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INTRODUCTION

Adverse drug reactions are common and can cause serious health problems.
They occur in about 10% of hospitalized patients and in about 7% of patients who
require ambulatory care. A widely used classification system divides hypersensitivity
reactions into 2 types. Type A reactions are common (80%) and are caused by the
pharmacological or toxic properties of a drug. Such reactions are predictable and may
occur in anyone. Type B reactions are uncommon and unpredictable and occur only in
people with a certain predisposition1.
The term drug hypersensitivity refers to the symptoms or signs initiated by
an exposure to a drug at a dose normally tolerated by nonhypersensitive persons.
Drug allergy refers to immunologically mediated drug hypersensitivity reactions,
which may be either Immunoglobulin E (IgE)mediated (immediate) or nonIgE
mediated (delayed). Nonallergic hypersensitivity reactions refer to adverse drug
reactions that are not mediated by immunologic mechanisms1.
Drug allergies are type B reactions that are mediated by the adaptive immune
system. In practice, it is often difficult to differentiate between immune and non
immune-mediated reactions. Because clinical signs and symptoms of most immune
reactions are observed only in the elicitation phase and not in the preceding
sensitization phase, the dogma has been that allergic reactions to drugs are only
observed on reexposure or longer lasting exposure (at least 3 days) to the drug. 2
NSAIDs are non-steroidal anti-inflammatory drugs, also known as nonsteroidal anti-inflammatory agents/ analgesics (NSAIAs) or non-steroidal antiinflammatory medicines (NSAIMs). They are medications with analgesic (pain
reducing), antipyretic (fever reducing) effects. In higher doses they also have antiinflammatory effect, reduce inflammation (swelling). Non-steroidal distinguishes
NSAIDs from other drugs which contain steroids, which are also anti-inflammatory.
NSAIDs are non-narcotic (they do not induce stupor)7.
NSAIDs induce allergic and nonallergic hypersensitivity reactions. The second
group of reactions is commonly described in medical literature as intolerant,
pseudoallergic, or idiosyncratic reactions. In this article, the current knowledge on
hypersensitivity reactions to NSAIDs is discussed.

CONTENT
MECHANISM OF NSAIDs-INDUCED DRUG ALLERGY
IMMUNOLOGIC REACTION
Aspirin and NSAIDs can cause both antibody (IgE) mediated true allergic
reactions and non-antibody mediated pseudoallergic reactions. The mechanism of this
type of reaction is allergic sensitization with the synthesis of IgE antibodies specific
for the drug which functions as a hapten. An incomplete antigen (hapten) is a
chemically defined substance of low molecular weight that cannot induce an adaptive
immune response by itself. The hapten can react with the paratope on an antibody.
Haptens can produce antibodies if they are conjugated to a larger carrier molecule
(normally proteins). Haptens contain a single epitope. The hapten is too small to
engage T and B cells simultaneously. If the hapten is conjugated to a carrier protein, a
T cell recognizes epitopes of this protein and a B cell recognizes the hapten. Drugs are
haptens if they can bind covalently to molecules, be they soluble or cell bound. They
can even bind directly to the immunogenic major histocompatibility complex
(MHC)/peptide complex on antigen-presenting cells (APC), either to the embedded
peptide or to the MHC molecule itself. Thus, the chemical reactivity of haptens leads
to the formation of many distinct antigenic epitopes, which can elicit both humoral
and cellular immune responses3.
In IgE mediated reactions a specific IgE antibody directed against NSAID
(ibuprofen for example) is formed following initial exposure to the medication. This
is called sensitization. Following sensitization subsequent exposure to the same
medication could result in a true allergic reaction consisting of hives, swelling of lips,
eyes, tongue and throat, respiratory difficulties, low blood pressure and even death.
True IgE mediated allergy to NSAIDs is rare and usually there will be history of prior
exposure to the drug in question in such patients. The allergy is also usually specific
for the medication in question and other forms of NSAIDs are usually tolerated well3.
NON-IMMUNOLOGIC REACTION
In pseudoallergic reactions caused by Aspirin and NSAIDs, the clinical picture
resembles a true allergic reaction; however no antibody is involved in causing these
reactions. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of substances
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of variable chemical composition that antagonize inflammation by interfering with the


function of cyclooxygenases (COXs). COXs are enzymes that participate in the
conversion of arachidonic acid (AA) into prostaglandins (PGs) and thromboxanes,
which are strong mediators of the inflammatory process. This inhibition results in the
shunting of AA metabolism toward the 5-lipoxygenase pathway, resulting in the
increased release of cysteinyl leukotrienes1.

Cysteinyl leukotrienes is over 1000 times more potent than histamine in


causing

contractions

of

isolated

human

bronchi.

Cysteinyl

leukotriene

receptors CysLT1 and CysLT2 are present on mast cells, eosinophil, and endothelial
cells. During cysteinyl leukotriene interaction, they can stimulate proinflammatory
activities such as endothelial cell adherence and chemokine production by mast cells.
As well as mediating inflammation, they induce asthma and other inflammatory
disorders, thereby reducing the airflow to the alveoli. In excess, the cysteinyl
leukotrienes can induce anaphylactic shock8.
There are 2 isoforms of COXs: constitutive and inducible. COX-1 is the
constitutive form present in all cells, whereas the inducible isoenzyme COX-2 is
expressed exclusively in inflammatory cells after stimulation by cytokines, growth
factors, bacterial lipopolysaccharide, tumor promoters, and other factors. While
acetylsalicylic acid (ASA), also known as aspirin, and the classic NSAIDs inhibit both
isoforms of COX, the new, selective COX-2 inhibitors are devoid of COX-1

inhibition and therefore have less ability to decrease gastric PG E2 (PGE2), producing
less gastric irritation and ulceration1.

Since there is no antibody involved in these reactions, they are called


pseudoallergic reactions. Pseudoallergic reactions are much more common than true
allergic reactions. Since these medications act by inhibiting Cyclooxygenase one
enzyme, more than one medication belonging to this group can cause similar
problems in a given individual1.
MECHANISM OF REACTION
Since NSAID hypersensitivity has multiple clinical manifestations, the
mechanisms incriminated in each of them are different. Reactions to aspirin and
NSAIDs observed in patients with AERD are mediated by inhibition of COX-1,
leading to a shunting of arachidonic acid metabolism towards the 5- lipoxygenase
pathway and increased production of cysteinyl leukotrienes 4. A decreased production
of PGE2, a modulator of mediator release from mast cells and other inflammatory
cells, also plays a role 5.
Urticaria and angioedema exacerbations in patients with CIU are also
mediated by COX-1 inhibition, as suggested by Mastalerz et al. They observed
increased levels of urinary LTE4 (uLTE4) in patients with chronic urticaria that
showed symptom exacerbations during challenges with aspirin, as compared with
CIU patients that did not respond to the aspirin provocation. Further increases of
uLTE4 occurred in the first group, but not in tolerant patients, after ASA challenge 6.
The mechanisms of induction of acute urticaria, angioedema and anaphylaxis by
multiple NSAIDs in patients who do not have chronic urticaria have not been defined.

Nevertheless, it is provocative to hypothesize that, since these drugs have as their


major mean of action the inhibition of COX-1, this mechanism could also be involved
in the production of these clinical manifestations6.
Reactions to a single NSAID are mediated by drug-specific IgE antibodies, as
can be demonstrated by means of immediate-type skin tests or in vitro measurement
of specific IgE7,8 .
Delayed reactions to NSAIDs are mediated by drug-specific cytotoxic T cells
through type IV allergic reactions. These can be subclassified in 4 subtypes (IVa, IVb,
IVc and IVd) according to the main effector cells involved in their production
(monocytes, eosinophils, CD4 and CD8 lymphocytes, or neutrophils 9.

CLINICAL MANIFESTATION, DIAGNOSIS AND MANAGEMENT


Hypersensitivity to NSAIDs can be classified according to the time of onset
and the clinical manifestations into acute and delayed. Acute reactions start
immediately to several hours after drug administration and include:
Respiratory reactions:
Observed in patients with Aspirin Exacerbated Respiratory Disease (AERD),
also called aspirin triad, Samters disease, or aspirin intolerant asthma. These
individuals experience a chronic disease characterized by chronic rhino sinusitis,
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severe persistent and steroid-dependent asthma, with or without nasal polyposis.


AERD has been estimated to be prevalent in the range of 4.3% to 11% in adult
asthmatics and in about 25% of patients who have asthma and nasal polyposis. One
study reported prevalence between 11% and 20% determined through a questionnaire,
3% through a medical record, and 21% through an oral provocation test. AERD has
similar effects on women and men. Acute asthma exacerbations occur when they
receive aspirin or classic NSAIDs. Intake of aspirin or any other NSAID causes,
within a few minutes to approximately 120 minutes, symptoms such as a flush
reaction in the face and upper thorax, rhinitis, conjunctivitis, feeling of blocked nose,
and an often severe exacerbation of asthma with severe breathlessness, which may
require emergency treatment. The underlying asthma is generally severe and steroid
dependent, and it may be life threatening. Various genetic polymorphisms have been
associated with this condition. 6 In patients with AERD, ingestion of aspirin or other
NSAID induces within 30 to 120 min nasal congestion and watery rhinorrhea
followed by shortening of breath and rapidly progressing bronchial obstruction.
Respiratory symptoms are usually accompanied by other extrabronchial
symptoms including ocular, cutaneous (flushing, urticaria and/or angioedema) or
gastric symptoms. The threshold dose of aspirin during oral challenge defined as the
smallest dose evoking a significant fall in FEV1 seems to be an individual feature of a
patient and varies from 10 mg (or even lower dose) up to 600 mg 11.
Diagnosis
The diagnostic approach for AERD is based on the clinical picture of chronic
rhinosinusitis and moderate to severe asthma, with exacerbations occurring when
NSAIDs are taken. Aspirin hypersensitivity is confirmed by single-blind oral
provocation, which is commonly used in the United States. The test should be
performed when asthma is stable (forced expiratory volume in the first second of
expiration [FEV1]>70%, withdiurnal variability <10%). In Europe, inhalation or nasal
challenges with lysine-aspirin are used. All these tests bear the risk of severe asthma
exacerbations, and should be done only by trained specialists with easily available
equipment and medication for the treatment of acute asthma attacks if they develop.
In vitro assays measuring sulfidoleukotriene release, such as basophil
activation tests and the 15-hydroxyeicosatetraenoic acid generation assay (Aspirin
Sensitive Patient Identification Test), are still under study and need further validation
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at this time. Multiple protocols for oral ASA provocation are used in different centers
and some provocation tests are immediately followed by desensitization. 6
Management
Patients with AERD are advised to avoid all COX-1 inhibitors, including
aspirin and the classic NSAIDs, to prevent serious asthma exacerbations. For the
treatment of pain and inflammation, NSAIDs that do not inhibit (or weakly inhibit)
COX-1, such as acetaminophen in doses less than 1000 mg, and COX-2 inhibitors are
recommended. It is advisable to challenge these alternatives under supervision to
exactly define the tolerated dose, because approximately 10% of patients with AERD
also react to acetaminophen, at least in higher doses (>500800 mg) It is also
advisable to strictly instruct the affected patients to use only the controlled alternative
drugs, if needed. A list of available and forbidden NSAIDs should be explained and
given to the patients10.
Aspirin desensitization is useful for patients who require continuous therapy,
such as those with ischemic heart disease or chronic arthritis. 10 Persistent asthma and
rhinosinusitis should be treated with the approaches given by international guidelines
such as the Global Initiative for Asthma and European Position Paper on
Rhinosinusitis and Nasal Polyps. Repeated administration of aspirin may induce
tolerance to aspirin. To maintain desensitization, a patient has to ingest aspirin on a
regular, usually daily basis because the tolerance state disappears within 25 days
after aspirin treatment has been interrupted. Aspirin desensitization may be indicated
for patients who need daily treatment with aspirin and NSAIDs because of other
diseases (e.g. coronary ischaemic disease or rheumatologic disorders). Moreover,
chronic treatment with aspirin following desensitization alleviates the symptoms of
rhinosinusitis and to less extent of asthma, reducing the requirement for systemic
corticosteroids and decreases the number of polypectomies. Thus, for selected
patients, chronic treatment with aspirin after desensitization can be considered as an
additional option for pharmacological management of AERD 6. Management of
asthma exacerbations requiring urgent medical care (e.g., in the urgent care setting or
emergency department (ED)) includes:
-

Oxygen to relieve hypoxemia in moderate or severe exacerbations

SABA to relieve airflow obstruction, with addition of inhaled ipratropium


bromide in severe exacerbations
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Systemic corticosteroids to decrease airway inflammation in moderate or severe


exacerbations or for patients who fail to respond promptly and completely to a
SABA

Consideration of adjunct treatments, such as intravenous magnesium sulfate or


heliox, in severe exacerbations unresponsive to the initial treatments listed above

Monitoring response to therapy with serial measurements of lung function12

Cross reacting urticaria and angioedema:


Exacerbations of urticaria and/or angioedema induced by COX-1 inhibitors
are observed in up to one third of patients with chronic urticaria, more often with
drugs of the heteroaryl group (naproxen, diclofenac, ibuprofen). Various genetic
polymorphisms, including genes coding for HLA antigens, LTC4 synthase, 5lipooxygenase, and the high affinity receptor for IgE have been observed in these
patients. Because patients with NSAIDs-induced urticaria/angioedema cross-react
only with COX-1 inhibitors, it has been postulated that the mechanism of reaction is
similar to that of AERD. According to this hypothesis, inhibition of cyclooxygenase
by NSAIDs may lead to a decrease in protective prostaglandins production, leading to
activation of mediator release from inflammatory cells in the skin. This hypothesis
was further supported by observations that skin eruptions after oral aspirin challenge
were accompanied by the release of eicosanoids similarly to patients with AERD.
Symptoms of urticaria and/or angioedema appear usually 14 h after ingestion
of the drug, although both immediate (within 15 min of ingestion) and late (up to 24
h) reactions have been described. Skin eruptions usually subside within few hours but
may persist for several days. The degree of sensitivity to NSAIDs may show
temporary fluctuations related to activity of underlying chronic disease and may even
disappear in some patients. A certain proportion of patients with cutaneous adverse
reactions may also develop respiratory symptoms. Based on recent studies, the
incidence rates of asthma and nasal polyps are increased in patients with chronic
urticaria with NSAIDs hypersensitivity compared to those with chronic urticaria
only6.
Diagnosis

In general, patients have a history of recurrent urticaria without a known


precipitating factor, and they may provide, spontaneously or after questioning,
information on the aggravation of cutaneous symptoms when exposed to NSAIDs.
Some patients may have had only a generalized pruritus with scarce urticarial
wheals (eg, after pressure), but NSAID intake may have caused a generalization and
aggravation of their urticaria and first manifestation of angioedema. Confirmation by
oral challenge may be necessary in some patients. 6
Management
The first-line of therapy in urticaria is directed at blocking the effects of
histamine through its H1 receptor activity. The second generation H1 antihistamines
such as loratadine, cetrizine and acrivastine or their newly introduced derivatives such
as desoloratidine, fexofenadine and levocetirizine are now the treatment of choice for
urticaria and has replaced the old traditional antihistamines. The use of the old
traditional antihistamines is limited by their side effects, including sedation,
anticholinergic effects and some excitation in children. However they can still be
useful if night-sedation is needed or in combination with second generation H1 or H2
antihistamine in some patients.
Urticaria, angioedema and anaphylaxis induced by multiple NSAIDs:
Urticaria and angioedema are induced by various NSAIDs in otherwise
healthy subjects without history of underlying chronic skin and/or respiratory
disorders. The most frequent reactions are urticaria and facial angioedema occurring
within minutes or up to 24 h after ingestion of different NSAIDs4.
Diagnosis
The medical history discloses the presence of episodes of urticaria or
angioedema occurring after exposure to various COX-1 inhibitors of unrelated
chemical groups. If necessary, confirmation by means of single-blind oral provocation
is performed. 6
Management
Up to 80% of patients with hypersensitivity to multiple NSAIDs (including
aspirin) tolerate paracetamol and nimesulide. Thus, weak COX inhibitors can be

recommended as alternative drugs, if their tolerance is confirmed by a negative


challenge6.
Urticaria, angioedema and anaphylaxis induced by a single NSAID:
These reactions constitute about 30% of adverse reactions to NSAIDs and are
observed with increased frequency in patients with previous history of atopic disease,
food or drug allergy. Generalized urticaria and/or angioedema appear within minutes
after oral or intravenous administration of the culprit drug. Both skin swelling and
mucosal (laryngeal) angioedema may be present, and progression of these reactions to
anaphylactic shock and death has been described (67, 68). Anaphylactic shock was
observed in 18-30% of patients hypersensitive to pyrazolones (e.g. metamizole).
Other symptoms, such as generalized pruritus, rhinitis, and bronchospasm,
may also be present in some patients. In single-drug reactors to acetaminophen,
generalized urticaria and angioedema are most prevalent, although anaphylactic shock
has also been described5.
The NSAIDs most frequently reported to induce this type of reaction are
pyrazolones , paracetamol, ibuprofen, diclofenac and naproxen. The data from
Netherlands (years 19741994) showed that NSAIDs which most frequently caused
anaphylaxis were glafenine (withdrawn from the market for this reason), pyrazolones,
diclofenac and ibuprofen 6 .Patients with this type of hypersensitivity tolerate other
chemically unrelated NSAIDs with strong anti-inflammatory activity, arguing against
involvement of COX-1 inhibition-related mechanisms. The clinical pattern of
symptoms as well as the timing of the reaction strongly suggests immunological IgEmediated type of reaction. Positive skin tests to a culprit drug or drug-specific serum
IgE may be found in a significant proportion of patients with noncross-reactive type
of hypersensitivity to pyrazolones. However, only anecdotal reports were able to
detect presence of specific IgE in other single NSAIDs reactors. In patients with
pyrazolone drug hypersensitivity, strong association with HLA-DQ and HLA DR loci
was found5.
Diagnosis
In patients with a history of reaction to a single NSAID and no additional
exposure to a second NSAID, skin testing is possible and may reveal a selective
sensitization. Skin prick and intradermal tests with different dilutions of
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noraminophenazone, propyphenazone or aminophenazone were used in patients with


suspected pyrazolone hypersensitivity. The diagnosis of propyphenazone allergy
could be confirmed with the combination of skin prick tests and intradermal skin test
in the majority of the patients. This study demonstrated a lack of complete crossreactivity between different pyrazolone derivates, suggesting that the culprit
pyrazolone derivative should be used for skin testing. IgE tests are not commercially
available. It may be convenient to confirm the diagnosis by oral challenge, although
this should be done cautiously because low concentrations of the drug may already
cause symptoms. If the results are positive, another NSAID of a different chemical
group should be tested to demonstrate single reactivity. A history of systemic
anaphylaxis would be a contraindication to perform the provocation tests with the
incriminated substance. 6
Management
Strict avoidance of the culprit and potentially cross-reactive chemically similar
compounds should be recommended. Alternative NSAIDs can be proposed, but
should be preceded by oral challenge to confirm tolerance6.
Possibility of desensitization to a culprit drug in patients with IgE-mediated noncrossreactive type of NSAIDs hypersensitivity has not been documented6.
The emergency treatment for acute nonhereditary angioedema with impending
anaphylaxis is parenteral corticosteroids, antihistamines and epinephrine given by
S.C., I.M. or I.V. injection every 10-15 minutes until recovery from an attack.

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SUMMARY
1. Reactions to NSAIDs are a major cause of hypersensitivity to drugs,
occupying second place after reactions to antibiotics.
2. The most common acute clinical manifestations involve the respiratory tract
(rhinosinusitis and asthma), the skin (urticaria and angioedema), or are
generalized (anaphylaxis).
3. The affected patients often already have an underlying respiratory or
cutaneous disease, and the intake of various NSAIDs can precipitate more
severe symptoms.
4. Early diagnosis and treatment, proper medical advice on drug use, and referral
to an allergy specialist when indicated are of paramount importance to prevent
unnecessary morbidity and the potential risk of death from these severe
reactions.

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REFERENCE
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Generalized Anaphylactic Symptoms), Med Clin N Am 94 (2010) 853864,
2010
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3. E. Kucharska, Involvement of Haptens in Allergic and Non-Allergic
Hypersensitivity. 2008
4. Fernan Caballero-Fonseca, Hypersensitivity Reactions to Nonsteroidal AntiInflammatory Drugs: An Update, 2010
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