Decline in 2 Serial Postmortem Tryptase Measurements Beyond 72 Hours After Death in an Antibiotic-Related Anaphylactic Death.

Anaphylaxis can be difficult to diagnose in the postmortem setting. Postmortem tryptase is a widely used ancillary test in aiding the diagnosis in which an elevation supports a death from anaphylaxis. Postmortem tryptase can be difficult to interpret, and the effects of postmortem kinetics are not fully understood. Clinically, mast cell tryptase returns to baseline 24 to 72 hours after an anaphylactic stimulus. We report another anaphylactic death from antibiotic administration in which 2 serial postmortem total tryptase measurements at 3 days (72 hours) and 6 days (144 hours) after death declined from 522 µg/L to 300 µg/L (baseline, 5.6 µg/L). The declination appears to be slower than what is expected in the clinical setting. This case highlights yet another example of the difficult and complex interaction of postmortem interval on postmortem tryptase, especially in an anaphylactic death. We suggest that early blood sampling and serial tests be performed if possible in suspected anaphylactic death.

Selective sensitization to Penicillin V with tolerance to other betalactams.

BACKGROUND: Penicillin G and V have the same betalactam ring. Penicillin V (phenoxymethylpenicillin) results from the substitution of the phenyl acetic acid of benzylpenicillin by the phenoxy methyl side chain. METHODS: Our patient was a 34-year-old man who experienced generalized urticaria after ingestion of Penicillin V. We performed skin prick tests and intradermal tests with a battery of betalactams including Penicillin V. We also determined specific IgE against penicillin V, penicillin G, amoxicillin, and ampicillin and performed a single-blind oral challenge with Penicillin V, amoxicillin, cefuroxime, and ceftazidime. RESULTS: The results of skin prick and intradermal tests with the betalactams included were negative. Specific IgE with betalactams was < 0.10 IU/L. The result of a single-blind oral challenge with Penicillin V was positive: 40 minutes after receiving 125 mg of Penicillin V, the patient presented generalized pruritus with hives on his back and chest. He tolerated oral administration of amoxicillin, cefuroxime, and ceftazidime. CONCLUSION: We report an exceptional case of sensitization to Penicillin V with negative results in the allergy workup. Diagnosis was based on a positive single-blind oral challenge result. The patient tolerated other betalactams. We provide a brief summary of the most relevant recent patents.

The specificity of tests for anti-beta-lactam IgE antibodies declines progressively with increase of total serum IgE.

BACKGROUND: Immediate allergic reactions to beta-lactam antibiotics are mediated by specific IgE antibodies. The Phadia CAP System FEIA is a commercial method for quantification of specific IgE. We wished to determine anti-beta-lactam IgE antibodies in patients without penicillin allergy but with high levels of total IgE. METHODS: Sera from 41 patients (31 with high total IgE, 10 with low total IgE) were analyzed for IgE antibodies specific to penicilloyl G, penicilloyl V, amoxicilloyl and ampicilloyl using the CAP FEIA((R)) method that was available up to 2006. Seven sera that tested positive were rechecked in a new improved system available after 2006. RESULTS: In patients without a history of penicillin allergy, the specificities of commercial tests for anti-beta-lactam IgE antibodies were 100%, 60%, 27% and 20% at total IgE levels of 8-263 kU/l, 500-664 kU/l, 1000-2000 kU/l and > 2000 kU/l, respectively. In seven retested sera, only 2 (28%) were still positive for penicillin-specific IgE antibody. CONCLUSION: Before 2006, tests for anti-beta-lactam IgE antibody in patients with total IgE > 500 kU/l were probably often false positive. Patients who were diagnosed as penicillin allergic before 2006 solely on the basis of a positive CAP FEIA test for specific IgE should be considered for diagnostic reevaluation.

Management of tolerance induction in patients with suspected penicillin allergy--a case study.

BACKGROUND: In some diseases penicillin is the treatment of choice. Case studies have shown a good response for the treatment of circumscribed scleroderma or scleroderma adultorum of Buschke. A suspected allergy to penicillin in a patient's history may limit this helpful therapy option. Allergy testing is often inconclusive. If indicated, tolerance induction leading to therapy with penicillin can be carried out. PATIENTS AND METHODS: We present two patients with circumscribed sclerosis and scleredema Buschke, who had a suspected allergy to penicillin. Due to limited therapy options and in insufficient response to other therapeutics, the decision for a tolerance induction with penicillin was made. Penicillin was successfully administered by following a scheme of tolerance induction starting with oral doses and ending with high doses of intravenous penicillin G. RESULTS: In both cases, penicillin G, administered over a period of three weeks, was well tolerated up to the high dose of 3 x 10 Mega IU/day. Substantial clinical improvement was achieved in all cases without any complications. CONCLUSION: This case study demonstrates that a suspected allergy to penicillin does not preclude an eventual treatment with this valuable drug. Allergy testing should routinely be carried out first. If suspicion of an allergy persists, tolerance induction can be attempted according to the new scheme described here. Starting with a careful, initial oral dose regimen, treatment can be continued with an increasing intravenous dose followed by maintenance therapy with high-dose penicillin G. It should be clear that this policy is only restricted for patients who are at risk for a hypersensitivity to penicillin, i.e., because of a clinical manifested incompatibility in the past.

Skin testing and oral penicillin challenge in patients with a history of remote penicillin allergy.

BACKGROUND: Penicillin administration is usually contraindicated in penicillin-allergic patients with positive skin test results. OBJECTIVE: To examine whether penicillin oral challenge for patients with a history of remote non-life-threatening allergic reaction to penicillin can be well tolerated irrespective of skin test results. METHODS: In a prospective open-label trial, 8,702 individuals were screened between November 1998 and January 2000. Of 687 patients with a non-life-threatening allergic reaction to penicillin, occurring longer than 3 years earlier, 169 were enrolled. Regardless of the response to penicillin skin testing, patients received the usual 1-day dosage of penicillin and amoxicillin, on 2 separate occasions. Two to 6 years later, a follow-up was conducted to assess the outcomes of further penicillin administration. RESULTS: A total of 272 combined skin tests and oral challenges were performed on 169 patients. Among 137 challenges with a positive skin test result and 135 patients with a negative skin test result, 9 (6.6%) and 5 (3.7%) (P = .29), respectively, developed a mild rash to oral challenge. At follow-up, 2 to 6 years afterward, 3 of 55 patients (5.5%) who were given a full treatment course of penicillin developed a mild skin eruption. CONCLUSIONS: Positive penicillin skin test results for patients with a remote history of non-life-threatening allergic reaction to penicillin were not associated with a greater prevalence of adverse reactions to oral challenge with penicillin than negative results. Because skin testing is considered the gold standard and the safest method for predicting tolerance to penicillin administration, oral penicillin challenge may be used as a diagnostic method only in these specific patients when skin testing is not feasible.

Intrapartum anaphylaxis to penicillin in a woman with rheumatoid arthritis who had no prior penicillin allergy.

BACKGROUND: Little is known about the development of drug allergy during pregnancy or in patients with altered immune status. OBJECTIVE: To report a case of new-onset penicillin allergy during pregnancy in a woman with rheumatoid arthritis. METHODS: A 39-year-old woman with rheumatoid arthritis developed intrapartum anaphylaxis that led to fetal demise. She had previously received penicillin-based antibiotics without any allergic reactions. Because of group B streptococcus colonization, an intravenous infusion of penicillin G was started during labor. Within minutes, she developed severe anaphylaxis. RESULTS: A fluorescent enzyme immunoassay revealed a moderate level of specific IgE to penicilloyl G and penicilloyl V (3.15 kU/L and 2.77 kU/L, respectively). Given the patient's history, these positive results were considered confirmatory of penicillin allergy. This case raises a number of salient points. First, patients can develop severe allergy to penicillin despite having safely received penicillins in the past. Possible factors that influenced the development of severe penicillin sensitivity in this patient are discussed. Second, unexpected intrapartum anaphylaxis can occur, which can be life threatening to the mother or fetus. Third, safe and reliable methods for diagnosis of drug allergy must be available. CONCLUSIONS: This case illustrates that during the current unavailability of skin testing reagents in the United States, a positive result on in vitro testing can be helpful in confirming penicillin allergy in cases in which drug challenge is deemed unsafe.

Hypersensitivity to penicillin V with good tolerance to other beta-lactams.

A 24 year-old man developed an anaphylactic reaction within thirty minutes of an oral administration of penicillin V. He suffered from recurrent streptococal pharyngitis that was usually treated with penicillin V with good tolerance. Skin prick and intradermal tests with penicilloyl-polylysine, minor determinant mixture, amoxicillin, ampicillin and cefuroxima were negative. However, a skin prick test with penicillin V was positive in the patient and negative in 10 controls. Determination of specific (Immunogloblulin (Ig) E to penicillin V was 0.64 kU/L. Specific IgE to penicillin G, amoxicillin and ampicillin were all negative. Single blind controlled oral challenge with amoxicillin and cefuroxime were both negative. This is an exceptional case of an anaphylactic reaction induced by phenoxymethylpenicillin with positive allergologic study in vivo and in vitro tests and with negative allergological study to other beta-lactams.

Mechanism for acute oral desensitization to antibiotics.

BACKGROUND: Despite the widespread use of an acute oral desensitization procedure in patients with allergic reactions to a variety of antibiotics, the precise mechanism of this procedure is poorly understood. OBJECTIVE: To investigate the mechanisms underlying acute oral desensitization to antibiotics. METHODS: Using a murine model of active systemic anaphylaxis to penicillin V (Pen V), mice previously sensitized to Pen V were desensitized by oral feeding of Pen V. The dose was doubled every 15 min and five feedings were given. The achievement of acute oral desensitization was evaluated by induction of active systemic and active cutaneous anaphylaxis, and by measuring the plasma levels of platelet-activating factor and histamine. Antigen-specific serum IgE antibody (Ab) levels were determined by passive cutaneous anaphylaxis. RESULTS: Mice fed more than 3 mg of cumulative dose of Pen V were completely protected from fatal systemic anaphylactic reaction and the desensitized state lasted approximately 1 h. Antigen-specific mast cell desensitization, but not hapten inhibition, consumption of IgE Abs, or depletion of mast cell mediators, occurred during acute oral desensitization. CONCLUSIONS: Acute oral desensitization to Pen V occurred in the mice, and antigen-specific mast cell desensitization was associated with the underlying mechanism for oral desensitization.

Helminth infection protects mice from anaphylaxis via IL-10-producing B cells.

Modulation of the immune system by infection with helminth parasites, including schistosomes, is proposed to reduce the levels of allergic responses in infected individuals. In this study we investigated whether experimental infection with Schistosoma mansoni could alter the susceptibility of mice to an extreme allergic response, anaphylaxis. We formally demonstrate that S. mansoni infection protects mice from an experimental model of systemic fatal anaphylaxis. The worm stage of infection is shown to mediate this protective effect. In vivo depletion studies demonstrated an imperative role for B cells and IL-10 in worm-mediated protection. Furthermore, worm infection of mice increases the frequency of IL-10-producing B cells compared with that in uninfected mice. However, transfer of B cells from worm-infected mice or in vitro worm-modulated B cells to sensitized recipients exacerbated anaphylaxis, which was attributed to the presence of elevated levels of IL-4-producing B cells. Worm-modulated, IL-10-producing B cells from IL-4-deficient, but not IL-5-, IL-9- or IL-13-deficient, mice conferred complete resistance to anaphylaxis when transferred to naive mice. Therefore, we have dissected a novel immunomodulatory mechanism induced by S. mansoni worms that is dependent on an IL-10-producing B cell population that can protect against allergic hypersensitivity. These data support a role for helminth immune modulation in the hygiene hypothesis and further illustrate the delicate balance between parasite induction of protective regulatory (IL-10) responses and detrimental (IL-4) allergic responses.

[Investigation of penicillin allergy. Procedures and retrospective statement of results for the period 1997 to 2001]. / Udredning af penicillinallergi. Procedurer og retrospektiv opgørelse af resultater for perioden 1997-2001.

INTRODUCTION: We describe procedures in and findings of investigation for allergy to penicillin as it was performed at the Dermatological Department and the Allergy Centre of Odense University Hospital in the 5-year period 1997-2001 and compare history with findings on skin tests and systemic challenge. MATERIAL AND METHODS: Retrospective evaluation of findings in the investigation of penicillin allergy. A total of 109 patients with a history of reaction to treatment with penicillins and a negative specific IgE for penicillins G and V were successively skin prick tested, intracutaneously skin tested, challenged orally and by intramuscular injection. Further testing was cancelled when a positive result occurred. RESULTS: Fifteen of 109 (13.7%) had positive reactions on investigation. There was no correlation between the type and severity of cutaneous or systemic reactions to penicillin or presence of other allergies and test positivity or negativity. 20% of the test-positive developed severe systemic reactions (respiratory, cardiovascular) upon systemic challenge. DISCUSSION: 13.7% in a selected patient material with a history of penicillin allergy and negative specific IgE were found to have reaction to penicillin upon investigation. A high percentage of patients (20%) experienced systemic reactions to provocation. This finding has resulted in new procedures for the investigation of allergy to penicillin in our clinic.

Successful desensitization to penicillin after diagnostic reassessment.

Clinical situations for which penicillin is indicated as the sole effective treatment are not infrequent, in these circumstances penicillin allergy complicates their medical management. No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women, it is not possible choosing an alternative non betalactam antibiotic. The management of the patient who has a history of penicillin allergy include skin testing to determine if penicillin-specific IgE antibodies exist, and desensitization if penicillin is the choice treatment. We report a case of successful desensitization to penicillin in a 30 year-old pregnant woman with latent syphilis and penicillin allergy, where the first penicillin study was not positive, but the repetition of diagnosis test (reassessment) with the same betalactam reagents than in the first study two weeks later the initial evaluation was positive, detecting allergic sensitization not detected at the previous examination.

Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses.

BACKGROUND: Up to 10% of the population reports an allergy to penicillin, yet more than 80% of these individuals lack penicillin-specific IgE antibodies. A negative result on a penicillin skin test is highly accurate in identifying who can safely receive the antibiotic at the time of testing. However, its negative predictive value for future courses is unknown because it is uncertain whether patients with a history of penicillin allergy are at risk of becoming resensitized. OBJECTIVE: To determine the rate of penicillin resensitization in adult patients with a history of penicillin allergy after they are challenged with repeated courses of oral penicillin. METHODS: Adult patients with a history of penicillin allergy consistent with an IgE-mediated mechanism were recruited and underwent penicillin skin testing. Those with negative skin test results were challenged with 3 successive 10-day courses of penicillin V potassium (250 mg by mouth 3 times a day), providing their penicillin skin test results remained negative prior to each course. Patients with positive skin test results were not challenged. RESULTS: Of 53 patients with initially negative skin test results, 46 completed the protocol, and each tolerated all 3 courses of penicillin with negative skin test results throughout. No patients had a converted skin test result from negative to a positive, yielding a resensitization rate of 0% (upper 95% confidence interval, 2.1%). CONCLUSIONS: Adult patients with a history of penicillin allergy are not at increased risk of resensitization after receiving 3 courses of oral penicillin. Because a negative penicillin skin test result is predictive for subsequent oral administrations beyond the time of testing, adult patients with a history of penicillin allergy can be skin tested electively, which may avoid unnecessary treatment with alternate broad-spectrum antibiotics.

Clinical usefulness of patch and challenge tests in the diagnosis of cell-mediated allergy to betalactams.

BACKGROUND: Literature reports dealing with cell-mediated allergy to betalactams have appeared with increasing frequency in the last years. OBJECTIVE: To evaluate patients with such reactions and to identify cross-reactivities among betalactams in order to provide safe guidelines for their further clinical management. METHODS: Thirty consecutive subjects with cell-mediated allergy to betalactams (history of adverse reactions to these antibiotics; serum total IgE within the normal range; absence of serum specific IgE antibodies to penicillin G and V, amoxicillin, and ampicillin; negative skin tests with a wide pattern of betalactam preparations; and positive patch-test to at least one betalactam antigenic determinant) were investigated. The subjects admitted to the study were patch tested with a wide variety of betalactam preparations in order to identify alternative molecules tolerated by the patient. To better evaluate the cross-reactivity pattern, tolerance challenges with patch-negative betalactams were also performed in each subject. RESULTS: Both specific IgE and skin tests were negative in all patients. The skin biopsies performed on the positive patch-tested area in four patients showed a clear T-lymphocyte, CD4+-type infiltrate, thus definitely proving the occurrence of a cell-mediated response. A total of 44 adverse reactions (mean: 1.47 episodes for each patient) were reported in history, with a mean interval of 15 hours after betalactam administration. The reported symptoms were mainly cutaneous (maculo-papular rash and urticaria) and the responsible drugs were chiefly aminopenicillins (86.4% of cases) and penicillin G (9.1%). We were able to identify three separate groups of patients on the basis of clinical history, patch-test, and tolerance challenge pattern: allergy to the side chain of aminopenicillins in 16 patients (53.3%); allergy to the thiazolidine ring in 3 patients (10.0%); undetermined specificity in the remainder 11 patients (36.7%). Cross-reactivity among different betalactam molecules (revealed by positive tolerance tests performed with patch-negative betalactams) was found in 4.8% of cases only (23.3% of all investigated patients). This fact demonstrates a very high (95.2%) predictive value of a negative patch-test in excluding the occurrence of a cross-reactivity. The mis-match between patch and tolerance tests was observed in 3 out of 178 cases only (1.7% of cases, 10.5% of patients) in groups A and B, and in as much as 12.2% of cases (45.5% of subjects) in group C (P < .05). CONCLUSIONS: Delayed allergy to betalactams (mainly to aminopenicillins) may be exerted by a cell-mediated response. Patch tests and tolerance challenges are extremely useful and safe for diagnosis and further clinical treatment of these patients, helping to identify safe alternative betalactam molecules that could be successfully tolerated by the allergic subjects.

Immunoglobulin E-dependent active fatal anaphylaxis in mast cell-deficient mice.

Mast cells have long been believed to be the central effector cells in the development of immunoglobulin (Ig)E-dependent anaphylaxis. In this study, we investigated the role of mast cells in IgE-dependent hapten-induced active fatal anaphylaxis using mast cell-deficient WBB6F1- W/Wv (W/Wv) and congenic normal (+/+) mice. Although a 5-min delay in shock signs and death were observed in W/Wv mice, 100% fatal reactions to penicillin V (Pen V) occurred in both +/+ and W/Wv mice. Administration of monoclonal anti-IL-4 antibody completely prevented the fatal reactions, and the effect of anti-IL-4 was associated with its suppressive activity on Pen V-specific serum levels of IgE, but not IgG. The platelet-activating factor (PAF) antagonist, BN 50739, completely prevented the fatal reactions in both strains of mice. Our kinetic study revealed, in contrast to no elevation of plasma histamine level in W/Wv mice, high levels of PAF in the circulation after challenge in both +/+ and W/Wv mice, albeit to a lesser degree in the latter case. These data indicate that cells other than mast cells are sufficient to induce an IgE-dependent active fatal anaphylaxis by elaborating PAF, which is the critical mediator for fatal murine anaphylaxis.

Anti-IL-4 monoclonal antibody prevents antibiotics-induced active fatal anaphylaxis.

We previously reported that anti-IL-4 mAb (11B11) failed to prevent protein-induced fatal murine anaphylaxis. To investigate the effect of anti-IL-4 on hapten-induced anaphylaxis, a model of murine anaphylaxis induced by antibiotics, penicillin V (Pen V) and cephalothin (CET), was developed, and the effect of anti-IL-4 on the anaphylaxis was observed. Pen V and CET induced 100 and 70 to 90% fatal reactions, respectively, when C57BL/6 mice were sensitized i.p. with 500 microg of antibiotic-OVA conjugate with 2 x 10(9) Bordetella pertussis and 1.0 mg of alum and challenged i.v. with 100 microg of antibiotic-BSA conjugate 14 days later. Serum taken from mice sensitized to Pen V passively sensitized normal mice to develop systemic anaphylaxis, and this ability of the serum was abrogated by heating at 56 degrees C for 2 h or depletion of IgE, but not IgG, Abs. Thus, the antibiotic-induced fatal reaction was an IgE-dependent anaphylactic reaction. Administration of anti-IL-4 at the beginning of sensitization completely prevented the fatal anaphylactic reactions to both Pen V and CET. This effect of anti-IL-4 was associated with its suppressive activity on antibiotic-specific serum IgE, but not IgG, levels. More importantly, anti-IL-4 therapy in previously sensitized mice was also effective in preventing the fatal reactions and rapidly reduced the established IgE levels. This study provides a new animal model of hapten-induced anaphylaxis and indicates that blocking of IL-4 activity may be beneficial in allergic diseases caused by a variety of haptens in which IgE Abs play a major role.

Allergy to penicillin: fable or fact?

OBJECTIVE: To assess whether, on the basis of one blood test, penicillin allergy might be excluded sufficiently for general practitioners to give oral penicillin to patients claiming a history of penicillin allergy. DESIGN: Prospective study of patients referred by general practitioners. SETTING: Outpatient allergy clinic in a district general hospital. PATIENTS: 175 referred patients who gave a history of immediate type reaction to penicillin, of whom 144 attended as requested and 132 completed the investigations. MAIN OUTCOME MEASURES: History and examination, serum radioallergosorbent test to phenoxymethylpenicillin and benzylpenicillin, and oral challenge with penicillin. RESULTS: Of 132 patients, four were confirmed to have penicillin allergy by the radioallergosorbent test and 128 had an oral penicillin challenge without ill effect. CONCLUSIONS: Most patients who gave a history of penicillin allergy are not so allergic, and their actual allergic state should be substantiated whenever feasible. For patients reporting minor or vague reactions negative findings with a radioallergosorbent test to phenoxymethylpenicillin and benzylpenicillin provide sufficient evidence to give oral penicillin safely.

Antibodies to penicillin in children receiving long-term secondary prophylaxis for rheumatic fever.

The occurrence of IgE and IgG antibodies to penicillin G and V in children on long-term treatment with penicillin as secondary prophylaxis for rheumatic fever was studied using Phadebas RAST (Pharmacia Diagnostics, Uppsala, Sweden) and ELISA respectively. The duration of the prophylaxis ranged between 1.5 months and 5 years (mean 1.8 years). Of 18 patients who had been given penicillin for more than 1.5 months, two had IgE antibodies and 12 had IgG antibodies to penicillin. Patients with acute rheumatic fever who had not yet received long-term treatment with penicillin had antibodies of the IgG class in two out of 12 cases. The patients gave no history of adverse reactions to the penicillin injections and there were no signs of immune complex-mediated disease. The two children who had IgE antibodies were switched to oral erythromycin instead of the penicillin injections. Penicillin is the drug of choice in the prophylaxis of rheumatic fever and can apparently be safely given as intramuscular injections of depot-penicillin to prevent recurrences of the disease and ensuing cardiac damage.

Penicillin in milk--its importance in urticaria.

Fifty patients with recurrent urticaria were tested by means of the RAST test for penicillin allergy. Fifteen patients had positive reactions and of these, thirteen received provocation tests with 0.1 U/ml of penicillin in milk. Four had definite positive reactions, three doubtful reactions and six had no reaction. Although there has been improvement in the purity of milk, penicillin residues remain a potential cause of urticaria even in very low amounts and could have contributed to the urticaria in at least 8% of our patients. Veterinary use of antibiotics and food quality should be strictly regulated to prevent contamination of our diet.