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F. BraidoF. Braido
Allergy & Respiratory Diseases DepartmentUniversity of Genoa
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RINITEALLERGICA
RINOSINUSITEPOLIPOSI
CONGIUNTIVITE
OTITEDISTURBI DELSONNO
ASMA
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Rinite Asma
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Associazione asma e rinite: dati epidemiologiciAssociazione asma e rinite: dati epidemiologici
• Studi trasversali: Studi trasversali:
– 70% 70% (Ciprandi et al. 1996 Int. Arch. Allergy Immunol.)(Ciprandi et al. 1996 Int. Arch. Allergy Immunol.)
– 90% 90% ((Kapsali et al. 1999 J. Allergy and Clin. Immunology)Kapsali et al. 1999 J. Allergy and Clin. Immunology)
Dei pazienti asmatici allergici soffrono di Dei pazienti asmatici allergici soffrono di
rinite.rinite.
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Leynaert B, et al., JACI 2000; 106: S201-5
Prevalenza di asma nei pazienti rinitici: 10.5 - 43.0%
L’asma è significativamente più frequente nei soggetti rinitici
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ASMA
Fino al 40% dei pazienti con Rinite Allergica hanno Asma
Oltre l’80% dei pazienti con Asma hanno Rinite Allergica
RINITE ALLERGICA
Paziente che si presenta
con sintomi rinitici
ASMAASMA e RINITE ALLERGICA
Paziente che si presenta
con sintomi asmatici
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“ Is the prevalence of adult asthma and allergic rhinitis still increasing?
Results of an italian study ”
Verlato G., et al.Verlato G., et al. JACI 2003
3.0%
21%
15%
9.0%
6876 ptsP<0.01
NS, P= .188
91-93 98-00 91-93 98-00
ASMA
RINITE
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Allergic inflammation is due to the release of mediators as a consequence of the interaction between allergen and allergen-
specific IgE antibodies bound to mast cells and/or basophils
Allergen
IgE
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La cascata allergica
Secrezioni nasali,Secrezioni nasali,starnutazionestarnutazione
BroncocostrizioneBroncocostrizione
Edema/arros. cuteEdema/arros. cute
Congestione nasaleCongestione nasale
Risposta broncospasticaRisposta broncospastica
tardivatardiva
OrticariaOrticaria
Stiintomi allergiciimmediati
Sintomi della faseritardata
Eosinfili
MastocitiFcRI
Allergene
Th2Th2
APC
LinfocitaLinfocita
CD80/86CD28
IL-4IL-13
VCAM-1
IL-3, IL-5GM-CSF
IstaminaIstaminaLeucotrieneLeucotrieneProstaglandineProstaglandineBradikinina, PAFBradikinina, PAF
BBLymphocyteLymphocyte
IgEIgE
LeucotrieniLeucotrieni
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Rapporti tra rinite ed asma: quali sono gli aspetti fisiopatologici?
1 - L ’infiammazione nasale è presente negli asmatici (con/senza sintomi
nasali)?
2- Nella rinite è presente infiammazione bronchiale ?
3- L ’allergia è una malattia sistemica ?
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Biopsie nasali nell ’asmaticoGaga et al, Clin Exp Allergy 2000
0
10
20
30
40
50
60
Cel
lule
pos
itive
per
cam
po
EG2 CD4 CD8
controls
A + R -
A+ R+
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Rapporti tra rinite ed asma: quali sono gli aspetti fisiopatologici?
1- L ’infiammazione nasale è presente negli asmatici (con/senza sintomi nasali)?
2- Nella rinite è presente infiammazione bronchiale?
3- L ’allergia è una malattia sistemica ?
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0
10
20
30
40
50
60C
ell./
mm
2
out inStagione pollinica
EG1+
CD45RO+
CD8+
CD4+
Biopsie bronchiali nei pazienti con rinite stagionale
Chakir et al, Allergy Clin Immunol 2000
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Rapporti tra rinite ed asma: quali sono gli aspetti fisiopatologici?
1- L ’infiammazione nasale è presente negli asmatici (con/senza sintomi nasali)?
2- Nella rinite è presente infiammazione bronchiale ?
3- L’ allergia è una malattia sistemica?
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Infiammazione bronchiale a seguito di challenge nasaleBraunstahl et al, J Allergy Clin Immunol 2001
Eosinofili / mm2 % vasi ICAM+
0
20
40
60
80
100
120
BM
K+
cel
l. ne
lla la
min
a pr
opria
T0 T +24 hrTempo dal challenge
140
+ v
asi
0
20
40
60
80
100
120
ICA
M
T0 T +24 hr
controls
AR patients
Tempo dal challenge
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La rinite è un fattore di rischio per l’asmaThe Copenhagen Allergy Study
Linneberg et al, Allergy 2002
0
5
10
15
20
25
30In
cide
nza
dell’
asm
a (%
)
polline ep. dom. acaro
rinite al basale
no
• 734 pazienti• 15-69 anni• dal 1990 al 1998
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La rinite è un fattore di rischio per l’asmaThe Copenhagen Allergy Study
Linneberg et al, Allergy 2002
0
5
10
15
20
25
30in
cide
nce
of a
sthm
a (%
)
polline animale acarorinite al basale
sìno
OR=8.1OR=18.9
OR=46.5
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0
2
4
6
8
10
12
14
16
18% con asma
No rinite
Prevalenza dell’asma nei
pazienti riniticiLeynaert et al, J Allergy Clin Immunol 2004
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0
2
4
6
8
10
12
14
16
18% con asma
norinite
SAR
Prevalenza dell’asma nei
pazienti riniticiLeynaert et al, J Allergy Clin Immunol 2004
p<0.001
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0
2
4
6
8
10
12
14
16
18% con asma
Norinite
SAR PAR
Prevalenza dell’asma nei
pazienti riniticiLeynaert et al, J Allergy Clin Immunol 2004
p=0.004
p<0.001
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0
2
4
6
8
10
12
14
16
18% con asma
Norhinite
SAR PAR SAR+ PAR
Prevalenza dell’asma nei
pazienti riniticiLeynaert et al, J Allergy Clin Immunol 2004
p<0.001
p=0.004
p=0.002
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C.Lombardi, G.Passalacqua et al, Resp Med 2001C.Lombardi, G.Passalacqua et al, Resp Med 2001
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Evoluzione della malattia
C. Lombardi, G. Passalacqua et al, Resp Med 2001
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Rinite - Sinusite
Asma bronchiale
Stimolazioneallergenica bronchiale
EosinofiliIL-5BasofiliDegranulazionemastocitaria
EosinofiliICAM-1VCAM-1
Stimolazioneallergenica
nasale
Riflessonaso-bronchi
Allergene
Gocciolamentoretronasale
Citochine
Perdita dellafunzionefiltrante
Infezionevirale
Midollo osseo
Precursori
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Shaaban, Lancet 2008
La rinite allergica è fattore di rischio per lo sviluppo di asma
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The Th1/Th2 paradigm
16th edition, 2004, p.1924Harrison’s. Principles of Internal Medicine
(adapted from Romagnani, 1999)
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Mechanism of Airway Inflammation in Allergy
and its markers
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Human effector CD4+ T cells before 2000
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Human effector CD4+ T cells in 2010Human effector CD4+ T cells TODAY
CD161
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Helper T cell differentiation.
J J O’Shea, W E Paul Science 2010;327:1098-1102
Non IgE-mediated Allergy (Evolution to chronicity)
IgE-mediated Respiratory Allergy
FLEXIBILITY AND
PLASTICITY
Th17 cells can switch in vivo to pathogenetic Th17/Th1, Th17/Th2 or Th1 cells by using tissue IL-12 in the absence of any parallel upgrowth of Treg cells
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Clinical Asthma Phenotypes and associated pathophysiological mechanisms
ClinicalAsthmaPhenotype
RequirementFor Th2 cells
Requirement For Th17 cells
Mechanisms orEffector cells
Allergic Yes Yes Th2 /Th17 associated molecules, IL-25, Il-33, TSLP
Eo, MC, Ba, NKT cellsViral Infection No Variable IL-13, IL-17, IFN-a
Alveolar Macrophages NKT cellsAir Pollution, SmokeDiesel Particles, Ozone No Yes IL-17, Oxidative stress
Neutrophils, NKT cellsAspirin No No Loss of PGE2, LeukotrienesObesity No No Oxidative stress?Severe, CCS resistant No Yes IL-17, Neutrophils , NKT cellsExercise, Cold air No No/Yes Changes in mucosal osmolarity
Cytokines?Intrinsic No No Smooth Muscle Irritability?
From Kim HY et al, Nat Immunol, 2010 (modified)
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Allergic Rhinitis and Asthma ad hoc survey: Clinical and Psychological perspectives F. Braido, I. Baiardini, S. Brandi, A. Porcu, G.W. Canonica
Allergy and Respiratory Diseases, DIMI, Genoa University, Genoa, Italy
27.8% of asthmatic patients experience three or less rhinitic 27.8% of asthmatic patients experience three or less rhinitic symptoms, symptoms, 41% from 4 to 6 symptoms, 41% from 4 to 6 symptoms, 31.2 % more than 6 symptoms. 31.2 % more than 6 symptoms.
These symptoms deeply interfere with daily life causing These symptoms deeply interfere with daily life causing sleep problems (87.3%), sleep problems (87.3%), lack of concentration (78.9%), lack of concentration (78.9%), difficulties in spare time (71.8%) and sport (71.7%). difficulties in spare time (71.8%) and sport (71.7%).
504 asthmatic patientsClin Exp Allergy. 2007 May;37(5):788-93.
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Braido et al. Clin Exp Allergy 2007
In presenza di sintomi rinitici, peggiora la vostra asma?
70,7
59
73,9
83,6
64,7
0 10 20 30 40 50 60 70 80 90
Frequenti risveglinotturni
Peggioramento delrespiro affannoso
Peggioramento dellatosse
Frequente dispnea
Uso frequente diSABA
Indagine ad hoc su rinite allergica ed asma(504 pazienti asmatici )
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La rinite non trattata aumenta il rischio di attacchi asmatici ericoveri per asma. Bousquet, Clin Exp Allergy 2005
Asma
Asma + rinite
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La rinite allergica raddoppia il rischio di visite al pronto soccorso in pazienti con asma bronchiale
Analisi Post hoc degli accessi al pronto soccorso in pazienti asmatici con e senza rinite allergica concomitante in un arco di tempo di 52 settimane.
% p
azie
nti
Patienti con asma + rinite allergica
(n = 893)
Patienticon asma(n = 597)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
p = 0.029
1.7
3.6
Adattato da Bousquet J et coll. Poster presentato all’European Academy of Allergology and Clinical Immunology (EAACI), Giugno 12–16, 2004, Amsterdam. Poster 141.
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Differenze nei domini riguardanti la qualità della vita tra pazienti controllati e non controllati
I pazienti con un’asma controllata (ACT >20) hanno una migliore qualità della vita rispetto ai soggetti non controllati
UA
20,06
31,64
0
5
10
15
20
25
30
35
40
ACT ≥ 20 ACT < 20
LA
17,53
44,09
0
5
10
15
20
25
30
35
40
45
50
ACT ≥ 20 ACT < 20
RAI
19,44
31,83
0
5
10
15
20
25
30
35
40
ACT ≥ 20 ACT < 20
GS
18,8
37,08
0
5
10
15
20
25
30
35
40
45
ACT ≥ 20 ACT < 20
p=0.047 p<0.0001
p<0.0001p<0.001
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ACT vs GS
0
5
10
15
20
25
30
0 20 40 60 80 100 120
1- GS
ACT
100 80 60 40 20 0
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La presenza di sintomi rinitici influenza la qualità della vita del
paziente asmatico?
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Differenze nei domini del Rhinasthma sulla base del livello di sintomi rinitici come misurati dal T5SS
Per quanto riguarda le vie aeree superiori, la qualità della vita è quasi ottimale (6) nei pazienti privi di sintomi, mentre nei pazienti sintomatici trattati e non la qualità della vita è intorno a 35, indicando una considerevole riduzione del proprio benessere
UA
6,72
35,23
0
5
10
15
20
25
30
35
40
TSS5 < 3,5 TSS5 ≥ 3,5
LA
22,54
32,96
0
5
10
15
20
25
30
35
40
TSS5 < 3,5 TSS5 ≥ 3,5
RAI
19,77
27,73
0
5
10
15
20
25
30
35
40
TSS5 < 3,5 TSS5 ≥ 3,5
GS
17,05
32,25
0
5
10
15
20
25
30
35
40
TSS5 < 3,5 TSS5 ≥ 3,5
p<0.0001
p<0.0001
p=0.001
p=0.07
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Grafico
UA in controlled patients
6,17
29,2
0
5
10
15
20
25
30
T5SS < 3,5 T5SS > 3,5
p < 0,001
LA in controlled patients
13,11
20,45
0
5
10
15
20
25
30
T5SS < 3,5 T5SS > 3,5
p = 0,066
RAI in controlled patients
15,63
21,95
0
5
10
15
20
25
30
T5SS < 3,5 T5SS > 3,5
p = 0,026
GS in controlled patients
11,7
23,48
0
5
10
15
20
25
30
T5SS < 3,5 T5SS > 3,5
p = 0,001
La rinite influenza la qualità della vita nei pazienti controllati?
Anche se il controllo dell'asma viene raggiunto, la presenza di sintomi rinitici peggiora la qualità della vita
del paziente
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Quale è l'importanza relativa di controllo e di rinite, sintomi nell’influenzare i differenti domini della qualità
della vita?
Regressione Logistica
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GOAL: Quality of life in controlled asthma patients
(analisi post hoc dello studio GOAL)
Bateman ED et al., ERJ 2007
La qualità della vita migliora raggiungendo livelli ottimali.
Pazienti con un punteggio > 6: 61% con SSFC vs. 52% con FP).
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Una qualità della vita ottimale è stata raggiunta da 78/209 (37.32%) pazienti
Il controllo dell’asma è significativamente associato con una qualità della vita ottimale (2=49.599; p<0.001).
I pazienti ben controllati e totalmte controllati differiscono significativamente nel raggiungimento della qualità della vita ottimale (2= 7.617; p < 0.006) .
Braido et Al PLOsone 2012
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Rhinitis & Asthma Patient’s PerspectiveRAPP scoring is simple: sum of responses to each item
Braido et Al Submitted
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ROC analyses, using RHINASTHMA GS score < 20 or >20 as criterion measure, to determine the RAPP score that indicates optimal HRQoL.
Scoring0.
000.
250.
500.
751.
00S
ensi
tivity
0.00 0.25 0.50 0.75 1.001 - Specificity
Area under ROC curve = 0.9128
A cut-off point of 15 demonstrated the best sensitivity (88.3%) and specificity (84.6%) in discriminating the achievement of an optimal HRQoL, with a percentage of correctly classified patients of 87.3%
Braido et Al Submitted
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Optimal QoL
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0
20
80
40
60
Percentuale media di pazienti “Controllati” al termine della fase incrementale studio GOAL
% d
i p
azi
en
ti c
on
trollatt
i Modified by Bateman et al, ARJCCM 2004
0
20
80
40
60
100
31% (42-19)
Controllo Totale
63.6% (71-51)
Buon Controllo
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0
20
80
40
60
Percentuale media di pazienti “Controllati” al termine dello studio GOAL
% d
i p
azi
en
ti c
on
trollatt
i Modified by Bateman et al, ARJCCM 2004
0
20
80
40
60
100
41% (50-29)
Controllo Totale
71.6% (78-62)
Buon Controllo
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3
4
2
75
10
0
5
10
15
20
25
30
35
40
45
50
Se
ttim
an
e
1098 pz non precedentemente trattaticon steroidi
1163 pz trattati con <= 500 mcgBDP/die (o equivalenti)
1155 pz trattati con > 500 mcg <=1000 mcg BDP/die (o equivalenti)
BUON CONTROLLO Settimana entro la quale il 50% dei pazienti ha raggiunto un buon
controllo
salmeterol/fluticasone
fluticasone
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16
24
21
45
38
0
5
10
15
20
25
30
35
40
45
50
Se
ttim
an
e
1098 pz non precedentemente trattaticon steroidi
1163 pz trattati con <= 500 mcgBDP/die (o equivalenti)
1155 pz trattati con > 500 mcg <=1000 mcg BDP/die (o equivalenti)
CONTROLLO TOTALE Settimana entro la quale il 50% dei pazienti ha raggiunto il
controllo totale
salmeterol/fluticasone
fluticasone
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Miglioramento dell’iperreattività bronchiale
Miglioramento dell’iperreattività bronchiale
Lundback B.& Dahl R. Allergy 2007; 62: 611-619 (data from ref. 49 - Lundback B. et al. Resp Med 2006; 100: 2-10)
Lundback B.& Dahl R. Allergy 2007; 62: 611-619 (data from ref. 49 - Lundback B. et al. Resp Med 2006; 100: 2-10)
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Lundback B. et al. Respiratory Medicine 2009; 103: 348-355Lundback B. et al. Respiratory Medicine 2009; 103: 348-355
RISULTATI A 3 ANNIRISULTATI A 3 ANNI
Andamento temporale delle modificazioni della media geometrica della PC20 (mg/ml)Andamento temporale delle modificazioni della media geometrica della PC20 (mg/ml)
La terapia continuativa ha infine comportato un continuo e progressivo miglioramentodell’iperreattività bronchiale
La terapia continuativa ha infine comportato un continuo e progressivo miglioramentodell’iperreattività bronchiale
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Severe Refractory AsthmaPatients who remain difficult to control despite an extensive
reevaluation of diagnosis, management, and an observational period of at least 6 months by an asthma specialist
Chanez P et al. JACI 2007
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Evaluation of patients with Refractory AsthmaProceedings on Refractory Asthma AJRCCM 2000
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NasoNaso BronchiBronchi
Antiistaminici
Profilassi ambientale
Immunoterapia specifica
NCSICS
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Antihistamines properties
EAACI ARIA Criteria
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Evaluation of patients with Refractory AsthmaProceedings on Refractory Asthma AJRCCM 2000
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122 patients
The level of asthma control results to be inversely correlated to the presence of sleep disturbances
Patients with good control report less frequent and less severe sleep disturbancescompared to uncontrolled subjects.
A significant percentage of subjects (11-20%) having achieved total control of asthma stillreport sleep disturbances, that contribute to increase the impact of the disease and to impair quality of life
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Patients with Chronic Night-time Rhinitis Symptoms are More Likely to Snore
Sleep Problem Odds Ratio for Chronic Nighttime Rhinitis
Symptoms
P Value
Snoring Never or rarely Occasional (1-3 nights/week) Habitual (>3 nights/week)
1.01.32.0
0.02<0.0001
Chronic excessive daytime sleepiness
2.4 0.001
Chronic non-restorative sleep 2.2 <0.0001
Patients with chronic nighttime rhinitis symptoms were 2 times more likely to be a habitual snorer
Young et al. J Allergy Clin Immunol. 1997;99:S757.
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Patients with Congestion Due to Allergy are More Likely to Snore
AHI Odds Ratio for Congestion Due to
Allergy
P Value
<5, non-snorer, no SDB
<5, habitual snorer
5-15
>15
1.0
1.5
1.0
1.8
0.04
NS
0.04
Patients with congestion due to allergy were 50% more likely to be a habitual snorer than patients without congestion
Young et al. J Allergy Clin Immunol. 1997;99:S757.
AHI=apnea/hypopnea index, determined as the total number of apnea and hypopneaepisodes (assessed by polysomnography) divided by hours of sleep.
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Nasal Congestion in Patients with SAR is Associated with Obstructive Sleep Apneas*
*5 men with SAR.
McNicholas et al. Am Rev Respir Dis. 1982;126:625.
Incr
ease
in o
bst
ruct
ive
slee
p a
pn
eas/
hou
r
Increase in nasal resistance (%)0 10 20 30 40 50 60 70
0
0.2
0.4
0.6
0.8
1.0
Apneas were longer and more frequent in patients with obstruction than in those without obstruction
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3488 pazienti asmatici
Paziente : lamenta sintomi rinitici ? Si in 3153 pazienti (90,3%)
MMG : ritiene che il suo paziente soffre di rinite? 68,6%
1553 MMG
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Nell’ultimo mese si è svegliato di notte perché non respirava bene a causa di
Campione totale di 3488 pazienti
Rinite = 58.5%Asma = 39.65
STOP BANG > 3 = 53,9%
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F. BraidoF. Braido
Allergy & Respiratory Diseases DepartmentUniversity of Genoa