NSAID or nonsteroidal anti-inflammatory drug hypersensitivity reactions encompasses a broad range of allergic or allergic-like symptoms that occur within minutes to hours after ingesting aspirin or other NSAID

nonsteroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...

. Hypersensitivity drug reactions differ from drug toxicity reactions in that drug toxicity reactions result from the pharmacological action of a drug, are dose-related, and can occur in any treated individual (see

section on adverse reactions for NSAID-induced toxic reactions); hypersensitivity reactions are idiosyncratic reactions to a drug. Although the term NSAID was introduced to signal a comparatively low risk of adverse effects, NSAIDs do evoke a broad range of hypersensitivity syndromes. These syndromes have recently been classified by the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity. __TOC__

Classification

The classification organizes the hypersensitivity reactions to NSAIDs into the following five categories: # NSAIDs-exacerbated respiratory disease (NERD) is an acute (immediate to several hours) exacerbation of

bronchoconstriction Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Causes The condition has a number of causes, the most common bein ...

and other symptoms of asthma (see

aspirin-induced asthma Aspirin exacerbated respiratory disease (AERD), also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inf ...

) in individuals with a history of asthma and/or

nasal congestion Nasal congestion is the blockage of nasal breathing usually due to membranes lining the nose becoming swollen from inflamed blood vessels. Background In about 85% of cases, nasal congestion leads to mouth breathing rather than nasal breathing ...

rhinorrhea Rhinorrhea, rhinorrhoea, or informally runny nose is the free discharge of a thin mucus fluid from the nose; it is a common condition. It is a common symptom of allergies (hay fever) or certain viral infections, such as the common cold or COVID-1 ...

or other symptoms of

rhinitis Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip. The inflammation is caused by viruses, bacteria, irritants ...

and

sinusitis Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, h ...

in individuals with a history of rhinosinusitis after ingestion of various NSAIDs, particularly those that act by inhibiting the

COX-1 Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of two cyclooxygenases. ...

enzyme. NERD does not appear to be due to a true allergic reaction to NSAIDs but rather at least in part to the more direct effects of these drugs to promote the production and/or release of certain mediators of allergy. That is, inhibition of cellular COX activity deprives tissues of its anti-inflammatory product(s), particularly

prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, a ...

while concurrently shuttling its substrate, arachidonic acid, into other metabolizing enzymes, particularly

5-lipoxygenase Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase fa ...

(

ALOX5 Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase ...

) to overproduce pro-inflammatory

leukotriene Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase. Leukotrien ...

and 5-Hydroxyicosatetraenoic acid metabolites and

15-lipoxygenase ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically import ...

(

ALOX15 ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically import ...

) to overproduce pro-inflammatory

15-Hydroxyicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S' ...

metabolites, including

eoxins Eoxins are proposed to be a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg ...

; the condition is also associated with a reduction in the anti-inflammatory metabolite,

lipoxin A4 A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolvi ...

, and increases in certain pro-allergic chemokines such as eotaxin-2 and CCL7. # NSAIDs-exacerbated cutaneous disease (NECD) is an acute exacerbation of

wheals A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this s ...

and/or

angioedema Angioedema is an area of swelling ( edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which a ...

in individuals with a history of chronic

urticaria Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...

. NECD also appears due to the non-allergic action of NSAIDs in inhibiting the production of COX anti-inflammatory metabolites while promoting the production 5-lipoxygenase and 15-lipoxygenase pro-inflammatory metabolites and the overproduction of certain pro-allergic

chemokines Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...

, e.g. eotaxin-1, eotaxin-2,

RANTES Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the ''CCL5'' gene. The gene has been discovered in 1990 by ''in situ'' hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTE ...

, and

interleukin-5 Interleukin 5 (IL5) is an interleukin produced by type-2 T helper cells and mast cells. Function Through binding to the interleukin-5 receptor, interleukin 5 stimulates B cell growth and increases immunoglobulin secretion - primarily IgA. It ...

. # NSAIDs-induced urticarial disease (NEUD) is the acute development of

and/or

in individuals with no history of chronic NSAIDs-induced

or related diseases. The mechanism behind NEUD is unknown but may be due to the non-allergic action of NSAIDs in promoting the production and/or release of allergy mediators. # Single NSAID-induced urticarial/angioedema or anaphylaxis (SNIUAA) is the acute development of

urticarial Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-last ...

, or

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the foll ...

in response to a single type of NSAID and/or a single group of NSAIDs with a similar structure but not to other structurally unrelated NSAIDs in individuals with no history of underlying relevant chronic diseases. SNIUAA is due to a true IgE-mediated

allergy Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...

reaction. # Single NSAID-induced delayed reactions (SNIDR) are a set of delayed onset (usually more than 24 hour) reactions to NSAIDs. SNIDR are most commonly skin reactions that may be relatively mild moderately severe such as

maculopapular rash A maculopapular rash is a type of rash characterized by a flat, red area on the skin that is covered with small confluent bumps. It may only appear red in lighter-skinned people. The term "maculopapular" is a compound: ''macules'' are small, flat ...

fixed drug eruption Fixed drug reactions, are common and so named because they recur at the same site with each exposure to a particular medication. Medications inducing fixed drug eruptions are usually those taken intermittently. Signs and symptoms A painful and it ...

s, photosensitivity reactions, delayed

, and

contact dermatitis Contact dermatitis is a type of acute or chronic inflammation of the skin caused by exposure to chemical or physical agents. Symptoms of contact dermatitis can include itchy or dry skin, a red rash, bumps, blisters, or swelling. These rashes are ...

or extremely severe such as the

DRESS syndrome Drug reaction with eosinophilia and systemic symptoms (DRESS), also termed drug-induced hypersensitivity syndrome (DIHS), is a rare reaction to certain medications. It involves primarily a widespread skin rash, fever, swollen lymph nodes, and ch ...

, acute generalized exanthematous pustulosis, the

Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythe ...

, and

toxic epidermal necrolysis Toxic epidermal necrolysis (TEN) is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and flu-like symptoms. A few days later t ...

(also termed Lyell's syndrome). SNIDR result from the drug-specific stimulation of CD4+ T lymphocytes and CD8+

cytotoxic T cell A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular ...

s to elicit a

delayed type hypersensitivity Delay (from Latin: dilatio) may refer to: Arts, entertainment, and media * '' Delay 1968'', a 1981 album by German experimental rock band Can * '' The Delay'', a 2012 Uruguayan film People * B. H. DeLay (1891–1923), American aviator and a ...

reaction.

References

{{Reflist Hypersensitivity