INTRODUCTION
Histamine is a biologically active amine found in various tissues of the body, exerting complex physiological and pathological effects [1]. Antihistamines form the cornerstone of allergy treatment and are widely used in managing conditions such as urticaria, allergic rhinitis, asthma, and atopic dermatitis [2, 3]. Chlorpheniramine maleate (chlorpheniramine) is a first-generation H1-antihistamine derivative that has been in use since the 1950s and is frequently preferred in treating urticaria, rhinitis, and conjunctivitis [4]. It exhibits non-selective effects by inhibiting peripheral and central cholinergic receptors as well as serotonin receptors. Side effects may include dizziness, drowsiness, constipation, anxiety, dry mouth, concentration difficulties, urinary retention, and tinnitus. Although cases of urticaria and angioedema triggered by antihistamines have been reported, anaphylaxis is extremely rare. Despite being a mainstay in urticaria treatment, antihistamines can rarely trigger urticaria/angioedema and anaphylaxis.
IgE-mediated type I hypersensitivity reactions are among the most common mechanisms. In this process, the drug or its excipients are recognized as antigens, leading to the production of specific IgE antibodies. Upon re-exposure to the drug, mast cells release histamine and other inflammatory mediators, resulting in findings such as urticaria, angioedema, dyspnea, and hypotension. Another mechanism involves non-IgE-mediated reactions, in which the drug directly stimulates mast cells or basophils to release histamine; in such cases, skin tests are typically negative. Certain additives (e.g., tartrazine) may directly activate cells, causing anaphylaxis.
AIM
This study aims to present a case of anaphylaxis following chlorpheniramine administration and increase awareness of this rare but serious adverse reaction.
CASE REPORT
A 14-year-old male received an intravenous infusion of chlorpheniramine maleate (10 mg IV) at an external/out- patient facility for complaints of nausea, vomiting, and mild abdominal pain. Approximately 5 min later, he developed generalized urticaria, periorbital angioedema, cough, and hoarseness. The infusion was immediately stopped, and intramuscular adrenaline was administered. His vital signs were stabilized.
Patient history: Allergic history: Atopic rhinitis (sensitivity to pollen and dust mites). Drug sensitivities: Mild urticaria to penicillin group antibiotics; mild gastrointestinal discomfort following NSAIDs (ibuprofen, aspirin). No history of severe systemic reactions. Family history: Asthma and allergic rhinitis in both parents.
The skin prick test (chlorpheniramine 1 mg/ml) was negative. Subsequently, an intradermal test diluted 1/100 showed a reaction increasing from 6 × 6 mm to 14 × 11 mm with surrounding hyperemic induration at 20 min, and the test was evaluated as positive. A provocation test with cetirizine was planned as a safe alternative.
DISCUSSION
Drug hypersensitivity reactions may be triggered not only by pharmacologically active molecules but also by excipients and preservatives, making identification of the causative agent challenging [5]. This group of drugs can lead to allergic side effects such as drug eruptions, urticaria, angioedema, and anaphylaxis. Anaphylaxis is an IgE-mediated type I hypersensitivity reaction and may present with mucocutaneous, gastrointestinal, respiratory, or cardiovascular symptoms.
Mucocutaneous symptoms include urticaria and perioral angioedema; gastrointestinal symptoms include nausea, vomiting, dysphagia, abdominal cramps, and diarrhea; respiratory symptoms include rhinorrhea, stridor, cough, hoarseness, aphonia, throat tightness, dyspnea, wheezing, hypopharyngeal or laryngeal edema, and cyanosis. Cardiovascular symptoms include chest pain, arrhythmia, hypotension, presyncope, syncope, tachycardia, bradycardia, orthostatic changes, seizures, and shock.
Although cases of urticaria due to antihistamines are frequently reported, anaphylaxis specifically due to chlorpheniramine maleate is exceedingly rare [6]. Due to its rarity, antihistamine hypersensitivity is often overlooked. This report is among the rare pediatric cases reporting anaphylaxis associated with chlorpheniramine maleate.
The pathophysiological mechanism of hypersensitivity to chlorpheniramine maleate is mostly associated with IgE-mediated type I reactions. The drug or its excipients act as haptens, binding to tissue proteins and leading to specific IgE synthesis. Upon re-exposure, mast cells release mediators such as histamine, prostaglandins, and leukotrienes. Additionally, chlorpheniramine may also trigger non-immunologic mechanisms involving direct mast cell degranulation. It is most often observed in adolescents and middle-aged adults, particularly women. There is a possibility of reaction recurrence with another drug in the same class. Skin tests and provocation tests are recommended for diagnosis. One study suggested that basophil activation testing could serve as an additional diagnostic method for chlorpheniramine maleate allergy [7]. Since the 1990s, the basophil activation test has been widely used in diagnosing immediate allergic reactions [8].
It is essential to identify at least one safe alternative from a different drug class through provocation testing. The risk of cross-reaction among antihistamines is especially high within the same chemical class. Cross-reactions have been reported among first-generation H1-antihistamines (e.g., chlorpheniramine, diphenhydramine), whereas the risk is lower with second-generation antihistamines. In patients with reactions to chlorpheniramine, second-generation antihistamines like cetirizine or loratadine are generally safer alternatives.
CONCLUSIONS
Long-term management and education are critical for individuals with a history of antihistamine-induced anaphylaxis. Patients should avoid the culprit drug, safe alternatives should be identified, an epinephrine auto-injector should be prescribed for emergency use, and both the patient and caregivers should receive comprehensive training on its administration.
A study found that while most medical students were knowledgeable about the definition of anaphylaxis and its basic management guidelines, a significant proportion reported a lack of confidence in their competence, highlighting a gap in practical experience. The students emphasized the importance of developing crisis management skills during medical training and the necessity of transferring this knowledge to the wider community [9]. Therefore, awareness must be raised not only among patients but also among healthcare professionals.
