Answers | | |
Why the diagnosis of drug-induced urticaria was made in this case?Two days after starting cefpodoxime, the patient developed a severe itchy urticarial rash with mild swelling of the lower lip. These wheals were evanescent in nature and lasted for <24 h.
Temporal relationship between the start of drug and the onset of symptoms and subsidence of urticarial rash following drug withdrawal is the most important indicator of its causality. Previous reports of adverse cutaneous reactions due to suspected drug in the literature help in making causality assessment. Beta-lactam antibiotics such as penicillins have been stated to be the most common cause of drug-induced urticaria.
[1],[2] Based on the application of Naranjo's algorithm used for causality assessment, cephalosporins are more likely to have induced urticaria in this patient as compared to paracetamol. Successful dechallenge and previous reports of cephalosporin-induced urticaria are pointers toward cephalosporins as the cause of urticaria.
Why urticaria in this patient is not of infective origin? how will you differentiate between drug-induced urticaria and infection-induced urticaria?Cephalosporins are frequently prescribed for infectious diseases such as sinusitis, URTI, and pneumonia. Infections can themselves precipitate urticaria. Although it is difficult to differentiate between the two, careful history, proper examination, and most importantly, clinical experience of a physician are helpful in such cases. In our patient, URTI was present. However, urticaria started resolving after drug discontinuation while viral infection continued to persist. Hence, in this case, fever and conjunctival congestion started before starting cefpodoxime and urticarial rash involving palms and soles started after talking cephalosporin. Hence, it can be assumed that the fever was infective in origin and the rash was drug induced. However, there is no definite diagnostic test to differentiate between infection-induced urticaria and drug-induced urticaria.
If this patient requires antibiotic, what drug substitution should be done in this case?Drug-induced urticaria has been reported with several classes of antibiotics including penicillins, cephalosporins, aminoglycosides, tetracyclines, and sulphonamides, besides many others. Penicillins are the most common cause of drug-induced urticaria.
[1] Patients with allergy to penicillin are more likely to have allergic reaction to cephalosporins than those who do not.
[2] Cross-reactivity is more common with the first-generation cephalosporins than second- or third-generation cephalosporins. Hence, safer alternatives include azithromycin, clarithromycin, aztreonam, clindamycin, and linezolid. This patient was prescribed clarithromycin. As most viral infections are self-limiting, substitute antibiotics may not be required. However, it should be noted that antibiotics are sometimes prescribed to treat secondary bacterial infection in cases of viral URTI.
What are the various mechanisms of drug-induced urticaria?Immunologically mediated drug-induced urticaria is type I hypersensitivity reaction and requires a prior sensitization. Usually, the first course of the drug is uneventful. During the second exposure, the reaction develops within 24–36 h. On re-exposure, reaction may develop in minutes to an hour. This type of reaction can be severe and may be associated with anaphylaxis or angioedema.
Nonimmunologically mediated drug-induced urticaria is a anaphylactoid drug reaction that resembles immediate hypersensitivity reaction, but does not have a sensitization phase. Usually, 50% of the reactions occur in the first 6–7 h.
[3] The most common cause of nonimmune drug-induced urticaria is due to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Proposed mechanism for the same is overproduction of leukotrienes following the inhibition of constitutive COX-1 pathway. NSAIDs have known to aggravate chronic urticaria. Selective COX-2 inhibitors are much better tolerated, but they too have been shown to aggravate chronic urticaria. Paracetamol has been used extensively for aspirin-sensitive urticaria, but there have been a few reports of anaphylaxis due acetoaminophen.
[4] Narcotic analgesics such as codeine and tramadol have also been implicated. Tramadol may also precipitate urticaria in patients who are sensitive to NSAIDs, hence may not be necessarily safe.
[5]Urticaria and angioedema due to angiotensin-converting enzyme (ACE) inhibitors are well known. This is due to decreased degradation of bradykinin due to the blockage of ACE. Since this is due to the basic mechanism, this is seen with all members of the class. This problem is not seen in angiotensin receptor blockers or ARBs as they directly block angiotensin receptor. However, one systemic review showed that angioedema may persist in up to 10% after switch from ACE-1 inhibitors to ARBs.
[6] Vaccines have been cited as the third most common cause of drug-induced urticaria.
[7] Acute or chronic urticaria has been shown to start within days to weeks following vaccination.
How drug-induced urticaria can be prevented in future?Once it is confirmed that patient has drug-induced urticaria due to specific drug(s), the patient should be counseled and educated about it. He/she should be told that such episode may recur in future with intake of offending drugs. Drug allergy card should be given to patient mentioning offending drugs. Patients should be instructed to show this card to doctors if they are required to take medications for any ailment. In country like ours, medications are sometimes taken from pharmacists who may be unaware of clinical details or drug history of the patient. Chances of drug reaction may increase due to this. Drug list should be kept as minimum as possible and essentiality of drugs should be discussed with the clinician treating the patient, particularly who is taking multiple drugs.
Are there any reliable diagnostic tests for identifying beta-lactam antibiotics as the cause of drug-induced urticaria?Detection of specific drug causing urticaria is the most important aspect of effective management. Various tests are claimed to be useful for detecting specific drug causing urticaria. They include intradermal skin tests, basophil activation test, fluoroenzymeimmunoassay (FEIA), and radioimmunoassay (RIA). While drug provocation tests such as intradermal tests (IDTs) and skin prick test are more popular with beta-lactam antibiotics such as penicillin, they are found to be less useful for detecting cephalosporin hypersensitivity as exact allergenic determinants of cephalosporins are not known. Cephalosporins degrade to form heterogeneous reactive antigenic determinants which are yet to be known.
[8] Similarly, IDTs can be done only when drug or allergen is available in injectable or in solution form. In a study by Yoon
et al., even when IDT with cephalosporins was positive, test-positive patients did not show immediate hypersensitivity reactions.
[9] While doing IDT, drugs such as cephalosporins tend to produce nonspecific irritant skin reactions resulting in false-positive reactions. Hence, the optimum concentration of cephalosporins that does not result in irritant reactions should be chosen. However, there is no consensus regarding this. ENDA/EAACI Drug Allergy Interest Group recommended a concentration of 2 mg/ml for cephalosporin skin tests.
[10] Several other studies indicated a concentration up to 20 mg/ml of cefuroxime, ceftriaxone, cefotaxime, ceftazidime, cefazolin, cephalexin, cefaclor, and cefatrizine that do not produce irritant reactions and increases the chances of detecting drug hypersensitivity.
[11],[12]Actual application of BAT in clinical practice in cases of drug hypersensitivity has been limited to a few drugs such as beta-lactams, neuromuscular blocking agents, NSAIDs, or radiocontrast media.
[13] Data about the clinical experience of BAT are limited.
The specificity of FEIA ranged from 83.3% to 100% and sensitivity from 0% to 25% whereas the specificity of RAST was between 66.7% and 83.3% and sensitivity between 42.9% and 75%. Their study suggested that owing to high specificity, serum-specific IgE assays may be more useful than a drug provocation test in the patients with a history of beta-lactam anaphylaxis and negative skin tests.
[14]1. | Shipley D, Ormerod AD. Drug-induced urticaria. Recognition and treatment. Am J Clin Dermatol 2001;2:151-8. |
2. | Petz LD. Immunologic cross-reactivity between penicillins and cephalosporins: A review. J Infect Dis 1978;137Suppl:S74-9. |
3. | Juhlin L. Recurrent urticaria: Clinical investigation of 330 patients. Br J Dermatol 1981;104:369-81. [ PUBMED] |
4. | Schwarz N, Ham Pong A. Acetaminophen anaphylaxis with aspirin and sodium salicylate sensitivity: A case report. Ann Allergy Asthma Immunol 1996;77:473-4. |
5. | Asero R. Chronic urticaria with multiple NSAID intolerance: Is tramadol always a safe alternative analgesic? J Investig Allergol Clin Immunol 2003;13:56-9. |
6. | Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: A meta-analysis. Ann Allergy Asthma Immunol 2008;101:495-9. |
7. | Tan EK, Grattan CE. Drug-induced urticaria. Expert Opin Drug Saf 2004;3:471-84. |
8. | Kim MH, Lee JM. Diagnosis and management of immediate hypersensitivity reactions to cephalosporins. Allergy Asthma Immunol Res 2014;6:485-95. |
9. | Yoon SY, Park SY, Kim S, Lee T, Lee YS, Kwon HS, et al. Validation of the cephalosporin intradermal skin test for predicting immediate hypersensitivity: A prospective study with drug challenge. Allergy 2013;68:938-44. |
10. | Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M, Barbaud A, Bilo MB, et al. Skin test concentrations for systemically administered drugs-an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013;68:702-12. |
11. | Romano A, Gaeta F, Valluzzi RL, Caruso C, Alonzi C, Viola M, et al. Diagnosing nonimmediate reactions to cephalosporins. J Allergy Clin Immunol 2012;129:1166-9. [ PUBMED] |
12. | Testi S, Severino M, Iorno ML, Capretti S, Ermini G, Macchia D, et al. Nonirritating concentration for skin testing with cephalosporins. J Investig Allergol Clin Immunol 2010;20:171-2. |
13. | Song WJ, Chang YS. Recent applications of basophil activation tests in the diagnosis of drug hypersensitivity. Asia Pac Allergy 2013;3:266-80. |
14. | Fontaine C, Mayorga C, Bousquet PJ, Arnoux B, Torres MJ, Blanca M, et al. Relevance of the determination of serum-specific IgE antibodies in the diagnosis of immediate beta-lactam allergy. Allergy 2007;62:47-52. |