Page 611 - Clinical Immunology_ Principles and Practice ( PDFDrive )

588 ParT fivE Allergic Diseases

reflex-mediated flare-up. Histamine is also the main mediator Aspirin and NSAIDs can trigger acute urticaria as well as
of itch in urticaria. However, histamine-induced wheals are causing flare-ups of preexisting chronic spontaneous (but not
short-lived in contrast to urticarial lesions that may persist up physical) urticaria. Aspirin-induced exacerbations have been
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to 24 hours, implying that other proinflammatory mediators reported in 20–40% of patients with CSU. In some patients,
and/or cellular infiltrates contribute to CSU pathogenesis. aspirin can act as a cofactor in food- or exercise-induced
anaphylaxis.
Mast Cell–Independent Mechanisms of Urticaria Urticaria can develop from a few minutes to 24 hours after
Pseudoallergy (Intolerance) aspirin ingestion but usually within 1–2 hours. Angioedema of
Pseudoallergy, or nonallergic hypersensitivity, mimics immediate- the lips and tongue, impaired swallowing, and laryngeal edema
type allergic reactions clinically without evidence of underlying develop occasionally. Aspirin-induced skin symptoms usually
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immunological mechanisms. The most common triggers of subside 24–48 hours after discontinuing the drug. However, severe
pseudoallergic reactions are aspirin and other nonsteroidal exacerbations of CSU caused by aspirin and other NSAIDs can
antiinflammatory drugs (NSAIDs), as well as some food ingre- last from several days to several weeks after aspirin intake. 13
dients and additives, such as salicylates, benzoates, and tartrazine. There are no skin tests or reliable in vitro diagnostic techniques
These reactions do not involve IgE sensitization and can, therefore, for patients with aspirin-induced urticaria, and the diagnosis
occur on first exposure. Pseudoallergic reactions are dose- can only be established by challenge tests. Patients should avoid
dependent and usually occur with chemically nonrelated sub- aspirin and other NSAIDs, but COX-2 inhibitors (coxibs) are
stances. The diagnosis is difficult because skin tests and serology usually well tolerated and can probably be used safely.
are uninformative. Diagnosis of nonallergic hypersensitivity is
based on a distinctive clinical pattern, time course, clinical signs, Food-Induced Pseudoallergic Reactions in CSU
and response to elimination of the cause. In the appropriate Pseudoallergic food reactions appear to be important in some
clinical context, pseudoallergy can be confirmed with oral chal- patients with CSU. Pseudoallergic food triggers include natural
lenge tests. salicylates in fruit and vegetables and artificial food additives in
processed foods, such as benzoates and tartrazine. Low-molecular-
NSAIDs weight aromatic compounds in tomatoes, white wine, and herbs
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Aspirin and other NSAIDs inhibit constitutive cyclooxygenase have also been implicated. Clinically, exacerbations of CSU
(COX-1) and inducible cyclooxygenase (COX-2), thereby diverting resulting from dietary pseudoallergens gradually subside within
arachidonic acid metabolism toward the 5-lipoxygenase pathway 10–14 days on an exclusion diet; in contrast, in 1–3 days in acute
in some cell types, notably eosinophils. This modulation of allergic urticaria. One study showed increased gastroduodenal
arachidonic acid metabolism results in overproduction of and intestinal permeability in patients with CU. Responders to
cysteinyl-leukotrienes LTC4, -D4, and -E4, leading to vasodilata- elimination of pseudoallergens in their diet demonstrated
tion and edema. Furthermore, reduction of PGE 2 formation by normalization of mucosal permeability and skin symptoms.
COX inhibition has two further effects that promote urticaria: Although the underlying mechanisms for pseudoallergic reactions
first, by reducing inhibition of cysteinyl leukotriene production in CU remain unproven, an impaired gastroduodenal barrier
and second, by reducing an inhibitory effect on immunologically- function may be a contributory factor. 14
mediated mast-cell degranulation (Fig. 42.5). Cross-sensitivity
occurs with other nonselective NSAIDs in susceptible individuals, Kinin-Mediated Angioedema
depending on their pharmacologic potency for COX inhibition The mediator of angioedema resulting from hereditary and
but not their chemical structure. acquired C1 esterase inhibitor (C1-INH) deficiency and
angiotensin-converting enzyme inhibitor (ACEI)–induced
angioedema is bradykinin rather than histamine or leukotrienes.
There is currently no evidence that kinins are involved in other
Arachidonic acid NSAIDs types of urticaria or angioedema. Bradykinergic angioedema is
COX-1
not considered a type of urticaria.
COX-2
LTA 4 PGH 2 CLINICAL CLASSIFICATION
COX-2i
CU may be spontaneous, inducible, or both.
LTB 4 LTC, D, E 4 PGE 2 PGD 2 Spontaneous Urticaria
PGI 2
TXA 2 Spontaneous urticaria is the most common presentation. The
term “spontaneous” makes no assumption about etiology, which
may include autoimmunity, allergy, pseudoallergy, or infection.
Those cases for which a cause cannot be ascertained with reason-
Mast cell able confidence are called idiopathic. In practice, this is the
majority of patients. Spontaneous urticaria can be further
fiG 42.5 Arachidonic acid pathways illustrating potential diversion classified by duration and frequency of attacks into acute, chronic,
from prostaglandin synthesis to cysteinyl leukotrienes (LTC4, and episodic urticaria.
-D4, -E4) by blocking cyclooxygenase (COX), leading to increased
vasopermeability. Reduction of prostaglandin E 2 also reduces Acute Spontaneous Urticaria
its direct inhibitory effect on leukotriene production and on Acute urticaria is defined as continuous disease lasting <6 weeks.
immunological mast cell degranulation. Individuals with an atopic predisposition are at higher risk of