- Drug Reaction - 12/12/2005 RE: Reaction to I -131 I am a radiation oncologist and I have a patient with advanced thyroid cancer in need of radioactive Iodine [I-131] therapy. She has had 2 previous reactions to IV RCM [I believe non-ionic] during a CT. The first time she developed hives and early laryngeal edema within ~ an hour of the administration. The second time she was per her report pretreated with steroids +/- Benadryl and still developed a anaphylactic reactions requiring resuscitation. I think it is probably safe to administer oral I-131 but I would like your advice. If you feel this is safe would you pre-treat her with Prednisone and Benadryl or not? The exact pathogenesis of anaphylactoid reactions to radiocontrast media (RCM) is still not well-defined. The leading theory is that hyperosmolarity of the RCM plays a role, with less frequent reactions occurring with use of iso-osmolar RCM. However, all experts in this area are agreed that such reactions do not involve an immune or other adverse reaction to the iodide component of the RCM. Therefore, your patient should be at no increased risk for an "allergic" reaction to I-131. 11/15/05 re: Coronary vasospasm due to epinephrine effect? I am an RN in an ER. We had a 41 y/o female patient sent via ambulance from a surgiclinic with question of an MI. The patient was scheduled for an intrascalene node block for shoulder surgery and as soon as the LAs Bupivacaine/Lidocaine} were injected she became nauseous and severe headache for about 5 minutes, her EKG became abnormal, BP went very high and then bottomed out. The EKG returned to normal in 3 minutes and no more abnormalities since. The patient was positive for an MI with her cardiac cath showing normal vessels and no previous heart history with 2 areas of LV wall motion abnormality, EF between 25-30% which shows damage to the heart muscle. The cardiologist gave diagnosis of Non Q MI and an allergy to epinephrine with severe vasospasm secondary to epinephrine causing the MI, with normal coronaries. He told the patient she must never have epinephrine again and to say it caused an MI. The anesthesiologist disagrees and gave diagnosis of amides allergy and not epinephrine. Is patient allergic to amides and epinephrine? Have you heard of either causing MI in a heart healthy patient? Should the patient be tested for allergies to these meds? None of us have ever heard of epinephrine causing this kind of reaction or anything close to this type of reaction. The case you described sounds very unusual to me. There have been a few individual case reports of postulated coronary vasospasm associated with epinephrine treatment. In some of these cases, there was an overdose of epinephrine injected intravenously (see enclosed abstract). I would not describe such cases as "epinephrine allergy" since there has been no evidence of IgE antibody mediation or the symptoms suggestive of an allergic response. One might call some of such cases idiosyncratic reactions whereas others (involving I.V. injection of sizable doses of epinephrine) were more likely toxic reactions. Could the reaction in your patient fit into one of these two categories? It would depend on how much epinephrine was injected over a short time period. The amount of epinephrine present in 1.0 ml of most local anesthetics is quite small. However, if a large volume of the local anesthetic were injected over a short time period, an idiosyncratic reaction to epinephrine could possibly have occurred. Could the reaction in your patient be due to a reaction to the amide local anesthetic? Large amounts of such local anesthetics injected over a short time period can exert adverse effects on the heart. However, such effects are usually arrythmias or suppression of cardiac muscle function with resultant hypotension and other adverse effects, not coronary vasospasm. A marked increase in blood pressure, even if transient, would be more likely due to epinephrine than to the amide local anesthetic. The question arises whether this patient can receive the local anesthetic (containing epinephrine) in the future if there are no alternative approaches feasible for a future procedure. It would be prudent to inject small amounts of the local anesthetic at a time (not by the I.V. route), keeping a careful record of the total amount injected. The procedure should be carried out in a facility equipped for emergency cardiac treatment with careful monitoring of vital signs. Pre-treatment with a selective beta blocker such as atenolol should be considered. Pre-treatment with an alpha blocker is another consideration but the patient would require even closer monitoring of vital signs to make sure that hypotension is not induced. It would be prudent to obtain written informed consent from the patient before any such procedure is carried out. Am J Emerg Med. 1989 Sep;7(5):485-8. Related Articles, Links Coronary artery spasm induced by intravenous epinephrine overdose. Karch SB. Department of Emergency Medicine, University Medical Center, Las Vegas. A 27-year-old man was accidentally given 2 mg intravenous epinephrine instead of 2 mg naloxone. He immediately developed chest pain, nausea, and diaphoresis. An ECG taken shortly after the epinephrine administration showed widespread ischemia. Forty-five minutes later the tracing still showed an early repolarization pattern, but ST elevation was less marked and the patient was asymptomatic. Serum potassium was 3.2 mEq/L and serum catecholamines, drawn approximately 20 minutes after the epinephrine administration, were 10 times normal (dopamine, 173 ng/L; epinephrine, 1,628 ng/L; norepinephrine, 1,972 ng/L). There are seven other reports of intravenous epinephrine overdose in the English literature. Two of the previously reported cases had 12-lead ECGs within the first hour. In both there was evidence of transient ischemia similar to that observed in this case. Most of the patients had symptoms consistent with angina, and several developed pulmonary edema. These findings suggest that, in humans, large intravenous doses of epinephrine are likely to produce coronary artery spasm and may decrease coronary artery perfusion. 9/16/05 re: Thimerosal in patch tests and autism In patch testing, what is the amount of Thimerosal placed and what is the absorption rate in the skin? Many parents are concerned about risk for Autism, etc. How safe do you think it is, and how early do you recommend patch testing? First, I should say that there is still considerable debate about the possible adverse effects of thimerosal in some vaccines where it is present in much greater amounts delivered systemically by injection than might be absorbed from any present in any patch tests. Most experienced observers have concluded that there is no pathogenic relationship of thimerosal in vaccines and autism (see enclosed abstract). However, because of concerns about the cumulative effects of thimerosal present in a number of vaccines given over relatively short time periods to young infants, a number of groups have strongly recommended development of thimerosal-free vaccines. To my knowledge, the majority of vaccines currently given to infants in the USA have little or no thimerosal. I have had difficulty finding the concentration of thimerosal in different patch test preparations. In some cases, there must be none because some studies of contact sensitization to thimerosal must use control patches that contain little or no thimerosal (see enclosed abstract). In any event, I would estimate that the risk of any minute amount of thimerosal that might be present in a patch being absorbed systemically to cause adverse effects in the nervous system is very small. Nevertheless, I think it advisable to avoid patch testing (if such patches contain thimerosal) within several months of the time when the patient is receiving injections of thimerosal -containing vaccines. Pediatrics 2001 May;107(5):1147-54 Comment in: Pediatrics. 2001 May;107(5):1177-8 An assessment of thimerosal use in childhood vaccines. Ball LK, Ball R, Pratt RD. Division of Vaccines and Related Products Applications, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852, USA. balll@cber.fda.gov BACKGROUND: On July 7, 1999, the American Academy of Pediatrics and the US Public Health Service issued a joint statement calling for removal of thimerosal, a mercury-containing preservative, from vaccines. This action was prompted in part by a risk assessment from the Food and Drug Administration that is presented here. METHODS: The risk assessment consisted of hazard identification, dose-response assessment, exposure assessment, and risk characterization. The literature was reviewed to identify known toxicity of thimerosal, ethylmercury (a metabolite of thimerosal) and methylmercury (a similar organic mercury compound) and to determine the doses at which toxicity occurs. Maximal potential exposure to mercury from vaccines was calculated for children at 6 months old and 2 years, under the US childhood immunization schedule, and compared with the limits for mercury exposure developed by the Environmental Protection Agency (EPA), the Agency for Toxic Substance and Disease Registry, the Food and Drug Administration, and the World Health Organization. RESULTS: Delayed-type hypersensitivity reactions from thimerosal exposure are well-recognized. Identified acute toxicity from inadvertent high-dose exposure to thimerosal includes neurotoxicity and nephrotoxicity. Limited data on toxicity from low-dose exposures to ethylmercury are available, but toxicity may be similar to that of methylmercury. Chronic, low-dose methylmercury exposure may cause subtle neurologic abnormalities. Depending on the immunization schedule, vaccine formulation, and infant weight, cumulative exposure of infants to mercury from thimerosal during the first 6 months of life may exceed EPA guidelines. CONCLUSION: Our review revealed no evidence of harm caused by doses of thimerosal in vaccines, except for local hypersensitivity reactions. However, some infants may be exposed to cumulative levels of mercury during the first 6 months of life that exceed EPA recommendations. Exposure of infants to mercury in vaccines can be reduced or eliminated by using products formulated without thimerosal as a preservative. Am J Contact Dermat. 2003 Sep;14(3):138-43. Related Articles, Links Patch testing with thimerosal in a Canadian center: an 11-year experience. Freiman A, Al-Layali A, Sasseville D. Division of Dermatology, McGill University Health Centre, Royal Victoria Hospital, Montreal, PQ, Canada. BACKGROUND: Thimerosal has been used for decades as an antiseptic, a disinfectant, and a preservative in various consumer products. It is also a notoriously frequent contact allergen, but the significance of positive patch-test reactions has been debated over the past decade. OBJECTIVE: The aim of this study was to assess the prevalence and relevance of positive patch-test reactions to thimerosal in a large Canadian center and to compare our results with those of previous publications. METHODS: A retrospective analysis of data collected over the course of 11 years in the contact dermatitis clinic of a university hospital was performed. RESULTS: Of 2252 subjects patch-tested for thimerosal, positive reactions were observed in 102 individuals (4.53%), placing thimerosal as the fifth most common allergen in our practice. The sensitization rate was equivalent between the patients who underwent aimed patch testing and those who were routinely tested for reaction to thimerosal when this allergen was included in our standard patch-testing series 8 years into the study. There was an increased incidence of thimerosal sensitization in chemists and laboratory technicians, as well as in health care workers, including medical doctors, registered nurses, dentists, and dental assistants. While eight reactions were deemed possibly relevant, in none of the cases was it possible to definitely establish the relevance of positive reactions to thimerosal, either because the presence of this allergen could not be verified in patients' products or because patch testing with these products gave negative results. CONCLUSION: In agreement with previous reports, we conclude that even though positive reactions to thimerosal are frequent, very few seem to be clinically relevant. J Am Acad Dermatol. 2001 Jul;45(1):23-7. Related Articles, Links Thimerosal in the detection of clinically relevant allergic contact reactions. Suneja T, Belsito DV. Division of Dermatology, University of Kansas Medical Center, Kansas City, USA. Thimerosal, a mercuric derivative of thiosalicylic acid, is a preservative used in several types of consumer products, including cosmetics, ophthalmic and otolaryngologic medications, and vaccines. As a result of allergic reactions and environmental concerns, its use has declined significantly during the past 2 decades. During a 5-year study at the University of Kansas Medical Center, 574 patients were patch tested to the North American Contact Dermatitis Group's standard allergen tray, which included thimerosal. The demographic data from thimerosal-allergic and non-allergic persons were compared. Statistically significant increases in thimerosal allergy were found among women, health care workers, secretaries, and cooks. Thimerosal-allergic persons were more likely to be allergic to neomycin, bacitracin, and tixocortol pivalate. Despite a high percentage of thimerosal-allergic patients in our test population, very few of these allergic reactions were found to be clinically relevant to the patient's current dermatologic condition. Using the Significance-Prevalence Index Number for thimerosal and contrasting this number with the Significance-Prevalence Index Number for other allergens on the North American Contact Dermatitis Group's standard tray, we propose that either ethyleneurea/melamine formaldehyde or bacitracin would be more useful than thimerosal as a commercially available screening allergen.   12/10/04 re: Epinephrine-induced arrhythmia A patient received an influenza vaccine at a public clinic. She returned a short time later complaining of numbness in her thumb and a red rash that rapidly developed over the arm, chest and neck She was not exhibiting respiratory distress, however, it was noted that she had a change in quality of her voice and she was very pale and anxious. Per clinic protocol, epi 0.5 mg was administering SQ and she was transported to a local ER. Her BP at the time the epi was administered was 184/57. At the ER it was noted that she was in a trial fibrillation with a rapid ventricular response and had ST depression in an infererolateral distribution. She was treated with >IV Cardizem and converted to normal sinus rhythm. An MI was ruled out. Even though the patient was not in full blown shock, the rapid progression of her rash, the changed in vocal quality, and physical presentation, an impending anaphylactic reaction was suspected and therefore epi was administered. Could the epi have caused the artial fib or could that have been a result of an anaphylactic reaction? Should epi have been delayed until more signs of anaphylaxis were observed? Although tachycardia, often with association pallor and palpitations occur commonly following epinephrine (Epi) administration, true arrhythmias occur only rarely in individuals without underlying significant cardiac disease, including as history of arrhythmias. As pointed out in an enclosed (below) excerpt from a very good review of epinephrine use in anaphylaxis (Ana) by Dr. Estelle Simons, an authority in this subject, arrhythmias may also been seen after receipt of very high dosage/IV epinephrine. However, a recent report describing effects of IV epinephrine used in the E.R. concluded that no serious cardiac adverse effects were seen. However, as noted in my previous review of that report for this AADMC website (enclosed below), the patients treated with IV Epi described in that report were all relatively young. Another recent review of Epi (called adrenaline in the UK ) treatment in anaphylaxis concluded that Epi may need still warranted in individuals with cardiac disease who have manifested hypotension (see enclosed excerpt). Another review from Yale concluded that no increased risk of serious adverse cardiac effects, even in older individuals provided no significant underlying cardiac disease. (see abstract of that review enclosed below). How does all this information related to the clinical situation described by you? To respond to your questions: 1) You did not mention the patient's age or past cardiac history. It is possible for Ana to involve the heart. However, if cardiac involvement by the Ana caused the arrhythmia in this case, I would think that hypotension would have been present. 2) If epinephrine induced the arrhythmia, there is a fair likelihood that there is some underlying cardiac problem (intermittent A. Fib is not unusual in older individuals). Consider checking thyroid function, cardiac response to exercise, maybe even a full electro- physiologic assessment if any question. 3) Should the use of Epi been delayed until more definitive signs of Ana? Much depends on the suspicion that laryngeal edema was starting. Some authorities feel that Epi may not be needed if there is just skin manifestations. However, any evidence of upper or lower airways obstruction or hypotension warrants more aggressive treatment, including Epi. As reviewed by Simons in her article noted above, in a review of cases of fatal Ana reactions despite treatment with Epi the Epi treatment was delayed at least 30 minutes after onset of the reaction manifestations. So, if they suspected laryngeal involvement, the Epi treatment is likely warranted right away plus getting an anesthesiologist or otolaryngologist to look at the larynx right away if the laryngeal symptoms increase despite the Epi treatment (in case airway maintenance is needed). 4) As an aside, if there is a question whether an Ana reaction had occurred, a blood specimen should be obtained for clotting, removal of the serum for storage in the usual freezer and subsequent shipment to a lab that does a reliable serum tryptase assay. Tryptase is a mast cell enzyme released during acute allergic systemic reactions. Serum tryptase levels are more sensitive than plasma histamine levels in diagnosing an Ana reaction because the released histamine is rapidly catabolized whereas the tryptase levels stay elevated for up to several hours after the onset of the reaction. The best tryptase assays, in my opinion, are done in the lab of Dr. Lawrence Schwartz in Med Coll Virginia in Richmond where they assess both total and beta-tryptase levels (beta-tryptase level increase are a more sensitive probe). 5) Another aside - If the reaction you described was induced by the influenza vaccine, it is possible that the reaction was induced by egg components in the vaccine. This happens occasionally in egg-sensitive recipients. Suggest checking for a history of current egg allergy. From review of eoinephrine treatment of anaphylaxis by Simons - JACI 2004;113: 837-44) Rarely, and especially after overdose, it (epinephrine) may lead to ventricular arrhythmias, angina, myocardial infarction, pulmonary edema, sudden sharp increase in blood pressure, and intracranial hemorrhage. The risk of epinephrine adverse effects may be increased in individuals with some pre-existing cardiovascular, central nervous system, or thyroid diseases; in persons using monoamine oxidase inhibitors, which block epinephrine metabolism; or in those using tricyclic antidepressants or cocaine, in whom epinephrine duration of action is prolonged Current Lit Item TITLE - Is IV epinephrine treatment safe in severe asthma? SUMMARY Parenteral epinephrine (Epi) injections are often used in the treatment of acute severe asthma unresponsive to inhaled beta agonists. In very severe (life- threatening) cases. Some physicians would prefer to inject the Epi by the IV route. However, concerns have been raised about the potential for serious adverse effects of IV Epi. To determine if this was a major concern, Smith et al of the UCLA Medical Center in Los Angeles, CA retrospectively reviewed the cases of 27 asthmatics (ages 19-58 years) with acute severe asthma treated with IV Epi when unresponsive to inhaled beta agonists. In 24 of these individuals receiving loading doses of 50-1000 mcg of 1:10,000 solution followed in 14 patients with a continuous infusion of 1000mcg/hour. The other 3 patients received a continuous infusion without a prior loading dose. No deaths or serious adverse events were recorded during the IV Epi treatment. One patient with pre-treatment chest pain experienced increased pain during the IV Epi infusion. However, there were no acute changes noted in the EKG or increases in serum levels of cardiac enzymes in any of the patients. REFERENCE - Ann Emergency Med 2003;41:706-11 EDITOR'S COMMENTS The IV Epi treatments described above were all given under close observation in the well-staffed Emergency Depts of two large hospitals and then observed closely in the ICU of these institutions. The patients appeared to tolerate the IV Epi well. However, several questions and concerns can be raised about this study and the authors' conclusions: 1) there were no patients above the age of 57 years and/or with underlying cardiac disease. Although it is true that many asthmatics would be younger individuals without cardiac problems, one has to be selective when seeing patients in a very acute situation; 2) one can raise the question why epinephrine was not tried by the IM route first (apparently not done in these patients). The authors' rationale for Epi use by the IV route is the rapid reliable effects seen. However, other studies have shown that Epi injected IM is absorbed very rapidly except in individuals with severe hypotension. Of note, recent studies by Simons et al have shown that Epi injected IM is absorbed more rapidly than Epi injected by the traditional subcutaneous route. Excerpt from review of adrenaline treatment in anaphylaxis BMJ 2003;327:1332-35 Is adrenaline safe? Adrenaline is the recommended first line treatment in anaphylaxis (fig 1).10 Confusion arises because systemic allergic reactions can be mild, moderate, or severe. For example, generalized angioedema and urticaria without airway involvement would not be described as anaphylaxis. A good working definition is that an anaphylactic reaction involves one or both of the two severe features: respiratory difficulty (which may be due to laryngeal oedema or asthma) and hypotension (which may present as fainting, collapse, or loss of consciousness). Inappropriate use of adrenaline may be dangerous. Most adverse events with adrenaline usage occur when it is given in overdose or intravenously. Those particularly at risk include elderly patients and patients with hypertension, arteriopathies, or known ischaemic heart disease.7 8 10 w2 w3 As there are no controlled trials there is no way to estimate the risk in relation to benefit. Based on the current evidence, the benefit of using appropriate doses of intramuscular adrenaline far exceeds the risk (grade C). It should be stressed that adrenaline is not contraindicated in individuals with underlying ischaemic heart disease, as the decrease in filling pressure due to anaphylaxis is likely to result in further coronary is chaemia (grade C).1 Careful monitoring and avoidance of adrenaline overdose is necessary in these patients. Prehosp Emerg Care. 2001 Apr-Jun;5(2):200-7. Subcutaneous epinephrine in the prehospital setting. Safdar B, Cone DC , Pham KT. Division of EMS, Section of Emergency Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. basmah98@hotmail.com OBJECTIVES: To outline current practice regarding the prehospital use of subcutaneous epinephrine, and systematically review the existing literature to determine the level of support for its use in the elderly. Many health care personnel are reluctant to administer subcutaneous epinephrine for potentially life-threatening conditions such as asthma and anaphylaxis in older patients. This sytematic review examined the following focused question: "For older patients not known to have coronary artery disease, does administration of subcutaneous epinephrine carry a significant enough risk of cardiovascular side effects to mandate age as a relative contraindication to self-administration or emergency medical services administration in the prehospital setting?" METHODS: The MEDLINE and Health Star databases were searched to identify studies evaluating the use of subcutaneous epinephrine in the treatment of asthma and anaphylaxis. Bibliographies from included studies, known reviews, and textbooks were examined to identify additional studies. The strength of evidence presented in each study was assessed in accordance with the classification system proposed by the American Heart Association's Emergency Cardiovascular Care Committee. RESULTS: The review of the literature revealed only three case reports (level VII evidence) that record adverse reactions of epinephrine when used for anaphylaxis and allergy, while several level III and V studies found no adverse effects when used for asthma. No controlled trials documenting adverse effects were found. CONCLUSIONS: The authors did not find significant evidence to contraindicate the use of subcutaneous epinephrine in older patients who are not known to have coronary artery disease, who present with either asthma or allergic reaction   11/24/04 re: Codeine challenge procedure I'm an FIT and was asked to see a patient with chronic cough secondary to radiation pneumonitis (breast Ca). Her pulmonologist believes the cough can be controlled with a codeine-based cough suppressant, however the patient claimed to be "allergic" to codeine. She gave a strong history of "throat closure" after previous ingestion. We would therefore like to administer an oral codeine challenge for which I've seen no protocol. Doyou have any recommendations? As you know, true allergic reactions to opiates such as codeine are quite unusual. The situation is complicated by the fact that opiates bind directly to mast cells in the skin, activating them in a non-immune manner to release pre-formed mediators such as histamine. This interferes with the diagnostic significance of skin testing. However, a previous study employing serially diluted opiate solutions found no difference in the skin test reactivity of individuals with vs without histories of previous adverse reactions to opiates (see abstract enclosed below at the bottom). If there is no reasonable alternative to opiates in the control the patient's cough, one might consider the approach described below: 1) Obtain written informed consent in advance to the planned approach (which should be carried out under direct medical supervision in a facility equipped for resuscitation, etc.) 2) Make 1:10. 1:50. and 1:100 dilutions of a codeine solution ordinarily used as positive controls in skin testing. We have used codeine solution 30 mg/ml as the stock solution. The dilutions should be made using the buffered salt solution employed to dilute allergenic extracts.. 3) Do intradermal skin test injections on a distal extremity, starting with the 1:100 dilution and sequentially injecting the higher concentrations. This is not to determine the size of the whealing response but as a way of first assessing the patient's symptomatic response to introduction of very small amounts of the codeine. 4) If the patient tolerates the intradermal series well, then give I.M injection of 1.0 ml in an extremity (so that one can place a tourniquet proximal to the injection site if there is a sign of a systemic reaction). Start with the 1:100 dilution, then observe for 30-60 minutes for any reaction before proceeding to the 1:50 dilution, etc Alert the patient in advance that there may be some local stinging in the injection site when the higher codeine concentrations are used. If the patient tolerates the injection of 1.0 ml containing 30 mg codeine, she should tolerate the amount of codeine usually used as a cough suppressant. I have recommended giving the codeine by I.M. injection rather than orally so that one can apply a tourniquet proximal to the injection site in case of a systemic reaction. There is a remote possibility that the previous reaction to codeine described by the patient may have been a contact urticaria in the oropharynx leading to a sense of throat closure. Such a type of reaction may not be detected by the protocol I described above. If one wishes to screen for this unlikely possibility, one can also do a patch test on the buccal mucosa (inside the cheek) using a micropore filter soaked in the codeine 30 mg/ml solution. Clin Exp Allergy. 2001 ;31:1014-20. Opiate-sensitivity: clinical characteristics and the role of skin prick testing. Nasser SM, Ewan PW. Department of Medicine, University of Cambridge Clinical School, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. BACKGROUND: The value of skin prick testing in opiate-sensitive individuals is uncertain as opiates cause non-specific weals by direct degranulation of mast cells. OBJECTIVE: To define whether skin prick test (SPT) responses to opiates in opiate-sensitive individuals are different to those seen in the normal population and to describe the clinical characteristics of this group of subjects. METHODS: The SPT responses of eight opiate-sensitive subjects to morphine 10 mg/mL, ethidine (meperidine) 50 mg/mL and papaveretum 15.4 mg/mL at four different concentrations (undiluted, 1/10, 1/50 and 1/100) were compared with the responses of 100 (32 atopic) non-opiate- sensitive control subjects. Four of the opiate-sensitive subjects had a clinical history of asthma, rhinitis or urticaria on occupational exposure to morphine. One subject developed urticaria with codeine, one developed urticaria and asthma with morphine and diamorphine and two subjects reacted to intravenous papaveretum with anaphylaxis or urticaria. Five out of the eight cases had opiate sensitivity confirmed by single-blind placebo-controlled oral challenge. RESULTS: Skin prick tests to all three opiates were not significantly different when the eight opiate-sensitive subjects were compared with either the entire normal control group or the subgroup of 47 definite opiate-tolerant controls that had previously received opiates for clinical indications. Furthermore, there were no significant differences in size of opiate SPT responses between atopic and non- atopic control subjects. In the control subjects, there was a positivecorrelation in SPT weal size between the three opiates. CONCLUSION: Skin prick testing is not useful in the diagnosis of opiate sensitivity and placebo-controlled challenge should be considered. 11/16/04 re: Reaction to dental adhesive I have a question regarding possible allergy to dental adhesive. A 12 year old girl was fitted with an expanding device in the orthodontist's office. Within minutes of placement, she developed itching of the mouth, swelling of the lips and redness of the skin around the mouth. There were no latex products used during the procedure. The girl is known to have documented food allergies (very high peanut IgE) but no food contamination is suspected. The orthodontist sent her for a consult. Is there any experience with testing to dental adhesive? Is there anything else I should be considering? To help respond to your questions, I obtained input from Dr. Martin Greenberg, Chief of the Oral Medicine Section in our medical center. Dr. Greenberg has had a very extensive experience in the diagnosis of conditions within the oral cavity. His comments are enclosed below. I agree with Dr. Greenberg that determination of the exact adhesive/bonding ingredients used in your patient is very important. In my review of relevant literature, I was impressed that particular acrylate compounds are particularly suspect in such local reactions to adhesives (see abstracts enclosed below). I share the impression with Dr. Greenberg that reactions to such adhesive compounds are usually of the delayed hypersensitivity types. However, a contact urticaria reaction is a possibility to give immediate-onset local itching, etc. Patch testing with the suspect adhesive with reading for both immediate and delayed onset reactions may yield helpful information. If a positive response is seen and assuming that this is not an irritant effect, one can proceed with subsequent patch testing with individual components of the adhesive. You will likely need cooperation of the adhesive manufacturer to carry out such component testing. A pragmatic response would be to avoid that adhesive, urging the orthodontist to use a chemically unrelated adhesive agent. Dr. Greenberg's comments The reaction you describe certainly appears to be highly suspicious of anallergic rxn to dental materials. I believe that most orthodontists use resinsor occasionally acylics to bond brackets and palatal expanders, which rarely cause allergic reactions. Most of the reactions I have seen to those materials have been contact "delayed-type" hypersensitivity reactions, but IgE type impossible would call the orthodontist to see which bonding material was used so it can be avoided in the future. Perhaps allergy testing to dental metals and cements should be considered before proceeding with ortho tx. Acta Derm Venereol. 2000 Nov-Dec;80(6):435-7. In vivo testing of the protection provided by non-latex gloves against a 2- hydroxyethyl methacrylate-containing acetone-based dentin-bonding product. Andersson T, Bruze M, Gruvberger B, Bjorkner B. Department of Biomedicine and Surgery, University Hospital, Linkoping, Sweden. Thomas.Andersson@lio.se In dentistry, allergic contact dermatitis to acrylates and allergic contact urticaria to latex are important occupational hazards. There is a need to identify non-latex gloves which are suitable for dental work but at the same time provide adequate protection against acrylate monomers. In a previous study, a new open-chamber system was used for testing the in vivo protection of 6 different gloves against an acrylate-containing ethanol-based dental adhesive. A nitrile glove gave the best protection among the gloves suitable for dental work. In the present study, the test model was used to investigate the in vivo protection of 7 non-latex gloves against a dental bonding product containing 2-hydroxyethyl methacrylate (2-HEMA) in an acetone/water vehicle. Eight 2-HEMA-allergic patients participated. Two neoprene gloves gave the best protection. The protection of the poorest glove was comparable to that of the positive control (no glove). The study produced in vivo data useful in the implementation of individual preventative measures against contact allergy to acrylates.   dental adhesive, Scotchbond 1, containing 2-hydroxyethyl methacrylate (2-HEMA) and triethylene glycol dimethacrylate (TREGDMA). 8 patients with known contact allergy to 2-HEMA Am J Contact Dermat. 2001 Jun;12(2):83-7. A multicenter study of patch test reactions with dental screening series. Kanerva L, Rantanen T, Aalto-Korte K, Estlander T, Hannuksela M, Harvima RJ, Hasan T, Horsmanheimo M, Jolanki R, Kalimo K, Lahti A, Lammintausta K, Lauerma A, Niinimaki A, Turjanmaa K, Vuorela AM. Section of Dermatology, Finnish Institute of Occupational Health, Helsinki, Finland. BACKGROUND: Dental products contain many allergens, and may cause problems both for patients undergoing dental treatment and for dental personnel because of occupational exposure. Individual patch test clinics may not study sufficient numbers of patients to collect reliable data on uncommon allergens. OBJECTIVE: To collect information on dental allergens based on a multicenter study. MATERIALS AND METHODS: The Finnish Contact Dermatitis Group tested more than 4,000 patients (for most allergens, 2,300 to 2,600 patients) with dental screening series. Conventional patch testing was performed. The total number and percentage of irritant (scored as irritant [IR] or doubtful [?]) and allergic (scored as +, ++, or +++) patch test reactions, respectively, were calculated, as well as the highest and lowest percentage of allergic patch test reactions recorded by the different patch test clinics. A reaction index (RI) was calculated, giving information on the irritancy of the patch test substances. RESULTS: The most frequent allergic patch test reactions were caused by nickel (14.6%), ammoniated mercury (13%), mercury (10.3%), gold (7.7%), benzoic acid (4.3%), palladium (4.2%) and cobalt (4.1%). 2-hydroxyethyl methacrylate (2.8%) provoked most of the reactions caused by (meth)acrylates. Menthol, peppermint oil, ammonium tetrachloroplatinate, and amalgam alloying metals provoked no (neither allergic nor irritant) patch test reactions. CONCLUSION: Patch testing with allergens in the dental screening series, including (meth)acrylates and mercury, needs to be performed to detect contact allergy to dental products 11/4/04 re: Immediate urticarial reaction/ DaPT injection As the allergist at our Health Center, I was asked by one of our pediatricians to see a 3 year old boy who developed an urticarial rash over his face and body within a minute after receiving the following vaccines: HEPATITIS B, IPV, and DTaP#3. He was treated with Benadryl orally and improved greatly. He had no respiratory symptoms, cough, or anaphylactic symptoms (except urticaria that occurred within a minute or two after the shots). This patient has since received an IPV vaccine without reaction, and another HEPATITIS B vaccine without symptoms. I suspect that the original urticarial eruption was due to the DTaP. Since he will be due for his fourth DTaP vaccine soon, I would appreciate your thoughts and experience on the following questions: 1) I understand that a transient urticarial reaction many hours after a dose of DTaP or DTP is not uncommon and does not usually contraindicate further doses of DTaP. HOWEVER, DOES THE VERY RAPID onset of urticaria (within one minute of the vaccine), suggest a more worrisome scenario if he were to get another dose of DTaP? 2) Should he be skin tested to the vaccine, prior to the next dose----perhaps a prick test initially, and then an intradermal test to 1:1000 AND THEN 1:100 OF THE DTaP vaccine --- or should he just be given the next dose directly, with epinephrine handy, waiting for at least an hour after the administration of the next dose? 3) Do you feel that the benefits outweigh the risks of further doses of DTaP needed to complete the series in this case? There have been reports of immediate urticarial, and very occasionally anaphylactic, reactions following DaPT injection. Most of these reports appear to come from outside the USA which raises questions whether one can extrapolate those findings to practice in the USA where the vaccine components may not be the same. For example, there appears to be gelatin as a stabilizer in the some of the DaPT vaccines used in Japan. However, from what I found in the current PDR, there is no gelatin in the FDA-approved DaPT vaccines made by either Aventis-Pasteur or Glaxo (It sounds from your description that the injected agent followed by urticaria in your patient was Pediarix, made by Glaxo). A study in Japan of patients with immediate urticarial reactions following DaPT injection could not find an underlying IgE mechanism (see enclosed abstract). A group in Serbia found that children with such histories tolerated a repeat standard dose of the vaccine if the response to skin testing with the suspect vaccine was negative (see enclosed abstract). If the skin test response was positive, they used a graded dose injection of the DaPT vaccine similar to that described by Eli Meltzer in a case report (see enclosed abstract). In a pragmatic approach, it would be reasonable to do prick testing with the undiluted vaccine (along with positive and negative controls). If the response to this prick test is negative, I am less sure about the value of intradermal tests with the vaccine. For most intradermal tests of this type, one generally makes a 1:100 or 1:1000 dilution of the test agent (vaccine in this case). However, not knowing whether there is any non-specific irritant or histamine-releasing activity of such diluted test material, it may be prudent to first do such intradermal tests in a few volunteers with no histories of adverse reactions to DPT immunization. If the vaccine skin testing elicits a positive reaction, then one may consider the graded dose approach described in the article by Carey and Meltzer. I suggest that you get the details from their article. I also suggest obtaining written informed consent from the parents before carrying out the approaches described above. If the vaccine is administered (either undiluted or in the graded dose approach) it would be advisable to do this in facilities equipped for treating anaphylactic reactions even though the likelihood of such reactions should be very small. Therefore, it appears that the benefit/adverse reaction consideration is in favor of the benefit. Vaccine. 1998 Jul; 16(11-12):1138-40. Cases of systemic immediate-type urticaria associated with a cellular diphtheria- tetanus-pertuss is vaccination. Sakaguchi M, Nakayama T, Inouye S. Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan. The authors found eight children who had systemic urticaria within 30 min after administration of acellular diphtheria-tetanus-pertussis (DTP) vaccines which contain gelatin as a stabilizer. The authors measured the specific IgE to gelatin and DTP toxoids in their sera, and found that none of the children had anti-gelatin IgE. Of the eight children, two had detectable levels of anti-toxoid IgE. As a negative control, of the 10 children who showed no allergic reaction to the a cellular DTP vaccines, four also had detectable levels of anti-toxoid IgE. From these results, there was no obvious relationship between the specific IgE to the vaccine's component proteins and systemic urticaria to a cellular DTP vaccines. Srp Arh Celok Lek. 2003 Nov-Dec; 131(11-12):427-31. [Desensitization to diphtheria, tetanus and pertuss is vaccine] [Article in Serbian] Atanaskovic-Markovic M, Nestorovic B. University Children's Hospital, Belgrade.marinaa@eunet.yu Immunization with DTP vaccine (diphtheria, tetanus and pertuss is) is a part of the vaccination calendar offered in childhood. Adverse allergic reactions vary from minimal urticarial reactions to life-threatening anaphylaxis. In infancy these reactions usually interrupt the vaccination calendar, but immunization in these children should be done. At the University Children's Hospital of Belgrade, a group of 137 children with suspected allergic anaphylactic reaction to DTP, DT, TT and monopertussis vaccine was studied for the last six years. Skin (prick and intradermal) tests were performed with corresponding vaccine. If both tests were negative, the vaccine could be given as a single dose of 0.5 ml. If one of these tests were positive desensitization with vaccine could be done (according to the protocol described by Carey and Meltzer). In one group of 52 children three days before desensitization, premeditation with antihistamines was done, whereas in the other group of 52 children premeditation was not done. Two (3.8%) children in a group of 52 children with premeditation had a minor (local) reaction after vaccination and 50 children (96.2%) had no reaction after vaccination, whereas no children (0%) had systemic reaction after desensitization. Ann Allergy. 1992 Oct; 69(4):336-8. Diagnosis and "desensitization" in tetanus vaccine hypersensitivity. Carey AB, Meltzer EO. Scripps Clinic and Research Foundation, Dept of Allergy, La Jolla, California. A 5-year-old boy was evaluated for a history of an anaphylactic reaction to a DPT immunization at 18 months of age. Cutaneous tests and RAST disclosed high titers of IgE antibody to tetanus toxoid vaccine. Variable sensitivity to different vaccine commercial preparations was demonstrated. Immunization was achieved using a 9-step graded dosing schedule with the tetanus toxoid vaccine to which the patient was least sensitive. 11/4/04 re: Approach to multiple drug sensitivities I am a 24 year old nurse who suffered numerous ear infections as a child. I was given the gamete as far as antibiotics are concerned until finally my tonsils and adenoids were surgically removed. I have since been left with a grocery list of antibiotics that I "cannot" take due to allergic reactions. The aforementioned antibiotics include: sulfa, ceclor, erythromycin, clavulin, cipro, zithromax, as well as Sudafed and Dimetapp. The reactions ranged from severe lethargy and systemic swelling of joints requiring emergency treatment with steroids (ceclor) to generalized rashes. I understand that the ceclor reaction was a common one and so the drug is seldom used anymore; however, the problem that I have run into is that physicians simply do not see an option to treat any infections that I acquire. This has resulted in bladder infections becoming kidney infections and trips to the emergency room without any treatment outcome. I have recently seen an allergist who told me that these allergies cannot be tested to determine whether they are true allergies, and offered no advice other than an elimination diet of foods (with which I have no problems/sensitivities), and a prescription for Sudafed for congestion (which I do not suffer from) one of my stated allergies (rash I believe). My fear of course is that one day I will need treatment and will be unable to receive it. Do you have any suggestions as to what to do next? Thank you. It is quite unusual for individuals to have true allergies to many antibiotics of different chemical types but such "multiple drug sensitivities" in a single patient have been reported occasionally. Your description did not give enough information to estimate whether your reactions were true IgE-mediated allergies or another type of drug sensitivities. IgE-mediated reactions practically always start within several hours after intake of the offending drug dose and are usually manifested in the skin as urticaria (hives). The mechanisms underlying later onset rashes, which often are morbilloform (looks like measles rash) are not well- defined despite a lot of research in this area. From the practical standpoint, the only group of antibiotics for which reliable diagnostic skin testing is available are the beta-lactams, which include the penicillin drugs and the cephalosporins. Ceclor is an exception and should be avoided as you noted. A negative response to skin testing with a panel of penicillin agents means that the tested person is at no increased risk (compared to the general population) for an IgE-mediated (early onset) reaction to beta-lactam antibiotics. Negative penicillin skin tests do not rule out the possibility of a later onset rash. Unfortunately, there are no reliable skin or blood tests for sensitivities to sulfa drugs, macrolides (erythromycin, Zithromax) or floxacin (e.g.- Cipro) antibiotics. If you wish to be tested for the penicillin group of antibiotics, this requires a facility that has a full panel of penicillin antigens. Unfortunately, there has been a shortage of the relevant testing materials. You can check with the allergist whom you have already consulted whether he/she has such a penicillin testing panel. If not, perhaps that allergist can recommend the nearest facility so equipped. 11/4/04 re: Systemic reaction to lidocaine I have a 43 year old female patient who had several episodes of what appears to be an anaphylactic episode (decreased HR, BP, Bell's Phen.) after receiving local lidocaine with Epi for skin lesion removal and IV start. She states she has had lidocaine in the past for dental work with no problems. Could this be a reaction to the Epi or perhaps the preservatives? She had allergy testing done with lidocaine and that was negative. As you may know, true allergic reactions to lidocaine are very unusual, perhaps even rare. I am hesitant to make a definitive statement about the adverse reaction you described since I have not observed the reactions and/or reviewed the medical record in detail. However, the description sounds atypical for a true anaphylactic reaction. In anaphylaxis, if the heart rate is altered, it is almost always a tachycardia in response to the volume depletion as fluid exudes rapidly from the vascular space. There is an outside possibility that direct involvement of the heart in anaphylaxis could result in an arrhythmia, but this is usually not manifest by bradycardia. Also the absence of skin manifestations and/or respiratory symptoms is unusual (cutaneous manifestations present in over 80% of anaphylactic reactions). I am not familiar with Bell's phenomenon (I assume you mean the eye changes) as a sign of anaphylaxis. Therefore, I wonder whether this patient had a vaso-vagal reaction, in which a slow, bounding pulse, along with hypotension, is typical. I think that an adverse reaction to the epinephrine added to the lidocaine is an unlikely cause of her reaction since adverse reactions to Epi are usually manifest by tachycardia. If the skin testing with appropriate concentrations of lidocaine were negative, a pragmatic approach can be to do a cautious challenge with sub cutaneous injections of graded increasing doses of the lidocaine prep desired for future use. Such challenges should be carried out under close medical supervision with emergency facilities on hand. I have enclosed an abstract of an article that describes one procedure for this challenge approach. Dermatology. 2004; 208(2):109-11. Evaluation of re-challenge in patients with suspected lidocaine allergy. Amsler E, Flahault A, Mathelier-Fusade P, Aractingi S. Service d'Allergologie, Hospital Tenon, Paris, France. Background: Lidocaine is an anesthetic agent used worldwide in various clinical specialties. Although lidocaine hypersensitivity is very rare, clinicians frequently encounter patients with such an alleged diagnosis. Using a questionnaire, we evaluated the results of re-challenge with lidocaine, the gold standard for assessing hypersensitivity reactions in patients who claim to be allergic to this drug. Methods: A detailed questionnaire was sent to members of the French Dermatological Society, targeting the management of patients claiming lidocaine intolerance. After analysis and recall of doubtful episodes, 199 re-challenges were made. True lidocaine hypersensitivity was finally demonstrated in only 1 patient. Conclusions: The results of this study demonstrate that patients claiming to be allergic to lidocaine are usually not, their symptoms corresponding in most cases to a vasovagal episode. Re-challenge is safe and may constitute an easy and cheap alternative to skin testing. This should be performed in specialized centers except in case of a vasovagal episode. 11/1/04 re: Reaction to iodine in amiodarone We're working on resuscitation guidelines involving the risk/benefit of Amiodarone administration to patients who have an Iodine allergy. The prescribing information (as well as the PDR) state that Amiodarone should not be given to patients who are "allergic to any ingredient" in its composition (Amiodarone is 37% Iodine by mass). If I'm understanding this correctly, the question becomes if a patient suffers from an 'Iodine allergy' is it a true allergy to iodine, or simply an allergy to preservatives in some forms of iodine. We've found all sorts of optinions on this one but no solid data to support them. Are you aware of any data related to anaphylaxis following Amiodarone administration and/or true iodine allergies vs. preservatives? As you pointed out iodide is a sizable component of amiodarone. Cutaneous reactions (along with lab evidence of thyroid dysfunction) are among the most common side effects of amiodarone therapy. These are usually seen during chronic therapy involving sizable cumulative doses of amiodarone. Iodide "sensitivity" is a relatively rare disorder usually manifest as ioderma, a condition with a particular type of rash (see abstract enclosed below). The case reports describing ioderma have generally involved introduction of sizable doses of iodide products, either orally, as in potassium iodide-containing preparations, or (rarely) iodide-containing radiocontrast agents. These ioderma reactions are not typical allergies but may be cell-mediated immune reactions. I am not aware of anaphylactic reactions to iodides. It is conceivable that the cutaneous reactions to amiodarone might be directed against the iodide component in this agent. However, from what I can tell in the limited descriptions of the amiodarone-associated rash, it does not sound like typical ioderma lesions. Therefore, I would think that iodide is a potential cause of the rash seen in some amiodarone-induced reactions but there is no solid proof of this cause. Pediatric Dermatol. 1996 Jan-Feb; 13(1):51-3. Iododerma: an unusual side effect of iodide ingestion. Alpay K, Kurkcuoglu N. Department of Dermatology, KTU Faculty of Medicine, Trabzon, Turkey. A 13-month-old girl developed multiple pruritic, 1- to 7-cm, vegetating and ulcerative masses on the neck, extremities, and trunk after a one-week course of an antibiotic and an expectorant that contained potassium iodide, prescribed for treatment of a respiratory tract infection. Clinical and histopathologic findings were consistent with the diagnosis of iododerma. A thorough search for an underlying disease was negative. On cessation of potassium iodide and administration of oral prednisolone 1 mg/kg/day, a dramatic response was achieved. 10/28/04 re: Drug-induced TEN (follow-up) In reviewing your previous response, is it correct to say that TEN can develop within 24 hours after 1 dose of a medication? The patient had taken amoxicillin at least 7 times in the past. As far as we know, she had never taken augmentin. I have also read that viruses play a role TEN. Notably, even the Epstein Barr virus has been implicated in TEN. Here is some additional information about this case. The below mentioned patient did not have hepatosplenomegaly on ultrasound evaluation. She did not have any atypcial lymphyocytes on the CBC. She was functionally back at school, and clinically did not have active “mono.” How long after a patient had “mono” can amoxicillin be given? One dose of Augmentin 875mg was given to a this 16 year old patient who had a 2 week history of cough with brown sputum, known history of sinus infections. Two days later, the patient developed the early rash of toxic epidermal necrolysis. The rash progressed, and conjunctival and oral mucous membrane involvement occurred. The patient had been diagnosed with EBV-mono 5 weeks earlier. Could 1 dose of augmentin cause TEN within 2 days? Can the rash that occurs when amoxicillin is given to a patient with “mono” progress to TEN? I've read that the rash with amoxicillin and mono occurs 5 to 9 days after initiation of the drug. Could the cough have been the patient's prodromal symptoms of TEN? To answer your question, I obtained input from Dr. Rebecca Gruchalla of the Univ. of Texas Southwestern Medical center in Dallas. Dr. Gruchalla is an expert in drug allergies and other drug-induced adverse reactions. She has written about TEN. She has reviewed your messages and my previous responses to them. Her comments are enclosed below. Dr. Gruchalla has also kindly obtained additional information from her colleague Dr. C. Cruz who apparently has a considerable experience with TEN reactions. His comments are also enclosed below. Dr Gruchalla's comments: Regarding your question about amoxicillin-induced TEN, I have contacted Dr. Cruz of about the onset of drug-induced TEN. From your note, it appears that the patient developed an eruption within 2 days of starting amoxicillin and that the rash then progressed. Typically, with TEN, there is prodromal period with flu-like symptoms (malaise, fever, rhinitis, and conjunctivitis) that lasts 2-3 days. However, the prodrome may last from 1 day to 3 weeks before signs of skin involvement develop. Thus, it is possible, I think, for the beginnings of TEN to occur after only a few doses of a drug (however, I am waiting to hear from Dr. Cruz). I agree with you, I don't think the amoxicillin-induced rash was related to the mono since the patient was no longer symptomatic (if indeed she even had the disease!). On another note, I have never heard of mono-associated amoxicillin rashes progressing to TEN. Dr. Cruz's comments: I assume the patient had not developed previous skin eruptions with previous exposures to amoxicillin. If he/she has developed skin reactions with previous amoxicillin treatment, then a one day incubation period is possible since repeated challenges increases the likelihood of more rapid and more severe reactions. If no previous skin reactions to amoxicillin, then a one day incubation period after the recent amoxicillin exposure is less likely, but still possible. 10/27/04 re: Iodide sensitivity I'm a registered dietitian and need to know about the relationship between iodine allergy and table salt. Should a hospital restrict salt when a person has an allergy to iodine? Does allergy to iodine mean an allergy to ordinary salt that contains iodine? Does it mean people may be sensitive to salt? Or is this not related. Iodide “sensitivity” is a very unusual disorder in my experience and from what I can tell from a literature search (see enclosed abstract). It generally presents as cutaneous manifestations (e.g.- ioderma) and usually follows ingestion of much more iodide product than would be present in the trace amounts added to salt in preparation of table salt products. There is no evidence of which I am aware that these adverse reactions are due to a typical (IgE-mediated) allergy to iodide compounds. I am not aware of reports of ioderma or iodide-induced salivary gland problems in which there was convincing evidence for table salt as the offender. Therefore, I would think that the likelihood of adverse reactions to iodide being induced by ingestion of reasonable amounts of iodide-containing table salt would be very small. Thus, it would seem that precautions with avoiding use of table salt you mentioned would not be necessary. Pediatr Dermatol. 1996 Jan-Feb;13(1):51-3. Iododerma: an unusual side effect of iodide ingestion. Alpay K, Kurkcuoglu N. Department of Dermatology, KTU Faculty of Medicine, Trabzon, Turkey. A 13-month-old girl developed multiple pruritic, 1- to 7-cm, vegetating and ulcerative masses on the neck, extremities, and trunk after a one-week course of an antibiotic and an expectorant that contained potassium iodide, prescribed for treatment of a respiratory tract infection. Clinical and histopathologic findings were consistent with the diagnosis of iododerma. A thorough search for an underlying disease was negative. On cessation of potassium iodide and administration of oral prednisolone 1 mg/kg/day, a dramatic response was achieved. 9/8/04 re: Definition of hypoallergenic When a product is said to be “hypoallergenic,” does it mean that people will not be allergic to it? In one report I have seen, the test lab stated the “test material is not irritating to the skin of New Zealand rabbits.” Would this material be hypoallergenic? We sell filtering face pieces and note some companies label theirs as “hypoalleric” and wanted to know if we could correctly use the term. The term “hypoallergenic” is generally applied to a product which has an extremely low likelihood of sensitizing patients to become allergic to that agent during chronic/repeated use. The evidence supporting such claims about prescription products is generally based on findings during the clinical trials carried out to obtain FDA approval of the prescription product in hand. For example, if allergic reactions to repeated application of a non-irritating product to the skin occurs rarely, if at all, in studies of a sizable number of subjects, that may qualify the product for a hypoallergenic status. Of course, statements are made in advertisement about over the counter products that may or may not be supported by convincing evidence. The irritant test (often using rabbits) deals with another matter. Many products applied to the skin have the potential to irritate the skin if a sufficiently large concentration/dose is used. Unlike an allergic reaction which usually occurs in a small percentage of people using the product, generally after repeated applications over a period of weeks/months, irritant reactions can affect a sizable percentage of the people using the product if enough is applied to the skin. Also, such irritant reactions usually occur after the initial doses. The rabbit skin test to which you referred is used to determine what concentration/dose of the product is irritating to the skin. 8/19/04 re: Reaction during pupil dilation I have a 60 year old patient with a history of “passing out.” Twenty years ago shortly after he was given an eye drop to dilate his eyes, he reported being unconsciousness for over 10 - 15 minutes. He denied having any shortness of breath, angioedema, itching, or hives. He was not given any particular treatment and remembered returning back to normal over the next hour. He was told to avoid dilating eye drops. He had been given dilating eye drops his entire life without any reactions before that episode. He has avoided these eye drops since. His ophthalmologist now wants to use phenylephrine, tropicamide, or cyclopentolate to dilate his eyes and wants him to be evaluated for allergies. My patient is a hypertensive, diabetic, with coronary artery disease (2 CABGs) and is currently on a beta blocker. I have reviewed the literature and have found that each of these medications have been associated with allergic contact dermatitis or conjunctivitis. There is one case report of generalized urticaria with cyclopentolate. My understanding is that skin testing is not available for these medications since an allergic (IgE) basis has never been shown. It seems that his reaction 20 years ago was a vasovagal episode. I came across a letter to the FDA outlining three serious adverse events which have occurred in 1997 following the use of Paremyd (hydroxyamphetamine hydrobromide/tropicamide ophthalmic solution) 1%/0.25% for routine diagnostic purposes. The three events included a patient who sustained a fatal myocardial infarction, a second patient who developed ventricular fibrillation who was successfully resuscitated, and a third patient who developed hypotension, bradycardia, and syncope requiring intervention. So, it seems that a combo vasoconstrictor and anticholinergic medication may be harmful, especially in an individual with coronary artery disease. I think the best medication to use would be an anticholinergic such as cyclpentolate. Testing is not standardized and likely will not be helpful since an allergic basis has not been established. Am I on the right track? Would you do anything differently? Thank you for your insight. I am not aware of any IgE mediated reaction causing the symptoms you described for which skin testing (or other approaches) with suspect drugs can be diagnostically helpful. I obtained input about your questions from Dr. Leonard Bielory, Director, Division of Allergy, Immunology and Rheumatology and Professor of Medicine, Pediatrics and Ophthalmology UMDNJ - New Jersey Medical School. Dr. Bielory is an expert in allergies involving the eyes. His response to you is enclosed below. Dr. Bielory's Response: I agree that you are on the right track. There are reports of vasovagal events while dilating. I would recommend that the ophthalmologist sit/recline patient in chair and provide a blood pressure while administering the choice agent that is decided upon. No allergy testing will assist in this matter as it is a physiological response. Leonard Bielory, M.D. Director, UMDNJ - Asthma & Allergy Research Center Director, Division of Allergy, Immunology and Rheumatology Professor of Medicine, Pediatrics and Ophthalmology UMDNJ - New Jersey Medical School 4/21/04 re: Excess salivation after radiocontrast injection I am a Radiology Technologist with a question about a recent patient that experienced an iodine contrast reaction unlike any our clinic, or Radiologist, have ever seen. The patient was a 40 year old female with no signs of apprehension before her CT scan. Upon injecting our iodine contrast, she began to produce massive amounts of saliva. The patient produced such a large amount, that it became necessary for us to allow her to spit into a garbage can. After further examination, she was found to have one hive on the arm of her IV. The patient had never been given IV contrast, nor did she have prior diagnostic imaging done before. Patient was not diabetic, no sign of kidney disease, nor any other known allergies. Is this a normal reaction to iodine contrast? The reaction you described does sound very unusual. Indeed, when I reviewed adverse reactions occurring during a very large number of radio contrast media (RCM) studies carried out in my institution, I do not recall seeing reports of similar salivation reactions. However, the iodide in the injected RCM agent can concentrate in the salivary glands and there have been very occasional reports of salivary gland enlargement occurring in a delayed onset after intravenous RCM injection. This has been called "iodide mumps" by some authors (see enclosed title of such a report). To my knowledge, such reactions have usually led to decreased salivary function, not hyper-salivation. I suggest that you contact the manufacturer of the RCM used in your patient to see if they have reports of hyper-salivation during RCM studies in their adverse reporting files. The single hive you described does not sound like convincing evidence of a true anaphylactoid reaction. Pragmatically, if your patient requires a repeat RCM study, I would consider pre-treatment with atropine or another systemic anti-cholinergic drug to decrease salivary flow temporarily. Reference: Iodide mumps: acute sialadenitis after contrast administration for angioplasty. Circulation. 2001 Nov 6;104(19):2384 2/2/04 re: Reaction to radiocontrast media A patient states that they have had a past iodine reaction. Probably with the ionic dye. Is it ok to inject the patient with non-ionic iodine or are they at risk for an allergy again? I think that the reaction you are referring to is an adverse reaction to an intravascular injection of a radiocontrast media (RCM). Such reactions have nothing to do with the iodine content of the RCM. There is also no convincing evidence that they are truly allergic reactions. Since you did not describe the clinical manifestations in the reported previous reaction, my responses about RCM reactions will have to be general: 1) The incidence of most types of RCM adverse reactions are definitely less frequent when using the non-ionic RCM agents than with use of the older ionic RCM agents. However, very occasionally individuals with past histories of RCM reactions will react to injection of non-ionic RCM agents. 2) If the previous RCM reaction was just flushing, paresthesias but no objective signs of hypotension, respiratory difficulties, etc, one can usually avoid reactions by injecting the RCM at a slower infusion rate. 3) If theprevious reaction was an anaphylactoid type (angioedema, wheezing, mild hypotension), the incidence of a similar repeat reaction to a RCM injection can be reduced considerably (though not completely eliminated) by a pre-treatment program using: a) Oral prednisone 50 mg each at 12 hours, 6 hours, and 30 minutes prior to the RCM injection. Then steroids can be stopped at this point without further tapering of the dosage. b) IM injection of diphenhydramine (Benadryl) 50 mg at 30 minutes prior to the RCM injection. 12/23/03 re: Nature of a drug reaction I recently saw a 14 year old febrile boy with multiple petichiae on his body and legs. (His mono spot test was positive for infectious mononucleosis). Because of his fever and increasing petichiae, a blood culture was obtained and he was started on CEFTRIAXONE 2 gm ql2h intravenously to treat the possibility of bacteremia. About 15 minutes after his first dose of Ceftriaxone, he developed a "head to toe" erythematous rash which was NOT urticarial and was NOT itchy. He was treated with IV Benadryl and the rash subsided quite rapidly. He was pretreated with Benadryl 30 minutes prior to his 2nd dose of Ceftriaxone and the rash did NOT recur after the 2nd dose. Because of the possibility of an allergic reaction to Ceftriaxone as the cause of the rash following the 1st dose, I suggested not giving any further Ceftriaxone. (Besides, his blood culture was negative by then). Do you feel the rash 15 minutes after the 1st dose of IV ceftriaxone in this boy with INFECTIOUS MONONUCLEOSIS was due to: 1) Allergic reactiont to Ceftriaxone 2) Non-allergic reaction of patients with Infectious Mononucleosis to beta-lactam antibiotics (well described with Ampicillin, but not to my knowledge described with cephalosporins). Should this boy avoid beta-lactam antibiotics (penicillin and cephalosporins) in the future? I look forward to hearing you thoughts on this issue.   The reaction you described sounded atypical for the sort of response seen in infectious mono patients treated with amoxicillin. Therefore, I consulted Dr. Franklin Adkinson of Johns Hopkins Medical Center, an expert in allergic reactions to beta lactam-containing antibiotics and related matters. His response is enclosed below. Dr. Adkinson's comments: The non-pruritic macular rash described in the case below is not compatible in time course (immediate) or description with the late-onset typically maculopapular eruption, usually non-pruritic, which is reported to occur with nearly 100% frequency when patients with mononucleosis are treated with an aminopenicillins (amoxicillin or ampicillin). Since ceftriaxone is not an amino-cephalosporin and cannot therefore polymerize like amoxicillin, on theoretical grounds I would not suspect it to behave like the aminopenicillins. Furthermore the "rash rate" for ceftriaxone according to the PDR is 1.7%, far below the rate for aminopenicillins even in non-mono subjects (5-12%). I suspect that the boy's rash in this case was non-immunologic since it was non-urticarial and non-pruritic and because it responded very promptly to benadryl and watchful waiting. Therefore future use of beta-lactams should not be denied, but to confirm this clinical impression I would do penicillin skin testing to confirm. What caused this rash? One speculative possibility is a reaction to a bacterial product released by the antibiotic, a type of the old Hertzheimer reactions that use to be seen when syphilis was treated with penicillins. Another is some vasoactive response to rapid infusion of the antibiotic in a patient perhaps made vulnerable by mono (a novel form of drug idiosyncracy)-another speculation. Since it did not recur with the second dose under benadryl prophylaxis, whatever the mechanism, it's not likely to represent a serious medical toxicity, and certainly not likely to represent IgE dependent allergy. I hope these speculations are useful for your purposes. I can guess as well as anyone!   10/15/03 re: Delayed reaction to radiocontrast media (follow-up)   Addendum: Since I responded recently to your Ask the Expert question, I came across an abstract of a recent article dealing with delayed onset adverse reactions occurring after radiocontrast media (RCM) intravascular infusions. I am enclosing it here for your interest. Note that this committee did not state the exact frequency of such late onset reactions (I believe that the the 2%. figure they listed is the estimated incidence of all skin reactions occurring at any time after the RCM injection). They did comment that a significant proportion of the reported delayed reactions appeared to be unrelated to the RCM infusion itself. ___________________________________________________________ Eur Radiol. 2003 Jan;13(1):181-4. Epub 2002 Sep 10. Late adverse reactions to intravascular iodinated contrast media. Webb JA, Stacul F, Thomsen HS, Morcos SK; Members Of The Contrast Media Safety Committee Of The European Society Of Urogenital Radiology. Department of Diagnostic Imaging, St. Bartholomew's Hospital, London EC1A 7BE, UK. Late adverse reactions to intravascular iodinated contrast media are defined as reactions occurring 1 h to 1 week after contrast medium injection. They have received increasing interest over the past decade, but their prevalence remains uncertain and their pathophysiology is not fully understood. The Contrast Media Safety Committee of the European Society of Urogenital Radiology decided to review the literature and to issue guidelines. An extensive literature search was carried out and summarized in a report. Based on the available information, simple guidelines have been drawn up. The report and guidelines were discussed at the 8th European Symposium on Urogenital Radiology in Genoa. Late adverse reactions after intravascular iodinated contrast medium include symptoms such as nausea, vomiting, headache, itching, skin rash, musculoskeletal pain, and fever. A significant proportion of these reactions is unrelated to the contrast medium; however, allergy-like skin reactions are well-documented side effects of contrast media with an incidence of approximately 2%. Late reactions appear to be commoner after non-ionic dimers. The majority of late skin reactions after contrast medium exposure are probably T-cell-mediated allergic reactions. Patients at increased risk of late skin reactions are those with a history of previous contrast medium reaction and those on interleukin-2 treatment. Mostskin reactions are self-limiting and resolve within a week. Management is symptomatic and similar to the management of other drug-induced skin reactions. 10/15/03 re: Delayed reactions to radiocontrast media I am a clinical pharmacist and write frequently on the subject of drugs used with imaging procedures. Presently, I am writing an article that addresses the issues of "iodine allergy" and its relationship to "allergic" reactions to iodinated radiocontrast. I understand that anaphylactoid reactions to iodinated radiocontrast appear unrelated to the iodide moiety of the radiocontrast molecule and, therefore, rationally do not suggest a cross-reactivity with iodine and inorganic iodides. Now I will lead into my question. I am thinking of not just anaphylactoid reactions to iodinated radiocontrast but to delayed reactions manifesting themselves from an hour to a couple of days after radiocontrast administration. Of course, these delayed reactions are reported in the literature. I am thinking that it is one thing to say the iodide moiety of the radiocontrast molecule is unrelated to anaphylactoid reactions and quite another to say it is unrelated to the delayed reactions. Below you will find an abstract of a case report that includes documentation in a single patient of delayed reaction to iodinated radiocontrast and delayed positive results of skin testing to the contrast agent and iodine. Although just one patient, it does seem to bear out my notion that sensitivity to iodine/inorganic iodides could indeed to related to at least the delayed reaction to iodinated radiocontrast. I am very interested to get your opinion in regard to this matter. The abovementioned case report is below. ______________________________________ All Abstracts for Sydney 2000 Page 1 of 1 Abstract No.: P-574 Session Title: Adverse reactions to drugs Presentation: Poster Date of Presentation: 1 8-Oct-2000 Time of Presentation: 10:00:00 Keywords: iopentol;adverse reaction Corresponding author: C Garcia Presenting author indicated by italics Delayed reaction to the non-ionic contrast medium iopentol due to iodine allergy JC Garcia Ortiz , JA Navarro A Jorat F Villas JF Garmcndia I C'omplejo Hospitalarlo N"S' Arßnzazu, San Sebastian, Guipnzcoa, ES 2 Hospital de Zumthrraga, Zumc Gulp ßzcoa, ES Case Report: In a 54 year old man with right vestibular neuritis a contrast- enhanced computed tomographic scan was performed using iopentol, a low osmolar non-ionic radiographic contrast media. Approximately ten hours after, he developed a generalized pruriginous maculo-papular rash and marked swelling of genitals which resolved within 3 weeks without complications. Material and methods: Patch tests were performed with the European standard series (Marti Tor Lab.), iodine (0.5% pet.), a series of iodine derivatives (potasium iodine 10% pet., iodine alcohol, povidone iodine) and iopentol (as is), according to international guidelines (International Contact Dermatitis Research Group). Results: Late positive patch test results were observed after 48 and 96 hours to iodine, iopentol and some of the iodine derivatives. These patch tests were negative in ten controls. Conclusion: We describe a patient with late dermatological reaction to iopentol in which delayed hypersensitivity to iodine may explain the reaction. In this case, we consider that the iodine is the allergen. To our knowledge, there is no report of dermatitis due to iopento or others non-ionic contrast media because of iodine allergy. The situation you describe could conceivably occur but must be quite rare following radiocontrast media (RCM) studies (see enclosed abstract). I have personally questioned hundreds of individuals about reactions to previous RCM studies as part of a project we previously carried out. I do not recall anyone mentioning a delayed onset rash as described in the enclosed abstract and in the one you enclosed with your message. If patch testing were to be recommended, I would suggest using the RCM agents as described in the enclosed abstract rather than the inorganic iodides employed in the study described in the abstract you sent. The relatively small amount of iodine bound up in the organic RCM molecules likely behaves quite differently than the sizable amounts of inorganic iodide in salts such as KI or in a tincture of iodine when it comes to binding to skin proteins, etc. Another type of dermal complication very occasionally occurring after iodide treatment is iododerma. (see enclosed abstract). There have been scattered case reports of iododerma occurring post RCM studies (see enclosed abstract). There have also been scattered reports of salivary gland swelling as delayed onset adverse reactions following RCM studies. This also must be a very unusual complication. ______________________________________________________ Allergy. 1998 Dec;53(12):1221-4. Delayed-type hypersensitivity to a nonionic, radiopaque contrast medium. Courvoisier S, Bircher AJ. Department of Dermatology, University Hospital, Basel, Switzerland. BACKGROUND: True allergic reactions to iodinated radiocontrast media are rare, and only a few well-documented cases of delayed-type hypersensitivity reactions caused by contrast media have been described. METHODS: We report a 61-year-old patient in whom percutaneous transluminal coronary angioplasty (PTCA) was performed with iopamidol, a nonionic contrast medium. Seven days later, the patient developed generalized maculopapular exanthema. Repeated patch tests with several iodinated agents were performed. RESULTS: A first patch test with iopamidol was positive. Repetition of the patch tests showed positive results to iopamidol as well as to iohexol and ioversol, two other nonionic contrast media, but not to other iodinated substances. Three months later, PTCA was repeated, and iopamidol was used again. Despite premedication, pruritic macular exanthema developed 1 day later. Whether iopamidol or trometamol -- an additive substance in the contrast medium -- was causative could not be determined, since a third set of patch tests was negative. CONCLUSIONS: Delayed-type hypersensitivity reactions to iodinated contrast media are rare. We recommend that patients with delayed exanthematous reactions undergo patch or intradermal tests with different contrast media and their additives, and that readings be performed immediately and later at days 2 and 3. __________________________________________ Cutis. 1985 Oct;36(4):335-7. Iododerma occurring during thyroid protection treatment. Wilkin JK, Strobel D. A patient with rheumatoid arthritis developed nodules and ulcers shortly after treatment with supersaturated potassium iodide (SSKI) drops. The SSKI was administered for thyroid protection during an iodide fibrinogen uptake test to detect phlebothrombosis of the legs. Discontinuation of SSKI was accompanied by regression of all lesions. Previous case reports include other patients who experienced iododerma after receiving low doses of iodides. This should be borne in mind if ever a mass iodide prophylaxis program is undertaken following a nuclear event. __________________________________________________________ Clin Exp Dermatol. 1990 May;15(3):232-3. Iododerma and acute respiratory distress with leucocytoclastic vasculitis following the intravenous injection of contrast medium. Vaillant L, Pengloan J, Blanchier D, De Muret A, Lorette G. Department of Dermatology, Hospital and University of Tours, France. A 72-year-old woman with chronic renal failure requiring haemodialysis developed acute iododerma twice, after receiving iodide contrast dye for radiological procedures. Iododerma was localized to the face, scalp and elbows and was associated with papular purpura of the legs. Histopathology of the skin lesions showed acute necrotizing vasculitis. During the second skin eruption the patient developed acute respiratory distress, which was treated with corticosteroids. During the first eruption asymptomatic infiltrates were present on chest X-ray which disappeared 2 months later. At the present time iododerma seems more frequent in patients with renal failure. Iodides may also be responsible for pulmonary abnormalities, which are sometimes asymptomatic. All these features may be due to leucocytoclastic vasculitis following iodide ingestion. 10/1/03 re: Approaches to sulfite sensitivity I am a 43 year old physician with a 13 year history of sensitivity to sulfites consisting of severe headache, generalized flushing, and N/V/D beginning 60-90 after ingestion of a sulfite-containing food and lasting 2-4 hours. I am not asthmatic and am on no medications. An allergist I consulted confirmed the probability of sulfite sensitivity from history; I declined an oral challenge. Although most authoritative sources I have consulted list this as a sulfite sensitivity or intolerance, it looks and feels very much like an immune mediated reaction to me (stereotypic response to any level of sulfite in labeled food e.g. >10ppm). Any comments? Also, any recommendations for management especially with regards to general anesthesia? I am looking at a possible ovarian cystectomy and am horrified to find so many drugs, including general anesthetics, containing sulfites. Your reaction patterns sounded quite atypical for sulfite sensitivity since almost all the reported cases of sulfite sensitivity were manifested as asthma (possibly due to sulfur dioxide release during sulfite catabolism). Therefore, I consulted Dr. Ronald Simon of the Scripps Clinic, one of the leading investigators of sulfite sensitivity (see enclosed reference for a review of sulfite sensitivity by Simon). His prompt response is enclosed below. As you can see, he also questions whether sulfite sensitivity is the cause of your symptoms. Therefore, a sulfite challenge may be appropriate in your case. He does provide the name of a sulfite-free general anesthetic as you requested. I know of no evidence that sulfite-sensitive individuals cannot tolerate sulfate salts (see Dr. Simon's comment). The question does remain as to the source of the symptomatic episodes you describe if sulfites are not the cause. Flushing and headache with/after eating have been reported in some individuals as reactions to tyrramines (in certain foods). Large amounts of MSG (a common food additive) have been considered to cause similar symptoms (e.g.- the " Chinese restaurant syndrome") although this is still somewhat controversial. Reference: Allergy 1998;53 Suppl 78-9 __________________________________________ DR. SIMON'S RESPONSE: You are correct (as always); anything besides asthma from sulfite sensitivity is extremely rare & therefore I'm not at all sure sulfite sensitivity is the nature of this person's problems. There is no new data that the reactions are immunologic. Brand name (not the generic) Diprovan is sulfite free & hopefully will be an acceptable general anesthetic for the surgery. I'm sure there other GA's that are sulfite- free a swell. Many patients think that sulfates are also a problem since many medications are sulfate salts. 9/26/03 re: Isotretinoin treatment and nasal ulceration I recently saw an 18 year old girl who has been taking Isotretinoin 40 mgrs qd for the last two months. Suddenly her nose started to wheeze and her ENT doctor found a nasal septum perforation that neither the patient nor her doctor was aware of. I could not find any report of this adverse reaction in the literature. Have you any information? I have not observed such an adverse event during Isotretinoin (Iso-t) therapy or heard/read about nasal septum perforations during such treatment. However, I think that several mechanisms/effects might possibly contribute to the formation of an ulceration and then perforation: 1) Excessive drying of the nasal passages does occur in some people treated with Iso-t (see enclosed abstract). If such drying was very uncomfortable for the patient, she may have "picked" the nasal cavity excessively leading to an ulceration, then perforation. 2) Nasal colonization with Staph aureus occurs in some individuals treated with Iso-t (see enclosed abstract). A local abscess could form and damage the septum. However, I would expect the patient to exhibit pain well before a perforation occurs. 3) Psychiatric abnormalities have been reported in some Iso-t treated individuals (see enclosed abstract). Has the patient been observed doing excessive picking or inserting some item in the nose? Of course, the septal perforation could be unrelated to the Iso-t treatment, - consider Wegener's, other granulomatous diseases, syphilis. Consider leprosy if the patient comes from an endemic area and the surrounding septal tissue is anesthetic. You did not mention it so I assume that the patient has not been on chronic nasal steroid therapy. I would expect to see blood-stained mucus first if nasal steroid treatment was the cause of a septal perforation. Dermatology. 1997;195 Suppl 1:22-8; discussion 38-40. How safe is oral isotretinoin? Meigel WN. Department of Dermatology, Allgemeines Krankenhaus St. Georg, Hamburg, Germany. Since oral isotretinoin (Roaccutane/Accutane) is the only therapy to address all major acne causes, it remains the most effective antiacne therapy available. Due to this unique efficacy and its potential side effects that are predictable and can be managed easily and effectively, it is widely used also in acne patients suffering from serious systemic diseases. As the primary mechanism of action of oral isotretinoin is suppression of sebaceous gland activity, mucocutaneous side effects such as dry lips, nasal passages and eyes are predictable. Pretreatment counseling and concomitant use of moisturizing agents usually manage these side effects effectively; in unusual cases of particularly poor tolerability, dose adjustments suffice. Severe side effects are rare, the most common being aches and pains requiring no therapy, aspirin or paracetamol. As with other retinoids, reliable contraception is mandatory for women of childbearing potential. Acne patients with serious concomitant systemic disease, such as insulin-dependent diabetes, epilepsy or spina bifida, transplant patients, patients with renal failure, multiple sclerosis motor neuron disease and other can also safely be treated with a standard cumulative dose of 120 mg/kg per treatment course. Arch Dermatol. 1986 Jul;122(7):815-7. Isotretinoin and Staphylococcus aureus infection. A possible association. Graham ML 2nd, Corey R, Califf R, Phillips H. The use of isotretinoin (13-cis-retinoic acid) in the treatment of numerous dermatologic disorders, as well as the side effects encountered with use of the drug, have increased remarkably since its release. We encountered a case of Staphylococcus aureus endocarditis in a patient with chronic stable aortic insufficiency undergoing therapy with isotretinoin for extensive actinic keratoses. Although significant dysfunction of the immune system has not been demonstrated with isotretinoin, nasal colonization with S aureus has been shown to occur. Changes in skin fragility caused by the drug may provide a portal of entry for the organism. Physicians should be alert for this potential complication in patients with an underlying cardiac valvular lesion; antibiotic prophylaxis may be indicated in this group during isotretinoin therapy. Am J Ther. 2003 Mar-Apr;10(2):148-59. Overview of existing research and information linking isotretinoin (accutane), depression, psychosis, and suicide. O'Donnell J. Department of Pharmacology, Rush Medical College, Chicago, Illinois, USA. Isotretinoin (Accutane; Hoffmann-La Roche, Nutley, NJ) is a drug closely related to the chemical structure of vitamin A. The pharmacology and toxicology of these two retinoids are similar enough to warrant comparison. Accutane is a powerful drug that its manufacturer, Roche, indicates is limited for severe recalcitrant nodular acne. This potency is also reflected in Accutane's well-known ability to produce severe birth defects if taken during pregnancy. Less well known is the risk of this lipid-soluble chemical to affect the central nervous system. Reports of intracranial hypertension, depression, and suicidal ideation with Accutane use have prompted an examination of its serious and life-threatening potential. Although Roche has added a warning to its product label for signs of depression, and suicidal ideation, this product is overprescribed for all forms of acne, including mild and moderate cases that have not been treated with alternative medications with less risk of depression and suicide. There is no contesting that this drug is effective at clearing up the most severe forms of acne, but the public must be informed of the proper limited indication for its use, because depression and suicide can follow in patients with no prior history of psychiatric symptoms or suicide attempts. 6/2/03 re: Reaction to azathioprine I saw a 36 yo woman with autoimmune hepatitis. She was treated with azathioprine for 1 yr. without problem. It was discontinued in 8/02 when she had a ruptured appendix. In 9/02 the azathioprine was restarted and she had immediate nausea, vomiting x2 and lightheadedness, lasting 24 hours. Similar symptoms occurred 2 other times when she was again challenged with the drug. She denies SOB, rash, diarrhea, fever, chills or throat closing. These symptoms do not fit the case reports I can find - either on allergic reactions to azathioprine or on the azathioprine hypersensitivity reaction, which usually seems to involve fever and rash. Since it seems that if the azathioprine hypersensitivity reaction occurs, the pt. should not be rechallenged with the drug, how do I categorize this patient's reaction? Adverse G-I side effects of azathioprine therapy are not unusual, including a sometimes-atypical presentation of pancreatitis. Some investigators feel that some of these adverse effects may be related to the imidazole component in the azathioprine (which contributed to the "Im" in the original naming of Imuran) (1). I have not been able to say whether such adverse effects are more common in individuals with underlying autoimmune hepatitis (although it is usually considered that azathioprine is converted in the liver). Therefore, if mercaptopurine therapy is considered highly desirable one might consider a cautious trial of 6-mercaptopurine which contains the basic mercaptopurine moiety without the imidazole component. One may also consider use of 6 thioguanine although I believe that this approach is still considered investigational (see enclosed abstract) _______________________________________________ Aliment Pharmacol Ther 2003 Feb 15;17(4):503-8 6-thioguanine--efficacy and safety in chronic active Crohn's disease. Herrlinger KR, Kreisel W, Schwab M, Schoelmerich J, Fleig WE, Ruhl A, Reinshagen M, Deibert P, Fellermann K, Greinwald R, Stange EF. Robert-Bosch-Hospital, Stuttgart, Germany. BACKGROUND: Azathioprine and mercaptopurine are commonly used in chronic active Crohn's disease. They share the disadvantage of a delayed onset of action and potentially serious side-effects, and are metabolized to thioguanine nucleotides which are thought to be the active metabolites. The direct use of 6-thioguanine may offer a more rapid and safer alternative. We conducted an open prospective study to investigate the efficacy and safety of 6-thioguanine in chronic active Crohn's disease. METHODS: Thirty-seven patients with chronic active Crohn's disease and a Crohn's disease activity index of > 150 were enrolled in this study. Inclusion criteria were steroid dependence (n = 19), steroid refractoriness (n = 9) and/or intolerance (n = 16) or refractoriness (n = 6) to azathioprine. Patients were treated with 40 mg/day of 6-thioguanine for 24 weeks; a dose escalation to 80 mg was allowed at week 12. Remission was defined as a Crohn's disease activity index of < 150 associated with a decrease of > 70 points; response was defined as a decrease of > 70 points in the Crohn's disease activity index. RESULTS: In the intention-to-treat analysis, 13 of 37 patients achieved remission (35%). Twelve of these 13 patients achieved remission after 4 weeks. Fifty-seven per cent of patients (21/37) achieved a response. The mean Crohn's disease activity index decreased from 284 +/- 74 to 153 +/- 101. 6-Thioguanine was more effective in azathioprine-intolerant than in azathioprine-refractory patients. Twelve of 16 patients intolerant to azathioprine tolerated 6-thioguanine. Adverse events included phototoxicity, pancreatitis, headache, nausea, alopecia, arthralgia, minor infections and reversible elevation of transaminases. Six patients required discontinuation of medication, two because of leucopenia. CONCLUSIONS: In this patient group with chronic active Crohn's disease, 6-thioguanine appeared to be effective with acceptable short-term toxicity, but long-term controlled trials are clearly needed to further define its role. 5/21/03 re: Nitrous oxide-induced reactions I am an EMT with a question. I am trying to locate any information about anaphylaxis due to exposure to nitrous oxide and resulting rapid onset asthma in a previously non-asthmatic patient. Patient stated a family dentist told her when she was a child that she was allergic to nitrous oxide. As well as she can remember she had only been on the nose mask for several breaths before she lost consciousness. She remembers waking up on oxygen. When she was 22 she was undergoing reconstruction by a maxillo-facial surgeon and told him of the allergy. According to the patient the surgeon had never heard of such an allergy and the patient could not give an accurate account of the type of reaction she may have had so decided to go ahead with the planned nitrous oxide induction Immediately the patient lost consciousness and remembers "coming around" to being ventilated with ambu bag and mask with oxygen and injections of "some kind". They told her that her pressure had dropped and she had gone into anaphylactic shock. She was to obtain and wear an alert emblem and inform all new treating physicians/dentists that she was severely allergic to nitrous oxide. In 1991 she underwent minor laparoscopic exploratory surgery to check patency of her fallopian tubes. Despite her informing the anesthesiologist of the nitrous oxide allergy it was used anyways for both general anesthesia and for inflation of the abdominal cavity during the procedure. Patient claims she awoke in recovery and had several coughing fits where she could not catch her breath due to uncontrollable cough. There was no wheezing. After 2 weeks of continued episodes of coughing her family doctor diagnosed her with mild asthma and attributed it to smoking. She underwent another surgical procedure in 1998 for bilateral removal of mortons neuromas in her feet and again states she woke up with coughing problems. She has also had violent coughing episodes following exposure to chlorine bleach for which she received treatment in the local emergency department. She had PFT in 11/01 which showed severe asthma and major reduction in function following one breath of methacholine challenge which was eventually partially reversed with bronchodilator. In 12/01 she underwent abdominal surgery again and as she states actually threatened the anesthesiologist with litigation if he used nitrous oxide on her after he told her he had never heard of an allergy to nitrous oxide before. Nitrous oxide was used and patient required bronchodilator during surgery. Patient also has an allergic history to sulfa and was also given propofol as part of the anesthesia modality. Within 2 weeks of the surgery patient's breathing had deteriorated to such an extent that she sought treatment in the emergency department. The ER doctor told her she had severe mediastinal pneumonia and put her on Levaquin for several weeks. On her 3 month follow up xray the mediastinal area had not changed and the only information she was given was that it had not been pneumonia after all. Her breathing continued to worsen and she was seen by a pulmonologist and placed on albuterol nebulizer 4 times a day but told she did not have severe asthma. No PFT was done at that time. Recently she has experienced several bouts of breathing difficulties which last for 2 or more weeks. She has pronounced stridor, wheezing and coughing with thick sticky mucous plugs that are difficult to expel. She was experiencing feelings of drowning and fear of dying. She stated she would cough so much and so hard that she would be very weak and unable to lift her head or arms and would remain slumped where she was until she could eventually catch her breath all the while still having spasm in her chest. Her family arranged for her to be seen by her mother's doctor and while waiting for her appointment she had a severe asthma attack in the waiting room. She was transported by ambulance and was treated in the ER. She received epi, albuterol and oxygen in the doctor's office, albuterol oxygen and atrovent in the ambulance and solumederol, albuterol atrovent and tequin in the ER. She was placed on flovent, serevent, prednisone, singulair, tequin and aciphex (for reflux and ulcer) and albuterol nebulizer. After 2 weeks of treatment she has not responded well. She is concerned about the continued forced exposure to what she has been told she is highly allergic (nitrous oxide). Her respiratory function is extremely compromised and despite medications she is still having 3 or 4 asthmatic episodes daily and has required rescue inhalers at night. I have become aware of asthma and other breathing problems associated with dental care workers who are exposed to nitrous oxide but cannot find any literature on it. Can you direct me to any information regarding anaphylaxis with nitrous oxide, adult onset asthma as a result of exposure to nitrous oxide, any findings of permanent or temporary lung damage or other side effects of nitrous oxide exposure. I also want to explore the possibility of a multiple chemical sensitivity, a metabolic disorder which may have caused a breakdown of the nitrous oxide into another form such as nitrogen dioxide, One other interesting aspect for which she claims she has been given no explanation is a positive anticardiolipin antibody and extremely high serum B12 level.   I am not aware of any convincing reports of nitrous oxide (N20) - induced allergic/anaphylactic reactions. I cannot make any valid interpretation or comment about the very complex clinical history you described without a detailed review of all the examinations and tests done. Lack of time does not permit such a review in this program. I will try to make some general comments that may be of help to you: 1) It is conceivable that inhalation of N20, like certain other chemicals, could trigger a constriction of the airways in an individual with underlying bronchial hyper-reactivity. However, N20 is generally well-tolerated by individuals with known asthma and is often recommended as an inhalational anesthetic for such individuals. 2) To my knowledge, N20 is not metabolized into NO2 or any other irritating chemical. There is no convincing evidence for the postulated so-called multiple chemical syndrome. To the contrary, there is strong evidence against this concept. 3) When individuals considered to have atypical asthma also complain of recurrent stridor and other voice changes, two conditions should be considered: a) the vocal cord dysfunction syndrome; b) a recently described reflux condition involving the upper esophageal sphincter (not the lower sphincter typically involved in GERD). If there is evidence of true laryngeal edema associated with swellings in the skin (angioedema), an allergic or non-allergic cause must be investigated.   2/21/03 re: Evaluation of slow acetylator I am a board certified allergist and clinical immunologist in private practice. I have a patient who claims that the patient was told by "a specialist" that the patient had slow acetylator genotype/ phenotype. Apparently the patient experienced adverse reactions to multiple drugs in the past. "Allergy, side effect, overdose or idiosyncrasy" were offered as explanations to the patient in the past following these adverse reactions. The patient would like me to test for "slow acetylator status"! -Assuming the patient is justified in this request, is there any commercial test available for determining N-acetyl transferase 2 (NAT2) level? -Where can I request a test for Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (RFLP)assay for NAT2 gene? -Is there a protocol available for using Caffeine or Dapsone to determine the slow acetylator phenotype? -How should persons with slow acetylator phenotype/ genotype be managed with reference to administration of drugs, advised cancer risk and food allergy risk etc.? I am not expert in the evaluation of slow acetylator status but will try to respond with my limited knowledge. Acetylator studies are generally carried out in pharmaceutical companies or in med school/ research institute pharmacology departments. I do not know which commercial labs do such assays. I would try contacting the Specialty Labs, Inc. in Santa Monica CA at their 800 telephone number (call 1-800-555-1212 to get their number). Ask if they perform such assays - if not, can they refer you to a lab that does do such assays. There are established protocols for determining acetyltransferase activity using caffeine as a benign probe (see enclosed abstracts). To obtain the PCR and RLFP assays you desire, I suggest that you refer the patient to the Medical Genetics Dept of a nearby medical school for consultation (assuming that such school has a clinical genetics consultation service). Your question concerning advising the patient is very complex and open-ended. The answer depends on what drugs the patient needs, what environmental exposures are involved, etc. I suggest that you include such question in your consultation request to the clinical genetics service once you have definite evidence of impressively slow acetylator activity in your patient. Clin Pharmacol Ther 1983 Mar;33(3):355-9 Polymorphic N-acetylation of a caffeine metabolite. Grant DM, Tang BK, Kalow W. In the course of investigations into variability in the metabolism of caffeine in human populations, urinary levels of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), a newly discovered ring-opened metabolite of caffeine, were found to be both bimodally distributed and interethnically variable in samples (Caucasian: n = 42; Oriental: n = 26) from the Toronto population. To test the premise that the polymorphic N-acetyltransferase enzyme (E.C.2.3.1.5) could be responsible for the production of AFMU, 20 of the subjects were phenotyped for acetylator status using sulfamethazine (SMZ). Concordance for all subjects between AFMU production and SMZ acetylation strongly suggests that the acetylation polymorphism is involved in the formation of AFMU Clin Pharmacol Ther 1988 Aug;44(2):152-7 Interindividual and intraindividual variability in acetylation: characterization with caffeine. Hardy BG, Lemieux C, Walker SE, Bartle WR. Department of Pharmacy, Sunnybrook Medical Centre, University of Toronto, Ontario, Canada. The degree of interindividual and intraindividual variability in acetylator activity was investigated with caffeine used as a probe of enzyme activity. Acetylator phenotype and relative N-acetyltransferase