Pediatric drug allergy

No overview is complete without some reference to another aspect of drug reactions; that of toxicity. Several mechanisms apply here: the direct effect of oxidizing drugs on the hematopoietic mass, cell-cell toxicity, and drug-and heavy metal-induced hyperpigmentation are other good examples. Toxicity can also be relative, in that normal dosages of drugs given in combination with other drugs that compete for metabolism or carrier proteins can result in elevated toxicity when perfectly normal and appropriate dosages are being used. This has become very significant in increased use of chemotherapeutic and cytotoxic agents in pediatric practice. Much of these adverse reactions are anticipated, including the classic alopecia from the various cytotoxic agents, which, in some incidences, can be minimized by cooling of the scalp, etc. Additionally, the use of systemic agents and extravasation of same has been a frequent cause for consultation to dermatology to assess the possibilities of minimizing the tissue loss after extravasation of intravenous agents. Many of these intravenous agents are cytotoxic as the direct action of the drug, but in others, including some of the antibiotics (historically, tetracycline was one), were indirect, where the infusion material was cytotoxic by basis of excipients, additions, or pH that is toxic to the dermis where it infiltrates. This type of reaction is nonimmunologic and is virtually always predictable, well-known, and should in many incidences be preventable.

Although often a “wastebasket” term, the so-called “idiosyncratic reaction” has become an increasingly significant one in the spectrum of drug reactions. The idiosyncratic reaction, by definition, lacks precision and specificity in etiology and development, but with the increasing awareness of these reactions, a clearer picture is evolving of the development and evolution of such. With this new knowledge, better predictability in the future seems certain. Of significance is the role of reactive drug metabolites in these reactions. This partially explains some of the differences within classes of drugs, such as the interesting predominance of cefaclor as a major cause of such reactions to antibiotics in pediatrics. The recent excellent review covering reactions to the antibiotics underscores the significance of these drug, which seem particularly prevalent in the pediatric age group, and is of much less significance in antibiotic drug reactions in adults. Whether this is a function of differences in metabolism of these drugs in the pediatric patient versus adults, related to maturation of such enzyme systems for oxidation-reduction (redox), hydrolysis, and subsequent conjugation that render these inactive compound water soluble for renal excretion, is uncertain. The list of various idiosyncratic reactions does include many antibiotics and antibiotic-like drugs, including the sulfas and sulfones. Also, the anemia with such (oxidizing) drugs in patients with glucose 6-phosphate dehydrogenase deficiency and various hepatic reactions, such as cholestasis and others reactions, still have an unclear biochemical basis.

After determination of the drug, within a reasonable certainty, and discontinuation, careful awareness of drug half-life is important to determine the nature of therapy and the aggressiveness of it. It is true that with many antibiotics, the cutaneous reaction worsens for the first few days after discontinuance. This is a function of increasing antibody production as well as increasing avidity and affinity of the antibodies outstripping the slow and steady decrease of the drug as an antigen. Because of this, early on the reaction may get significantly worse, as the enhanced binding results in immune complexes that enlarge and multiply, significantly worsening the patient’s cutaneous symptoms. This frequently raisies the question as to the correct identity of the offending drug. When there is a question of type I or type III reactions, it may be important to use high-dose steroids to decrease the patient’s reactivity to the antigen and diminish the reactions to the large immune complex lattices that create problems in the cutaneous vasculature and the subsequent symptoms of vasculitis and urticaria. The worst-case scenario includes anaphylaxis and anaphylactoid reactions.

In the case of type I reactions, the specter of upper-airway obstruction also mandates the use of epinephrine and other beta-agonists, as well as steroids when the urticarial vasculitis or urticarial reaction is at its peak to forestall major airway problems. Less severe reactions may be very successfully treated with a low tapering dose of steroids and appropriate use of antihistamines, both of the sedating and nonsedating type, which is determined according to the severity of the reaction and the physician’s comfort with any given class of antihistamines and availability of the drug for pediatric indices. One cannot stress enough the importance of adequate dosing, especially of the antihistamines, where inadequate drug blood levels often are the cause of treatment failure. One should always choose and prescribe the antihistamine of the physician’s choice in adequate dosage to achieve tissue effect. Some examples of the most common antihistamines for maculopapular, pruritic, and urticarial reactions are seen on the accompanying table (Table 7). It is important to recognize that for the pediatric patient, there is available in the United States a number of antihistamines without prescription that are effective, but effectiveness mandates appropriate dosing related to body mass/surface area/weight, which is usually higher dosing than that recommended for over-the-counter (OTC). Often, the family will bring the patient in, having already used Benadryl, Chlor-Trimeton, or Dimetapp, without success (which is available OTC at a low and safe dosage schedule), but when dosage is pushed to appropriate levels per body mass/surface area, they can be quite effective. The prescription agents Claritin®, Allegra®, Zyrtec®, Atarax®, and Periactin® (see Table 6) all are available for pediatric dosing in one form or another. In the case of urticarial drug reactions and those with potential concern for airway involvement, the use of epinephrine may be an essential safeguard. This can be prescribed with the use of the self-administrated Epi-pen® device, so that those patients (both the patient and the family) who manifest IgE hypersensitivity should be aware of and comfortable with the use of such an emergency instrument, for it may be life-saving. The essence of therapy is discovery of cause, elimination of the cause, and treatment of the symptoms. Antihistamines are the primary modality, but should those fail, steroids are often the next step. A short burst of steroids starting at 1 mg/kg prednisone or equivalent tapering over a 2-week course is usually sufficient to control symptoms. This is usually sufficient for all but the most long-acting drugs that have significant tissue distribution/storage and subsequently long half-lives.

While it is not the usual approach in the United States in Europe and other parts of the world, challenge to the suspect drug has and can be done to confirm hypersensitivity. This has certain utility, in allowing and assuring the avoidance of certain drug exposure in the future.

In patients deemed prone to allergic reactions, an awareness of relatively safe medications (see Table 8) is an equally important therapeutic choice—always try to avoid the common drugs causing allergy when possible.