Common and differential patterns in the inflammatory mediator release Paloma Campo MD, PhD U.G.C. Allergy Carlos Haya Hospital, Málaga- SPAIN EAACI SUMMER SCHOOL 19-21 September 2013 Málaga, Spain
Disclosure In relation to this presentation, I declare that there are no conflicts of interest. 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.
NSAIDs are the drugs more frequently prescribed worldwide Drugs most frequently involved in hypersensitivity drug reactions Doña I JIACI 2012 Selective 24% Selectivos 156 (24%) Cross Intolerant 76% Intolerancia cruzada 503 (76%) Doña I CEA 2011
CLASSIFICATION Type of reaction Clinical manifestation Timing Underlying disease Cross reactivity Putative mechanism NSAIDs exacerbated respiratory disease (NERD) NSAIDs exacerbated cutaneous disease (NECD) NSAIDs induced urticaria/angioede ma (NIUA) Single NSAIDs induced urti/angio/ anap (SNIUAA) Single NSAIDsinduced delayed reactions (SNIDR) Rhinitis/asthma Acute Asthma/ rhinosinusitis Urticaria/angioe dema Urticaria/angioe dema Urticaria/angioe dema/anaphyla xis various symptoms and organs involved Delayed Chronic urticaria No underlying chronic diseases No underlying chronic diseases No underlying chronic diseases YES Nonallergic Cox-1 inhibition Cox-1 inhibition Unknown, probably COX-1 inhibition NO Allergic IgE-mediated T cell mediated ENDA NSAID TF (Kowalsky M, 2013)
Mediators release SAME MECHANISM??
NSAIDs exacerbated respiratory disease (NERD) NSAIDs induced urticaria/angioedema (NIUA) REPRESENT <10% of all CI Doña I, 2011 MOST COMMON MANIFESTATION: 60% of all CI Doña I, 2011 Reaction related to COX COX inhibition inhibition potency COX inhibition?? Reaction to different chemically-unrelated NSAIDs
NERD CLINICAL MANIFESTATIONS CHRONIC RS POLYPOSIS ASTHMA
NERD NATURAL HISTORY RHINITIS ASTHMA NSAID INTOLERANCE VIRUS TOBACCO CONTAMINATION
NSAIDs induced urticaria/angioedema (NIUA) CLINICAL MANIFESTATIONS Healthy subjects WITHOUT chronic urticaria Cutaneous response (urticaria/ae) after intake of different NSAIDs 60% of all CI: the most common manifestation Natural history: present in children Atopy as risk factor?
Atopy and hypersensitivity reactions to NSAIDs N= 112 Atopy NIUA NSAIDS Hypersensitivity (Acute urticaria) Cross-Intolerance Mites 48.71% Non Atopy 30% Atopy 70% Grasses 15.38% Others 24.36% Grasses + Mites 11.54% N= 112 Atopy NERD AERD Non atopy 41% Atopy 59% Grasses 32% Mites 18% Others 29% Grasses+ mites 21%
Atopy and hypersensitivity reactions to NSAIDs ELISA with purified D. pteronyssinus allergens Der p2 most recognized
Non-immunological mechanisms: COX hypothesis A. Szczeklik in 1975 NSAIDs with different chemical structures induce the same pattern of reactions NSAIDs capacity for inducing reactions directly positively correlates with the COX-1 inhibitory potency Non immunological mechanism (Szczeklik A, 1975; Szczeklik A, 1977; Stevenson DD, 1990; Quiralte J, 1996)
Membrane Phospholipids 12-HETE 15-LOX, 5-LOX 12-LOX PLA2 Araquidonic Acid COX-1 5-LOX ALOX-5 ALOX-5 AP 15-HETE PGG2 PGH2 FLAP LTA4 Specific LTC4S LIPOXINS Synthetases LTC4 LTB4 PGE2 PGI2 TXA2 PGF2X PGD2 LTD4 LTE4 RECEPTORS LX-R EP-R (EP-1, EP-2, EP-3, EP-4) IP-R TP-R FP-R DP-R CRTH2 LTcis-R (LTcis-R1, LTcis-R2) Pro-inflammatory Anti-inflammatory Szczeklik A, 1975; Szczeklik A, 1995; Szczeklik A, 2006
LTs 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
URINE Nizakowska ERJ 2000
NASAL LAVAGE Choi GS
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 Patients Controls > 3 episodes of urticaria/angioedema after intake of >2 nonchemically related NSAIDs and/or positive OPT > 3 episodes of respiratory symptoms after intake of >2 nonchemically related NSAIDs and/or positive OPT Asthmatics with good tolerance to NSAIDs 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) 0 15 60 120 NASAL LAVAGE ACOUSTIC RHINOMETRY VAS SPIROMETRY L-Aspirin NASAL LAVAGE ACOUSTIC RHINOMETRY VAS SPIROMETRY NASAL LAVAGE ACOUSTIC RHINOMETRY VAS SPIROMETRY NASAL LAVAGE ACOUSTIC RHINOMETRY VAS SPIROMETRY Positive Challenge: <70% vol 2-6 and >30% VAS Nasal Lavage: ECP Tryptase PGD2, PGE2 LTD4 LTE4 HPLC-MS Serum: % Eosinophils, ECP, Tryptase and IgE Campo et al Allergy 2013
Age (mean, range) NIUA n=25 38.2 (15-62) NERD n=60 39.4 (16-65) ASPIRIN TOLERANT ASTHMATICS n=15 37.3 (30-69) CONTROLS n=15 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
Tryptase (ng/ml) ECP (ng/ml) 80 70 60 Controls MNSAID-UA AERD Tolerant asthmatics * 50 40 30 * 20 10 0 4 3.5 3 2.5 Figure 1a. Time (minutes) 0 15 60 120 Controls MNSAID-UA AERD Tolerant asthmatics * 2 1.5 1 0.5 0 0 15 60 120 Time (minutes) Figure 1b. Campo et al Allergy 2013
PGD2 pg/ml LTE4 pg/ml PGE2 pg/ml LTD4 pg/ml 40 35 30 25 20 15 10 5 0 20 15 10 5 Time (minutes) 0 0 15 60 120 Figure 2a Controls MNSAID-UA AERD Tolerant asthmatics 40 35 30 25 Figure 2c Controls MNSAID-UA AERD Tolerant asthmatics * 0 15 60 120 Time (minutes) 40 35 30 25 20 15 10 5 0 20 15 10 5 Time (minutes) 0 0 15 60 120 Figure 2b Controls MNSAID-UA AERD Tolerant asthmatics 40 35 30 * 25 Controls MNSAID-UA AERD Tolerant asthmatics Time (minutes) 0 15 60 120 Figure 2d * * Campo et al Allergy 2013
BLOOD SAMPLES Campo et al Allergy 2013
Mediators Release NERD Mediators Release AERD: Baseline 15 minutes 60 minutes 120 minutes PGE 2 ECP Tryptase LTD 4 LTE 4 PGD 2 Mediators release NIUA: Eosinophil degranulation Mast Cell Activation Baseline 15 minutes 60 minutes 120 minutes PGE 2 LTE 4 * Campo et al Allergy 2013
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
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