ARTICLE
Auteur(s) :, Barbara Schubert1, Maria T Grosse
Perdekamp2, Petra Pfeuffer1, Petra
Raith1, Eva-B Bröcker1, Axel
Trautmann1,*
1Department of Dermatology, University of Würzburg,
Josef Schneider Strasse 2, D-97080 Würzburg, GermanyFax: (+49)
931 201 26700.
2Cancer Care Specialists of Central Illinois, Decatur,
Illinois, USA
accepté le 8 Février 2005
After rhinitis and asthma, drug hypersensitivity is the third-most
frequent cause for consulting an allergist. Following antibiotics,
nonsteroidal anti-inflammatory drugs (NSAID) are the second-most
frequently suspected agents causing drug hypersensitivity. Beside
predictable side effects such as gastric pain, non-allergic NSAID
hypersensitivity may cause or trigger urticaria/angioedema,
rhinitis, asthma, and anaphylactoid reactions [1, 2]. Previous
studies have described the clinical manifestations of NSAID
hypersensitivity and defined several subgroups: patients with
asthma, patients with asthma and rhinitis, patients with chronic
urticaria, and otherwise normal individuals [3, 4]. In the general
population the prevalence of NSAID hypersensitivity was estimated
to be 0.3 to 0.9% [5, 6], whereas in patients with asthma or
chronic urticaria, the prevalence was calculated in the range of 23
to 28% [7, 8]. Atopy seems to be a risk factor for NSAID
hypersensitivity [9, 10]. The exact mechanism of non-allergic
hypersensitivity to NSAID remains unclear. The term non-allergic
hypersensitivity was proposed because immunologic mechanisms cannot
be proven [11]. Some evidence does point to the overproduction of
leukotrienes and the inhibition of prostaglandin synthesis,
resulting in an imbalance of the arachidonic acid cascade as well
as non-specific activation of basophils and mast cells [12-14].
Oral drug challenge is currently the only way to diagnose or
exclude NSAID hypersensitivity; neither blood nor skin tests are
available [15].An increasing number of publications about NSAID
hypersensitivity during recent years may be one reason that NSAID
hypersensitivity is nowadays more often diagnosed. Symptoms
developing in temporal relationship with the intake of NSAID are
frequently attributed to and misinterpreted as signs of
hypersensitivity by patients and physicians. Other causes for the
symptoms, such as pharmacological side effects or infectious
diseases are not considered. Furthermore, based on patient history
of an adverse reaction to NSAID, the simple advice to avoid all
NSAID is often given. The frequent diagnosis of NSAID
hypersensitivity leads to avoidance of NSAID and may lead to more
frequent prescription of second line medications, with possible
less efficacy and increased toxicity.Challenge tests reveal that
approximately 50% of patients with reported NSAID hypersensitivity
are misdiagnosed with the result that effective treatment for fever
and pain is withheld from these patients.
Methods
Patients
260 patients were evaluated, 179 females and 81 males presenting
from 1997 to 2003 with a diagnosis of NSAID hypersensitivity (table
1)( Table 1 ). The average age at the
time of suspected NSAID hypersensitivity was 51 years (ranging from
9 to 88 years). 216 (83.1%) patients were diagnosed with NSAID
hypersensitivity 1 year prior to our testing procedure, 14 (5.4%)
between 1 and 5 years, 10 (3.8%) between 6 and 10 years, and 17
(6.5%) more than 10 years previously; in 3 patients the time was
not known.
Table 1 Clinical features of the subjects studied
|
No. of patients
|
260
|
|
Mean age, yr (range)
|
51 (9 – 88)
|
|
Male / female
|
81 / 179
|
|
Patients with
|
|
-atopic disease
|
59 (22.7%)
|
|
-asthma/rhinitis
|
57 (21.9%)
|
|
-chronic urticaria
|
23 (8.8%)
|
|
-infectious disease
|
56 (21.5%)
|
Single-blinded, placebo-controlled oral NSAID challenge
To rule out allergic IgE-mediated hypersensitivity every patient
underwent a skin prick test with the suspected drug and a standard
panel of NSAID before oral challenge. Skin tests and readings were
carried out according to international guidelines [16]. Then all
patients were included in an established challenge protocol using
standardized doses (table 2)( Table 2 ).
General principles of our challenge protocol were as follows: (a)
Asthma and urticaria were in remission, (b) Patients were denied
β-blockers and H1-antihistamines for 1 week before the
NSAID challenge, (c) Oral NSAID challenges were conducted in
hospital by experienced personnel who could treat the reactions.
Patients had intravenous catheters in place during the entire
procedure. During the entire challenge procedure the patient was
observed, vital parameters were regularly checked, and equipment
for emergency treatment was available, (d) The dosage of NSAID
increased stepwise to the maximum of daily intake.
Only one NSAID was challenged every day with intervals of 1 hour
between the individual doses until the usual daily dose was
administered or symptoms of hypersensitivity occurred. Principally,
the order of the different NSAID administered to each patient was:
paracetamol, ibuprofen, diclofenac, and acetylsalicylic acid.
Successive additional challenges were performed with suspected
NSAID. In most patients this time consuming procedure was
shortened, challenging only one alternative and then the suspected
NSAID. The challenge test was considered positive, if objective
cutaneous, respiratory or anaphylactoid symptoms occurred up to 3
hours after the last dose was administered. All patients signed an
informed consent form about the procedure, detailing its aim and
risks.
Table 2 Single-blinded, placebo-controlled drug
challenge: drugs and doses
|
Drug
|
Dose (mg)
|
|
Acetylsalicylic acid
|
50; 100; 250; 500; 1000
|
|
Paracetamol
|
125; 250; 500; 1000
|
|
Diclofenac
|
10; 50; 100
|
|
Ibuprofen
|
50; 100; 200; 400
|
|
Indomethacin
|
12.5; 25; 50; 100
|
|
Piroxicam
|
5; 10; 20
|
|
Nefopam
|
3.75; 7.5; 15; 30
|
|
Mefenamic acid
|
125; 250; 500; 500
|
|
Celecoxib
|
25; 50; 100; 200
|
|
Rofecoxib
|
3.13; 6.25; 12.5
|
Results
Patients
57 (21.9%) patients reported a history of asthma or rhinitis, 23
(8.8%) patients suffered from chronic urticaria (table 1). 59
(22.7%) patients were finally labelled as atopic due to a positive
skin prick test with aeroallergens or evident atopic diseases such
as atopic dermatitis, rhinitis or asthma. 56 (21.5%) patients
received the suspicious NSAID in the context of an acute infectious
disease, like common cold or flu. In 45.0% acetylsalicylic acid was
the suspected NSAID (table 3)( Table 3
), followed by diclofenac (29.2%), and propionic acid derivates
(10.0%). Nearly all patients (237; 91.2%) took the NSAID orally, 20
patients (7.7%) received intramuscular injections and in three
patients the route of administration was not known. Episodes of
suspected NSAID hypersensitivity included urticaria/angioedema
(61.5%), asthma/rhinitis (24.2%), and systemic anaphylactoid
reactions (3.5%); 10.8% described uncertain symptoms or did not
remember the symptoms (table 4)( Table 4
). In all patients skin prick tests with NSAID were negative.
Table 3 NSAID assumed as a cause for the adverse
reaction
|
Acetylsalicylic acid
|
117 (45.0%)
|
|
Diclofenac
|
76 (29.2%)
|
|
Propionic acid derivates
|
26 (10.0%)
|
|
Paracetamol
|
24 (9.2%)
|
|
Piroxicam
|
10 (3.8%)
|
|
Indomethacin
|
6 (2.3%)
|
|
Celecoxib
|
1 (0.4%)
|
Table 4 Clinical history of the adverse reaction to
NSAID
|
Cutaneous (urticaria, angioedema)
|
160 (61.5%)
|
|
Respiratory (asthma, rhinitis)
|
63 (24.2%)
|
|
Anaphylactoid
|
9 (3.5%)
|
|
Uncertain
|
28 (10.8%)
|
Single-blinded, placebo-controlled oral NSAID challenge
In 260 patients, 606 challenge tests were carried out, on average
2.3 NSAID were challenged per patient. In none of the 606
individual challenge tests with standardized increasing doses
(table 2) did we experience anaphylactoid reactions requiring
emergency treatment. All positive reactions were mild and
controlled by symptomatic therapy (antihistamines, glucocorticoids,
inhalative β-mimetics) without adrenaline. Acetylsalicylic acid was
challenged 110 × (table 5)( Table 5 ).
We observed 12 × urticaria/angioedema, 1 × rhinitis, and 1 ×
asthma. 25 cutaneous reactions occurred; after diclofenac (10 ×),
Ibubrofen (10 ×), piroxicam (2 ×), paracetamol (2 ×) and mefenamic
acid (1 ×). Diclofenac and ibubrofen resulted in four emergent
respiratory reactions. The challenge tests with indomethacin,
nefopam, celecoxib and rofecoxib were all well tolerated without
any adverse reactions. In summary, among 606 challenge tests we
observed 43 (7.1%) positive reactions, 37 (6.1%) skin reactions and
6 (1.0%) respiratory reactions.
143 patients (55.0%) presenting with a diagnosis of NSAID
hypersensitivity in fact tolerated the suspected NSAID when
assessed by oral challenge (table 6)( Table
6 ). Among these 143 patients 118 (82.5%) were diagnosed as
NSAID hypersensitivity 1 year prior to our testing procedure, 7
(4.9%) between 1 and 5 years previously, 4 (2.8%) between 6 and 10
years previously, and 11 (7.7%) more than 10 years before; in 3
patients this time was not known. 36 patients (13.8%) were truly
NSAID sensitive. Our basic aim was to challenge all patients not
only with alternative NSAID but also with the suspicious NSAID.
Unfortunately 72 patients rejected a challenge test with the
suspicious NSAID. In the case of documented anaphylactoid reactions
(9 patients) we ourselves abandoned challenge tests with the
suspicious NSAID for ethical reasons. These 81 (31.2%) patients all
tolerated alternative NSAID.
Table 5 Single-blinded, placebo-controlled drug
challenge: symptoms and results
|
|
|
|
|
|
Drug
|
No.
|
Cutaneous
|
Respiratory
|
|
Acetylsalicylic acid
|
110
|
12
|
2
|
14 (12.7%)
|
|
Paracetamol
|
175
|
2
|
0
|
2 (1.1%)
|
|
Diclofenac
|
98
|
10
|
2
|
12 (12.2%)
|
|
Ibuprofen
|
100
|
10
|
2
|
12 (12.0%)
|
|
Indomethacin
|
17
|
0
|
0
|
0
|
|
Piroxicam
|
47
|
2
|
0
|
2
|
|
Nefopam
|
24
|
0
|
0
|
0
|
|
Mefenamic acid
|
10
|
1
|
0
|
1
|
|
Celecoxib
|
5
|
0
|
0
|
0
|
|
Rofecoxib
|
20
|
0
|
0
|
0
|
|
Total
|
606
|
37 (6.1%)
|
6 (1.0%)
|
43 (7.1%)
|
Table 6 Final diagnosis in relation to clinical
history
|
Final diagnosis
|
|
Clinical history
|
Tolerance ofNSAID
|
NSAIDhypersensitivity
|
Tolerance ofalternative NSAID
|
|
Cutaneous (160 x)
|
91
|
23
|
46
|
|
Respiratory (63 x)
|
27
|
13
|
23
|
|
Anaphylactoid (9 x)
|
0
|
0
|
9
|
|
Uncertain (28 x)
|
25
|
0
|
3
|
|
Total 260
|
143 (55.0%)
|
36 (13.8%)
|
81 (31.2%)
|
Discussion
Frequently, the diagnosis of NSAID hypersensitivity is based upon
history only without further diagnostic evaluation. Until proof of
the opposite, patients with NSAID hypersensitivity should avoid all
members of this drug class for safety reasons. The clinical
management of patients with the label NSAID hypersensitivity is
difficult, because they often refuse to take any other NSAID and
general practitioners are reluctant to prescribe alternative NSAID.
Our study shows that history is a vague and unreliable indicator of
true NSAID hypersensitivity. Oral challenge tests rule out NSAID
hypersensitivity in approximately 50% of the patients who had
previously been labelled as such.
How can we explain the symptoms leading to the incorrect
diagnosis of NSAID hypersensitivity? First, adverse reactions to
NSAID are relatively common, especially in the elderly, and may be
related to the pharmacological properties of these drugs. These
side effects are sometimes incorrectly reported as NSAID
hypersensitivity by patients and physicians.
Secondly, infectious diseases may lead to acute urticaria. The
most frequent reason for acute urticaria appears to be viral
infections, especially of the upper respiratory tract, which are
usually present a few days before the onset of wheal formation [17,
18]. The urticaria is then frequently attributed to NSAID which
were taken for symptom relief. Oral challenge can exclude NSAID
hypersensitivity and render the infectious disease as the most
likely cause of the urticaria.
Thirdly, about three quarters of health care professionals are
not aware of the nocebo phenomenon [19]. Patients taking drugs
frequently experience side effects that are not a result of
pharmacological action or hypersensitivity. Approximately one
quarter of patients taking placebo report adverse side effects [20,
21]. A significant number (12.7%) of our patients had adverse
reactions to placebo as well. The higher occurrence of NSAID
hypersensitivity in women as well as the reactions to placebo are
difficult to explain on a pathophysiological basis. This implies
that a psychological component in a subgroup of patients with a
suspected NSAID sensititvity exists; the so-called nocebo reactions
have been well described [15, 22, 23]. Barsky et al. identified
several factors which appear to be associated with the nocebo
phenomenon: patient’s expectations of adverse effects at the onset
of treatment; a process of conditioning in which the patient learns
from prior experiences and psychological characteristics such as
anxiety, depression, and the tendency to somatize [24]. In summary,
when a patient reports side effects to NSAID, the physician should
take a more detailed history, instead of attributing them
automatically to NSAID hypersensitivity.
Finally, we have to consider that drug challenges can also
reveal falsely negative results. The NSAID challenge test may have
been falsely negative in patients with a long interval between the
hypersensitivity reaction and the challenge procedure. However, the
time interval prior to the testing procedure was similar in the 143
patients with final tolerance of NSAID (82.5% within 1 year) as in
all patients (83.1% within 1 year). Furthermore, missing cofactors
(e.g. exercise) or tolerance induction during the challenge may be
reasons for falsely negative results [25, 26].
The association of bronchial asthma, non-allergic and
non-infectious rhinitis with or without nasal polyposis, and
intolerance to acetylsalicylic acid (ASA) or other NSAID, known as
the Fernand Widal syndrome, is also known in the world literature
as the ASA triad [4, 8, 14, 27]. Associated features may include
eosinophilia of bronchial and nasal secretions and of circulating
blood, urticaria, and/or angioedema. Taking into account the
symptoms of positive challenge tests, i.e. rhinitis and asthma, we
could identify 5 (13.9%) with proven Widal syndrome among our 36
patients with NSAID hypersensitivity (2 × acetylsalicylic acid, 2 ×
ibuprofen, 1 × diclofenac).
There is some evidence that the selective COX-2-inhibitors,
celecoxib and rofecoxib, might be safe alternatives for patients
with true NSAID hypersensitivity [28-30]. However, approximately
20% of NSAID sensitive patients also potentially react to
COX-2-inhibitors [31, 32]. In our study, all challenges with
celecoxib (5 ×) and rofecoxib (20 ×) were well tolerated.
Paracetamol very rarely causes hypersensitivity, mainly because the
mechanism of action is not related to the inhibition of
cyclooxygenase. We observed only 2 cutaneous reactions in 175
challenges with paracetamol. However, the tolerability of
paracetamol and COX-2-inhibitors should be always assessed in a
proper clinical setting [25, 31, 33].
In summary, the results of controlled challenge tests reveal
that NSAID hypersensitivity is overestimated by the medical
community. Many cases of reported NSAID hypersensitivity arise from
the misinterpretation of clinical history. For this reason we
recommend that all suspected cases of NSAID hypersensitivity should
be clarified by challenge tests.
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