary outcomes: Changes vs baseline in the 3 domains of Rhinasthma -Upper airways (UA) -Lower airways (LA) -Respiratory Allergy Impact (RAI) -Nasal symptom score - Nasal + asthma scores

Enrolled n = 57 Randomized n = 52 Mometasone n = 26 Placebo n = 26 Completed n = 25 Completed n = 22 Discontinuations n = 4 Adverse event, n = 1 Consent withdrawn, n = 2 Treatment failure, n = 1 Discontinuations n = 1 Consent withdrawn Screening failures n = 5 Entry criteria not satisfied, n = 1 Refused to continue for reason unrelated to study drug, n=2; Privacy Form not signed, n = 2

Primary endpoint: Rhinasthma Global Score Mean changes from baseline (V2) to endpoint (V4) ITT Population p<0.001 Mean change vs baseline MFNSPlacebo -10,3 0,4

<.001 baselineweek 2week 4 Rhinasthma GS mean MFNS Placebo Rhinasthma global summary

baselineweek 2week 4baselineweek 2week 4baselineweek 2week 4 <.001 UAS LASRAI MFNS Placebo

Global Symptom Score (GSS) Weekly score Mean score * * GSS Placebo GSS MFNS basale1234

Treating persistent rhinitis with mometasone furoate nasal spray resulted in a significant improvement in QoL for both upper and lower respiratory tract domains There was a significant improvement of the global symptom scores (rhinitis + asthma) No significant change in rhinitis symptoms when analyzed separately (trial powered on the basis of the primary outcome) Good safety profile Conclusions

SPECIFIC IMMUNOTHERAPY IN ASTHMA AND RHINITIS

SYMPTOMS MEDICATIONS Meta-analysis of the efficacy of sublingual immunotherapy in allergic asthma in pediatric patients, 3 to 18 years of age. M Penagos, G Passalacqua, E Compalati, C Baena-Cagnani, S Orozco, A Pedroza GW Canonica

ASTHMA SYMPTOMS SYMPTOM DETERIORATION MEDICATIONS Abramson, Puy, Weiner Cochrane 2010

Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite Maestrelli et al, JACI 2004

PLACEBO SLIT WINTER 99 SPRING 99 SPRING 01 WINTER 99 SPRING 99 SPRING PC20 mgmL NS Pajno GB & Passalacqua G, Allergy 2004 Effect of SLIT to Parietaria on seasonal BHR in children

CONCLUSIONS Based on the literature, SIT is effective in allergic asthma associated with rhinitis, and should be used in association with standard medications SIT reduces bronchial hyperresponsiveness, that is an indirect marker of bronchial inflammation.

RISK FACTORS Based on nonfatal reactions Uncontrolled asthma Severe asthma Use of betablockers Rush immunotherapy Use of new vials Technical errors Based on fatal reactions Uncontrolled asthma Severe asthma Use of betablockers Rush immunotherapy Build-up phase Use of new vials Technical errors Estimated incidence of fatalities < 1/ injections

RHINITIS BHR/ ASTHMA MONO- SENSITIZATION POLY- SENSITIZATION

Allergic rhinitis as a predictor for wheezing onset in school- aged children. Rochat et al, JACI 2010 Cohort of 1,314 children followed from birth to 13 yrs

MARTINEZ,PEDERSEN Long-Term Inhaled Corticosteroids in Preschool Children at High Risk for Asthma Guilbert T, NEJM 2006

Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study Jacobssen, Allergy 2007

SLITNO SLIT NO ASTHMA ASTHMA PRESENCE OF ASTHMA AFTER 3 YEARS Coseasonal SLIT reduces the development of asthma in children with allergic rhinitis. Novembre E. et al, JACI 2004 Randomized, open, controlled 79 children Allergic rhinitis only Follow-up: 3 yrs

PREVENTIVE EFFECTS OF SUBLINGUAL IMMUNOTHERAPY IN CHILDHOOD. AN OPEN RANDOMIZED CONTROLLED STUDY MAURIZIO MAROGNA MD 1, D.TOMASSETTI 1, A. BERNASCONI 1, F.COLOMBO 1, ALESSANDRO MASSOLO BS 2, A. DI RIENZO BUSINCO 4, GIORGIO W CANONICA MD 3, GIOVANNI PASSALACQUA MD 3 AND SALVATORE TRIPODI MD 4 1 Pneumology Unit, Cuasso al Monte, Macchi Hospital Foundation, Varese 2 Department of Animal Biology, University of Pavia, Pavia 3 Allergy & Respiratory Diseases,Department of Internal Medicine, Genoa University 4 Pediatric Allergy Unit, S. Pertini Hospital, Rome AAAI 2008, 101: 261

Diary card Visit Skin test MCh challenge 144 SLIT 72 CONTROLS 14 dropout 6 dropout 1 year BASELINE RANDOMIZED PHASE Year 1 PATIENTS 216 Year 2Year 3 * ****** * * * * * 130 SLIT 66 CONT

CONTROLS NS *** baseline3rd year PERSISTENT ASTHMA % PATIENTS SLIT *** baseline3rd year MONOSENSITIZED PATIENTS % PATIENTS

CONCLUSIONS Patients with rhinitis should be investigated also for asthma Uncontrolled Rhinitis may affect the severity/control of co-morbid asthma. In patients with rhinitis and asthma, treating rhinitis can improve asthma. Specific immunotherapy, either SCIT or SLIT, is of benefit also for asthma.

ARIA RECOMMENDATIONS 1- Patients with persistent AR must be assessed for asthma 2- Patients with asthma should be assessed for rhinitis 3- The optimal strategy must combine the treatment of lower and upper airways, aslo in terms of safety and costs