Gianenrico SennaGianenrico SennaUnità Operativa di Allergologia

Azienda Universitaria-Ospedaliera

Istituti Ospitalieri di Verona

Ospedale Civile Maggiore di VeronaAllergia : una malattia

sistemica con localizzazione

d’organo

Legame allergene

Mastcell

istamina

B

IgE

Contrazione m. liscioPermeabilitàVasodilatazioneStimolazione term.nervose

Recettore H1

The early phase

Broncospasmo, starnuti, prurito, pomfi, tosse, eritema.lacrimazione, anafilassi…

JACI 2011

JACI 2011

Stone et al. JACI 2009

Stone et al. JACI 2009

APC

ALLERGEN

Th1

Th2

Eos

IL-5

BIL-4Y

Y Y Y

Y Y IgE

MASTFibro

IL-13

MEDIATORS

ALLERGEN

ECPEDXMBP

CD4 ITSII-12

EARLYPHASE

HistamineLTs

ADHESIONMOLECULES

LATE PHASEINFLAMMATION

REMODELLING

ADJUVANTS

RECRUITMENT

ENDOTHELINSiNOS

Neu

CELL

The allergic reaction:today

Eosinophils

0 30’ 1h 6h 12h 24h

challenge

Kinetics of the allergic reaction after nasal challenge

symptomseosinophils

Bronchial hyperresponsiveness and airway inflammationmarkers in nonasthmatics with allergic rhinitis.Polosa R et al. ERJ 2000

RhinitisControls

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

Heffler, 2006

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

Ann Allergy Asthma Immunol 2008: 100 : 12

La stimolazione nasale con allergene

Aumenta la reattività bronchialeInduce infiammazione bronchiale

Littell NT, Changes in airways resistance following nasal provocation. Am Rev Respir Dis 1990Corren 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

La stimolazione bronchiale segmentale endoscopica con allergene

Induce infiammazione nasale

allergene Fattori chemotattici

Progenitorimidollari

ProgenitoriIL-5R+

Allergia: malattia sistemica

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

RINITE

ALTERAZIONIDEL SONNO

CONGIUNTIVITE

OTITE

SINUSITEPOLIPOSI

ALTERAZIONISCHELETRICHE

FACCIALI ASMA

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

Image of congested nasal passage in rhinosinusitis courtesy of Professor J.-M. Klossek.Image of congested nasal passage in rhinosinusitis courtesy of Professor J.-M. Klossek.1. Minshall et al. 1. Minshall et al. Otolaryngol Head Neck SurgOtolaryngol Head Neck Surg. 1998;118:648; 2. Bachert et al. . 1998;118:648; 2. Bachert et al. J Allergy Clin Immunol.J Allergy Clin Immunol. 1997;99:837; 1997;99:837;3. Bachert et al. 3. Bachert et al. AllergyAllergy. 1998;53:2; 4. van Drunen et al. . 1998;53:2; 4. van Drunen et al. Allergy.Allergy. 2005;60(suppl 80):5. 2005;60(suppl 80):5.

Allergic RhinitisAllergic Rhinitis RhinosinusitisRhinosinusitisInflammationInflammation1-41-4

Nasal PolyposisNasal Polyposis

CongestionCongestion44

Influence of comorbid conditions on asthma

Boulet LP, ERJ 2009; 33 : 897

Rhinosinusitis in severe asthmaBresciani et al. JACI 2001; 107 .73

88% 100%

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

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

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

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

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

            

     

> 3 exacerbation/yr

< 1 exacerbation/yr

            

     

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

Predictors of habitual snoring and obstructive sleep apnea risk in patients with asthmaTeodorescu 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 eosinophiliaAirway 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 allergyMagnusson 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

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

Sgouros et al. 2006; 18 : 211

Bas. Membrane

Thickening Collagen Deposition Hypertrophy

Hallmarks of Remodelling in asthma

Submucosa Smooth muscle

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 dominated cytokine pattern

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

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

63%

67%

87%

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

ASTHMA

Allergy 2011

G. SennaP. BonadonnaA. DamaM. SchiappoliS. Dal PonteE. ConteE. Olivieri

N. ControP. LavariniC. Melotti

Collaborations

A. BonerB.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)

Centro di riferimento regionale per la Centro di riferimento regionale per la prevenzione, la diagnosi e la terapia delle prevenzione, la diagnosi e la terapia delle

malattie allergichemalattie allergiche

Unità Operativa di AllergologiaUnità Operativa di Allergologia

Ospedale Civile Maggiore di VeronaOspedale Civile Maggiore di Verona

Azienda Ospedaliera di VeronaAzienda Ospedaliera di Verona

Aknowledgement