**3.3 Isolated periorbital angioedema (iPA), or the infanto-juvenile form of NH**

This type of reaction usually affects children and young people, with an onset in the first or second decade of life in more than 80% of cases and, in all cases, an associated respiratory allergy is detected, mostly caused by mites, suggesting a close relationship with aspirin exacerbated respiratory disease (AERD) with which they share not only the concomitant disease, but also the pattern of multiple reactivity among NSAID [3, 6].


*Drugs were administered in an opaque capsule at the following intervals between each dose: a 60 minutes, <sup>b</sup> 120 minutes and <sup>c</sup> 180 minutes. d Three doses, <sup>e</sup> four doses or f two doses were administered on the first day, and d, eone dose or f two other doses on the second day.*

#### **Table 2.**

*NSAIDs and doses used for single-blind, placebo controlled oral challenge.*

*Clinical Phenotypes in NSAID-Induced Urticaria/Angioedema DOI: http://dx.doi.org/10.5772/intechopen.96718*

Within this group of patients and in close relationship with the atopic phenomenon, a new syndrome has been described: the systemic anaphylaxis triggered by ingestion of food contaminated by mites (NSAIDs sensitivity mite-ingestion reaction syndrome or also recently called oral mite anaphylaxis) [11, 12]. Most of the patients presented common clinical characteristics: they had respiratory allergy to mites, presented mostly periorbital angioedema and presented anaphylactic episodes of variable severity in relation to the ingestion of food made with cereal flour (wheat, oat and corn), without any evidence of food allergy during the clinical study. 87% of the study group presented intolerance to aspirin, contrasting with the frequency of less than 2% that we observed in the population of patients allergic to domestic dust mites. This meant that an atopic aspirin intolerant was up to 300 times more likely to suffer a severe reaction from ingestion of mites than a tolerant patient. Microscopic analysis of the flour revealed extreme contamination of the flour by *Dermatophagoides farinae* and other mites of the Acaridae family (specifically *Tyreophagus entomophagus* and *Suidasia medinensis*). At present, the cause of the association of aspirin intolerance with systemic reactions by ingestion of food contaminated by mites is unknown.

#### **3.4 NSAID-induced recall urticaria**

Recall urticaria (RU) is a rare biologic phenomenon characterized by the existence of hives only in the previously injected site when the patient is exposed again from another source. The most common example are patients who have received previously subcutaneous allergen immunotherapy (sq AIT) and present focal skin reaction at the sites of previous allergens injection when a new kind of allergen shot was administered or after heavy ambiental exposure to the allergen [13].

We recently described a patient with allergic respiratory disease who underwent sq. AIT to house dust mites after a 5 year-period. Two years after allergen immunotherapy discontinuation, patient first experienced an immediate local urticarial reaction with multiple hives at previous sq. AIT injection sites after metamizole and ibuprofen intake. SBPCOC with ibuprofen and aspirin was performed and elicited multiples hives in a circumscribed area in both arms, although a controlled challenge with celecoxib was negative.

In our patient, the symptoms were elicited by different NSAIDs (Ibuprofen, metamizol and aspirin) which resembles the pattern of patients with skin crossreactive phenotypes of NSAID hypersensitivity. This suggests that the enzymatic inhibition of COX type I isoform could play a role in the development of this specific reaction. The tolerance of highly selective COX type 2 inhibitors such as celecoxib in our patient reinforces this hypothesis. However, the nature of the relationship between COX-1 inhibition and the local immunological trace of mite remains largely unknown. This phenomenon might be a new phenotype of skin NSAID hypersensitivity which would appear in those patients with respiratory allergy treated with sq. AIT [7].

#### **3.5 Selective acute urticaria/angioedema and anaphylaxis**

The existence of underlying diseases is common in NECD, NIUA and IPA. However, there is another phenotype of otherwise healthy patients, (i.e. without any concomitant disease associated) who experience immediate reactions of urticarial or anaphylactic type after the administration of a specific NSAID [1, 3–5, 8].

Up to 15% of patients with NSAID-induced urticaria present a selective pattern of sensitivity to NSAIDs, [8] with a predominance of certain NSAID groups, such as those derived from the pyrazole group (metamizole) followed in order of frequency by ibuprofen, diclofenac and paracetamol, A selective pattern involves SBPCOC tolerance to other NSAIDs not involved in the clinical reaction, including those that are potent inhibitors of COX isoform 1.

Immediate systemic reactions present clinical and biological features that are compatible with a possible immunological mechanism: they are generally anaphylactic, selective and, on certain occasions, can be associated with positive skin tests that can be read immediately (such as metamizole) [14].

Recently, Doña et el have described some patients who may develop immediate reactions to several NSAIDs but tolerate ASA (the NSAIDs-multiple selective immediate reaction phenotype). Patients usually present with a biselective or triselective pattern: they presented different episodes of anaphylaxis to ibuprofen and diclofenac while tolerate an aspirin challenge or developing hypersensitivity reactions to three non chemically related NSAIDs [1].

Although the selective form is the most frequent clinical form of NSAID anaphylaxis (96%), a small subgroup of patients with phenotypes associated with multiple reactivity can present an anaphylactic reaction during SBPCOC. Patients with NIUA and exceptionally periorbital angioedema may present with a systemic reaction after administration of a potent COX-1 inhibitor NSAID. In rare cases, the systemic reaction may be a clinical phenotype in itself, with patients exhibiting this clinical response to any exposure to NSAID [3].
