common and differential patterns in the inflammatory mediator … school 2013... · 2013-09-26 ·...

Paloma Campo MD, PhD

U.G.C. Allergy

Carlos Haya Hospital, Málaga- SPAIN

Common and differential patterns in the

inflammatory mediator release

EAACI SUMMER SCHOOL

19-21 September 2013

Málaga, Spain

A conflict of interest is any situation in which a speaker or immediate family members have interests, and those may cause a conflict with the current presentation. Conflicts of interest do not preclude the delivery of the talk, but should be explicitly declared. These may include financial interests (eg. owning stocks of a related company, having received honoraria, consultancy fees), research interests (research support by grants or otherwise), organisational interests and gifts.

Disclosure

In relation to this presentation, I declare that there are no conflicts of interest.

NSAIDs are the drugs more frequently prescribed worldwide

Drugs most frequently involved in hypersensitivity drug reactions

Doña I JIACI 2012

Selectivos 156 (24%)

Intolerancia cruzada 503 (76%)

Selective 24%

Cross Intolerant 76%

Doña I CEA 2011

Type of reaction

Clinical manifestation

Timing Underlying disease

Cross reactivity

Putative mechanism

NSAIDs exacerbated respiratory disease (NERD)

Rhinitis/asthma Acute Asthma/ rhinosinusitis

YES Non-allergic

Cox-1 inhibition

NSAIDs exacerbated cutaneous disease (NECD)

Urticaria/angioedema

Chronic urticaria

Cox-1 inhibition

NSAIDs –induced urticaria/angioedema (NIUA)

Urticaria/angioedema

No underlying chronic diseases

Unknown , probably COX-1 inhibition

Single NSAIDs –induced urti/angio/ anap (SNIUAA)

Urticaria/angioedema/anaphylaxis

No underlying chronic diseases

NO Allergic IgE-mediated

Single NSAIDs-induced delayed reactions (SNIDR)

various symptoms and organs involved

Delayed No underlying chronic diseases

T cell mediated

CLASSIFICATION

ENDA NSAID TF (Kowalsky M, 2013)

SAME MECHANISM?? Mediators´

release

NSAIDs –induced urticaria/angioedema (NIUA)

Reaction related to COX inhibition potency

MOST COMMON MANIFESTATION:

60% of all CI Doña I, 2011

NSAIDs exacerbated respiratory disease (NERD)

REPRESENT <10% of all CI

Doña I, 2011

Reaction to different chemically-unrelated NSAIDs

COX inhibition COX inhibition ??

NERD CLINICAL MANIFESTATIONS

CHRONIC RS POLYPOSIS

ASTHMA

RHINITIS ASTHMA NSAID INTOLERANCE

VIRUS

TOBACCO

CONTAMINATION

NERD NATURAL HISTORY

Healthy subjects WITHOUT chronic urticaria

NSAIDs –induced urticaria/angioedema (NIUA) CLINICAL MANIFESTATIONS

Cutaneous response (urticaria/AE) after intake of different NSAIDs

Atopy as risk factor?

60% of all CI: the most common manifestation

Natural history: present in children

Non atopy 41%

Grasses 32%

Mites 18%

Grasses+ mites 21%

Others 29%

Atopy 59%

Atopy AERD

N= 112

Non Atopy 30%

Grasses 15.38%

Mites 48.71%

Grasses + Mites

11.54%

Others 24.36%

Atopy 70%

Atopy NSAIDS Hypersensitivity (Acute urticaria)

Cross-Intolerance

N= 112

Atopy and hypersensitivity reactions to NSAIDs

NERD

NIUA

ELISA with purified D. pteronyssinus allergens

Der p2 most recognized

Atopy and hypersensitivity reactions to NSAIDs

NSAIDs with different chemical structures induce the same pattern of reactions

Non immunological mechanism

NSAIDs capacity for inducing reactions directly positively correlates with the COX-1 inhibitory potency

Non-immunological mechanisms: COX hypothesis

(Szczeklik A, 1975; Szczeklik A, 1977; Stevenson DD, 1990; Quiralte J, 1996)

A. Szczeklik in 1975

Szczeklik A, 1975; Szczeklik A, 1995; Szczeklik A, 2006

LTB4

Araquidonic Acid

PLA2

COX-1

PGG2

PGH2

12-HETE 12-LOX

15-LOX, 5-LOX

15-HETE

LIPOXINS

5-LOX

ALOX-5

ALOX-5 AP

LTA4

Specific

Synthetases

PGE2 PGF2X

PGD2

LTC4

LTD4

LTE4

LTC4S

RECEPTORS LX-R EP-R

(EP-1, EP-2, EP-3, EP-4)

IP-R

PGI2 TXA2

TP-R

FP-R DP-R CRTH2

LTcis-R (LTcis-R1, LTcis-R2)

FLAP

Pro-inflammatory

Anti-inflammatory

Membrane Phospholipids

Basophil-mast cells-eosinophils express LTC4 synthase key enzime for LT production LTC4 overexpressed in bronchial byopsies,mast cells and eosinophils Increased number of leukotrien receptors (Cys LTR1 and 2) in nasal mucosa and inflammatory cells Increased baseline urine and bronchial epithelia levels of LTs Increased LTs after ASA challenge in urine, nasal and bronchial lavage

Szczeklik A, 2003

Setkowicz M, 2009

LTs

Nizakowska ERJ 2000

URINE

Choi GS

NASAL LAVAGE

EXHALED BREATH CONDENSATE: Distinctive pattern for NERD

NERD

ATA

CONTROLS

Polymorphisms of candidate genes of arachidonic acid pathway

NERD NIUA

Cornejo-García JA, Allergy 2012; Kim SH, Pharmacogenomics 2008

Evaluate differences in clinical characteristics mediators release in subjects with CI reactions to NSAIDs with cutaneous involvement (NIUA) comparing to NERD subjects as a well-stablished model. NIUA n=25 NERD n=60 ATA n=15 CG n=15

Allergy Dept Carlos Haya Hospital Málaga Infanta Leonor Madrid

2010 - 2011

> 3 episodes of urticaria/angioedema after intake of >2 non- chemically related NSAIDs and/or positive OPT Patients > 3 episodes of respiratory symptoms after intake of >2 non- chemically related NSAIDs and/or positive OPT Asthmatics with good tolerance to NSAIDs Controls Non asthmatics with good tolerance to NSAIDs

Nasal Challenge with Lysine-aspirin

290 mg/ml lysine: 100 µl in each nostril (29 mg of lysine= 16 mg of ASA)

NASAL LAVAGE ACOUSTIC RHINOMETRY VAS SPIROMETRY

0 15´

60´

120´



NASAL LAVAGE ACOUSTIC RHINOMETRY VAS SPIROMETRY L-Aspirin

Positive Challenge: <70% vol 2-6 and >30% VAS Nasal Lavage: ECP Serum: % Eosinophils, ECP, Tryptase Tryptase and IgE PGD2, PGE2 HPLC-MS LTD4 LTE4 Campo et al Allergy 2013

NIUA n=25

NERD n=60

ASPIRIN TOLERANT

ASTHMATICS n=15

CONTROLS n=15

Age (mean, range)

38.2 (15-62)

39.4 (16-65)

37.3 (30-69)

36.6 (24-65)

Sex (F/M) 15F/10M 40F/20M 11F/4M 12F/3M

Smoking (active, ex- smoker) 24% active

12% active/ 32% ex

50% ex 22% ex

Clinical symptoms due to NSAID intake

Urticaria=8 Angioedema=6

Urticaria+Angioedema=11

Rhinitis=12 Asthma=29

Rhinitis+Asthma= 19

Tolerant Tolerant

Atopy (≥1 positive SPT) 66.7% * 57.5% * 55% * 38.9%

Rhinitis 68% 85.4% 75% 36.8%

Asthma 16% 75% 100% 0%

% Positive nasal challenge

L-ASA 12%

80%

Negative Negative

Campo et al Allergy 2013

Time (minutes)

Figure 1a.

Figure 1b.

Time (minutes)

*

*

*

0

10

20

30

40

50

60

70

80

0 15 60 120

ECP

(n

g/m

l)

Controls MNSAID-UA AERD Tolerant asthmatics

0

0.5

1

1.5

2

2.5

3

3.5

4

0 15 60 120

Tryp

tase

(n

g/m

l)



Figure 2a

Figure 2b Figure 2d

Figure 2c

Time (minutes)

Time (minutes)

Time (minutes)

Time (minutes)

*

*

*

*

0

5

10

15

20

25

30

35

40

0 15 60 120

PG

E2 p

g/m

l


0

5

10

15

20

25

30

35

40

0 15 60 120

LTD

4 p

g/m

l


0

5

10

15

20

25

30

35

40

0 15 60 120

PG

D2

pg/

ml


0

5

10

15

20

25

30

35

40

0 15 60 120

LTE4

pg/

ml



BLOOD SAMPLES


Eosinophil degranulation

Mast Cell Activation

PGE2

Mediators release NIUA:

LTE4 *

Baseline 15 minutes 60 minutes 120 minutes

PGE2

Mediators Release AERD:

ECP Tryptase

LTD4

LTE4

PGD2

Baseline 15 minutes 60 minutes 120 minutes

Mediators Release NERD


NIUA

¿MECHANISM?

¿COX INHIBITION?

Numerous reports in NERD – Pattern of mediators´release Sanak M, 2011; Mastalerz L, 2008, Gaber F, 2008

¿NIUA? – Same mechanism assumed based on clinical observations NIUA –different pattern of mediators release

MEASUREMENT OF MEDIATORS IN SKIN

PROTEOMICS

TRANSCRIPTOMICS

Allergy Service

Carlos Haya Hospital Miguel Blanca

Mª José Torres

Carmen Rondón

Paloma Campo

Inmaculada Doña

Francisca Gómez

María Salas

Mª Angeles Zambonino

Luisa Galindo

Laboratory Research

Fundación IMABIS

Lina Mayorga

José A. Cornejo

Tahía Fernández

Enrique Gómez

Ana Aranda

Pedro Ayuso

Adriana Ariza

Mª Carmen Plaza

Miguel

Luisa Macías

Lidia Meléndez

Miriam Osorio

THANK YOU FOR YOUR ATTENTION

common and differential patterns in the inflammatory mediator … school 2013... · 2013-09-26 ·...

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