ARTICLE
Pseudo-allergic reactions are inflammatory, immediate-type reactions
with clinical symptoms such as rhinitis, asthma, or urticaria. IgE is
not involved, but after provocation, histamine release and sulfidoleukotriene
(sLT) production can be found in vivo in pseudo-allergic patients
[1]. Since IgE is not involved in intolerance reactions, in vitro
(e.g. RAST) and in vivo (e.g. prick tests) diagnostic
procedures have not been available. However, a new diagnostic method has
been developed over the last few years, which is based on the production
of sulfidoleukotrienes (sLTC4, sLTD4 and sLTE4) upon challenge with antigens.
It has been reported that the cellular allergen stimulation test (CAST-ELISA)
provides a useful tool for the diagnosis of allergic as well as intolerance
reactions, e.g. due to nonsteroidal antiinflammatory drugs (NSAID)
[2, 3]. Here, we report one case which showed rhinoconjunctivitis, after
ingestion of NSAID, as the major symptom of intolerance. The determination
of the release of sLTs after stimulation of leukocytes as well as provocation
tests clearly proved NSAID to be the cause of the rhinoconjunctivitis.
Materials and methods
CAST-ELISA (DPC Biermann GmbH, Bad Nauheim, Germany) was performed as
published earlier [4]. Briefly, leukocytes were isolated from whole blood
via dextran sedimentation. Leukocytes were then incubated for 40
minutes at 37° C in a buffer containing interleukin 3 (16 ng/ml),
and one of the following stimulants obtained from the supplier (DPC Biermann
GmbH, Bad Nauheim, Germany): anti-IgE (100 ng/ml), ionomycin (150 ng/ml),
or one of the non-steroidal analgesics, indomethacin (20 µg/ml),
ibuprofen (200 µg/ml), diclofenac (20 µg/ml), or acetyl-salicylic
acid (ASA; 200 and 20 µg/ml). In the case of ASA, tests in the presence
or absence of C5a (10 7 M), Sigma, Deisenhofen, Germany
were performed since earlier in vitro and clinical studies demonstrated
increased sLT release from leukocytes in the presence of C5a and IL-3
[4-6]. Supernatants were then analysed in duplicate using an ELISA technique
with a monoclonal antibody that recognised sLTC4, sLTD4 and sLTE4 [7].
Furthermore, ten volunteers with negative provocation tests to NSAIDs
(ASA, indomethacin, ibuprofen, diclofenac) served as controls. The patient
and the controls had not taken any antiinflammatory drugs for eight weeks
prior to the CAST-ELISA. Provocation tests were started after blood had
been drawn for the CAST-ELISA. Total IgE and specific IgE was analysed
using the CAP system from Kabi Pharmacia Diagnostics, Freiburg, Germany
[8].
Case report
A 28-year-old, Caucasian woman who was admitted to our clinic had been
suffering from recurrent, non-seasonal rhinoconjunctivitis for 3 years.
The patient's and family medical history was negative for atopy. One occurrence
of rhinoconjunctivitis had been associated with general urticaria. The
patient had dysplasia of both hips which was the cause of repeated ingestion
of NSAID. In several instances, rhinoconjunctivitis occurred about 30
minutes after ingestion of NSAID (diclofenac, indomethacin, ibuprofen
and combined preparations which contained ASA). However, in a few instances
of rhinoconjunctivitis, the history regarding intake of NSAID was unclear.
Therefore, the patient was prick tested with a variety of typical aero-allergens
(grass and tree pollen, house dust mites, latex) without any positive
results. Prick tests and patch tests were negative for a broad panel of
NSAID including paracetamol, indomethacin, ibuprofen, ASA, and diclofenac.
Total IgE was within the normal range (26 kU/l). Furthermore, specific
IgE was negative for various pollen allergens, house dust mites, yeasts
and latex. CAST-ELISA was performed using the following pseudo-allergens:
indomethacin, ibuprofen, diclofenac, and ASA in the presence and absence
of C5a. The test showed increased levels of sLT release after stimulation
with diclofenac, ibuprofen and indomethacin compared to 10 provocation
test-negative, age matched controls (Table
I). In contrast, values of sLT release similar to provocation
test negative controls were observed after stimulation with ASA in the
absence or presence of C5a. To analyse the clinical relevance of these
in vitro results, we performed double-blind, placebo controlled
provocation tests with ibuprofen (cumulative amount: 1,500 mg), diclofenac
(187.5 mg), indomethacin (75 mg), and ASA (1,900 mg), respectively. The
patient developed rhinoconjunctivitis after ingestion of ibuprofen (cumulative
amount: 300 mg), diclofenac (37.5 mg), and indomethacin (25 mg) within
30 to 90 minutes (Fig. 1).
In contrast, provocation tests with placebo and ASA (cumulative amount:
1,900 mg) were tolerated.
Discussion
Allergic reactions of the immediate type result from the production
and/or release of cellular inflammatory mediators such as histamine, leukotrienes,
platelet activating factor or cytokines in response to IgE antibodies.
Although specific IgE is not involved in pseudoallergic reactions, histamine
and leukotrienes are the most important mediators responsible for inflammatory
reactions and the symptoms of intolerance reactions. Because of their
relatively cumbersome manipulation and their cost, histamine release tests
are not used in routine allergologic investigations [3]. However, the
newly developed CAST-ELISA allows the determination of the cellular sLT
release from leukocytes in vitro. This is thought to be of major
clinical relevance especially in the diagnosis of intolerance reactions.
It has been shown that sLT4 concentrations are increased after NSAID challenge
in NSAID-sensitive patients [9, 10]. In this case, history, conventional
in vitro tests such as specific IgE-determination, as well as prick
and patch tests to NSAID and aeroallergens gave no diagnostic clue. In
general, challenge tests have to be performed for
diagnostic purposes despite their risk to the patient. Therefore, predictive
in vitro tests especially in cases of intolerance reactions are
of major clinical importance since they are economical and safe. In our
patient, the intolerance reaction to ibuprofen, diclofenac, and indomethacin
and tolerance of ASA is unusual. However, the results of the in vitro
tests confirmed the challenge tests. The reason for the uncommon incidence
of intolerance to the above mentioned NSAID and tolerance to ASA remains
unclear. A recently published study confirms the predictive value of the
CAST-ELISA in the diagnosis of pseudoallergy to ASA [4]. However, to our
knowledge there are no large scale prospective studies analysing the predictive
value of sLT release from leukocytes in intolerance reactions to NSAID
other than ASA. In our case report, clinical relevance of sLT determination
in intolerance reactions to substances other than ASA is implicated. Further
prospective studies to identify the predictive value of the sLT determination
in the diagnosis of intolerance to NSAID other than ASA are ongoing.
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