- Drug Allergy - 12/7/05 re: Characteristics of ampicillin/amoxicillin rashes Hi, I have a question regarding infectious mononucleosis rash in association with amoxicillin (Trimox) use. Where on the body does the rash usually start? And does it necessarily have to be generalized from head to toe? I have seen one patient with a rash only on the trunk after ampicillin use. Of course, the medication was almost immediately discontinued after the rash appeared. Is the locality of the rash a diagnostic factor? To help respond to your question, I obtained input from Dr. Franklin Adkinson of the Johns Hopkins Medical Institutions, an expert in penicillin allergy. His comments are enclosed below. Dr. Adkinson's comments: Re: aminopenicillin rashes/monorashes/interactive rashes. I agree that I am not aware of any diagnostic characteristics of these rashes which are usually described as "morbiliform." Most I have seen are highly variable in distribution and some tend to migrate over hours to days. Trunk is commonly involved, but face and extremities can also be part of it. My clinical bias (non-EBM based) would be to be skeptical of rashes that are exclusively head and neck and involve more erythema than papules, as well as exclusively lower extremity rashes. Best guess on immunopathogenesis would be that they are T cell mediated, and it has been speculated that the epitope may involve some penicillin polymers, since the highest rate is with the aminopenicillins (amox and amp) which are the only penicillins that can spontaneously polymerize. 11/21/05 re: Allergies to corticosteroids; aspirin-induced urticaria I have seen a pt today that needs an intra articular steroid injection and she is also on a beta blocker. In Jan 1993 she received an injection into a muscle with DepoMedral and Marcaine and 10 hrs later had a rash which she said only effected her various joints and she doesn't think the rash was hive like. It took over a week for that rash to resolve. Also no other meds were introduced at that episode. My sense was that it was the local anesthetic, but I would appreciate your advise in how to approach this case i.e. skin testing to the steroid and is that really accurate and what dosing would I do for the steroid and if negative is a challenge appropriate esp. if she is on a beta blocker??? If I may ask a second case which I just saw, A female who needs to go on ASA 81 mg daily and about 7 yrs ago had hives twice with cataflam (Voltaren) and no NSAIDs since then. If I challenge her or desensitize her could you suggest a protocol. My understanding is that ASA urticaria occurs at about 150- 325 mg, but I would not feel comfortable to tell this pt to just go ahead and use ASA 81 mg. She has not asthma. It is possible, though very unusual, to see a delayed reaction to a ‘caine-type local anesthetic (LA), assuming no reaction to a preservative or other added agent in the particular LA preparation. To investigate this unusual possibility our group has long used the approach described by Drs Rick DeShazo and Hal Nelson in 1979 (see reference enclosed below). We rarely see any documented allergic reactions to amide LA. Allergic reactions to systemic corticosteroids are also rare. However, there have been several reports of reactions apparently due to particular corticosteroids while certain other corticosteroid agents are tolerated (see enclosed abstracts). In the case you described one might test with methyl prednisolone solution but Depo-Medrol would not be suitable for testing. It would appear that if this patient truly had a reaction induced by methylprednisolone then betamethasone might be a choice with a reasonable chance of eliciting a negative reaction in testing and would later be tolerated if challenged with increasing doses. In their extensive experience, Stevenson et al of the Scripps Clinic usually start their aspirin challenges with a 30 mg dose whether the previous aspirin-induced manifestations were respiratory or urticaria. They generally give doubling increasing doses if the lower dose was tolerated. You may need assistance from your hospital pharmacist to prepare these doses. Comments from Dr. Stevenson are enclosed in my response to a recent Ask the Expert question dealing with aspirin sensitivity. deShazo RD, Nelson HS. An approach to the patient with a history of local anesthetic hypersensitivity: experience with 90 patients. J Allergy Clin Immunol. 1979 Jun;63(6):387-94.   Br J Dermatol. 2003 Jan;148(1):139-41. Related Articles, Links Alternative glucocorticoids for use in cases of adverse reaction to systemic glucocorticoids: a study on 10 patients. Ventura MT, Calogiuri GF, Matino MG, Dagnello M, Buquicchio R, Foti C, Di Corato R. Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari, Policlinico, Piazza G. Cesare 11, Italy. BACKGROUND: Reactions to systemically administered corticosteroids are rare, despite their widespread use. OBJECTIVES: To identify alternative glucocorticoids for emergency use in patients with adverse reactions to systemic glucocorticoids. METHODS: Ten patients were identified as having adverse reactions after the use of systemic corticosteroids. Skin prick tests and intradermal tests to hydrocortisone (HC) and methylprednisolone (MP), and intradermal tests to betamethasone and dexamethasone, were performed in all patients, and oral challenge tests to betamethasone (n=10) and deflazacort (n=6). RESULTS: Skin prick tests were negative in all patients, whereas intradermal tests to HC and MP were positive in eight; two patients showed only an isolated cutaneous sensitivity to MP. Intradermal tests to betamethasone and dexamethasone were negative, and oral challenge tests were negative in all patients. CONCLUSIONS: Our results suggest the possibility of an IgE-mediated mechanism for allergic reactions to HC and MP, probably due, at least in part, to a steroid-glyoxal. We suggest that betamethasone and deflazacort could be reserved for emergency use in patients with adverse reactions to other corticosteroids Dermatology. 2002;204(3):248-50. A case of cutaneous delayed-type allergy to oral dexamethasone and to betamethasone. Nucera E, Buonomo A, Pollastrini E, De Pasquale T, Del Ninno M, Roncallo C, Schiavino D, Patriarca G. Department of Allergology, Policlinico 'A. Gemelli', Universita Cattolica del Sacro Cuore, Roma, Italia. Corticosteroids are drugs that may cause allergic contact dermatitis, but systemic allergic reactions to these drugs are rare. A 29-year-old man developed a maculopapular rash during an oral therapy with betamethasone. Patch tests demonstrated a delayed-type allergy to dexamethasone, betamethasone and fluocortolone. Oral, intramuscular or topical provocation tests with other corticosteroids - deflazacort, hydrocortisone, methylprednisolone, fluticasone dipropionate, triamcinolone and prednisone - were all negative. This demonstrates that a patient with a systemic allergy to a group of corticosteroids can tolerate those of other groups. 11/15/05 re: Resolution of allergic reaction to clopidogrel I am a cardiologist who is seeing a patient in clinic after a suspected allergic reaction (with cutaneous manifestations) to clopidogrel. a.) What is the usual time course of resolution of symptoms after discontinuing the drug? and b.) does adjunctive treatment with corticosteroids and antihistamines shorten the time course to recovery? My response to your questions would depend in part on the type of skin reaction experienced by the patient. An early onset (within one day) urticarial type rash usually last no longer that a few days at most. It would likely be at least partially controlled by treatment with an antihistamine such as fexofenadine without adverse cognitive effects. However, a more delayed onset macular-papular rash would more likely last for days, possibly even a few weeks in unusual cases. Such rashes are generally not decreased by antihistamine therapy. They may or may not be controlled by moderate doses of corticosteroids. If you have further questions concerning drug allergy problems, I strongly suggest that you consult Dr. Rebecca Gruchalla, Chief of the Allergy Division in your institution, or one of her colleagues. Dr. Gruchalla is a leading clinical investigator of drug allergies. 11/7/05 re: Sulfites in generic propofol I am an anesthesiologist and have a question on the sodium metabisulfite in the generic propofol. First, is there any cross reactivity in patients with a sulfa allergy? Second, is it worth avoiding the generic propofol in asthmatic patients or even smokers? To respond to your questions, I obtained input from Dr. Ronald Simon of the Scripps Clinic in La Jolla, CA. Dr. Simon is an expert in sulfite sensitivity. His response is enclosed below. As you know, allergy to "sulfa" (sulfonamide) antibiotics has nothing to do with sulfite sensitivity. There have been concerns about the sulfite in generic propofol above and beyond the asthmatic issue (see: Am J Anesth, 2000; 27:1.). I would recommend to not give generic propofol to a sulfite-sensitive asthmatic. We recommend to not give it to any persistent asthmatic either. Being a smoker is not an issue per se insofar as tolerance of sulfite-containing agents. 11/4/05 re: Delayed reactions to penicillin The question I have is in regards to a delayed hypersensitivity reaction to a Penicillin or Cephalosporin antibiotic. It is not in regards to a specific patient but I was wondering about the use of delayed ID testing and patch testing. I have read several articles regarding its use but I would like to know if it is something that has been used in more routine clinical practice. It was not a procedure we used during my training at Northwestern Memorial Hospital in Chicago. Some groups, particularly Pichler's group in Switzerland, are convinced that sensitized T lymphocytes play a major pathogenic role in some delayed-onset morbilloform reactions to penicillins (see enclosed abstracts). They claim that such sensitized T cells can be isolated from positive patch test reactions to the suspect beta lactam antibiotic. Other groups are now seeking to confirm these findings. A committee of the EAACI has promulgated guidelines for further investigation (see enclosed abstract). However, at present, such patch test and in vitro diagnostic approaches to penicillin allergy are still considered investigational, and not a routine approach in clinical practice in the USA. Curr Opin Immunol. 2004 Dec;16(6):732-7. Related Articles, Links Cellular mechanisms of T cell mediated drug hypersensitivity. Gerber BO, Pichler WJ. Division of Allergology, Clinic for Rheumatology and Clinical Immunology/Allergology, PKT2 D572, Inselspital, CH-3010 Berne, Switzerland. Noncovalent drug presentation leads to the activation of drug-specific T cells. In some patients with hypersensitivity, such a response occurs within hours even upon the first exposure to the drug. Thus, the reaction to the drug might not be due to a classical, primary response, but rather mediated by existing, preactivated T cells that are cross specific for the drug, and have an additional (peptide) specificity as well. Clin Exp Allergy. 2000 Apr;30(4):590-5. Skin and laboratory tests in amoxicillin- and penicillin-induced morbilliform skin eruption. Schnyder B, Pichler WJ. Clinic for Rheumatology and Clinical Immunology/Allergology, Bern, Switzerland. BACKGROUND: Cutaneous amoxicillin- and penicillin-mediated reactions can be classified as immediate and delayed-type reactions. Immediate reactions are thought to involve IgE antibodies and have been studied extensively. In contrast only few data exist about delayed reactions such as morbilliform or maculopapular rash. OBJECTIVE: To assess the predictive value of immediate skin tests, skin-patch tests, specific IgE and lymphocyte transformation tests with regard to the diagnosis of delayed skin eruptions. METHODS: Skin and in vitro tests were performed in 18 subjects. Twelve subjects had penicillin- or amoxicillin-induced morbilliform exanthema and six were controls without hypersensitivity reaction, tested before and after exposure. RESULTS: Specific IgE to penicillin and immediate penicillin skin tests were negative in amoxicillin- or penicillin-induced delayed skin eruptions. In contrast, skin-patch testing and LTT were positive in 9/12 or 10/12, respectively, but negative in all six controls. CONCLUSION: These findings substantiate a T-cell-mediated immune pathomechanism in the majority of penicillin-induced delayed skin reaction. Moreover, they underline the necessity to adapt the test procedures to underlying pathomechanisms and support the diagnostic value of skin-patch testing and LTT in delayed cutaneous reactions to penicillins Allergy. 2004 Nov;59(11):1153-60. Related Articles, Links Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Romano A, Blanca M, Torres MJ, Bircher A, Aberer W, Brockow K, Pichler WJ, Demoly P; ENDA; EAACI. Oasi Maria SS, Troina, and C. I. Columbus, Rome, Italy. 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. Copyright 2004 Blackwell Munksgaard.   10/24/05 re: Approach to cephalosporin treatment in penicillin- allergic individual I received a call from a woman who has a history of allergy to penicillin and levaquin. She now needs surgery and her surgeon wants to use cefitizoxime, clindamycin and gentamycin. He is asking me to tell him if she can receive these drugs. As we do not have pre-pen and cannot do a complete skin test, and the other two drugs do not have standardized skin testing, how would you proceed? I assume that your question is how to approach cephalosporin (Ceph) treatment in someone who may be allergic to penicillin (no way of testing for penicillin allergy at present, though hopefully, at least a Pre-Pen type material will become available before too long). Your question, dealing with possible cross reactions between allergies to penicillin and Ceph agents, deals with a subject of considerable current debate. The preciously reported 8-18% frequency of allergic reactions to Ceph in penicillin-allergic individuals was not based on really definitive evidence and appears to be relevant to only the early-generation Ceph agents. There appears to be much less frequency of allergic reactions to the newer Ceph agents such as you mentioned in penicillin-allergic subjects unless there is a close similarity of the side-chains in the individual penicillin and cephalosporin agents involved. Nevertheless, some groups recently consider penicillin-allergic individuals at increased risk for allergies to any Ceph agent (see enclosed abstract). Some groups find that Ceph skin tests and in vitro IgE antibody tests to be helpful (see enclosed abstract) while other investigators feel that testing with diluted Ceph agents is unreliable. There is even evidence that the responses in penicillin skin tests are not predictive of whether the patient will have an allergic reaction to Ceph treatment. A different conclusion was reached by a committee of the American Academy of Pediatrics. As recently reviewed in Pediatrics, these experts concluded that the more recent Ceph agents could be given safely to someone with a history of penicillin allergy provided that the previous allergic reaction was not severe. I strongly suggest that you read this article in Pediatrics 2005;115:1048 (abstract enclosed) if you have not already seen it since it reviews the evidence dealing with your question. Also, I strongly recommend the article by Daulat et al in the JACI (see reference below). What does the clinician do in face of this debate? If there is any question about side-chain similarity between the penicillin agent to which the patient reacted and cefitizoxime, one should consider another Ceph agent with a different side chain. If the patient's medical status is unstable and/or includes cardio-pulmonary disease, the prudent approach may be to use a graded dose challenge, starting with a marked dilution of the Ceph agent to be used. Also, obtaining written informed consent in advance of any challenge may be advisable. Pediatr Allergy Immunol. 2005 Jun;16(4):341-7. Related Articles, Links Immediate allergic reactions to cephalosporins and penicillins and their cross-reactivity in children. Atanaskovic-Markovic M, Velickovic TC, Gavrovic-Jankulovic M, Vuckovic O, Nestorovic B. Department of Allergology and Pulmonology, University Children's Hospital, Belgrade, Serbia and Montenegro. Penicillins and cephalosporins are the most important betalactams inducing IgE-mediated reactions. The safety of administering cephalosporins to penicillin-allergic children is a particular problem, because cephalosporin allergenic determinants have not been properly identified. A study was undertaken to evaluate the frequency of anaphylactic reactions to cephalosporins and penicillins and their cross-reactivity in a pediatric population. A prospective survey was conducted in a group of 1170 children with suspected immediate allergic reactions to cephalosporins and/or penicillins, which were examined during aperiod of 8 yr. In vivo (skin tests and challenges) and in vitro tests (for specific IgE) were performed with standard concentration of penicillins and cephalosporins. When 1170 children with a clinical history of allergy to penicillins and/or cephalosporins were tested in vivo for immediate hypersensitivity to betalactams, 58. 3% cases overall were found to be skin or challenge test positive. Among them, 94. 4% patients were positive to penicillins and 35. 3% to cephalosporins. The frequency of positive reactions in the in vivo testing was in the range from 36. 4% to 88. 1% for penicillins and from 0. 3% to 29. 2% for cephalosporins. However, 31. 5% of the penicillin allergic children cross-reacted to some cephalosporin. If a child was allergic to a cephalosporin, the frequency of positive reactions to penicillin was 84. 2%. The cross-reactivity between cephalosporins and penicillins varied between 0. 3% and 23. 9%. The cross-reactivity among different generations of cephalosporins varied between 0% and 68. 8%, being the highest for first and second-generation cephalosporins and 0% for third generation cephalosporins. The frequency of immediate allergic reactions to cephalosporins is considerably lower compared to penicillins, and the degree of cross-reactivity between cephalosporins and penicillins depends on the generation of cephalosporins, being higher with earlier generation cephalosporins. The cross-reactivity among cephalosporins is lower compared to cross-reactivity between penicillins and cephalosporins. Clin Exp Allergy. 2005 Sep;35(9):1234-42. Related Articles, Links Diagnosing immediate reactions to cephalosporins. Romano A, Gueant-Rodriguez RM, Viola M, Amoghly F, Gaeta F, Nicolas JP, Gueant JL. Department of Internal Medicine and Geriatrics, UCSC-Allergy Unit, Complesso Integrato Columbus, Via G. Moscati 31, 00168 Rome, Italy. BACKGROUND: After penicillins, cephalosporins are the betalactams that most often induce IgE-mediated reactions. The development of diagnostic tests has been delayed, however, because the cephalosporin allergenic determinants have not been properly identified. OBJECTIVE: To evaluate the usefulness of skin tests, serum specific IgE assays, and challenges in diagnosing immediate reactions to cephalosporins and to clarify the pathogenic mechanism of such reactions. METHODS: We studied 76 adults with immediate reactions to cephalosporins, mainly ceftriaxone, cefotaxime, and ceftazidime. Skin tests and serum specific IgE assays were performed for culprit cephalosporins and cefaclor, as well as for penicillin, amoxicillin, and ampicillin. Some subjects with negative results underwent challenges and re-evaluations. Responses to cephalosporins other than the culprit ones were also studied. RESULTS: In the first allergologic work-up, an IgE-mediated hypersensitivity to penicillins and/or cephalosporins was diagnosed in 63 (82. 9%) of the 76 patients on the basis of skin-test and/or specific IgE assay positivity. Of the 13 negative patients, eight accepted challenges and underwent re-evaluations. Considering both first- and second-evaluation results, the skin-test-positivity rate increased from 76. 3% to 85. 5% and that of sepharose-radioimmunoassay positivity from 67. 1% to 74. 3%. Overall, an IgE-mediated hypersensitivity was diagnosed in 70 patients (in seven after retesting). On the basis of skin-test and CAP-FEIA results, we classified our 76 patients into five groups: group A (three patients), positive only to penicillin reagents; B (17), positive to both cephalosporin and penicillin reagents; C (24), positive to more than one cephalosporin; D (21), positive only to the responsible cephalosporin; E (11) negative to skin tests and CAP-FEIA, including five sepharose-radioimmunoassay positive. CONCLUSIONS: Most immediate reactions to cephalosporins appear to be IgE-mediated. Cephalosporin skin testing and sepharose-radioimmunoassay are useful tools for evaluating these reactions. Cephalosporin IgE-mediated hypersensitivity may be a transient condition; therefore, allergologic exams should be repeated in patients with negative initial allergologic work-ups, including challenges. Daulat S, Solensky R, Earl HS, Casey W, Gruchalla RS. Related Articles, Links Safety of cephalosporin administration to patients with histories of penicillin allergy. J Allergy Clin Immunol. 2004 Jun;113(6):1220-2 Pediatrics. 2005 Apr;115(4):1048-57. Related Articles, Links A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pichichero ME. University of Rochester Medical Center, Elmwood Pediatric Group, 601 Elmwood Ave, Box 672, Rochester, NY 14642, USA. The American Academy of Pediatrics, evidence-based guidelines endorse the use of cephalosporin antibiotics for patients with reported allergies to penicillin, for the treatment of acute bacterial sinusitis and acute otitis media. Many physicians, however, remain reluctant to prescribe such agents. Although such concern is understandable, lack of consistent data regarding exactly what constitutes an initial penicillin-allergic reaction and subsequent cross-sensitivity to cephalosporins may be preventing many patients from receiving optimal antibiotic therapy. This article reviews evidence in support of the American Academy of Pediatrics recommendation. Included is an examination of the types and incidence of reactions to penicillins and cephalosporins; the frequency of cross-reactivity between these 2 groups of agents; experimental and clinical studies that suggest that side chain-specific antibodies predominate in the immune response to cephalosporins, thereby explaining the lack of cross-sensitivity between most cephalosporins and penicillins; the role of skin testing; and the risks of anaphylaxis. Specific recommendations for the treatment of patients on the basis of their responses to previously prescribed agents are summarized. 10/21/05 re: Characteristics of drug reactions I am a pediatrician. Although I feel fairly confident in not diagnosing a viral exanthem associated with amoxicillin as allergy, I still struggle with this question at times. What are the hallmark features of a non-urticarial drug allergy rash? For both urticarial and non-urticarial drug allergic rashes, how soon into taking an antibiotic for the first time can they appear? There are a variety of skin manifestations in non-urticarial drug reactions. In the type of reaction you mentioned ("viral/ ampicillin" induced), the most common skin presentation is a macular-papular rash, generally starting at least 24 hours after starting the antibiotic therapy.. However, there are other less common types of reactions such as the TEN/Stevens Johnson type with bullae/scaling (generally starting at least 24 hours after onset of antibiotic therapy. Onset of urticarial drug reactions is generally within 1-2 hours (depending to a degree on whether injected or oral antibiotics) when the individual is already quite allergic to the antibiotic in question. If this is a newly developing allergy, the onset may be delayed for days. There are occasional cases of a serum sickness- like reaction, particularly with cefaclor therapy, generally starting 5-7 days after onset of the antibiotic therapy and manifest by urticaria, joint symptoms and fever. I have enclosed, FYI, abstracts of two articles dealing with this subject. Allergy. 2004 Nov;59(11):1153-60. Related Articles, Links Diagnosis of non-immediate reactions to beta-lactam antibiotics. Romano A, Blanca M, Torres MJ, Bircher A, Aberer W, Brockow K, Pichler WJ, Demoly P; ENDA; EAACI. Oasi Maria SS, Troina, and C. I. Columbus, Rome, Italy. Non-immediate 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 non-immediate 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 non-immediate 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 non-immediate reactions to beta-lactams J Paediatr Child Health. 2003 Dec;39(9):677-681. Related Articles, Links Adverse skin and joint reactions associated with oral antibiotics in children: The role of cefaclor in serum sickness-like reactions. King B, Geelhoed G. Emergency Department, Princess Margaret Hospital for Children and School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia. OBJECTIVE - To review presentations to Princess Margaret Hospital Emergency Department (PMH ED) with adverse joint and skin reactions associated with the use of oral antibiotics, to describe the clinical course of children with cefaclor-related serum sickness-like reactions (cefaclor SSLR) and compare these with cases reported to the Adverse Drug Reactions Advisory Committee (ADRAC). METHODS: Twelve-month retrospective review of presentations to a tertiary paediatric ED (42 000 visits annually) via an ED computer database search and review of medical charts of children presenting with joint or skin reactions. Telephone interviews were conducted with the caregivers of children with cefaclor SSLR. RESULTS: Adverse skin or joint reactions occurred in 150 children; 70 after cefaclor alone, 10 after cefaclor in combination with other antibiotics and 70 after other antibiotic courses. SSLR occurred in 44 children; 32 after cefaclor alone, five after cefaclor in combination with other antibiotics and seven after other single antibiotics. In children with cefaclor SSLR, otitis media was the most common indication (59.4%), another 18.8% had viral illnesses. Prolonged sequelae occurred in four children, a situation not previously reported. Sixty reports of paediatric cefaclor SSLR were made to ADRAC during the study period, none originated from PMH ED. CONCLUSIONS - Cefaclor was associated with 53.3% of oral antibiotic related skin and joint adverse reactions and 84.1% of SSLR. The indications for its use in paediatric illness require careful reconsideration. ADRAC data under-represents the incidence of cefaclor SSLR. 9/23/05 re: Seizures after lidocaine infusion I am an RN who works in a surgical unit. We recently had a patient who had a partial seizure disorder. He stated that his seizures were discovered when he was given lidocaine by his dentist. Over several years each time the dentist gave him lidocaine the seizures became worse. Now he states he has the same response to opiates. He claimed that he was tested by an allergist for lidocaine allergy, and that while not an allergy, he had a “sensitivity” to caines and opiates. He now takes anti-epileptics for seizure control. I have read your response to the question about the rarity of allergy to lidocaine. But I am very curious about the possibility of lidocaine “sensitivity,” possibility of seizures. Investigators have used the term “caine allergy” to apply to the relatively rare cases when lidocaine or a related compound triggers an adverse reaction with characteristics of an allergic-type response (e.g.- urticaria/angioedema, asthmatic-type reaction, anaphylaxis). As reviewed by me, previous studies have concluded that such “allergic” type reactions are very unusual, even rare. However, there are other possible idiosyncratic (infrequent, but not necessarily immune) reactions to caine drugs. I have enclosed below a portion of a recent report describing seizures occurring after intravenous injection of lidocaine. As the authors point out, large doses of lidocaine can commonly induce seizures. It is conceivable that a small percentage of the population may be excessively sensitive to lidocaine so that even “usual” doses of lidocaine can trigger seizures. Such triggering may be particularly related to lidocaine injected in the oral mucosa (as done before dental procedures) because of the rapid absorption of the lidocaine into the blood stream from such sites. One could say that individuals manifesting such adverse reactions are "sensitive" to caine drugs. Also, a number of patients have described to me peculiar generalized neural sensations within 1 hour after mucosal injection of what were probably sizable doses of caine drugs before dental procedures. Another possibility is that the patient has a decreased seizure threshold for other reasons. You mentioned that the patient had a history of a partial seizure disorder. The injection of a sizable, but not huge, amount of lidocaine in such an individual may have been sufficient to trigger seizures. The implication of such a situation is that one must be quite cautious in limiting the amount and speed of injection of caine drugs in such an individual. Another possible approach is to pre-treat the patient before a caine injection with an increased dose of whatever anti-epilepsy medication has been found to control his seizure disorder when used daily. Discussion (from Ahmed et al, Anesth Analg. 2004 ;99(2):593-4) Lidocaine decreases neuronal excitability by blocking voltage-gated sodium channels. At small concentrations, it has an antiepileptic effect and may be used as a treatment for status epilepticus (2). At large concentrations, it causes cortical hyperstimulation related to selective depression of inhibitory cortical synapses and neurons (3). Serum concentrations larger than 15 g/mL often result in seizures in humans and laboratory animals (4). The lidocaine metabolites mono-ethylglycinexylidide and, to a lesser extent, 2,6-glycine xylidide can also decrease the seizure threshold. In animals, the monoethylglycinexylidide serum level that correlated with seizures was 4-6 g/mL (5). In general, seizures induced by lidocaine under experimental conditions begin in the amygdala (4) or elsewhere in the limbic system (6) and are tonic-clonic in nature (4). However, complex partial seizures related to lidocaine have been reported (7). 9/21/05 re: Reactions to amoxicillin in penicillin-allergic individuals I am a registered pharmacist and have probably a very basic question for you. Can you tell me the incidence of an amoxicillin allergy when given to a patient with a penicillin allergy? First, one must be sure that the patient is truly penicillin-allergic at this time. Although 10% of adults claim to be penicillin (PC)-allergic, investigation of such individuals has shown that about 90% of them are not PC-allergic at this time (see enclosed abstract), either because they never really had an allergic reaction in the past or such PC allergy has waned. If the patient has documented PC allergy, there should be close to 100% chance that the person would have an allergic reaction to amoxicillin (Amox) (see enclosed abstract). In addition, some individuals who are not PC-allergic may manifest a delayed onset macular-papular rash while taking Amox. The mechanism underlying such reactions is still not well defined. The rash frequently clears even if the Amox treatment is continued. It is uncertain how often this delayed onset rash will recur if the patient takes Amox again in the future. Clin Rev Allergy Immunol. 2003 Jun;24(3):201-20 Hypersensitivity reactions to beta-lactam antibiotics. Solensky R. The Corvallis Clinic, 3680 Samaritan Drive, Corvallis, OR 97330, USA . ronald.solensky@corvallis-clinic.com Clinicians commonly encounter patients with a history of allergy to penicillin and other beta-lactam antibiotics, since about 10% of the population reports such an allergy. At the same time, it is known that about 90% of these patients are not truly allergic and could safely receive beta-lactam antibiotics. Instead, these patients are treated unnecessarily with alternate broad-spectrum antibiotics, which increases costs and contributes to the development and spread of multiple drug-resistant bacteria. In the case of penicillin, relevant allergenic determinants that elicit immune responses are known. Hence, validated diagnostic skin testing to detect the presence of drug-specific IgE antibodies is available. For non-penicillin beta-lactams, the immunogenic determinants that are produced by degradation are unknown, and diagnostic skin testing is of more limited value. Ideally, patients with a history of penicillin allergy should be evaluated when they are well and not in immediate need of antibiotic therapy. Patients who are found to be penicillin skin test-negative may be safely treated with all beta-lactam antibiotics. Penicillin skin test-positive patients should only receive a penicillin-class antibiotic via rapid desensitization, and only in cases when an alternative agent cannot be substituted. Penicillin skin test-positive patients may be safely treated with monobactams. The extent of allergic cross-reactivity between penicillin arid cephalosporins/carbapenems is uncertain; therefore penicillin skin test-positive patients should only receive these antibiotics via cautious graded challenge or desensitization. Identification of patients who erroneously carry a label of beta-lactam allergy leads to improved utilization of antibiotics and slows the spread of multiple drug-resistant bacteria Curr Opin Allergy Clin Immunol. 2004 Aug;4(4):261-6. Related Articles, Links Immediate allergic reactions to betalactams: facts and controversies. Gomez MB, Torres MJ, Mayorga C, Perez-Inestrosa E, Suau R, Montanez MI, Juarez C. Allergy Service, Carlos Haya Hospital, Malaga, Spain. PURPOSE OF REVIEW: To analyze the available data in the field of immediate allergic reactions to beta-lactams, with particular emphasis on more recent studies, and to comment on the future role of this group of antibiotics. RECENT FINDINGS: The world of beta-lactams has become more complex than initially thought, due to the increased number of chemical structures available, the wide variety of indications for their use in treating different infectious diseases, and possibly also due to the interaction of other as yet undetermined factors. Benzyl penicillin, the original inducer of allergic reactions, has now largely been replaced by amoxicillin and, to a lesser extent, by cephalosporins in inducing IgE-mediated allergic reactions. These structures often share extensive cross-reactivity, eliciting clinical reactions to many compounds, especially amongst penicillins. In other circumstances selective responses are observed which are restricted to one group or one single compound, as occurs in the group of cephalosporins. The application of new determinants for skin testing and the use of adapted in-vitro studies have enabled these findings to be confirmed in detail. SUMMARY: Results indicate that evaluation of immediate reactions to beta-lactams requires the use of several determinants for both in-vitro and in-vivo testing, and which must reflect the relevant drug involved in eliciting the response. This tendency will be strengthened in the future if use of benzyl penicillin continues to decrease as a drug to which populations are exposed.   9/20/05 re: Adverse reaction to Copaxone I am consulting with a 39yo female w/ MS who has developed a hypersensitivity type rxn to Copaxone. The pt was dx'd w/ MS based on sx, MRI and LP results. She was started on daily Copaxone injections IM in Jun '05. Tx was generally well tolerated w/ exception of routine large local reactions (erythema and mild indurtation) at the injection site; these would develop w/in mins-hrs and defervesce w/in 24 hours. On 9/02/05 she developed a systemic rxn. Sx began 20-30min post injection and included dyspnea, chest tightness of a moderate-severe degree (but w/o associated stridor, wheezing, or coughing) generalized pruritis, anxiety, nausea, HA. She did not seek immediate medical attention (she is an RN), took Benadryl 25mg, and reports resolution of sx w/in a few hours. She skipped her next dose, obtained an EpiPen form PCP via phoneconsultation, and re-dosed on 9/04/05 . A similar but milder reaction pattern ensued, w/in the same time frame. Her brother, an allergist, was visiting from out of town, and apparently noted several urticaria on her back, but the pt states she did not see any hives except in the area immediately surrounding the injection site. The respiratory sx were somewhat milder. She was again treated w/ PO Benadryl w/ resolution of sx over a couple of hours. The pt is trying to minimize her reaction, and wishes to resume tx. Her Neurologist informs me that these types of reactions are relatively common, sporadic, and not typically repeated; therefore, the 2nd reaction 2 days later is unusual and unexpected. The package insert similarly relates that this type of reaction occurs in~10% of the time, and "a given pt may experience one or several of these episodes of these reactions." It further states that it is unknown whether there is a uniform immune mechanism underlying these reactions. Do you have any further information or recommendations. I do not want to be cavalier and recommend full dose reinstitution of tx. Given hx of large local reactions post injections, the ability to do titrated skin testing seems to be of limited or dubious benefit. The secondary reaction suggests true sensitization, possibly weaker d/t proximity to the primary event now that she's 10+ days past that episode, she may well be primed for a more serious anaphylactic anaphylactoid response. Should we not have a suitable alternate treatment, how do you suggest we proceed? Incremental SC or IV challenge? In what setting (ie. Outpt v. ICU) is there a center or specialist w/ broader experience? To help answer your questions, I obtained input from Dr. Robert Lisak, Chair of Neurology in Wayne State Univ Medical School in Detroit. Dr. Lisak is an expert in the treatment of Multiple Sclerosis and has participated in the extensive clinical trials of Copaxone. As you can see from his comments below, Dr. Lisak feels that the evidence pf more prominent reactions to repeat Copaxone injection warrant stopping this agent and switching to one of the interferon-beta treatment agents. If this is not feasible because of lack of efficacy and/or adverse reaction to interferon-beta agents, the a cautious “desensitization” procedure may be worth trying. My personal preference would be doing this by the subcutaneous route. With regards to your questions about centers near you with considerable experience with Copaxone treatment, I know of no such centers from Seattle north to Bellingham . Dr. Stephen Hauser, Chair of Neurology in the Univ Calif, San Francisco is an expert in multiple sclerosis (MS);- see his recent review in J Neurol Sci. 2005;228:193-4. Therefore, I would think that there must be a very active M.S. clinic in his department in which Copaxone treatment is carried out. Dr. Lisak's comments: We call this a post injection systemic reaction. The mechanism is not clear with the 2 leading theories either mediator release by getting the injection into small venules or Ag-Ab reaction related to Th1 to Th2 shift. About 10% of Copaxone-treated patients get some part of these reactions but often of shorter duration and not full blown. Having reactions this severe and this often is a good reason to stop Copaxone if the patient has not been on a trial of IFN beta. Then start Rebif or Betaseron assuming no contraindications. 9/20/05 re: Desensitization to allopurinol A 64 y/o male developed SOB, vertigo and loss of appetite after 2nd day on allopurinol. No other symptoms. Already on colchicine (which is causing loose stools). On Atenolol and Norvasc for hypertension. Uric acid greater than 10 Pt. is otherwise non-allergic. Does it make sense to try to desensitize this patient, and if so, would one use a rapid protocol similar to penicillin or a 2 day protocol similar to aspirin? My understanding is that allopurinol desensitization has been attempted mainly in cases where the patient has manifest a rash (generally pruritic), sometimes with associated, during allopurinol treatment. Therefore, I could not say whether the adverse reaction in your patient would be amenable to the allopurinol desensitization procedures described in the literature. If you decide to undertake attempted allopurinol desensitization, I think that a slow oral protocol is preferable to a more rapid, intravenous schedule. I have enclosed below an abstract of a report by Fam et al described their relatively extensive experience with such slow allopurinol desensitization. Following this abstract is a description of their desensitization protocol itself, which I copied from the article. Also enclosed below that material, FYI, are abstracts dealing with others aspects of allopurinol desensitization, including rapid intravenous procedures. Arthritis Rheum. 2001 Jan;44(1):231-8.Related Articles, Links Efficacy and safety of desensitization to allopurinol following cutaneous reactions. Fam AG, Dunne SM, Iazzetta J, Paton TW. Sunnybrook Health Science Centre, University of Toronto, Ontario, Canada. OBJECTIVE: To evaluate the long-term efficacy and safety of slow oral desensitization in the management of patients with hyperuricemia and allopurinol-induced maculopapular eruptions. METHODS: A retrospective evaluation of an oral desensitization regimen using gradual dosage-escalation of allopurinol in 32 patients (30 with gout and 2 with chronic lymphocytic leukemia) whose therapy was interrupted because of a pruritic cutaneous reaction to the drug. RESULTS: Twenty-one men and 11 women with a mean age of 63 years (range 17-83 years), a mean serum urate level of 618 micromoles/liter (range 495-750) (or, mean 10.4 mg/dl [range 8.3-12.6]), and a mean serum creatinine level of 249 micromoles/liter (range 75-753) (or, mean 2.8 mg/dl [range 0.8-8.5]) were studied. Desensitization failed in 4 patients because of unmanageable recurrent rash. Twenty-eight patients completed the desensitization procedure to a target allopurinol dosage of 50-100 mg/day, 21 without deviation from the protocol for a mean of 30.5 days (range 21-56 days) and 7 requiring dosage adjustments because of a recurrent rash over 53.8 days (range 40-189 days). Seven of these 28 patients developed late cutaneous reactions 1-20 months post desensitization, 4 responding to dosage modification and 3 discontinuing the drug. Twenty-five of the 32 patients (78%) continued to take allopurinol; their mean duration of follow-up was 32.6 months (range 3-92 months) and the mean post desensitization serum urate level was 318 micromoles/liter (range 187-452) (or, mean 5.3 mg/dl [range 3.0-7.5]). CONCLUSION: The study confirms the long-term efficacy and safety of slow oral desensitization to allopurinol in patients with maculopapular eruptions, particularly in those with gout, who cannot be treated with uricosurics or other urate-lowering drugs. Although pruritic skin eruptions may recur both during and after desensitization, most of these cutaneous reactions can be managed by temporary withdrawal of allopurinol and dosage adjustment. From Fam et al (Arthritis Rheum. 2001 Jan;44(1):231-8.) Desensitization procedure Desensitization was performed as previously described([10]). Briefly, a suspension of allopurinol was prepared by the outpatient pharmacy as follows: two 100-mg tablets of allopurinol were crushed in a mortar, and 33 ml of 1% methylcellulose solution was slowly added to make a slurry. Both 4 ml of cherry flavor and simple sugar were then added and mixed to a volume of 100 ml to yield a concentration of allopurinol of 10 mg/5 ml. Ten milliliters of this suspension was further diluted with the same ingredients to 100 ml, yielding a 1 mg/5 ml (200 g/ml) concentration. Using the high- and low-concentration suspensions, unit doses containing 10 g, 25 g, 50 g, 100 g, 200 g, 500 g, 1 mg, 5 mg, 10 mg, and 25 mg of allopurinol were prepared; 50-mg and 100-mg doses were then administered as one-half and whole 100-mg tablets, respectively. Predesensitization intradermal tests using a solution of allopurinol and oxypurinol were not performed. The desensitization procedure and its potential risks were discussed with each patient and after obtaining the patient's informed consent, the standard protocol was administered as follows (Table 1): an initial dosage of 50 g of allopurinol/day, which was progressively and cautiously increased every 3 days to 100 g, 200 g, 500 g, 1 mg, 5 mg, 10 mg, 25 mg, and finally to a target dosage of 50-100 mg of allopurinol/day. Further dosage increments were based upon the individual patient's serum urate and creatinine levels, aiming at reducing and maintaining serum urate levels at <300-350 moles/liter (or, <5-6 mg/dl), which is well below the levels at which urate saturates the extracellular fluid (404 moles/liter [or, 6.8 mg/dl] at 37¦C). Table 1. Standard allopurinol desensitization protocol* Daily dose Preparation Days (approximate) On days 50 g 0.25-ml suspension (1 mg/5 ml) 1-3 100 g 0.5-ml suspension (1 mg/5 ml) 4-6 200 g 1-ml suspension (1 mg/5 ml) 7-9 500 g 2.5-ml suspension (1 mg/5 ml) 10-12 1 mg 5-ml suspension (1 mg/5 ml) 13-15 5 mg 2.5-ml suspension (10 mg/5 ml) 16-18 10 mg 5-ml suspension (10 mg/5 ml) 19-21 25 mg 12.5-ml suspension (10 mg/5 ml) 22-24 50 mg One-half a 100-mg tablet 25-27 100 mg One 100-mg tablet 28+ For high-risk patients, a modified desensitization protocol, with initial allopurinol doses of 10 g and 25 g (0.05 ml and 0.12 ml of 1 mg/5 ml suspension, respectively), and a dosage escalation every 5-10 days or longer, is recommended. Two concentrations of allopurinol suspension were used: 1 mg/5 ml and 10 mg/5 ml, depending on the dosage required. A modified desensitization protocol, with initial daily doses of allopurinol of 10 g and 25 g, and a dosage change every 5-10 days or longer, was initially prescribed for frail, elderly patients with multiple comorbid medical conditions, including renal impairment, as well as for patients with more widespread, confluent, allopurinol-induced eruptions, particularly when associated with facial or tongue swelling, fever, stomatitis or eosinophilia. All patients undergoing desensitization were cautioned about possible severe reactions and were instructed to stop allopurinol and consult their physician if an adverse reaction, such as fever, pruritus, or skin eruption, occurred. In such an event, allopurinol was withheld until the reaction had resolved, reintroduced cautiously at one-half the previously tolerated dosage, and the rate of dosage escalation was slowed to every 5-10 days or longer. Curr Rheumatol Rep. 2001 Feb;3(1):29-35. Related Articles, Links Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient. Fam AG. Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue M-1402, Toronto, Ontario, M4M 3M5, Canada. kathy.carey@swchsc.on.ca A major obstacle to the treatment of hyperuricemia in patients allergic to allopurinol is the limited availability of suitable, equally effective, alternative, urate-lowering drugs. Conventional uricosuric drugs, including probenecid and sulfinpyrazone, are recommended for allopurinol- intolerant patients with gout and “underexcretion” hyperuricemia who have normal renal function and no history of nephrolithiasis. Therapeutic options in those in whom traditional uricosuric drugs are contraindicated, ineffective, or poorly tolerated include slow oral desensitization to allopurinol and cautious administration of oxipurinol. Allopurinol desensitization is useful particularly in those who have failed other treatment modalities. If available (as in Europe , South Africa , and Japan ), benzbromarone may be tried in patients with gout and mild-to-moderate renal insufficiency. Recombinant urate oxidase can be used in the short-term prophylaxis and treatment of chemotherapy- associated hyperuricemia in patients with lymphoproliferative and myeloproliferative disorders. Hyperuricemia and gout occur with increased frequency in cyclosporine-treated allograft transplant recipients. The management of gout in these patients is complicated by two main factors: cyclosporine-induced renal impairment, and interactions with medications used to preserve the allograft. Ann Allergy Asthma Immunol. 2004 Mar;92(3):374-6. Related Articles, Links Intravenous desensitization to allopurinol in a heart transplant patient with gout. Schumacher MJ, Copeland JG. Department of Pediatrics, University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA. schumach@u.arizona.edu BACKGROUND: Oral desensitization with allopurinol presents a problem for patients with allopurinol hypersensitivity and gout that needs to be controlled rapidly. To our knowledge, only 1 case report of intravenous (i.v.) desensitization has been previously published. OBJECTIVE: To present a case report of a patient with cutaneous reactions to allopurinol who underwent i.v. allopurinol desensitization. METHODS: Intravenous infusion of allopurinol was performed using an escalating, 19-dose protocol. RESULTS: No adverse reactions were precipitated by 2 i.v., escalating dose procedures, allowing continuation of effective treatment of the patient's hyperuricemia. CONCLUSIONS: This case of safe and effective desensitization with allopurinol by the i.v. route should emphasize the need for a trial of this protocol in additional patients in whom rapid desensitization would be advantageous. 9/19/05 re: Reactions to penicillin in semen Can a person who is allergic to a drug (i.e. penicillin) have an allergic reaction from having sexual intercourse with a person who is taking the drug? It seems this might be plausible since drugs are excreted in breast milk, sweat, tears, etc. To help respond to your question, I obtained input from Dr. Roland Solensky, an expert in penicillin allergy reactions. His response is enclosed below. I should emphasize the importance of determining whether the woman has had a reaction to the semen of her partner when the partner had not taken any medications for several days. If a reaction has occurred, she could well be reacting to a component in the fluid portion of the semen itself. Dr. Solensky's comments: I know I have seen a case report (probably in abstract form only) of a woman reacting to her sexual partner's semen due to the presence of trace amounts of penicillin. I don't recall how severe the reaction was. I don't recall the exact reference. So, while it is theoretically possible, I would see this occurring only in the most exquisitely pcn-sensitive individual. The vast majority of pcn-allergic women should not experience any reaction in such a situation. There is of course also the issue of whether the women is truly allergic, since, as you know, pcn-specific IgE antibodies are known to wane over time. Therefore, it would make sense to perform pcn skin testing on such a female patient (once we hopefully have PrePen back on the market next year), since overall only 5-10% of patients with a history of pcn allergy turn out to have positive skin tests. Lastly, if a women has reacted to her partner's semen, an allergy to the semen itself should also be evaluated. I hope that helps. 9/13/05 re: Sulfite skin testing I have a patient with suspected sulfite allergy. She does not have asthma. She has experienced urticaria on several occasions when eating or drinking foods with sulfites. I have read references to skin testing as a confirmatory test but I have not been able to find a method for doing such testing. I am reluctant to give the patient an oral challenge without first attempting a prick skin test. Can you refer me to a reference or an expert who has experience in this circumstance? I suggest that you contact Dr. Ronald Simon of the Scripps Clinic. Dr Simon is an expert in sulfite sensitivity who has carried out sulfite skin testing in his studies. 9/13/05 re: Multiple antibiotic allergies Can you tell me if allergy to ALL antibiotics is found in many individuals? I have a client who I am told is allergic to all antibiotics. What specialty should he be referred to? Is there a center in Northern California where he can be referred? Can you point me to some articles or other documentation about treatment of such a person? Thank you for any assistance you can offer! I have been a nurse for 36 years and have not come across this problem to such a degree! One would instinctively think that development of allergies to many, if not all, antibiotics would be extremely unusual because the different antibiotic classes are chemically dissimilar. However, as an allergy consultant, I have evaluated a small number of patients who claim to have manifested allergic reactions to a wide variety of antibiotics. In most cases where we have done cautious blinded challenges in such patients, we have found antibiotics that such individuals can tolerate. However, there are very occasional patients who do appear to manifest allergic-type reactions to most (not necessarily all) antibiotics tried. This subject has been discussed in a limited number of articles in the medical literature. The mechanisms involved in such reactions are not well-defined. Evaluation of such patients is very difficult. I do not know a physician in Northern California with a particular interest/experience in this problem. However, Dr. R. Solensky, an allergist practicing in Corvallis Oregon (which shouldn't be too far from your location), has a strong interest in the subject of allergy to antibiotics and has written fairly extensively about this subject (see enclosed abstract). I have requested input from Dr. Solensky about previous questions dealing with antibiotic allergies. Hypersensitivity reactions to beta-lactam antibiotics. Solensky R. Clinicians commonly encounter patients with a history of allergy to penicillin and other beta-lactam antibiotics, since about 10% of the population reports such an allergy. At the same time, it is known that about 90% of these patients are not truly allergic and could safely receive beta-lactam antibiotics. Instead, these patients are treated unnecessarily with alternate broad-spectrum antibiotics, which increases costs and contributes to the development and spread of multiple drug-resistant bacteria. In the case of penicillin, relevant allergenic determinants that elicit immune responses are known. Hence, validated diagnostic skin testing to detect the presence of drug-specific IgE antibodies is available. For non-penicillin beta-lactams, the immunogenic determinants that are produced by degradation are unknown, and diagnostic skin testing is of more limited value. Ideally, patients with a history of penicillin allergy should be evaluated when they are well and not in immediate need of antibiotic therapy. Patients who are found to be penicillin skin test-negative may be safely treated with all beta-lactam antibiotics. Penicillin skin test-positive patients should only receive a penicillin-class antibiotic via rapid desensitization, and only in cases when an alternative agent cannot be substituted. Penicillin skin test-positive patients may be safely treated with monobactams. The extent of allergic cross-reactivity between penicillin arid cephalosporins/carbapenems is uncertain; therefore penicillin skin test-positive patients should only receive these antibiotics via cautious graded challenge or desensitization. Identification of patients who erroneously carry a label of beta-lactam allergy leads to improved utilization of antibiotics and slows the spread of multiple drug-resistant bacteria. 8/18/05 re: Hydroxyurea desensitization I'm a doctor here in the Philippines. I have a patient who developed cutaneous eruptions of rashes and wheal formation after 3 days intake of Hydroxyurea (he is currently diagnosed to have chronic myelogenous leukemia, Hydroxyurea is the cheapest drug that we can avail here). Can I subject him to desensitization procedure? As you likely know, a variety of adverse cutaneous effects during hydroxyurea treatment have been reported. These do not sound like IgE-mediated reactions. I have had no personal experience trying to desensitize a patient to hydroxyurea. I could also find no report of such an attempt in a Medline search. Therefore, I would have to consider an attempt to "desensitize" to hydroxyurea as an investigational approach, not standard clinical practice. However, theoretically the relatively low molecular weight of hydroxyurea would make it more likely that tolerance may be achieved by the introduction of graded increasing doses of hydroxyurea. If you decide to try this approach, I would obtain written informed consent from the patient in advance. Most attempts at desensitization have generally started with administration of about 1/1000 the usual clinical dose. If this is tolerated without an adverse effect, proceed to 1/500 of the usual clinical dose, then 1/100 of the clinical dose, then 1/50 of the clinical dose, then 1/10 of the clinical dose, then the clinical dose as tolerated. You may need the help of a pharmacist in preparing these diluted doses. 8/8/05 re: Is the ampicillin rash pruritic? I was wondering, is the ampicillin macular rash associated with Epstein-Barr infectious mononucleosis pruritic (itchy) or not? It seems to me I have read various contradictory observations from various literature. The cases of macular-papular rash associated with ampicillin (or amoxicillin) therapy in patients with infectious mono seen by me have been either non-pruritic or at most mildly pruritic. Itching has not been prominent, in contrast to the pruritis of the urticarial rash seen in other adverse reactions to ampicillin/amoxicillin therapy.. Most of the descriptions of such ampicillin-induced macular-papular rashes in the literature I have seen have been case reports of one or two patients. Therefore, it is difficult to get a statistically reliable estimate of the incidence of pruritis based on a sizable sample of patients on a single study. 7/15/05 re: Sensitivity to plastics I have been asked to consult on a 64yo female pt w/ a putative hx of allergy to plastic. She claims that she gets cutaneous reactivity form contact w/ any plastic or petroleum based product (e.g., blisters on her legs from sitting on a plastic lawn chair, intraoral lesions from mucous membrane contact w/ items such as straws, plastic spoons and forks, etc). She breaks out from topical contact w/petroleum jelly. Her hx is also suggestive of latex allergy, but that's not really the isue here. Her local rritation and rashes begin almost immediately (w/in 1 hour) but she does not have a hx of true anaphylaxis at any time in the past. The pt does not have an identifiable psychiatric hx, nad seems more annoyed than truly worried about this, stating that she's had to cope with this problem all of her adult life. Onset is poorly recalled, but sx have been recurring for the past 30-40yrs. She needs a semi-elective gynecologic surgical proceedure. The pt is convinced she will react adversely to the endotracheal tube, IV catheter, etc. The anesthesiologist called off the procedure at the last moment, and here we areèIs there any literature/experience to support this type of allergy, any test or treatment options/recommendations? The clinical picture you describe sounds atypical but conceivable, I suppose. There are numerous reports of contact skin and/or mucosal reactions to resins involved in making plastics, particularly epoxyresins (see enclosed abstract). Methyl methacrylate, a monomer of acrylic resin, is also a relatively common sensitizer. However, it is less clear how often true sensitivity develops to finished (polymerized) plastic materials, if at all. In any event, systemic manifestations apparently occur rarely, if ever, in association with such contact reactions. I would think that a pragmatic approach to this patient's situation is needed since the likelihood of identifying the offending chemical (and avoiding it completely) is small. The concern about reactions to intravenous plastic catheter may be approached by using an infusion set containing a larger bore metal needle instead of an intravenous plastic catheter for infusions/keep open the I.V. access, etc. The plastic "wings" typically present at the base of the needle in such infusion sets can be kept from contacting the skin by covering such wings with non-irritating tape. I think it highly unlikely that plastic connectors in the intravenous tubing would present a problem here. The question of what to do if an endotracheal tube placement is needed is more complex. First, has the patient undergone previous surgical procedures that involved general anesthesia in her adult life? If so, an endotracheal tube was likely placed at a time when the patient was reportedly having problems when contacting plastic chairs, etc (as described by you). Any reaction during such surgical procedures? If not, it would seem that she is not at increased risk for a reaction to an endotracheal tube. If there is no history of previous endotracheal tube use, perhaps the anesthesiologist can explore whether metal endotracheal tubes are available/feasible here. If not, one might consider coating the outside of the endotracheal tube with a solution of human serum albumin (similar to that used for I.V.infusions), allow to dry, then sterilize the tube. This albumin "coating" may act as a barrier between the plastic on the outside of the endotracheal tube and the oropharyngeal mucosa. Int Arch Occup Environ Health. 2005 Apr;78(3):211-7. Epub 2005 Mar 1. Related Articles, Links Rasmussen K, Carstensen O, Ponten A, Gruvberger B, Isaksson M, Bruze M. Department of Occupational Medicine, Herning Hospital, 7400, Herning, Denmark. Aims: To identify workplace and individual risk factors for occupational contact allergy and dermatitis. Methods: A cross-sectional study was carried out at an international company producing wind turbine systems in Denmark . A cohort of 724 production workers at four facilities was highly exposed to epoxy resin as well as other chemicals. A screening questionnaire (participation rate 84.7%) was followed by an interview by an occupational physician and a dermatological examination, including patch testing, for a comprehensive list of potential workplace sensitizers. Results: Clinically diagnosed dermatitis was found among 214 workers (35.8%) and contact allergy to materials used in the workplace was found in 66 workers (10.9% of the total population and 20.3% of those who underwent patch testing). Of the 66 workers with a work-related allergy, 40 (60.6%) were allergic to epoxy compounds, 25 (37.9%) to hardeners and ten (15.2%) to other workplace materials, where one person showed an allergy only to these materials. Experiencing contact allergy was related to older age and longer employment in the workplace-however, neither of these risk factors was significant. The main risk factor for current dermatitis was contact allergy to materials used in the workplace, determined by patch testing, OR=5.4 (95% CI 3.9-9.9). Fewer days of absence from work was also related to current dermatitis, OR=2.0 (95% CI 1.2-3.5). Conclusions: In a cohort of workers with extensive exposure to chemicals related to epoxy-resin systems, contact dermatitis and allergy was prevalent. Older age and longer duration of employment at the workplace were individual risk factors for allergy to workplace materials, whilst work-related allergies and longer duration of employment at the workplace were significant risk factors for current dermatitis. 6/16/05 re: Leflunomide desensitization Female patient, age 65 with reumatoid arthritis suffered non typical urticarial lessions following per leflunomide (Arava) administration (two flare ups). She is now under cortisone per os treatment but the supervising rheumatologist would like to continue leflunomide treatment. I would like to ask if there is a published desensitization protocol specific for leflunomide; if not what would be your proposal? I am unaware of any published desensitization protocol for leflunomide. Also, I could not find any reference to such a protocol in a Medline search. Therefore, I suggest that you first call the Professional Education/Information Dept. of the manufacturer (Arava is made by Aventis (now the sanofi-aventis corp.-see telephone number in the PDR) asking them to search their files for info about possible desensitization protocols tried previously in cases of suspected Arava allergy. If no such information is available, one could try a procedure starting with a very small amount of the Arava. You will likely need the assistance of a hospital-based pharmacist to make up the Arava amounts needed. I would start with 1/1000th the amount in a 10 mg tablet. If there is no reaction after 24-48 hours, try 1/100th the amount in a tablet. Then, following the same procedure, try 1/10th the amount in a tablet and finally a therapeutic dose as tolerated. I suggest that these challenges be done in a medical environment equipped for emergency treatment in the unlikely possibility that these re-challenges induce an immediate/sub-acute severe reaction. I would keep the patient under medical observation for several hours after each challenge. It would be advisable to obtain written informed consent in advance of such challenges. 6/16/05 re: Approach to Warfarin allergy This patient is a 69 year-old male admitted with acute left lower extremity pain due to an arterial occulsion. He reportedly has been treated with warfarin therapy twice in the past and after 2-3 days on both occasions he developed a pruritic, maculopapular rash that started on the trunk and faded shortly after the warfarin was discontinued. Since he has failed multiple antiplatelet agents, the decision has been made to rechallenge him with warfarin, the only remaining vitamin K antagonist on the US market. He cannot afford injectable medications. A literature search was not very revealing in the management of "allergic" adverse cutaneous reactions to warfarin. What would be your advice in this situation? As you likely know, true allergic reactions to warfarin are very unusual. Of course, there is always a possibility that the reactions you described were induced by some non-active ingredient in the warfarin preparation (excipient, preservative, etc). Unfortunately, there is no reliable in vivo or in vitro test to determine if the warfarin itself is an offender. If it is felt that there are no effective and feasible alternative treatments in this case, one may consider a graded dose challenge. I do not know whether this would be a true "desensitization" since I am unaware of any attempts to desensitize in true Warfarin allergy. Also, I could not find any reports of such desensitization in a Medline search. Therefore, I suggest that you first contact the Professional Education/Information Dept. of the manufacturer (Coumadin is made by Bristol-Myers Squibb) asking them to search their files for info about possible desensitization protocols tried previously in cases of suspected Coumadin allergy. If no such information is available, one could try a procedure starting with a very small amount of the Warfarin. You will likely need the assistance of a hospital-based pharmacist to make up the warfarin amounts needed. I would start with 1/1000th the amount in a 5 mg tablet. If there is no reaction after 24-48 hours, try 1/100th the amount in a tablet. Then, following the same procedure, try 1/10th the amount in a tablet and finally a therapeutic dose as tolerated. I suggest that these challenges be done in a medical environment equipped for emergency treatment in the unlikely possibility that these re-challenges induce an immediate/sub-acute severe reaction. I would keep the patient under medical observation for several hours after each challenge. It would be advisable to obtain written informed consent in advance of such challenges. 6/10/05 re: Nature of drug reaction I am a registered pharmacist and have a question about a patient with unusual reaction to antibiotics - doxycycline, Bactrim and now either Cipro or Flagyl (pt was on both). This occurs after multiple exposures and often several weeks into therapy. Patient describes that it begins with a whitehead appearance with slight redness surrounding, then appears to look like a pimple, may or may not swell (often just pimples are more pronounced although last time patient reports some did swell quite a bit), and then resolves in scab formation upon discontinuing the antibiotics. Rash is located on back and upper arms, although in past was on the face as well. I have observed the rash and several phases may be present at once. Each spot has well defined margins and in the beginning definitely has an acne appearance. Patient reports swelling responded to Benadryl, but rash persists and then turns to scabs after discontinuing of antibiotics with ultimate resolution. There is never an itch. My initial thought is delayed hypersensitivity (often will happen after multiple exposures) but it is unusual to be allergic to so many classes of antibiotics. Patient has seen numerous allergists, and at one time an infectious disease consult was obtained and the physician felt it looked similar to chicken pox (but pt had no titers to chicken pox). I am just wondering if there is an immune category (deficiency or allergy) that this would fit. Any advice would be appreciated. Thank you. To help respond to your questions, I obtained input from Drs Robin Carder and Rebecca Gruchalla of the Univ of Texas Southwestern Medical School in Dallas. They are experts in adverse drug reactions in the skin. The response written by Dr. Carder is enclosed below. The differential diagnosis of widespread pustules following antibiotic therapy would be: 1) AGEP (acute generalized exanthematous pustulosis), which is a form of drug reaction, most common with cephalosporins but can occur with a variety of antibiotics. It would be unusual to have this reaction to multiple different classes of antibiotics. Patients with AGEP (or any drug allergy for that matter) are always itchy and are often febrile, so the lack of these symptoms make the diagnoses of AGEP or a drug eruption much less likely. 2) Pityrosporum folliculitis can present as multiple pustules with erythema and is usually seen in the setting of patients on chronic antibiotic therapy or immunosuppressive therapy. This may better fit this patient's history. Since the history does not fit an infectious process, an infectious disease consult is probably not necessary. BUT, this case definitely falls within the realm of dermatology, so I would strongly recommend evaluation by a dermatologist, so that a more detailed history of medications, appearance/distribution of lesions, concommitant symptoms, etc. can be obtained in order to reach an accurate diagnosis and determine whether this patient truly has a drug allergy or not. (Note: if no current lesions, the family should bring any available photos of the eruption with them to the appt.) 5/26/05 re: Facial angioedema-propofol reactions 23 y.o. B male (physician) referred for allergic reaction resulting in 5 day ICU admission after wisdom tooth extraction, with laryngeal edema and facial swelling beginning 10 minutes after Fenatyl, Versed and Protofol(?). Surgeon only removed 1 of the asymptomatic teeth; wants to do the others. I advised pt to use local anesthesia but suspect he may need some of these drugs again. A latex RAST is negative. I suspect Protofol most likely but am not familiar with good technique for testing these agents. When I see a clinical picture consisting of angioedema limited to the facial area, oral mucosa and possibly laryngeal edema following oral surgery, I first look for local factors.1) One should look for the presence of hereditary angioedema or one its acquired variants by obtaining serum levels of C4,C3, C1 INH and C1q since the trauma of oral surgery is commonly a trigger for marked local angioedema in such disorders. Sometimes it is the first evidence of such disorders 2) Check for the possibility that the angioedema was not a reaction to some agent injected locally in the oral mucosa by the oral surgeon. If you settle on propofol as the most likely suspect agent in this problem, it should be mentioned that allergic reactions to this agent are quite unusual. I have enclosed below an abstract of a report of perhaps the largest series of patients (n=14) with suspected systemic allergic reactions to propofol. In this study, they carried out skin testing with propofol. I suggest that you read the whole article to get details of the testing method. Recall that propofol as used clinically is an oil in water suspension containing soy oil and some egg components (see enclosed description). Also, the generic propofol preparation contains sulfites as a preservative while the branded propofol (Diprivan) contains EDTA but no sulfites. I have enclosed comments of Dr. Ronald Simon of the Scripps Clinic, an expert in sulfite reactions. Curr Pharm Des. 2004;10(29):3639-49. Propofol: therapeutic indications and side-effects. Marik PE. Department of Critical Car Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. maripe@ccm.upmc.edu Propofol (2, 6-diisopropylphenol) is a potent intravenous hypnotic agent whichis widely used for the induction and maintenance of anesthesia and for sedationin the intensive care unit. Propofol is an oil at room temperature and insolublein aqueous solution. Present formulations consists of 1% or 2% (w/v) propofol,10% soybean oil, 2.25% glycerol, and 1.2% egg phosphatide. Disodium edetate(EDTA) or metabisulfite is added to retard bacterial and fungal growth. Propofolis a global central nervous system depressant. It directly activates GABA(A)receptors. In addition, propofol inhibits the NMDA receptor and modulatescalcium influx through slow calcium ion channels. Propofol has a rapid onset ofaction with a dose-related hypnotic effect. Recovery is rapid even after prolonged use. Propofol decreases cerebral oxygen consumption, reducesin tracranial pressure and has potent anti-convulsant properties. It is a potent antioxidant, has anti-inflammatory properties and is a bronchodilator. As a consequence of these properties propofol is being increasingly used in them anagement of traumatic head injury, status epilepticus, delirium tremens, status asthmatic us and in critically ill septic patients. Propofol has a remarkable safety profile. Dose dependent hypotension is the commonest complication; particularly in volume depleted patients. Hypertriglyceridemia and pancreatitis are uncommon complications. Allergic complications, which may include bronchospasm, have been reported with the formulation containing metabisulfite. In addition, this formulation has been demonstrated to result in the generation of oxygen free radicals. High dose propofol infusions have been associated with the "propofol syndrome"; this is a potentially fatal complication characterized by severe metabolic acidosis and circulatory collapse. This is a rare complication first reported in pediatric patients and believed to be due to decreased transmembrane electrical potential and alteration of electron transport across the inner mitochondrial membrane. Anesthesiology 1992 Aug;77(2):275-80 Life-threatening anaphylactoid reactions to propofol (Diprivan) Laxenaire MC, Mata-Bermejo E, Moneret-Vautrin DA, Gueant JL. Department of Anesthesiology and Surgical Intensive Care Unit, CHU-Hopital Central, Nancy, France. Fourteen patients who had had a life-threatening reaction within a few minutes after receiving propofol (Diprivan) were investigated for anaphylaxis 4-6 weeks after the incident. Three kinds of immunologic tests were carried out: skin tests (prick tests and intradermal tests with the drugs used and Intralipid, the solvent for propofol), aleukocyte histamine release test, and a radioimmunoassay (RIA) of immunoglobulin E (IgE) against propofol and muscle relaxants, when they had been given with propofol. It had been previously shown that these were always negative in patients anesthetized with propofol without any complications. Thirteen of the 14 patients hadat least one positive test supporting hypersensitivity to propofol; 2 patients had three tests positive; 4 had two tests positive; and 7 had one test positive. The skin tests with Intralipid were negative in 4 patients whose tests with propofol were positive. Two patients who had been given muscle relaxants at the same time as the propofol had positive IgE-RIA to both drugs. In one patient, results of all the tests remained negative, and the mechanism involved in the reaction remained unidentified. It is note-worthy that 9 patients of 14 had allergic histories that were known before the anesthetic (atopy; allergy to antibiotics, muscle relaxants, lidocaine, colloids) and that none of the patients had ever received propofol or Intralipid before. It is possible that the IgE that linked abnormally with the propofol had specific binding sites for the phenyl nucleus and the isopropyl groups, which are present in propofol and many other drugs. Propofol (2-6 diisopropylphenol) is an alkyl phenol in a lipid vehicle (soybean oil, egg lecithin, and glycerol) (5). Allergic reactions to propofol on first exposure are usually because of the isopropyl groups that may act as epitopes and that are present in various medications and cosmetics (5-6). Allergic reactions to propofol upon re-exposure are usually because of the phenol molecule (7). Dr. Simon's comments: There have been (anecdotal, but around the country) reports of increased Bronchial reactions to generic propofol. However, such reactions are actually NEVER seen with branded Diprivan. While I believe the sulfite added (in place of EDTA in Diprivan) is related and would cause reactions in those already sulfite sensitive; that's not the (only) possible factor in the reported reactions. I believe it is due to the physiochemical difference in the propofol itself when in a sulfite suspension. There have also been issues of the quality of the anesthetic effect and stability of the product and other issues with the generic propofol. I suggest reading:Am J Anesth, 2000;27. The whole supplement is devoted to this issue. I participated in the preparation of the supplement and authored one of the articles. 5/18/05 re: Evaluation for protamine allergy I WAS RECENTLY REFERRED A HEMODIALYSIS PT. WHO HAD AN INTRAOPERATIVE ANAPHYLAXIS PRESUMED TO BE TO PROTAMINE. I REVIEWED THE LITERATURE BUT WAS UNABLE TO GET ANY CLEAR INFORMATION ABOUT HOW TO PURSUE A WORK UP. ANY SUGGETIONS? THANKS. To help respond to your question, I obtained input from Dr. Franklin Adkinson of the Johns Hopkins Clinical Immunology Division. Dr. Adkinson was a co-author of several reports dealing with evaluation for protamine allergy (see abstracts enclosed below). I suggest that you obtain the IgE and IgG anti-protamine antibody levels from the DACI lab in Johns Hopkins (see Dr. Adkinson's comment below). A negative test may be more helpful in that it essentially rules out an antibody-based protamine reaction You may also wish to try skin testing with protamine, as Dr. Adkinson suggested. In a recent review of protamine-induced reactions by Park (International Anesthesiology Clinics 2004;42:135-144), the author describes intradermal testing with 0.02 ml of a 1 microgram/mL protamine solution. The criterion for a positive response was 8 mm diameter "induration" (I think he means wheal) at 10 minutes with a reported sensitivity of 91% and a specificity of 78%. What to use if the patient does have IgE-mediated protamine sensitivity? Another report (Heart and Lung 1999;28:418-28 ) refers to a report "that they have used hexamethrine, obtained as a compassionate-use drug through the Food and Drug Administration, to successfully treat two patients with prior life-threatening reactions to protamine". I had asked Dr.Adkinson about use of hexamethrine. As noted below, he had no recall of availability of this agent. Dr. Adkinson's comments Both the IgE and IgG anti-protamine assays are available from the DACI Laboratory. There have been few requests but we still do it from time to time. You can pass our toll free DACI telephone number (800-344-3224) to him if he wishes to call or he can just send a specimen. Regarding your other questions: 1)hard to know what the sensitivity of the DACI serologic tests is; our previous NEJM article (320:886-892, 1989) on protamine gives a better picture of IgE and IgG and risk of reactions in the context of by-pass surgery. We have never seen a positive ST to protamine, which is a puzzle as discussed in the paper you looked at. Others have reported + protamine STs, though, so it's always worth a try. I don't know about the current availability of hexamethrine; I've never used it and don't even recall what the source was (seems it was the CDC or NIH rather than a company). N Engl J Med. 1989 Apr 6;320(14):886-92. Comment in: N Engl J Med. 1989 Dec 14;321(24):1684-5. Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous protamine. Weiss ME, Nyhan D, Peng ZK, Horrow JC, Lowenstein E, Hirshman C, Adkinson NF Jr. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore. Life-threatening reactions to intravenous protamine, administered to reverse heparin anticoagulation, have been reported with increasing frequency as a consequence of the escalating use of cardiac catheterization and coronary bypass surgery. Retrospective studies have shown that such reactions are more common in diabetic patients receiving daily subcutaneous injections of protamine-insulin preparations. To determine whether anti-protamine IgE or IgG antibodies might explain the increased risk for protamine reactions among patients with protamine-insulin-dependent diabetes, we conducted a case-control study of 27 patients (diabetic and nondiabetic) who had acute reactions to intravenous protamine and 43 diabetic patients who tolerated protamine without a reaction during diagnostic or surgical procedures. Cases and controls were grouped according to previous exposure to protamine-insulin preparations. In diabetic patients who had received protamine-insulin injections, the presence of serum antiprotamine IgE antibody was a significant risk factor for acute protamine reactions (relative risk, 95; P = 1.0 X 10(-5), as was antiprotamine IgG (relative risk, 38; P = 1.2 X 10(-5). No patients without previous exposure to protamine-insulin injections had serum protamine IgE antibodies. In this group, anti-protamine IgG antibody was a risk factor for protamine reactions (relative risk, 25; P = 0.0062). We conclude that in protamine-insulin-dependent diabetics, the increased risk of serious reactions when intravenous protamine was given appeared to be caused largely by antibody-mediated mechanisms. In nondiabetic subjects, the presence of protamine IgG was significantly associated with an increased risk of acute protamine reactions, although many nondiabetic subjects who had reactions had no IgG antibodies Clin Exp Allergy. 1990 Nov;20(6):713-20. Serial immunological investigations in a patient who had a life-threatening reaction to intravenous protamine. Weiss ME, Chatham F, Kagey-Sobotka A, Adkinson NF Jr. Johns Hopkins University School of Medicine, Division of Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224. Reactions to intravenous protamine include rash, urticaria, bronchospasm, hypotension, and/or pulmonary artery pressure elevation. We have previously shown that in diabetic patients receiving daily protamine-insulin injections, the presence of anti-protamine IgE or IgG antibodies are significant risk factors for acute, life-threatening reactions when protamine is given intravenously. To study protamine reactions further, we measured serum anti-protamine IgE and IgG antibody levels, in-vitro basophil histamine release and intracutaneous skin testing to protamine serially in an NPH-insulin dependent diabetic who had a severe, protracted anaphylactic reaction to protamine. At the time of his protamine reaction, his serum contained 8.5 ng/ml of anti-protamine IgE and 1.3 micrograms/ml of anti-protamine IgG antibody. One month following the reaction both anti-protamine IgE and IgG increased to 16 ng/ml (twofold rise) and 90.5 micrograms/ml (70-fold rise), respectively. With time, both anti-protamine IgE and IgG antibody declined. Serial intradermal skin tests using protamine sulphate did not discriminate between the protamine reactor and nine normal control subjects who had no prior exposure nor any demonstrable serum IgE antibody to protamine. In-vitro basophil histamine release to protamine sulphate was inconclusive in discriminating between the protamine reactor and normal control subjects. We postulate that protamine may be an incomplete or univalent antigen that must first combine with a tissue macromolecule or possibly heparin to become a complete multivalent antigen capable of eliciting IgE antibody-dependent mediator release. Clin Rev Allergy. 1991 Fall-Winter;9(3-4):339-55. Allergy to protamine. Weiss ME, Adkinson NF Jr. University of Washington Hospital, Seattle. Recent advances in medicine, such as cardiac catheterization, phoresis, dialysis, and cardiopulmonary bypass technology, have increased the need for heparin anticoagulation. To antagonize heparin's effect and prevent hemorrhagicomplications after the procedure, protamine has likewise been used more frequently. With its increased use have come increased reports of adverse protamine reactions consisting of rash, urticaria, elevation of pulmonary artery pressure, systemic hypotension, and, at times, death. The elevation of pulmonary artery pressure, which appears to be a rather common occurrence in animals, maybe an isolated finding without clinical consequences in humans. However, this pulmonary vasoconstriction may, when severe, lead to acute right-sided heart failure and systemic hypotension. Other protamine reactions involve a decrease in systemic vascular resistance and systemic hypotension without changes in pulmonary artery pressure. Causes of acute protamine reactions may involve the generation of anaphyatoxins and prostanoids either from protamine-heparin complexes or complement-fixing antiprotamine IgG antibodies, from inhibition of plasma Carboxypeptidase N, from crosslinking of cell-surface antiprotamine IgE on mast cells and basophils with subsequent mediator release, or from potentiation of IgE-mediated release of histamine through a polycationin-recognition site. Although we have come a long way in understanding the mechanisms by which protamine can cause its ill effects in humans, more work is clearly needed to define, in prospective studies, the incidence of and risk factors for protamine reactions in various patient groups, and to delineate more clearly which mechanisms are involved in each clinical type of acute protamine reaction. Hopefully, this will lead to strategies and protamine alternatives that will prevent or diminish, in frequency or severity, adverse protamine reactions. Alternatively, a clearer picture of the risk factors important for protamine reactions and the predictive value of diagnostic tests (e.g., protamine IgE antibody) can also minimize the clinical impact of this increasingly common adverse event. 5/16/05 re: IV Ig as cause of rash I have a 55 year old patient with long standing MG (prominent ocular but also generalized fatigue) whose only significant disease modification/improvement came earlier this year 3 weeks after a 5 day 32 gm/day infusion with Panglobulin. The only problem is that this also coincided with a diffuse, highly pruritic MP rash read as "spongiotic dermatitis " on bx and necessitating an extended prednisone taper. The rest of his medications had been longstanding. He has also been receiving Cellcept for the past year. I contacted the Red Cross who is sending me one case report of such a delayed reaction assoc. with IVIG out of UMDNJ. My patient would like to have subsequent additional IVIG treatments, but not if they are associated with such a significant dermal side effect. Is this rash related to the IVIG or to his MG or an interaction ( T cell mediation in a MP rash?). Should I rechallenge with another IVIG maybe "purer" such as Octagam, and should I give him a smaller cumulative dose? Any suggestions would be welcome. As you have pointed out, a delayed onset MP rash must be a very unusual adverse reaction to most IV Ig preparations. I have seen an occasional urticarial reaction starting within a few hours after an IV Ig infusion but have not seen a delayed onset MP rash that could be definitely ascribed to the IV Ig infusion. Therefore, I wonder whether the reaction may be against a chemical agent left over in the Ig prep from prior processing. As you may know, the studies of Pichler et al in Europe have suggested that late onset MP rashes following use of certain other drugs may be T cell mediated. These conclusions have been based on in vitro lymphocyte studies which are not currently of practical clinical use. Therefore, my suggestion would be to choose another IV Ig preparation, preferably one that uses a different processing procedure (to reduce the likelihood of the same chemical agent left over in the Ig prep). If feasible, obtain a small amount of that chosen Ig prep to do ID skin testing (using a 1:1000 dilution of the Ig prep). Observe the site for both immediate and delayed onset reactions. If no prominent positive skin test reaction, then do graded dose IV administration, starting with low dose (say 1/10 th the amount in the intended dose). If no adverse reaction in one week, then give a full therapeutic dose. Although the likelihood of a severe adverse reaction to the Ig treatment is very small, it may still be prudent to obtain written informed consent in advance from the patient for the approaches described above (in view of the patient's expressed concerns about having another adverse reaction in future treatment). 4/29/05 re: Sulfite sensitivity I am a practicing primary care pediatrician in Massachusetts, employed by Boston University. and I wanted to know, is it safe to use an epipen in a patient suspected of having a sulfite allergy, or is there a preservative free source of epinephrine? The reaction occured after a dental injection of lidocaine with epinephrine, and consisted of initial perioral, intraoral and nose pruritus, followed by throat edema, rhinitis and eye pruritus and tearing. The progression of symptoms occured within 3-5 minutes. The throat swelling caused difficulty in swallowing the Benadryl capsule, and resolved after ~ 20 minutes with 50 mg of Benadryl. Subsequent exposure to preservative free Lidocaine and preservative free Mepivicaine did not cause any reaction. The patient carries an epipen for food allergies. To help respond to your questions, I obtained input from Dr. Ronald Simon of the Scripps Clinic in La Jolla CA, a leading expert in adverse reactions to sulfites. As you can see in his comments below, Dr. Simon questioned whether the reaction you described was caused by the sulfites in the local anesthetic (LA) because the usual adverse reaction to sulfites is almost always asthmatic. Dr. Simon feels that the amount of sulfite in an Epi-Pen injection would not be sufficient to trigger such an asthmatic reaction. On the other hand, the patient may have had a relatively rare anaphylactic reaction to sulfites which could be IgE-mediated. In such a case, Dr. Simon feels that the small amount of sulfite in Epi-Pen could trigger such a reaction. However, he raised the question of whether parabens in the LA were the more likely offender. Sorting out this matter may require sulfite skin testing and possibly cautious graded dose challenge (under close observation in an appropriate setting) with the sulfite-containing solution vs. a paraben-containing solution. Written informed consent in advance of such a challenge is advisable. I recommend that you consult a certified allergist in your community for participation if such an approach is considered On the other hand, you could advise use by your patient of epinephrine from a multi-dose vial for emergency use if such does not contain sulfites or parabens (see Dr. Simon's comments). Dr, Simon's comments: First I question whether the reaction was sulfite related. As you know almost all sulfite-reactive individuals are asthmatic & have asthmatic reactions to sulfites. This is the only group in which the safety of the sulfite inEpi-pens has been studied (by ourselves). We found that the dose of sulfite inepi; given alone, SQ did not cause any reaction even in our most sulfite sensitive asthmatics. With the epi added (in Epi-pen) I could not imagine are action occurring. However, if this patient is sulifte sensitive; it would have to be a true sulfite allergy so the situation with Epi-pen could be different, but I doubt it. A sulfite skin test (prick, at 1 and 10 mg/ml) should resolve that issue. I wonder if there was a paraben preservative in the suspect local anesthetic used? IgE meidated reactions to injected parabens in LA's has been reported. In a food allegic subject reacting in a dentists office; one also has to be concerned about latex sensitivity (although subsequent visits went smoothly; perhaps latex free materials were also used, "just to be safe". If not, I wonder whether the reaction could have been due to direct contact with one of the foods the patient is allergic too (contamination on dentists/assistants gloves/hands etc.). Finally; if there is still concern about the sulfite in Epi-pen; multidose vials of epienphrine don't contain sulfites; only unit doses. They do need preservatives (and can be parabens, so I brought up the issue above). Hope that helps. 4/28/05 re: Gelatin allergy I am an allergist. I saw an 18 month old for anaphylaxis after eating Little Debbie Rice Crispy Marshmallow Bar. I tested him and was negative to peanut, egg, wheat, and soy. I tested him to Knox unflavored gelatin and was 4+ positive. I tested myself and staff to the same and all were negative. He has had no further anaphylaxis on avoiding gelatin. He is now 3 1/2 years and skin test is still positive. He will be due MMR next year. He has already had natural varicella. What is the natural history of gelatin allergy? Is there a gelatin-IgE available? I will need to skin test him to MMR next year. Gelatin oral challenge is risky. He carries an EpiPenJR. To help respond to your questions, I obtained input from Dr. JohnKelso of the US Navy Medical Center in San Diego, CA Dr. Kelso is anexpert in gelatin allergy, having made the first report in the USAabout allergy to gelatin in vaccines. His responses are enclosed below. I should mention that studies in Japan, where most of the reportsabout sensitivity to gelatin in vaccines have originated, haveconcluded that many of the children with such reactions have nohistory of allergic reactions to gelatin-containing foods. Suchreactions to gelatin in vaccines may become much less of a problem ifgelatin-free vaccines are developed (see abstract enclosed at the bottom). Dr. Kelso's comments: What is the natural history of gelatin allergy? A very interesting question. Certainly most of the reported gelatin allergic reactions have been in children, but then children receive by far the majority of the vaccines. Our index case of gelatin allergy was 17 years old and was still allergic at last contact with her several years later, so it can persist in to adulthood. Given that some food allergies in children are routinely outgrown and other rarely outgrown, I suppose gelatin could fall into either camp, but I am not aware of any data on this. How to approach using MMR vaccine containing gelatin in a gelatin-allergic child? There is a Pharmacia ImmunoCAP assay for gelatin (code c74), so any lab that uses ImmunoCAP ought to be able to run it. If this assay is negative, I would still recommend a prick test with sugared gelatin (e.g. Jell-O": dissolve 1 teaspoon of gelatin powder in 5 cc normal saline). I would also test with the individual vaccine (prick full strength and if negative ID 1:100). Vaccine. 2005 Jan 26;23(10):1205-8. Related Articles, Links Safety and immunogenicity of gelatin-free varicella vaccine in epidemiological and serological studies in Japan. Ozaki T, Nishimura N, Muto T, Sugata K, Kawabe S, Goto K, Koyama K, Fujita H, Takahashi Y, Akiyama M. Department of Pediatrics, Showa Hospital, Konan, Aichi 483-8703, Japan. Following gelatin-containing varicella vaccine (1994-1999: 1,410,000 distributed doses), 28 serious anaphylactic reactions and 139 non-serious allergic reactions were reported, with no serious and only five non-serious reactions following gelatin-free vaccine (1999-2000: 1,300,000 distributed doses). All nine sera available from children with serious reactions tested positive for gelatin-specific IgE, whereas 55 of the 70 available from those with non-serious reactions were positive, with one false positive. There was no correlation between gelatin-specific IgE antibody titers and severity of allergic reaction. Post-immunization anti-varicella antibody titers were comparable for both gelatin-free and gelatin-containing vaccine groups. The new gelatin-free varicella vaccine is thought to be safe, with similar immunogenicity to the earlier gelatin-containing vaccine. 4/7/05 re: Reaction to immunization I have a 5 year old South-Asian patient who experienced an anaphylactic reaction after MMR vaccine 1 year ago. He had a known history of allergy to egg. History obtained after the reaction indicated he had also had respiratory symptoms after ingestion of gelatin in yogurts, so we assumed the MMR reaction was from gelatin. He returned a few weeks ago for 5 year old exam and received PPD, IPV and DTaP, and again experienced a full-blown anaphylactic reaction with skin and respiratory symptoms requiring epinephrine and transfer to the local ER within 30 minutes of the vaccinations. Reviewing the insert for IPV and MMR indicate presence of calf or fetal bovine serum as well as neomycin in both vaccines. Is it likely that either of these constituents caused the reaction? Are there any tests that should be performed? While he may not require any of these vaccines in the future the parents want to know the cause of the reaction if at all possible in order to avoid that agent in the future. To help respond to your questions, I obtained input from Dr. John Kelso, Chief of Allergy in the U.S. Naval Medical Center, San Diego. John is an expert in adverse reactions to immunizations. To my knowledge, he was the first to describe gelatin-induced adverse reactions to vaccines in the USA / His comments are enclosed below. Dr. Kelso's comments: The Tripedia brand of DTaP (Aventis Pasteur) does contain 28 micrograms of gelatin per 0.5 ml dose. I do not believe the IPV contains gelatin. There is a Pharmacia ImmunoCAP assay for gelatin (code c74), so any lab that uses ImmunoCAP ought to be able to run it. If negative, I would still recommend a prick test with sugared gelatin (e.g. Jell-O«: dissolve 1 teaspoon of gelatin powder in 5 cc normal saline). I would also test with the individual vaccines (prick full strength and if negative ID 1:100). I am not aware of any IgE mediated reactions to neomycin or to bovine or calf serum in vaccines. 4/4/05 re: Allergy to corticosteroids I am taking care of women with possible local anesthetic and steroid allergy as per pt on two separate occasions she developed urticaria following poprednisone and had similar reaction to cortisone injection, pt needs to have corneal transplant will need steroid topical what should be my approach please advise. True allergies to corticosteroid preparations are very unusual, with the evidence for this coming mainly from a limited number of case reports. I have enclosed below a review I wrote for this AADMC website about a review article discussing this subject. As noted in my discussion, the usual approach in such cases has been to use a corticosteroid agent with a chemical formula different from that in the corticosteroid thought to have caused the previous "allergic" reaction. Some investigators have tried to first screen with skin tests employing corticosteroid agents under consideration. However, I am not convinced that this is a reliable approach.In the case that you described, you did not mention whether the corticosteroid treatment in the eyes would be by eye drops or local injection. I mention this because some corticosteroid preparations are better absorbed into the eye from eye drops than others. If this is not a consideration, than a trial of dexamethasone eye drops might be a reasonable way to start, since its chemical formulation is less similar to prednisone. Current Lit Item Corticosteroid hypersensitivity reactions SUMMARY Allergic or pseudo-allergic systemic reactions to therapeutic corticosteroid (CS) preparations are rare but have been reported. Butani of the University of California , Davis Medical Center in Sacramento, CA extensively reviewed the English language literature from 1964 to 2002 for relevant reports. Excluding contact sensitivity reactions to topical CS, the author found 80 reports about this subject, mainly individual case reports. The adverse reactions described ranged from minor rashes to serious cardio-vascular collapse. The apparent un