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Allergy to dexchlorpheniramine. Study of a case
Abstract
Dexchlorpheniramine (DH) is a classical or first generation antihistamine belonging to the ethanolamine group. Adverse effects related to these antihistamines are frequent, but the hypersensitivity reactions described in the literature since 1940 are exceptional. We report the case of a 32-year-old woman who experienced two episodes of akathisia secondary to intravenous (i.v.) dexchlorpheniramine administration for a possible hypersensitivity reaction to local anesthetics.
Allergological study consisted of the following tests: skin prick tests with routine allergens, with a negative result; skin prick and intradermal tests with local anesthetics and DH, with a positive result to DH in the intradermal skin test (+ +); serum specific IgE, which was within normal levels; histamine release test with DH with a negative result, and the basophil activation test (BAT) with local anesthetics and DH, which was positive for DH and weakly positive to Lidocaine.
BAT is proving to be a highly useful tool in the field of drug allergy, with a higher sensitivity and specificity than other in vitro tests. Because it avoids the need for provocation tests, this is especially important in drug-induced allergic reactions in which in vivo tests are repeatedly negative despite a clear clinical history.
... Chlorpheniramine is one of the most classical H1-antihistamines, primarily prescribed for histamine-mediated hypersensitivity re-actions such as urticaria. In the literature, cases have been rarely reported for chlorpheniramine-induced immediate hypersensitivity reactions [1,2], even when including pheniramine [3] or dexchlorpheniramine [4][5][6]. The mechanisms are still unclear, but allergy 178 apallergy.org ...
... They may not assess the causal relationships but only the sensitization, but have potentially wider clinical applications for their better safety. In the literature, several tests have been utilized for chlorpheniramine allergy [1][2][3][4][5][6]. Oral or intramuscular provocation tests were performed in four cases [1,2,5], whereas skin tests were used in three cases [3,4,6]. ...
... In the literature, several tests have been utilized for chlorpheniramine allergy [1][2][3][4][5][6]. Oral or intramuscular provocation tests were performed in four cases [1,2,5], whereas skin tests were used in three cases [3,4,6]. ...
Chlorpheniramine is a widely prescribed H1-antihistamine for relieving urticaria or histamine-mediated allergic reactions. However, although rare, it may cause immediate hypersensitivity reactions. The diagnosis is usually made by provocation test, but its application is often limited due to comorbidities or potential risk of severe reactions. In those cases, skin tests and basophil activation tests can be considered as additional diagnostic tests for the drug allergy. Here, we report a 33-year-old female with underlying chronic urticaria, who recurrently developed anaphylaxis after chlorpheniramine administration. Intradermal test showed positive responses in the patient at 0.02 mg/mL of chlorpheniramine, but not in healthy controls. Basophil activation test showed significant up-regulation of CD63 and CD203c by chlorpheniramine. The present case reminds the rare but potential allergic risk of chlorpheniramine, and also suggests the potential utility of basophil activation test in making the diagnosis.
... The antagonistic action of dexchlorpheniramine blocks the activities of endogenous histamine, including histamine-induced bronchoconstriction, vasodilation, increased capillary permeability, and GI smooth muscle spasms. It is a classical, inexpensive drug with extensive clinical use, indicated mainly for allergic processes when histamine is the primary mediator (Calle, Fernandez-Benitez, 2004;Gobo-Oliveira et al., 2018). In cases of mild and chronic allergies, the dosage of the drug must be increased to avoid the development of drug tolerance. ...
... Dexchlorpheniramine maleate is a classical antihistamine widely used to treat allergic processes. However, its action is not selective, and it frequently inhibits the peripheral and central cholinergic receptors and serotoninergic receptors as well as affects other tissues (Calle, Fernandez-Benitez, 2004). In the present study, we evaluated the effects of DCPA. ...
... Antihistamine hypersensitivity is very unusual, with only a few published reports of hypersensitivity reactions to piperazine derivatives, such as cetirizine, hydroxyzine, and loratadine.3-6 In contrast, hypersensitivity to alkylamine derivatives such as chlorpheniramine is extremely rare,7,8 particularly a type I reaction.9 Recently, in Korea, the case of a 42-year-old male displaying urticaria, angioedema, dyspnea, and hypotension after ingesting chlorpheniramine and cetylpyridium was reported; this patient also suffered from aspirin-intolerant asthma.10 ...
... Several cases of hypersensitivity reactions against piperazine derivatives such as cetirizine, hydroxyzine, levocetirizine, and loratadine have been reported.3-6 However, hypersensitivity reactions to alkylamine derivatives such as chlorpheniramine maleate are extremely rare, particularly a type I reaction.7,8 To date, only one case of chlorpheniramine-induced type I hypersensitivity with aspirin intolerance has been reported. ...
Antihistamines are commonly used to treat allergic disease, such as allergic rhinitis, urticaria, and angioedema. Although several previous reports describe hypersensitivity to antihistamines such as cetirizine and hydroxyzine, documented cases of chlorpheniramine hypersensitivity are extremely rare. Here, we report the case of a 45-year-old Korean woman who presented with urticaria after ingesting a cold medication. Over the previous 5 years, she had also experienced a food allergy to crab and shrimp, allergic rhinitis, and repeated urticaria after ingesting cold medication. Provocation with aspirin elicited generalized urticaria. Intravenous chlorpheniramine and methylprednisolone was injected for symptom control, but in fact appeared to aggravate urticaria. A second round of skin and provocation tests for chlorpheniramine and methylprednisolone showed positive results only for chlorpheniramine. She was diagnosed with aspirin intolerance and chlorpheniramine hypersensitivity, and was instructed to avoid these drugs. To date, this is the second of only two cases of chlorpheniramine-induced type I hypersensitivity with aspirin intolerance. Although the relationship between aspirin intolerance and chlorpheniramine-induced type I hypersensitivity is unclear, physicians should be aware of the possibility of urticaria or other allergic reactions in response to antihistamines.
... There have been many reports of urticaria due to antihistamines but cases of anaphylaxis are rare, particularly to CPM. Only a few cases have been reported in English medical literature (Table 1) [4][5][6][7][8][9][10][11][12][13][14][15] . Skin tests (prick, intradermal, and patch) have not shown adequate diagnostic reliability in identifying the causative antihistamine preparations. ...
Chlorpheniramine maleate is commonly used antihistamine. Since antihistamines are the main therapeutic agents for symptomatic treatment of urticaria, anaphylaxis to antihistamines may lead to errors in diagnosis and treatment. We report a case of anaphylaxis induced by chlorpheniramine maleate confirmed by intradermal test. A 35-year-old female experienced history of anaphylaxis after intramuscular injection of chlorpheniramine maleate. Skin prick test was negative, but intradermal test was positive. Patient also experienced mild dizziness after intradermal test and refused to perform any further evaluation such as oral challenge test. Anaphylaxis for chlorpheniramine maleate is very rare but should be considered.
... Other alkylamines include the unsaturated analogues, pyrrobutamine, triprolidine, dimethindene, and phenindamine. Although there are isolated reports of cutaneous ADRs such as hypersensitivity reactions with chlorpheniramine and dexchlorpheniramine, FDEs have not been reported with any of the alkylamine antihistamines to date [9,10]. ...
Fixed drug eruption is a delayed type hypersensitivity reaction to a drug seen most frequently with antibiotics such as tetracyclines, sulfonamides, and NSAIDs such as naproxen and ibuprofen. Although H1-antihistamines rarely elicit cutaneous adverse effects, there have been a few reports in the literature implicating them in causing fixed drug eruption, particularly the piperazine derivatives (hydroxyzine, cetirizine, levocetirizine), and loratadine. However, cutaneous drug reactions with the alkylamine derivatives like pheniramine maleate are extremely uncommon and fixed drug eruptions have not been reported with any of the alkylamine antihistamines to date. We herein report a case of multifocal bullous fixed drug eruption following ingestion of pheniramine maleate.
... Other Drugs and Some Remarks on BiologicalsVarious other drugs causing immediate DHRs have been tested using BAT including atropine(Cabrera-Freitag et al., 2009), glatiramer acetate(Soriano Gomis et al., 2012), methylprednisolone(Aranda et al., 2010;Ben Said et al., 2010a), omeprazole(Gamboa et al., 2003b), the diuretic hydrochlorothiazideManso et al., 2010), or antihistamines(Caceres Calle and Fernandez-Benitez, 2004;Bobadilla-Gonzalez et al., 2011;Lee et al., 2011;Sanchez Morillas et al., 2011) to name a few. However, these reports, most of them case studies, are hard to judge from the perspective of validating BAT performance, as no experimental details were presented.Aranda et al. (2010) showed log-shifts in CD63 expression in the dot plots and indicated involvement of methylprednisolone-specific IgE as activation could be inhibited by wortmannin. ...
Immediate drug hypersensitivity reactions (DHRs) resemble typical immunoglobulin E (IgE)-mediated symptoms. Clinical manifestations range from local skin reactions, gastrointestinal and/or respiratory symptoms to severe systemic involvement with potential fatal outcome. Depending on the substance group of the eliciting drug the correct diagnosis is a major challenge. Skin testing and in vitro diagnostics are often unreliable and not reproducible. The involvement of drug-specific IgE is questionable in many cases. The culprit substance (parent drug or metabolite) and potential cross-reacting compounds are difficult to identify, patient history and drug provocation testing often remain the only means for diagnosis. Hence, several groups proposed basophil activation test (BAT) for the diagnosis of immediate DHRs as basophils are well-known effector cells in allergic reactions. However, the usefulness of BAT in immediate DHRs is highly variable and dependent on the drug itself plus its capacity to spontaneously conjugate to serum proteins. Stimulation with pure solutions of the parent drug or metabolites thereof vs. drug-protein conjugates may influence sensitivity and specificity of the test. We thus, reviewed the available literature about the use of BAT for diagnosing immediate DHRs against drug classes such as antibiotics, radio contrast media, neuromuscular blocking agents, non-steroidal anti-inflammatory drugs, and biologicals. Influencing factors like the selection of stimulants or of the identification and activation markers, the stimulation protocol, gating strategies, and cut-off definition are addressed in this overview on BAT performance. The overall aim is to evaluate the suitability of BAT as biomarker for the diagnosis of immediate drug-induced hypersensitivity reactions.
... Among corticosteroids, methylprednisolone [62, 67] and succinylated corticosteroids686970 have been tested. Hypersensitivity to anti-histamines such as cetirizine, desloratadine, ebastine, fexofenadine, or dexchlorpheniramine was also assessed by BAT71727374. Other reports included testing for pholcodine [75], glatiramer [63], gelofusine [64], amidotrizoate [76], pristinamycin [77], enoxaparin [78], heparin [79], afloqualone [80], cremophor EL [81], hydrochlorothiazide [82, 83], polyoxyethylene (20) sorbitan monooleate [84, 85], chlorhexidine [86], ophthalmic atropine [87], and carboxymethylcellulose [88] in allergic or non-immunologic adverse reactions (Table 7) [13, 27, 61,. ...
Immediate-type drug hypersensitivity is an increasingly significant clinical issue; however, the diagnosis is frequently hindered due to lack of safe and precise diagnostic tests. Flow cytometry-assisted basophil activation test is a safe in vitro diagnostic tool for assessing basophil activation upon allergen stimulation. In this review, we have summarized current literature on the diagnostic utilities, new indications, and methodological aspects of the basophil activation test for the diagnosis of drug hypersensitivity.
Background: although topical antihistamines were widely prescribed in the past, their current usage is mostly limited to treating sensitive reactions. Materials and methods: 82 consecutive patients with a medical history of adverse drug reactions, of various eczematous lesions or with no drug-induced urticarias were patch tested with eight formulations containing antihistamines, which are sold in Italy. In 8 subjects with eczematous manifestations, tolerability and efficacy against itching in 3 out of the 8 formulations were evaluated. Results: 4 positive patch tests in 2 subjects were recorded, and these were mainly due to commercial formulations containing promethazine (2 cases), maleate dimethindene and chlorhydrate hysotipendile. The 8 subjects with eczematous manifestations reported the 3 products tested to be useful against itching and very tolerable too. Conclusions: although the dermatologic profession has been prescribing these topical therapeutic formulations less than the systemic ones in recent years, owing to their large commercial diffusion and the frequency with which they are self-prescribed, we think that with the exception of some drugs such as promethazine which have been shown to be sensitising, some of the ingredients used should be revaluated for wider use including the dermato-allergologic field.
Skin tests with drugs can be helpful in determining the cause of cutaneous adverse drug reactions (CADR). Patch tests and prick tests can be done with any commercialized form of a drug, intradermal tests (IDT) normally rely on the availability of a sterile solution used for parental applications. There has been some experience with different concentrations and techniques, but a complete standardization has not been done with these tests. Prick tests and IDT are used to investigate immediate hypersensitivity, patch tests and IDT with delayed readings are helpful for symptoms appearing delayed. They can be positive in different skin symptoms, with or without involvement of internal organs (e.g. hepatitis). A great variety of drugs can be tested, including antibiotics, antiepileptics, drugs used in oncology, drugs used for diagnosis etc. Except for IDT, skin tests with drugs rarely induce adverse reactions. False positive results can occur and should be considered, if a product for skin tests is evaluated for the first time. The negative predictive value of skin tests with drugs is a crucial point that will have to be studied in detail in the near future.
Immediate hypersensitivity is mediated by IgE bound on mast cells and basophils through a high affinity receptor. Subsequent encounter with the antigen causes the aggregation of this receptor and then the degranulation of theses cells with release of mediators leading to clinical features sometimes fatal. The basophil activation test aims to reproduce in vitro the triggering of this hypersensitivity by incubating the cell with the putative allergen and to evaluate the result of this activation directly at the cellular level; thus the test provides its own pieces of information. The basophils are gated using a fluorescent antibody and their degranulation is evaluated with to a second one, conjugated with another fluorochrom. Some variations of the method have been reported with similar performances; and the test needs a laboratory experienced in the fields of allergy and flowcytometry. This test is not designed for a systematic screening but due to its versatility, it can fit for definite situations and for different goals. So the basophil activation test is a tool with interesting capabilities in service to physicians and patients.
Drug skin tests can be helpful in determining the cause of a cutaneous adverse drug reaction (CADR). Patch tests and prick tests can be performed with any commercialized form of a drug. Intradermal tests (IDTs) have a greater value, but their techniques have not been standardized. Moreover, IDTs can be done only if an injectable form of the drug is commercialized and are restricted to patients with nonsevere CADR. Prick tests and IDTs are used in investigating immediate hypersensitivity. Patch tests both with IDTs with delayed readings are helpful for maculopapular rash and generalized or localized eczema. Results obtained with drug skin tests in β-lactam sensitization have been extensively published, but fortunately, during the last few years the value of skin tests in CADR due to other drug classes (e.g., synergistins, platinium salts or radiocontrast medias) was also studied. The analysis of recent literature permits to propose which tests to choose for each clinical feature of CADR and to give the list of all drugs, having had patch tests with positive results but, emphasizes the lack of standardization in performing and reading IDTs. This standardization is absolutely necessary to determine the thresholds of specificity of the IDT. Except for IDTs, drug skin tests induce only rarely adverse reactions. False-positive results can occur and should be considered by testing new products. The negative predictive value of drug skin tests is a crucial point that will have to be studied in more detail in the near future.
This chapter discusses adverse effects and interactions of antihistamines. Accumulation of unmetabolized terfenadine and astemizole can result in blockade of cardiac potassium channels in the ventricular myocytes that regulate the duration of the action potential; subsequent prolongation of the QT interval can result in potentially life-threatening polymorphous ventricular tachycardias. First-generation H1 receptor antagonists readily cross the blood-brain barrier, and their consequent sedative and anticholinergic effects are well documented. Somnolence is the most frequent problem associated with cetirizine. Several case reports of skin intolerance of cetirizine, including cases of urticaria have also been reported. Daytime neurological impairment has been ascribed to diphenhydramine. Visual hallucinations have been reported with stimulant prolintane and diphenhydramine. Loratadine causes erythematous, edematous, pruriginous skin eruptions in a 19-yearold woman who complained of at least three episodes of eruptions located at the same sites each time.
The application of flowcytometry in the study of basophil activation for the diagnosis of allergic diseases has given interesting results in recent years. The quantification of basophil activation by flowcytometry has been proven to be a useful tool for the assessment of the immediate-type response to allergens mediated by IgE or by other mechanisms in drug allergic patients. Up to now, most basophil activation test studies reported in the literature have used CD69 or CD203c as markers to quantify basophil activation after antigen-specific stimulation. Some technical variations such as the use of whole blood or isolated leukocytes, the addition of IL-3, the conditions of storage of the blood sample, the time of incubation with allergens and their concentration can affect the results of the basophil activation tests. The basophil activation test is more sensitive and specific than other in vitro diagnostic techniques in drug allergy. In various studies, its sensitivity in allergy to muscle relaxant drugs ranges between 36 and 97.7%, with a specificity around 95%. For betalactam antibiotics, basophil activation test sensitivity is 50% and its specificity 90%. For NSAIDs, sensitivity varies between 66% and 75%; specificity is about 93%. Basophil activation test reproduces in vitro hypersensitivity mechanisms involved in immediate-type allergic reactions, allows the diagnosis of allergic and pseudo-allergic reactions particularly for drugs, which are often not detectable by serological techniques, such as determination of specific IgE.
An IgE-mediated allergic reaction to an antihistamine sounds like a paradox and is rare.
To describe 2 patients with anaphylaxis caused by mizolastine. In one patient, differential diagnosis from food allergy was necessary, whereas in the other patient, the history was clear.
History and in vivo skin testing were used for diagnosis. A challenge test to mizolastine was also proposed, but both patients refused to give consent.
Skin test results were positive to mizolastine, whereas tests to the inert ingredients of the mizolastine tablets and to other H1 and H2 blockers had negative results.
In vivo tests are highly sensitive, and they confirmed the diagnosis of the uncommon antihistamine allergy.
For the diagnosis of allergy, cellular basophil activation tests (BAT), e.g. histamine or sulfidoleukotriene release tests, have long been introduced, but the expression of basophil activation markers such as CD63 and CD203c detected by flow cytometry has attracted more recent attention. A recent opinion paper in this Journal has stressed not only the potential but also the possible pitfalls of flow-cytometric BAT. We have applied clinical validation of various BAT in various ways for several years, and our experience shows that these new technologies have more potentials and perspectives than pitfalls. A comprehensive review of clinically validated studies on allergy to aeroallergens, insect venoms, latex, food allergens and drugs, e.g. myorelaxants, beta-lactams, pyrazolones and non-steroidal anti-inflammatory drugs, as well as chronic urticaria shows clearly that even with different protocols, reproducible and meaningful results can be obtained. Although the available technologies may still be optimized and better standardized, there are no serious reasons to deprive allergic patients of clinically indicated BAT, which can be performed reliably by any laboratory with allergy and flow-cytometric capacity and expertise.
The clinical history and biological investigations of a patient presenting an immune complex disease induced by Peroben are reported. Biological signs were those of a drug-induced lupus syndrome. A provocation test allowed disclosure of its pathomechanism, since during Peroben intake a high C1q binding activity occurred and later regressed, while deposits of IgM and C3 were evidenced in the vessel walls. Complete or partial thrombosis succeeded accompanying a leukocytoclastic vasculitis.
• A 52-year-old man developed contact and photoallergic dermatitis caused by diphenhydramine hydrochloride as well as contact dermatitis from paraphenylenediamine.
The diphenhydramine photoallergy was elicited by long-wave ultraviolet light. The action spectrum differs from that noted in a recent report in which wavelengths shorter than 320 nm were responsible for eliciting diphenhydramine photoallergy.
To the best of my knowledge, this is the third case of diphenhydramine photosensitivity reported in the English literature. The combination of both contact and photosensitivity to diphenhydramine has not previously been described.
(Arch Dermatol 112:1124-1126, 1975)
In this study, we used flow cytometry to determine the percentage of activated basophils that expressed the CD63 marker after in vitro stimulation by different betalactam antibiotics. The diagnostic reliability of the technique was assessed, as well as its correlation with specific IgE.
Fifty-eight patients with clinical allergy to betalactam antibiotics and presenting positive skin tests to at least one of the allergens (minor determinant mixture (MDM), benzylpenicilloyl-polylysine (PPL), penicillin, ampicillin, amoxicillin, cephalosporins) were tested. Thirty subjects non-allergic to betalactams were also studied as controls. The flow assay stimulation test (FAST) uses flow cytometry to determine the percentage of basophils that express CD63 as an activation marker after in vitro stimulation with allergen. Double labelling with monoclonal antibodies anti-CD63-PE and anti-IgE FITC was used.
The allergic patients show a statistically greater number of activated basophils than the control subjects, after the incubation of cells with all the betalactams at various concentrations. The sensitivity of the technique is 50%, the specificity 93.3%, the likelihood ratio for a positive value 7.46 and the likelihood ratio for a negative value 0.54. In spite of having a greater sensitivity (37.9%) and specificity (86.7%) than CAP, differences between sensitivity and specificities of both techniques (CAP and FAST) do not reach statistical significance.
The basophil activation test is a particularly useful technique in the diagnosis of patients with IgE-mediated allergy to betalactams and allows the identification of 50% of patients. Used in conjunction with CAP, it allows the identification of 65.5% of such patients.
We report the cases of 2 women presenting allergy to paraphenylenediamine (PPD). Both patients had a history of eczema that worsened following the ingestion of the antihistamine Polaronil (dexamethasone/dexchlorpheniramine). This clinical presentation could be explained by cross-sensitivity to sulfanilic acid (4-aminobenzene sulfonic acid), a metabolite of sunset yellow (FD&C No. 6). Sunset yellow is an azo dye present in this tablet. Indeed, PPD-allergic subjects may suffer from cross-sensitivity to related compounds, especially to those that can be ingested such as azo dyes. Such compounds are used in some instances by the food and pharmaceutical industries, but their presence is often undisclosed.