Delayed hypersensitivity to cefazolin: report on a case involving lymphocyte transformation studies with different cephalosporins.

BACKGROUND: A cell-mediated immunopathogenic mechanism has been demonstrated in only a few cases of cutaneous reactions to systemically administered cephalosporins. OBJECTIVE: The aim was to investigate the pathogenic mechanism of a maculopapular rash experienced by a subject during cefazolin therapy. METHODS AND RESULTS: Prick, intradermal, and patch tests were carried out using penicillin determinants, ampicillin, amoxicillin, cefazolin, cephalothin, cefuroxime, ceftazidime, and ceftriaxone. Those tests for penicillin G and its determinants, as well as for ampicillin and amoxicillin, were negative. The patient displayed patch-test and delayed intradermal-test positivity to all the cephalosporins tested. No specific immunoglobulin E antibodies were found for penicillins or cefazolin. The lymphocyte-transformation-test results were negative for all the penicillins tested and showed a positive concentration-effect curve for cefazolin, ceftazidime, and ceftriaxone at concentrations up to 50 microg/mL. At 100 microg/mL the responses decreased with all the cephalosporins tested. Challenges with penicillin G and amoxicillin were well tolerated, but the challenge with cefazolin was positive. CONCLUSIONS: The data of this case demonstrate delayed hypersensitivity to cefazolin. Patch tests and delayed-reading intradermal tests can be a simple and effective means of diagnosing this type of reaction. Both in vivo and in vitro studies indicate that the responses were directed toward a determinant shared by all cephalosporins, but not by penicillins. The concentration of the cephalosporins used for the in vitro lymphocyte stimulation was critical, because at the concentrations normally used to test other beta-lactams the response decreased. This phenomenon may be attributable to an immunosuppressive, rather than toxic, effect.

Food-dependent exercise-induced anaphylaxis: clinical and laboratory findings in 54 subjects.

BACKGROUND: In some subjects, specific foods trigger anaphylaxis when exercise follows ingestion (specific food-dependent exercise-induced anaphylaxis, FDEIAn). Skin test and/or RAST positivity to foods suggest an IgE-mediated pathogenic mechanism. Others suffer from anaphylaxis after all meals followed by exercise, regardless of the food eaten (nonspecific FDEIAn). We sought to identify the culprit foods with a diagnostic protocol. METHODS: We collected detailed histories and performed skin prick tests (SPT) with 26 commercial food allergens, prick plus prick tests (P+P) with 15 fresh foods (including 9 assessed with SPT), and RAST for 31 food allergens. Treadmill stress tests were administered after a meal without any positive food (food plus exercise challenge, FEC). RESULTS: Among the 54 patients, 6 could not recall any suspect food. The other 48 suspected a specific food in at least one episode. The most frequent were tomatoes, cereals and peanuts. Fifty-two subjects were positive to at least one food (22 to more than 20), whereas 2 showed no positive results. All suspect foods were positive. SPT, P+P and RAST displayed different degrees of sensitivity. Each test disclosed some positivities not discovered by others. Two subjects reacted to FEC. Overall, 48 patients probably had specific FDEIAn and the other 6 nonspecific FDEIAn. CONCLUSION: It is useful to test both in vivo and in vitro an extensive panel of foods. Avoidance of foods associated with skin test and/or RAST positivity for at least 4 h before exercise has prevented further episodes in all our patients with specific FDEIAn.

Prevalence of sensitization to Cupressus sempervirens: a 4-year retrospective study.

In the last few years Cupressus sempervirens has been identified as the cause of an increasing number of cases of late winter-early spring pollinosis in Mediterranean countries. We conducted a 4-year retrospective study of a large group of subjects with documented allergic respiratory disease in order to determine the prevalence, clinical significance and annual rate of sensitization to C. sempervirens pollen. Anamnestic data and skin prick tests (SPT) with common aeroallergens and C. sempervirens extract were collected from 1397 subjects (712 male and 685 female) resident in Latium, a region in central Italy, with complaints related to upper- or lower-respiratory-tract disorders or conjunctival disease. Two hundred and forty-three subjects (17.4%) showed positive results to C. sempervirens extract: 47 (19.3%) of them were monosensitized. The annual sensitization rate of SPT positivity to C. sempervirens varied from 7.2% in 1995 to 22% in 1998. All the subjects monosensitized to cypress pollen had symptoms from January through April. Our study suggests that sensitivity to C. sempervirens is responsible for respiratory symptoms in an increasing percentage of subjects. Further studies are needed to determine its frequency at the national level.

Tolerability of meloxicam in patients with histories of adverse reactions to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequent, particularly among patients with chronic urticaria or asthma. The need to identify an alternative drug that is safe and reliable is a common problem in clinical practice. OBJECTIVE: To assess the tolerability of meloxicam, a new NSAID that selectively inhibits the inducible isoform of cyclooxygenase, in a group of NSAID-sensitive patients. PATIENTS AND METHODS: We studied 177 patients who had suffered adverse reactions to one or more NSAIDs. Cutaneous reactions were reported by 83.1% of the subjects (urticaria in 55, angioedema in 52, urticaria/angioedema in 39, and maculopapular rash in 1), respiratory symptoms by 3.9%, both cutaneous and respiratory symptoms by 9%, Stevens-Johnson's syndrome by 2.3%, and anaphylactoid reactions by 1.7%. All subjects underwent a single-blind, placebo-controlled oral challenge with divided therapeutic doses of meloxicam (1.9 mg + 5.6 mg 1 hour later = cumulative dose 7.5 mg). RESULTS: Positive reactions were observed in only two cases (1.1%), both manifested exclusively by cutaneous symptoms (urticaria/angioedema in one case and maculopapular rash/facial edema in the second). CONCLUSION: Meloxicam seems to be well tolerated by NSAID-sensitive subjects whose reactions are manifested by urticaria/angioedema. Additional study is needed for a more complete assessment of its tolerability in patients with aspirin-induced asthma and other severe manifestations of NSAID sensitivity.

Contact dermatoses in metal workers.

We studied 150 metal workers occupationally exposed to metals and metalworking fluids (MWFs) to determine the prevalence and nature of contact dermatitis. 150 office workers were used as non-exposed control group. Questionnaires were administered to evaluate occupational and non-occupational exposure. All subjects underwent a dermatological examination and patch-testing with standard allergen series and MWFs used in the plant. Twenty-eight metal workers (18.6%) presented minor skin disorders involving the hands (vs. only 2% of the controls), ten (6.6%) had major disorders (similar to the figure for the control group - 5.4%), and 112 (74.8%) had no lesions, as opposed to 92.6% of the control group. Positive patch tests were found in ten metal workers: eight had major skin disorders (six to nickel, cobalt and chromium, one to nickel and cobalt, one to nickel) and the remaining two were asymptomatic (one positive for nickel and chromium, one for nickel). Among the controls there were three cases of positivity, all among asymptomatic subjects. Patch tests with MWFs were negative. The prevalence of dermatoses among the metal workers was significantly higher than that of controls (p<0.01), and all cases of allergy in this group were provoked by metals themselves.

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.

Delayed hypersensitivity to diclofenac: a report on two cases.

BACKGROUND: Although skin reactions have been reported during use of diclofenac, a nonsteroidal anti-inflammatory drug, immunopathogenic mechanisms have been demonstrated in only a few cases. METHODS: We administered skin and patch tests to two subjects who had developed maculopapular rashes respectively 48 and 72 hours after initiation of treatment with diclofenac. RESULTS: In both cases, prick and intradermal tests with the drug were negative at 20 minutes, but 24 hours later an erythematous infiltrate had appeared at the intradermal test site. Patch tests with diclofenac were also positive at 48 and 72 hours. CONCLUSIONS: The features of both these cases are suggestive of delayed hypersensitivity to diclofenac. Delayed-reading intradermal and patch tests may be a simple and effective means of diagnosing reactions of this type.

Delayed hypersensitivity to aminopenicillins is related to major histocompatibility complex genes.

BACKGROUND: Although in some cases delayed hypersensitivity may be observed, beta-lactam antibiotics frequently induce immediate allergic IgE-mediated reactions with the specificity localized in the acyl-side chain structure. Generally, delayed immunologic reactions are related to sensitized T lymphocytes and major histocompatibility complex restricted. OBJECTIVE: To investigate the prevalence of HLA class I and II antigens in patients with delayed hypersensitivity to aminopenicillins in order to evaluate a relationship between major histocompatibility complex immune response genes and aminopenicillins hypersensitivity. METHODS: We assessed 24 patients with history of delayed hypersensitivity to aminopenicillins using (1) skin test with penicilloyl polylysine, minor determinant mixture, benzylpenicillin, amoxicillin, and ampicillin; (2) patch tests with benzylpenicillin, amoxicillin, and ampicillin; (3) RAST for penicilloyls G and V; and (4) oral challenges with amoxicillin, ampicillin, and penicillin V in 18/24 patients. All patients were typed by microlymphotoxicity standard test for HLA class I and II antigens. Statistical analysis by chi2 test 2 x 2 contingency tables, according to Svejgaard, were used for comparison between patients and random Italian population (522 subjects). RESULTS: In the patients group we found higher prevalence of HLA A2 (12/24 = 50%, RR = 6.76 P < .001, EF = 0.425), DRw52 (20/24 = 83.3%, RR = 9.28, P < .001, EF = 0.74), and lower frequency of DR4 (3/24 = 12% ns). CONCLUSIONS: These data suggest that the immune mechanisms involved in adverse reactions to aminopenicillins in vivo are related to genetic markers of immune response and confirms that the presentation of penicillin-hapten determinants to lymphocyte is major histocompatibility complex restricted.

Eosinophil-derived proteins in postprandial (food-dependent) exercise-induced anaphylaxis.

BACKGROUND: Postprandial exercise-induced anaphylaxis (PPEIAn) is a form of EIAn in which the ingestion of food before the exercise is associated with the onset of symptoms. Skin reactivity and the presence of specific serum IgE to several food allergens suggest the occurrence of food-dependent allergic mechanisms. METHODS: In order to study the involvement of eosinophils in the pathogenesis of PPEIAn we measured the changes in serum eosinophil cationic protein (ECP) and eosinophil protein X/eosinophil-derived neurotoxin (EPX/EDN) levels in 6 patients with PPEIAn, subjected to three separate challenges with either suspected foods only, exercise after a meal without or with suspected food ingestion. RESULTS: We found serum levels of both eosinophil-derived proteins increased only in challenges including both exercise and suspected food ingestion. Symptoms of anaphylaxis occurred in 3 of these patients. CONCLUSIONS: The increased release of eosinophil basic proteins in PPEIAn patients, caused by physical exercise following ingestion of suspected foods, is not obligatory for the definition of the syndrome.

Long-term tolerability of nimesulide and acetaminophen in nonsteroidal antiinflammatory drug-intolerant patients.

BACKGROUND: Oral challenges are used to identify alternative nonsteroidal antiinflammatory drugs (NSAIDs) for patients who react adversely to drugs of this class, but challenge conditions often differ from those in which the drug will actually be used. OBJECTIVE: To determine whether the results of oral challenges with nimesulide or acetaminophen, using cumulative administration of a single therapeutic dose while the patient is in good health, can predict the response to multiple doses of the drug during future illness. METHODS: Follow-up interviews were conducted with 248 NSAID-intolerant subjects who had tolerated oral challenges with nimesulide and/or acetaminophen 1 to 3 years earlier. We analyzed the adverse reaction rate in light of the febrile/non-febrile nature of the condition treated and the number of doses consumed. RESULTS: Nimesulide was tolerated by 115/122 (94.2%) of the patients who had tried it; acetaminophen by 71/75 (94.6%). A total of 8/159 (5%) patients had experienced reactions (seven urticarial and one asthmatic) to one or both drugs. Intolerance was unrelated to the nature of the condition treated or the number of doses administered, but all four patients who failed to tolerate acetaminophen and 3/7 of those who reacted to nimesulide had histories of chronic urticaria. CONCLUSIONS: Oral challenges can reliably predict long-term NSAID tolerability in patients with previous adverse reactions to other drugs of this class, except for patients with chronic urticaria.

Aminopenicillin allergy.

Eight two children with histories of maculopapular or urticarial rashes during aminopenicillin treatment underwent skin tests, patch tests, radioallergosorbent assays and, in some cases, oral challenges. Hypersensitivity was diagnosed in eight (9.8%): immediate in four with urticarial reactions and delayed (that is cell mediated) in four with maculopapular rashes. In 49 children (38 with maculopapular eruptions, 11 with urticarial/angiooedematous reactions), negative allergologic findings were confirmed using oral challenges with the suspected drug. Maculopapular rashes may reflect delayed hypersensitivity to aminopenicillins, which can be diagnosed on the basis of late intradermal reactions and/or patch test positivity. The allergen panel must include the suspected aminopenicillin itself, as many cases are side chain specific. Most patients with urticarial reactions (more typical of immediate hypersensitivity) will also react to penicilloyl polylysine and minor determinant mixture. The time elapsed between the reaction and testing must be considered if negative results emerge, because IgE mediated sensitivity (unlike cell mediated forms) declines in the absence of antigen exposure.

Allergic respiratory diseases and environmental pollution: experience in the printing/paper-manufacturing industry.

Several studies have shown a correlation between airborne pollutants and respiratory disorders. To determine whether professional exposure to industrial pollution might represent a risk factor for allergic respiratory diseases, we administered allergologic tests to 275 workers employed in a paper-making/printing factory and to a control population composed of 160 office workers from the same urban area. All subjects were evaluated on the basis of personal and family histories, the results of prick tests with common airborne allergens, specific serum IgE levels, pulmonary function test, and standard chest radiography. The percentage of subjects with allergies in the factory-worker group (67/275; 24.4%) was significantly higher than that observed among the office workers (20/160; 12.5%) (chi-square test: 8.17; P < 0.01). Of the 67 factory workers with allergies, 94% had histories of daily exposure to aliphatic hydrocarbons. The results of this study indicate that exposure to the latter type of industrial pollutants is associated with a significantly higher prevalence of allergic respiratory diseases.

Accelerated cell-mediated broncho-obstructive reaction to inhaled stepronin: a case report.

We describe the case of a 20-year-old man who developed an obstructive bronchial reaction accompanied by a maculopapular facial rash 8 h after an aerosol treatment with the mucolytic drug stepronin. The results of intradermal and patch testing with stepronin, together with those of bronchial challenge and histologic findings in patch-tested skin, indicate that the patient's reaction involved an accelerated cell-mediated mechanism of hypersensitivity. Bronchial challenges with methacholine demonstrated a transient increase in nonspecific bronchial hyperreactivity.