A diagnostic protocol for evaluating nonimmediate reactions to aminopenicillins

BACKGROUND: Maculopapular and urticarial rashes are nonimmediate manifestations common during aminopenicillin (AP) treatment, and the former often represent cell-mediated hypersensitivity. OBJECTIVES: We sought to determine the significance and incidence of skin test reactions to APs in adults reporting adverse reactions during therapy with these beta-lactams and, particularly, to evaluate the potential of patch tests, delayed-reading skin tests, and challenges in the diagnosis of nonimmediate reactions. METHODS: We used skin tests with penicilloylpolylysine, minor determinant mixture, benzylpenicillin, ampicillin, and amoxicillin, as well as patch tests with the last 3 drugs. We also performed in vitro assays for specific IgE and challenges with the suspect penicillin in subjects with nonimmediate reactions. RESULTS: Among the 144 patients reporting nonimmediate manifestations (mostly maculopapular rashes), delayed hypersensitivity was diagnosed in 62 on the basis of positive patch test and/or delayed intradermal test results and responses to challenges; negative reactions to challenges allowed us to reasonably exclude the possibility of allergy in 66 subjects, and the challenge confirmed that 1 patient had linear IgA bullous dermatosis. Definitive diagnoses could not be provided for the remaining 15 subjects, who had negative allergologic test results, because they did not consent to challenges. In 40 of 49 immediate reactors, a diagnosis of IgE-mediated hypersensitivity was made. CONCLUSIONS: Both patch and intradermal tests are useful in evaluating nonimmediate reactions to APs. Positive patch test and delayed intradermal responses together indicate delayed hypersensitivity. Intradermal testing appears to be more sensitive than patch testing, but the pattern of positive delayed intradermal test responses and negative patch test responses needs further investigation because of false-positive cases.     

Diagnosing nonimmediate reactions to penicillins by in vivo tests

BACKGROUND: Maculopapular and urticarial rashes are nonimmediate manifestations common during penicillin treatment; the former often represent cell-mediated hypersensitivity. Our objectives were to assess the incidence of allergy in adults reporting nonimmediate manifestations during penicillin therapy and to evaluate the diagnostic potential of patch tests, delayed-reading skin tests and challenges in such cases. METHODS: We used prick and intradermal tests as well as patch tests with penicillin determinants, ampicillin, amoxicillin and any other suspect penicillins. We also performed challenges with the suspect antibiotics. RESULTS: Such antibiotics were aminopenicillins in 93.1% of 259 patients, most of whom had suffered from maculopapular rashes followed by piperacillin (4.2%). Three subjects displayed immediate skin test positivity. Ninety-four subjects showed patch test and delayed intradermal test positivity to the culprit penicillin (90 to aminopenicillins and 4 to piperacillin) and were considered as having had delayed hypersensitivity reactions. Five of the 8 subjects who displayed delayed intradermal test positivity and patch test negativity to the suspect penicillin underwent challenges, 2 reacted positively to the responsible aminopenicillin. Among the remaining 154 with negative results in allergologic tests, 125 agreed to undergo challenges; only 3 reacted. In all, 98 patients -- 93 of whom had experienced maculopapular rashes -- displayed delayed hypersensitivity (94 to aminopenicillins and 4 to piperacillin). CONCLUSIONS: Both patch and intradermal tests are useful in evaluating nonimmediate reactions to penicillins, particularly maculopapular rashes. Patch test and delayed intradermal positivity together indicate delayed hypersensitivity. Intradermal testing appears to be slightly more sensitive than patch testing.     

Clinical presentation and time course in hypersensitivity reactions to beta-lactams

Background:  β-lactam hypersensitivity reactions are classified as immediate or nonimmediate. Diagnosis is usually based upon skin tests and provocation challenges.
Objective:  The time course of the reactions in proven β-lactam hypersensitivities was studied and then correlated with the symptoms to determine the relationship between the clinical presentations and the time course.
Method:  All of the patients who consulted between 1996 and 2004 for a suspected β-lactam hypersensitivity reaction were studied. Two hundred and ten patients with a proven hypersensitivity reaction diagnosed according to the European Network on Drug Allergy were included in the present study.
Results:  Of the patients, 36.7% had urticaria as a single symptom, 19.1% anaphylaxis without shock, 17.6% anaphylactic shock and 19.1% maculopapular exanthema. Anaphylactic shock and anaphylaxis mostly occurred within 1 h after drug administration. Exanthema mainly occurred after 24 h. Urticaria as a single symptom occurred at any time. A firm diagnosis was determined using immediate-reading skin prick (10.0%) and intradermal tests (38.1%), late-reading skin tests (19.1%) or provocation tests (32.9%).
Conclusion and clinical implication:  Depending on the time course of the reaction, three clinical groups were identified: anaphylaxis and anaphylactic shock (immediate reaction); maculopapular exanthema (late reaction) as well as urticaria (immediate and late reaction).     

Cross-reactivity and tolerability of imipenem in patients with delayed-type, cell-mediated hypersensitivity to β-lactams

Background:  Administration of imipenem-cilastatin to patients with IgE-mediated hypersensitivity to β-lactams has always been considered potentially harmful. Recent studies have demonstrated the tolerability of carbapenems (imipenem-cilastatin and meropenem) in patients with IgE-mediated hypersensitivity to β-lactams; there are no studies on this topic regarding patients with cell-mediated allergy to β-lactams. The aim of this study is to assess cross-reactivity and tolerability of imipenem in patients with cell-mediated allergy to β-lactams.
Methods:  From our database we selected 73 patients with cell-mediated allergy to β-lactams, diagnosed by means of immediate-type skin tests, delayed reading intradermal tests, patch tests and detection of specific IgE. Patients with negative patch tests with imipenem-cilastatin underwent an intramuscular test dosing.
Results:  Our patients had a total of 94 nonimmediate reactions to penicillins. All patients had positive patch tests and/or delayed reading intradermal tests for at least one of the penicillin reagent tested and negative immediate-type skin tests and specific IgE. Four patients out of 73 had a positive patch tests to at least one penicillin reagent and imipenem-cilastatin showing cross-reactivity. Sixty-four patients underwent the imipenem-cilastatin intramuscular test dosing and none of them had a clinical reaction.
Conclusions:  Our rate of cross-reactivity between imipenem-cilastatin and other β-lactams was 5.5%. This result is different from previous findings and this may be explained by the fact that we investigated patients with cell-mediated allergy to β-lactams. Patients with cell-mediated allergy to β-lactams should undergo patch tests and a tolerance challenge test before treatment with imipenem-cilastatin.     

Skin testing and drug provocation in the diagnosis of nonimmediate reactions to aminopenicillins in children

Background:  Nonimmediate allergic reactions (NIR) to aminopenicillin include several entities, the most common of which are urticaria-like and maculopapular exanthemas.
Aims of the study:  To evaluate a group of children who developed one or more episodes of skin reactions suggestive of NIR after aminopenicillin administration.
Methods:  The inclusion criteria required negative immediate skin tests and absence of specific IgE antibodies to different penicillins. Intradermal and patch tests were carried out with delayed readings and, if negative, a drug-provocation test including a full therapeutic course of the drug was given. Two different groups were compared: A) children with positive skin testing or a positive drug-provocation test and B) children with negative skin testing and good tolerance after a drug-provocation test.
Results:  Group A was composed of 20 patients. Positive intradermal/patch tests were found in one patient and in the remaining 19, a positive response to a drug-provocation test confirmed the diagnosis. Group B (the control group) consisted of 19 patients with similar symptoms after aminopenicillin intake but good tolerance. No differences in age, dose or number of previous treatments were observed between the groups. The clinical entities were also similar in both groups.
Conclusions:  Reproducible nonimmediate skin reactions to aminopenicillins may occur in children in spite of negative skin testing. The value of this diagnostic procedure seems to be limited in this type of reaction, with drug-provocation tests (DPT) being a reasonable and safe alternative if the diagnosis has to be confirmed.     

Practice parameters for diagnosing and managing iodinated contrast media hypersensitivity

Immediate and nonimmediate hypersensitivity reactions to iodinated contrast media (ICM) have been reported to occur in a frequency of about 0.5%-3% of patients receiving nonionic ICM. The diagnosis and management of these patients vary among guidelines published by various national and international scientific societies, with recommendations ranging from avoidance or premedication to drug provocation test. This position paper aims to give recommendations for the management of patients with ICM hypersensitivity reactions and analyze controversies in this area. Skin tests are recommended as the initial step for diagnosing patients with immediate and nonimmediate hypersensitivity reactions; besides, they may also help guide on tolerability of alternatives. Re-exposition or drug provocation test should only be done with skin test-negative ICMs. The decision for performing either re-exposition or drug provocation test needs to be taken based on a risk-benefit analysis. The role of in vitro tests for diagnosis and pretreatment for preventing reactions remains controversial.     

T cell-mediated reactions to iodinated contrast media: evaluation by skin and lymphocyte activation tests

BACKGROUND: In addition to immediate reactions, late adverse reactions to iodinated contrast media (ICM) were reported in 2% to 5% of patients exposed to ICM and, as a consequence, have recently gained more attention. A few well-documented case reports postulate a hypersensitivity mechanism. OBJECTIVE: The aim of this study is to demonstrate a T cell-mediated mechanism to the ICM by using in vitro and ex vivo tests. METHODS: We analyzed 12 patients with 13 adverse ICM reactions, 9 of whom were women. Clinical history suggested an immune reaction to ICM. Skin tests (skin prick, intradermal, and patch tests) were performed with various ICM and read after 15 minutes and 24 and 48 hours. Skin biopsy specimens of positive test sites of 11 patients were evaluated by means of immunohistology. T-cell reactivity to ICM in vitro was analyzed with lymphocyte activation tests. RESULTS: Seven patients showed generalized maculopapular eruptions, one of them with fever; 4 had a so-called drug hypersensitivity syndrome with exanthema, eosinophilia, and fever; 1 had maculopapular eruptions and fever; 1 had late-onset urticaria with loss of consciousness; and 1 had facial edema and respiratory distress. An immune reaction to ICM was inferred from positive skin prick test (2 patients), positive patch test (10 patients), and positive intradermal test (9 patients) at 24 and 48 hours. Skin biopsy specimens revealed a T-cell infiltrate in the dermis with predominantly CD4 + T cells in 8 patients, CD8 + T cells in 1 patient, and equal numbers in 1 patient. Cross-sensitivities to several ICM were observed (9/12). Other drug allergies were noted in 6 of the 12 patients. CONCLUSIONS: Delayed reactions to ICM are most likely caused by immune reactions to these drugs and can elicit different clinical features. The involvement of T cells is suggested by positive skin test, as well as positive proliferative responses, to the drugs in vitro . A high degree of cross-reactivity with other than the eliciting ICM was observed. Moreover, 50% of these patients reported another drug hypersensitivity, suggesting a predisposition to immune reactivity in some patients.     

Delayed-type hypersensitivity to a nonionic, radiopaque contrast medium

Background True allergic reactions to iodinated radiocontrast media are rare, and only a few well-documented cases of delayed-type hypersensitivity reactions caused by contrast media have been described.
Methods We report a 61-year-old patient in whom percutaneous transluminal coronary angioplasty (PTCA) was performed with iopamidol, a nonionic contrast medium. Seven days later, the patient developed generalized maculopapular exanthema. Repeated patch tests with several iodinated agents were performed.
Results A first patch test with iopamidol was positive. Repetition of the patch tests showed positive results to iopamidol as well as to iohexol and ioversol. two other nonionic contrast media, but not to other iodinated substances. Three months later, PTCA was repeated, and iopamidol was used again. Despite premedication. pruritic macular exanthema developed 1 day later. Whether iopamidol or trometamol - an additive substance in the contrast medium - was causative could not be determined, since a third set of patch tests was negative.
Conclusions Delayed-type hypersensitivity reactions to iodinated contrast media are rare. We recommend that patients with delayed exanthematous reactions undergo patch or intradermal tests with different contrast media and their additives, and that readings be performed immediately and later at days 2 and 3.     

Usefulness of intradermal test and patch test in the diagnosis of nonimmediate reactions to metamizol

BACKGROUND: Metamizole is a pyrazolone derivative, and its most common reactions are IgE-mediated reaction and idiosyncratic reactions. Non-immediate reactions are poorly described and there are very few reports on non-immediate reactions to pyrazolones. MATERIALS AND METHODS: We evaluated 12 patients (nine men) who consulted for a non-immediate reaction after metamizol administration. We performed cutaneous tests (skin prick tests and immediate and delayed intradermal tests) and epicutaneous tests, and, if necessary, an oral challenge test. RESULTS: All skin prick and intradermal tests, if necessary, were negative in immediate reading. Delayed intradermal tests were positive in six of 10 patients (60%) and epicutaneous tests were positive in four of 11 patients (36%). Three cases (25%), were diagnosed by a positive oral challenge test. DISCUSSION: Delayed-reading intradermal tests and patch tests are useful tools in the diagnosis of nonimmediate reactions to pyrazolones and should be considered the first step when evaluating these type of reactions. Intradermal test appears to be more sensitive than patch test. The positivity of skin tests suggests an immunological reaction, probably mediated by T lymphocytes, but further studies are required.     

In vitro T-cell responses to beta-lactam drugs in immediate and nonimmediate allergic reactions.

BACKGROUND: beta-Lactam drugs may induce both cellular and humoral allergic reactions, and there is evidence that T cells play an important role in the pathogenesis of these reactions. The aim of this work was to assess the sensitivity and specificity of the lymphocyte transformation test (LTT) as an in vitro diagnostic tool, in patients with either an immediate or a nonimmediate reaction to penicillin G and/or amoxicillin. METHODS: Fifty patients with a well-documented history of allergic reactions to beta-lactams (31 immediate and 19 nonimmediate) were studied by means of skin tests (prick and intradermal), radioallergosorbent test (RAST), and, when necessary, controlled administration of the drug. Twenty-eight healthy subjects with good tolerance to penicillins served as controls. LTT was performed in all subjects. RESULTS: Skin tests were positive in 77.4% of the patients with immediate reactions and in 36.8% of those with nonimmediate reactions. The overall sensitivity of LTT in the allergic patients was 62%, but, when analyzed separately, sensitivity was 64.5% for the immediate group and 57.9% for the nonimmediate group. The LTT specificity was 92.8%. CONCLUSION: The LTT should be considered a useful in vitro diagnostic tool to identify subjects allergic to penicillins, especially patients with nonimmediate reactions where the LTT has a better diagnostic value than skin tests. Interestingly, positive T-cell proliferative responses can be observed 10 or more years after the occurrence of the reaction without further exposure to the drug.     

Diagnosis of iodinated contrast media hypersensitivity: results of a 6-year period

Background Iodinated contrast media (ICM) hypersensitivity reactions represent a serious problem. Very few clinical data concerning systematic skin testing to ICM are available. Objective To evaluate the utility of ICM skin testing in patients with ICM hypersensitivity. Material and methods All patients referred over a 6‐year period for ICM hypersensitivity past reactions were skin tested for (a) the implicated ICM, or (b) a set of ICM if they were positive for the implicated ICM or if its name was unknown. Results Forty‐four patients, with a median age of 56 years, were studied (15 males, 29 females). The ICM skin tests were positive in 10 patients (23%): one had a positive skin prick test, seven an immediate positive intradermal test (IDT) and two a delayed positive IDT. Skin tests were more often positive in patients with immediate (9/32) as compared with those with non‐immediate reactions (1/11). The time interval between the reaction and skin testing was shorter for those patients with an immediate ICM reaction and a positive skin test result (3 months [2.5–174.0]) as compared with those with an immediate ICM reaction and a negative skin test (48 months [6.8–159.0]), (P<0.05). Respiratory allergy was more frequent in the positive group (6/10 vs. 7/34, P<0.05). Conclusions Skin tests with ICM are positive in a subgroup of patients with ICM hypersensitivity and may play an important role in the diagnosis of ICM allergy.     

Management of hypersensitivity reactions to iodinated contrast media

All iodinated contrast media (CM) are known to cause both immediate (≤1 h) and nonimmediate (>1 h) hypersensitivity reactions. Although for most immediate reactions an allergic hypersensitivity cannot be demonstrated, recent studies indicate that the severe immediate reactions may be IgE-mediated, while most of the nonimmediate exanthematous skin reactions, appear to be T-cell mediated. Patients who experience such hypersensitivity reactions are therefore advised to undergo an allergologic evaluation. Several investigators have found skin testing to be useful in confirming a CM allergy, especially in patients with nonimmediate skin eruptions. If a patient with confirmed allergy to a CM needs a new CM exposure, a skin test negative CM should be chosen and premedication may be tried. However, none of these precautional measures is a guarantee against a repeat reaction. More research focusing on pathomechanisms, diagnostic testing and premedication is therefore clearly needed in order to prevent CM-induced hypersensitivity reactions in the future.     

Recent advances in the diagnosis of drug allergy

PURPOSE OF REVIEW: The present review addresses the most recent literature regarding the diagnosis of drug hypersensitivity reactions, which can be classified as immediate or nonimmediate according to the time interval between the last drug administration and the onset. Immediate reactions occur within 1 h; nonimmediate ones occur after more than 1 h. RECENT FINDINGS: Clinical and immunological studies suggest that type-I (IgE-mediated) and type-IV (cell-mediated) pathogenic mechanisms are involved in most immediate and nonimmediate reactions, respectively. New diagnostic tools, such as the basophil activation test and the lymphocyte activation test, have been developed and are under validation. SUMMARY: In diagnosis, the patient's history is fundamental; the allergologic examination includes in-vivo and in-vitro tests selected on the basis of the clinical features. Prick, patch, and intradermal tests are the most readily available forms of allergy testing. Determination of specific IgE levels is still the most common in-vitro method for diagnosing immediate reactions. The sensitivity of allergologic tests is not 100%; in selected cases, therefore, provocation tests are necessary. The routine use of the basophil activation test and the lymphocyte activation test could increase the sensitivity of diagnostic work-ups, thus reducing the need for drug provocation tests.     

An approach to the patient with a history of local anesthetic hypersensitivity: experience with 90 patients.

We have studied the utility of skin testing and progressive challenge to detect local anesthetic hypersensitivity in patients with histories of reactions to local anesthetics. The likelihood of previous immediate hypersensitivity reactions was determined by history in 90 referrals. Fourteen had histories compatible with immediate hypersensitivity reactions, 24 did not, and the history was uncertain in 52. Of the 14, 12 were negative to lidocaine skin test and challenge, although 5 gave histories of immediate hypersensitivity reactions to it. The other 76 patients also underwent skin testing and progressive challenge. No skin tests were positive with 1:100 local anesthetics but 10 patients had positive intradermal skin tests to undiluted 1% local anesthetics. Proof of false positivity was confirmed in 4 of 10 cases by uneventful challenge to the local anesthetic giving the positive skin test. At least 1 local anesthetic was cleared for use in each of the 90 patients. Skin testing as part of a progressive challenge protocol is a useful approach to the management of alleged local anesthetic hypersensitivity. True immediate hypersensitivity reactions to local anesthetics are rare. Positive skin tests to dilutions of 1:100 local anesthetics are also rare and may suggest the possibility of true immediate hypersensitivity to the agent tested.     

Clinical value of radiocontrast media skin tests as a prescreening and diagnostic tool in hypersensitivity reactions

BackgroundSome radiocontrast media (RCM) hypersensitivity reactions may have underlying IgE- or T-cell–mediated mechanisms. RCM skin testing may be useful for predicting future reactions.ObjectiveTo investigate the clinical value of RCM skin testing before computed tomography and after RCM hypersensitivity reactions.MethodsPatients who underwent RCM skin testing were a prospective sample of convenience at a single medical center and were tested just before their pending nonionic RCM-enhanced computed tomogram. In addition, skin test data of patients who were referred to the allergy clinic because of their previous RCM hypersensitivity reactions were reviewed retrospectively.ResultsA total of 1048 patients enrolled in the study prospectively. Of these, 672 (64.1%) had never been exposed to RCM. Of the 376 previously exposed to RCM, 61 (16.2%) had a history of at least one mild RCM-associated reaction, 56 (91.8%) had immediate reactions, and 5 had no-immediate reactions. There was only 1 positive immediate hypersensitivity RCM skin test result (0.09%). There were 51 mild immediate reactions (4.9%), 1 moderate immediate reaction (0.09%), 8 mild nonimmediate reactions (0.76%), and 1 moderate nonimmediate reaction (0.09%). There was only 1 positive delayed hypersensitivity skin test result (0.09%), retrospectively determined, in 1 (11.1%) of the nonimmediate RCM-associated reactions. Sensitivity of RCM skin testing was significantly higher with severe immediate reactions (57.1%) than mild reactions (12.9%) and moderate reactions (25.0%) in the retrospective review of diagnostic skin test data (P = .03).ConclusionRCM skin testing for screening is of no clinical utility in predicting hypersensitivity reactions. RCM skin testing may have modest utility in retrospectively evaluating severe adverse reactions.     

Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins

Background:  Administration of meropenem to penicillin-allergic patients who might benefit from this treatment is usually avoided because of a 47.4% rate of cross-reactivity to imipenem, the prototype of the carbapenem class of β-lactam antibiotics, demonstrated in a single study on the basis of positive responses to skin tests with imipenem reagents. However, recent studies of ours have demonstrated a very low rate of cross-reactivity between penicillins and both meropenem and imipenem in adults.
Objective:  To assess cross-reactivity and tolerability of meropenem in children with documented penicillin allergy.
Methods:  One hundred and eight consecutive children who had suffered a total of 129 immediate reactions (120 urticarial and/or angioedematous manifestations and 9 anaphylactic shocks) to penicillins and had positive results to skin tests for at least one of the penicillin reagents tested underwent skin tests with meropenem and negative subjects were challenged with it.
Results:  One subject (0.9%) displayed a positive intradermal test to meropenem. The remaining 107 subjects with negative skin tests to meropenem tolerated challenges. Challenges were not followed by full therapeutic courses.
Conclusions:  Our results demonstrate a low rate of cross-reactivity between penicillins and meropenem. Therefore, the practice of avoiding meropenem in children with immunoglobulin E-mediated hypersensitivity could be abandoned; in those who especially require meropenem treatment, prophylactic skin tests are advisable, because negative results indicate tolerability.     

Negativization rates of IgE radioimmunoassay and basophil activation test in immediate reactions to penicillins

Background:  Skin test sensitivity in patients with immediate allergy to penicillins tends to decrease over time, but no information is available concerning in vitro tests. We analysed the negativization rates of two in vitro methods that determine specific immunoglobulin E (IgE) antibodies, the basophil activation test using flow cytometry (BAT) and the radioallergosorbent test (RAST), in immediate allergic reactions to penicillins.
Methods:  Forty-one patients with immediate allergic reactions to amoxicillin were followed up over a 4-year period. BAT and RAST were performed at 6-month intervals. Patients were randomized into groups: Group I, skin tests carried out at regular intervals; Group II, skin tests made only at the beginning of the study.
Results:  Differences were observed between RAST and BAT ( P  < 0.01), the latter showing earlier negativization. Considering different haptens, significant differences for the rate of negativization were only found for amoxicillin ( P  < 0.05). Comparisons between Groups I ( n  = 10) and II ( n  = 31) showed a tendency to become negative later in Group I with RAST.
Conclusions:  Levels of specific IgE antibodies tended to decrease over time in patients with immediate allergic reactions to amoxicillin. Conversion to negative took longer for the RAST assay, although the differences were only detected with the amoxicillin hapten. Skin testing influenced the rate of negativization of the RAST assay, contributing to maintenance of in vitro sensitivity. Because of the loss of sensitivity over time, the determination of specific IgE antibodies to penicillins in patients with immediate allergic reactions must be done as soon as possible after the reaction.     

Diagnosis of nonimmediate reactions to beta-lactam antibiotics

Nonimmediate manifestations (i.e. occurring more than 1 h after drug administration), particularly maculopapular and urticarial eruptions, are common during beta-lactam treatment. The mechanisms involved in most nonimmediate reactions seem to be heterogeneous and are not yet completely understood. However, clinical and immunohistological studies, as well as analysis of drug-specific T-cell clones obtained from the circulating blood and the skin, suggest that a type-IV (cell-mediated) pathogenic mechanism may be involved in some nonimmediate reactions such as maculopapular or bullous rashes and acute generalized exanthematous pustulosis. In the diagnostic work-up, the patient's history is fundamental; patch testing is useful, together with delayed-reading intradermal testing. The latter appears to be somewhat more sensitive than patch testing, but also less specific. In case of negative allergologic tests, consideration should be given to provocation tests, and the careful administration of the suspect agents. With regard to in vitro tests, the lymphocyte transformation test may contribute to the identification of the responsible drug. Under the aegis of the European Academy of Allergology and Clinical Immunology (EAACI) interest group on drug hypersensitivity and the European Network for Drug Allergy (ENDA), in this review we describe the general guidelines for evaluating subjects with nonimmediate reactions to beta-lactams.     

Clinical Features of Immediate Hypersensitivity to Isopropylantipyrine

Hypersensitivities induced by isopropylantipyrine (IPA), a pyrazolone derivative within the wider family of non-steroidal anti-inflammatory drugs (NSAIDs), are rarely reported. We characterized the clinical features of 12 patients with IPA-induced hypersensitivity. Twelve patients with immediate hypersensitivity to IPA were enrolled and classified into two groups: group I, consisting of eight patients (66.7%) with selective hypersensitivity; and group II, consisting of four patients (33.3%) showing cross-intolerance to other NSAIDs. Skin prick and intradermal and oral provocation tests with IPA were performed. To confirm selective hypersensitivity, an aspirin oral provocation test was also conducted. The most common manifestations were cutaneous reactions (91.7%), followed by anaphylaxis (66.7%), respiratory (41.7%), ocular (16.7%), and gastrointestinal reactions (16.7%). The median age and the median age at onset were 34.5 (range, 23-55) years and 28.0 (range, 7-47) years, respectively. In both groups I and II, all patients showed negative responses to skin prick testing, whereas only two patients in group I were positive in response to intradermal IPA tests. The response time after drug exposure was shorter in group I than in group II. Here, we report on two types of IPA hypersensitivity: selective and cross-intolerant NSAID hypersensitivity. An immediate IgE-mediated reaction may be involved in patients with selective hypersensitivity, whereas a cyclooxygenase-1-related inhibition mechanism may be a responsible mechanism for the patients with cross-intolerance to multiple NSAIDs.     

Benzylpenicillin skin testing is still important in diagnosing immediate hypersensitivity reactions to penicillins

Background:  The fact that both Hollister-Stier and Allergopharma ceased the production of penicilloyl-polylysine (PPL) and minor determinant mixture (MDM) in 2004 is severely hampering the diagnosis of β-lactam hypersensitivity and may produce negative consequences.
Objective:  To assess the contribution of skin testing with benzylpenicillin to the diagnosis of immunoglobulin E-mediated hypersensitivity to penicillins, in order to determine how much such testing could compensate for PPL and MDM unavailability.
Methods:  We selected patients with histories of immediate reactions to penicillins and positive results to skin tests for one or more penicillin reagents (PPL, MDM, or benzylpenicillin), one or more semi-synthetic penicillins (ampicillin, amoxicillin, or piperacillin), or both.
Results:  A total of 300 patients were selected, 105 in the French center and 195 in the Italian centers. Amoxicillin and ampicillin were the main responsible drugs. The most common clinical manifestation was anaphylaxis. The reagents most frequently positive to skin tests were amoxicillin (188, 62.7%), ampicillin (151, 50.3%), and benzylpenicillin (111, 37.0%). Among the 300 subjects, 113 (37.7%) were positive only to semi-synthetic penicillins, 109 (36.3%) to both semi-synthetic penicillins and the classic penicillin reagents, and 78 (26.0%) only to the latter. In the last group, 64 (21.3% of the 300 subjects) were positive only to PPL and/or MDM and 14 (4.7%) to benzylpenicillin, of whom 8 (2.7%) were positive only to the latter.
Conclusions:  Skin testing with benzylpenicillin can partially compensate for PPL and MDM unavailability. Moreover, it can slightly increase the allergologic workup's sensitivity and therefore reduce the number of potentially dangerous challenges.