Gianenrico Senna Unità Operativa di Allergologia Azienda Universitaria-Ospedaliera Istituti Ospitalieri di Verona

malattia sistemica con localizzazione d’organo

The early phase

B IgE Legame allergene Mastcell

Recettore H1

Contrazione m. liscio Permeabilità Vasodilatazione Stimolazione term.nervose

istamina

Broncospasmo, starnuti, prurito, pomfi, tosse, eritema.

lacrimazione, anafilassi…

JACI 2011

JACI 2011

Stone et al. JACI 2009

Stone et al. JACI 2009

II-12

CD4

ALLERGEN

ADJUVANTS

APC

ITS

Th1

Th2 IL-5 ECP EDX MBP Eos IL-4 IL-13 B

Y Y Y

ALLERGEN

Y Y Y

MAST IgE

Fibro

REMODELLING MEDIATORS Histamine LTs iNOS LATE PHASE INFLAMMATION ENDOTHELINS CELL RECRUITMENT

The allergic reaction: today

Neu EARLY PHASE ADHESION MOLECULES

Eosinophils

Kinetics of the allergic reaction after nasal challenge symptoms eosinophils 0 challenge 30’ 1h 6h 12h 24h

Rhinitis Controls

Bronchial hyperresponsiveness and airway inflammation markers in nonasthmatics with allergic rhinitis.

Polosa R et al. ERJ 2000

Exhaled nitric oxide as diagnostic test for asthma in rhinitics patients with asthmatic symptoms

Heffler, 2006

Ann Allergy Asthma Immunol 2008: 100 : 12

Increased expression of iNOS might have a role in the development of allergic inflammation in upper airways and in comorbidity of AR and asthma

La stimolazione nasale con allergene Aumenta la reattività bronchiale Induce infiammazione bronchiale 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

Induce infiammazione nasale La stimolazione bronchiale segmentale endoscopica con allergene

allergene Allergia: malattia sistemica Progenitori midollari Fattori chemotattici Progenitori IL-5R+

Rhinitis and onset of asthma : a longitudinal population based study

Shaaban et al. Lancet 2008; 372 : 1049 29 centres (14 countries) : 6.461 partecipants

Frequency and impact of allergic rhinitis in asthma patients in everyday general medical practice : a French observational cross sectional study Magnan et al Allergy 2008; 63 : 292

CONGIUNTIVITE OTITE ALTERAZIONI DEL SONNO

RINITE

ALTERAZIONI SCHELETRICHE FACCIALI

ASMA

SINUSITE POLIPOSI

Inflammation

is the Major Underlying Cause of Mucosal Congestion in Upper Respiratory Diseases

Inflammation 1-4 Allergic Rhinitis Nasal Polyposis Rhinosinusitis Congestion 4

Image of congested nasal passage in rhinosinusitis courtesy of Professor J.-M. Klossek.

1. Minshall et al.

Otolaryngol Head Neck Surg

. 1998;118:648; 2. Bachert et al.

J Allergy Clin Immunol.

1997;99:837; 3. Bachert et al.

Allergy

. 1998;53:2; 4. van Drunen et al.

Allergy.

2005;60(suppl 80):5.

Influence of comorbid conditions on asthma

Boulet LP, ERJ 2009; 33 : 897

Rhinosinusitis in severe asthma Bresciani et al. JACI 2001; 107 .73

CT scan abnormality was common to both groups, but the clinical (p<0.05) and the CT scan severity scores (p<.0005) were higher in the subjects with severe steroid-dependent asthma

88% 100%

Clinical aspects of the link between chronic sinonasal diseases and asthma.

Dursun et al. Allergy Asthma Proc 2006; 27 : 510

Risk factors of frequent exacerbation in difficult-to-treat asthma

Ten Brinke A et al Eur Resp J 2005; 26 : 812 51

Risk factors of frequent exacerbation in difficult to-treat asthma

Ten Brinke A et al Eur Resp J 2005; 26 : 812 51 > 3 exacerbation/yr < 1 exacerbation/yr

Influence of comorbid conditions on asthma Boulet LP ERJ 2009; 33 : 897

Predictors of habitual snoring and obstructive sleep apnea risk in patients with asthma Teodorescu et al Chest 2009;135: 132 Dose dependent relationship between habitual snoring and ICS dose Dose dependent relationship between high OSAS and ICS dose

Systemic aspects

Allergen sensititization is not just a local event, but also a systemic event

In animal models :  Allergen sensitization on the skin induced localized dermatitis and airway eosinophilia  Airway sensitization not only caused eosinophilic esophagitis, but also skin eosinophilia, accelerated bone marrow eosinophilopoiesis and blood eosinophilia Spergel JM. Clin Exp Allergy 2005; 35 : 1421

Systemic aspects

Allergen sensitization is not just a local event, but also a systemic event

In human models :  Allergen exposure in the asthmatic airway induced eosinophilia not only in the local airway, but distally in bone marrow with increased IL5 expression Wood et al. Am J Resp Crit Care Med 2002; 166: 883

Pollen and eosinophilic esophagitis Fogg et al. JACI 2003; 112 : 796

Seasonal intestinal inflammation in patients with birch pollen allergy

Magnusson et al. JACI 2003; 112 : 45 Marked increase of MBP-stained eosinophils in patients during the pollen season MBP-stained eosinophils in healthy control subjects

Eosinophilic esophagitis

Sgouros et al. 2006; 18 : 211

Prevalence : 4.3 cases per 10.000 individuals Males/female 3:1 Age : 30-40 yrs Symptoms : dysphagia (93%), food impaction(61%), hearthburn (23%) others : chest pain, odynophagia, vomiting Allergic history 51% Peripheral eosinophilia 31% Increase of IgE 55%

Hallmarks of Remodelling in asthma

Bas. Membrane Submucosa Smooth muscle Thickening Collagen Deposition Hypertrophy

Remodelling of the upper airways in allergic rhinitis : is it a feature of the disease ?

Salib & Howarth Clin Exp Allergy 2003 ; 33 : 1629

JACI, 2007

Jyonouchi et al Immunol Allergol Clin N Am 2009

CEA, 2010

Benedetto et al.JACI 2011

Van den Oord, 2010

Marenholtz et al JACI, 2009

Corrigan, JACI 2006

Benedetto et al, J Invest Dermatol 2008

CEA, 2010

CEA, 2010

CEA, 2010

2010

Rondon et al JACI 2011

Role of staphylococcal superantigens in upper airway disease

Bachert et al Curr Opin Allergy Clin Immunol 2008; 8 : 34 

Nasal polyps are characterized by Th2 cytokine pattern dominated



Cytokine environment is decisive regarding the impact of S.Aureus enteroxins, as superantigens



S.Aureus enteroxins B further shifts the cytokine pattern in nasal polyps toward Th2 cytokines (IL4- IL5)



Furthermore S.Aureus enteroxins influence local immunoglobulin syntesis and induce polyclonal IgE production, which may contribute to severe inflammation through a mastcell activation

Van Zele et al. JACI 2004; 114 : 983

63% 67% 87% Colonization rates in controls and subjects with CRS were 33.3% and 27.3%, whereas 63% in patients with nasal polyposis and 87.5% in subgroups with asthma and aspirin hypersensitivity

The role of sinus disease in asthma

Bachert et al Curr Opin Allergy Clin Immunol 2006; 6 : 29

Hypotheses explaining the link between sinus disease and asthma

Allergy 2011

Allergy 2011

ASTHMA

Unità Operativa di Allergologia Ospedale Civile Maggiore di Verona Azienda Ospedaliera di Verona Centro di riferimento regionale per la prevenzione, la diagnosi e la terapia delle malattie allergiche

G. Senna P. Bonadonna A. Dama M. Schiappoli S. Dal Ponte E. Conte E. Olivieri

Aknowledgement

N. Contro P. Lavarini C. Melotti

Collaborations

A. Boner B.Caruso (Verona) C. Le Pera (Verona) R. Zanotti (Verona) P. Gisondi (Verona) L. Castellani (Trento) M. Crivellaro (Padova) M. Pagani (Mantova) C. Lombardi (Brescia) GW Canonica (Genova) G. Passalacqua (Genova) L. Antonicelli (Ancona) S: Durham (Londra) M. Calderon (Londra) A. Romano (Roma)