1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

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

3. 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

4. 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

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

6. Rhinitis: comorbidities RHINITIS ASTHMA RHINOSINUSITIS CONJUNCTIVITIS OTITIS SLEEP DISORDERS polyps

7. Allergic rhinobronchitis: the asthma-allergic rhinitis link. Simons FER J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):534-40. United airways disease: therapeutic aspects. Passalacqua G, Ciprandi G, Canonica GW Thorax. 2000 Oct;55 Suppl 2:S26-7. Linking upper and lower respiratory airways. Aubier M. J Allergy Clin Immunol 1999; 83: 431-434.

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

9. Pariente Leynaert Wright Settipane Sibbad France ECRHS Tucson Providence England adults children adolesc adults 1367 262 129 162 319 rhin. 13.4 no rhin. 3.8 rhin. 22.5 no rhin. 4 rhin. 32 no rhin. 5 rhin. 10.5 no rhin. 3.6 SAR. 23 PAR 26 both 43 STUDYLOCUSSUBJECTS% ASTHMA Leynaert et al. JACI 2000 93% of asthmatics have concomitant rhinitis Kapsali T et al, JACI 1998

10. - 591 patients - 502 controls - allergic to pollens, mite, -epithelia 0 5 10 15 20 25 30 35 % subjects contrmildseveremildsevere intermittent persistent % pazienti Prevalence of asthma (physician diagnosed) in rhinitis Bousquet, CEA 2005

11. Shaaban, Lancet 2008

12. 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

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

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

15. 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

16. Bronchial endoscopic challenge With allergen Induces nasal inflammation

17. 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

18. Perennial rhinitis: independent factor for developing asthma Leynaert et al, J Allergy Clin Immunol 1999 0 5 10 15 20 25 % pazienti asmatici atopicnon-atopic controls rhnitis

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

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

21. 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?

22. THERAPY Immunotherapy Nasal steroids Antihistamines Combination therapy UNITED AIRWAYS

23. 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)

24. 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: 466-476 69 CLINICAL QUESTIONS ON THE TREATMENT RECOMMENDATION: CONDITIONAL/STRONG LEVEL OF EVIDENCE: HIGH/MODERATE/LOW/VERY LOW

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

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

27. Cruz, Allergy 2008

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

29. Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion. Berger et al. Ann Allergy Asthma Immunol 2002 14 8 2 15 5 30 WKS 1-2WKS 1-4 Mean % reduction of AM instantaneous asthma score Mean % reduction of AM/PM asthma score * *

30. Taramarcaz, Cochrane 2008

32. 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

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

34. 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

35. 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

36. Primary endpoint: Rhinasthma Global Score Mean changes from baseline (V2) to endpoint (V4) ITT Population p<0.001 Mean change vs baseline -12 -10 -8 -6 -4 -2 0 2 MFNSPlacebo -10,3 0,4

37. 5 10 15 20 25 30 <.001 baselineweek 2week 4 Rhinasthma GS mean MFNS Placebo Rhinasthma global summary

38. 5 10 15 20 25 30 35 40 baselineweek 2week 4baselineweek 2week 4baselineweek 2week 4 <.001 UAS LASRAI MFNS Placebo

39. Global Symptom Score (GSS) Weekly score Mean score * * 0 2 4 6 8 10 12 GSS Placebo GSS MFNS basale1234

40. 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

41. SPECIFIC IMMUNOTHERAPY IN ASTHMA AND RHINITIS

42. 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

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

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

45. PLACEBO SLIT WINTER 99 SPRING 99 SPRING 01 WINTER 99 SPRING 99 SPRING 01 0.008 0.005 10 5 PC20 mgmL 0.005 NS 0.001 Pajno GB & Passalacqua G, Allergy 2004 Effect of SLIT to Parietaria on seasonal BHR in children

46. 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.

47. 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 < 1/2.000.000 injections

48. RHINITIS BHR/ ASTHMA MONO- SENSITIZATION POLY- SENSITIZATION

49. 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

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

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

52. SLITNO SLIT 37 8 26 18 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

53. 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

54. 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

55. CONTROLS NS *** baseline3rd year PERSISTENT ASTHMA 10 20 30 40 50 60 70 % PATIENTS SLIT *** baseline3rd year MONOSENSITIZED PATIENTS 10 20 30 40 50 60 70 % PATIENTS

56. 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.

57. 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