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Adverse cutaneous reactions to drugs: an overview. VK Sharma, GG SethuramanDepartment of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India., India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 0009715291 Keywords: Adolescent, Adult, Child, Diagnosis, Differential, Drug Eruptions, classification,diagnosis,epidemiology,etiology,therapy,Human, Incidence, Risk Factors,
Cutaneous adverse drug reactions are not uncommon, affecting 2-3 percent of hospitalised patients[1]. There is a wide spectrum of cutaneous adverse reactions ranging from transitory exanthematous rash to the potentially fatal Toxic Epidermal Necrolysis (TEN). Drug reactions are not confined to skin but other organs like liver, intestine, central nervous system, joints and bone marrow can also be affected in certain conditions like vasculitis, serum sickness and hypersensitivity reactions like TEN.
An adverse reaction is a reaction which is noxious and unintended and which occurs at dosages normally used in man for prophylaxis, diagnosis or therapy of disease or for the modification of physiological function. This definition is independent of the mechanism of the adverse reaction and includes allergies, idiosyncrasies, pharmacological and toxicological mechanisms and interactions between different drugs[2]. In the case of clinical trials injuries by overdosing, abuse/dependence and interactions with other medicinal products should be considered adverse drug reactions[3].
Various adverse cutaneous drug reactions have been found in 2-3 percent of hospitalised patients. Many of the commonly used drugs have reaction rates above 1 percent. Most of the times adverse cutaneous reactions are not severe enough and only a few are fatal[4]. Complications of drug therapy are the most common type of adverse event in hospitalised patients, accounting for 19 percent of such events[5]. The reported percentage of cutaneous reactions that physicians diagnose as "Potentially Serious" varies greatly and is estimated to be above 2 percent[6],[7]. Classification and mechanism of adverse drug reactions: Adverse drug reactions [8],[9],[10],[11],[12],[13],[14],[15] may arise as a result of Immunological or nonimmunological mechanisms, the latter being more common which may be predictable (type A) or unpredictable (type B). * Type A (predictable) reactions: These are due to known pharmacological actions of the drugs and usually dose related which occur in otherwise normal individuals. Predictable drug reactions include toxicity or overdose, side effects, drug interactions and secondary effects. * Type B (unpredictable) reactions: Unpredictable reactions are dose independent, not related to the pharmacological actions of the drug and may have a genetic basis. These reactions are divided into three categories: intolerance, idiosyncratic reaction and hypersensitivity reaction. Intolerance refers to an expected drug reaction occurring at a lower dose whilst idiosyncratic and hypersensitivity reactions are qualitatively abnormal unexpected responses. * Type C reactions include those associated with prolonged therapy e.g. analgesic nephropathy. * Type D reactions consist of delayed reactions e.g. carcinogenesis and teratogenesis. Classification of Adverse Drug Reactions 1. Non Immunological A. Predictable B. Unpredictable Over dosage Intolerance Side effect Idiosyncrasy Cumulation Delayed toxicity Facultative effect Drug interaction Teratogenecity Non-Immunological activation of effect or pathways Exacerbation of disease Drug induced chromosomal damage 2. Immunological (Unpredictable) IgE dependent drug reaction Immune complex reaction Cytotoxic reaction Cell mediated reaction 3. Miscellaneous Jarisch Herxheirner reaction Infectious mononucleosis ampicillin reaction Factors influencing adverse drug reactions 1. Age: Drug reactions are considered to be rare in infants and children[16]. Though allergic reactions are considered to be less common in aged people due to dampening of Immunological responsiveness[8], adverse drug reactions occur frequently with increasing age, especially in those above 65 years. Factors which may predispose elderly to adverse drug reactions, includes polypharmacyage associated changes in pharmacokinetics and pharmacodynamics, altered homeostasis, multiple pathology and use of drugs with a narrow therapeutic margin[17]. 2. Sex: Cutaneous reactions are more frequent among women[18]. 3. Underlying diseases: * Presence of infectious mononucleosis increases the risk of hypersensitivity skin rash to ampicillin or its analogues[19],[20],[21],[22],[23],[24]. * Human Immunodeficiency Virus (HIV) increases the propensity for sulfonamide rash[25]. * Pre-existing diseases[26] (impaired hepatic and renal function) increase the risk of development of drug rashes. 4. Genetic: Genetic or constitutional factors are important in drug reactions. * Toxic epidermal necrolysis has been shown to be associated with HLA-B 12; TEN due to sulfonamides with HLA-A29, B12 and DR7; and oxicamrelated TEN with HILA-A2 and A-12[27]. * Erythema multiforme has been associated with 3. HLA B 62 (B15), HLA B-35 and HLA A-33, HLA DR-53, HLA DQB1* 0301 28-32. Recurrent erythema multiforme has been shown to be strongly associated with HLA DQB[33]. * A recent report from Italy also suggested a strong association of FDE with HLA-B22 and CW1 antigen[34]. 5. Multiple drugs: Use of multiple drugs is associated with higher incidence of drug reactions as observed with increased frequency in hospitalised patients[5]. 6. Drugs: Certain drugs are associated with higher incidence of drug reaction eg. amoxycillin in 5.1 %, ampicillin in 3.3% and cotrimoxazole in 3.2%[1]. Clinical manifestations of cutaneous adverse drug reactions: 1. Exanthematous (maculopapular) rash: It is the most frequent of all cutaneous reactions to drugs and may occur with almost any drug at any time upto three weeks (but usually two) after administration. The clinical features are variable which may be morbilliform or scariatiniform or rubelliform. They may consist of profuse eruptions of small papules or purpuric lesions, which are usually associated with severe pruritus. The distribution is generally bilaterally symmetrical involving trunk and extremities. Maculopapular eruptions usually fade with desquamation, sometimes with post inflammatory hyperpigmentation[31]. Ampicillin, amoxycillin and sulphonamides are amongst the most frequent causes[36], other common drugs indlude phenytoin carbamazepine, NSAIDS and ciprofloxacin[35]. Less common drugs: cephalosporins, barbiturates, thiazides. INK phenothiazines, naproxen and quinidine[35]. 2. Fixed Drug eruption (FDE): FDE are characterized by a single or a few sharply demarcated erythematous lesions, which resolve promptly but the local hyperpigmentation remains. Face, genitalia and the extremities are commonly affected. It characteristically recurs in the same site or sites each time the drug is administered: with each exposure however the number of involved sites may increase. The drugs that frequently have been associated with FDE are sulfonamides especially cotrimoxazole, NSAIDS, phenolphthalein, tetracyclines[37],[38],[39],[40],[41],[42],[43] and ciprofloxacin[44]. 3. Urticaria/angioedemalanaphylaxis: Immediate hypersensitivity reactions can produce a range of cutaneous findings from simple urticaria to angioedema or fatal anaphylaxis[2]. Most urticarial and angioedema reactions caused by antibiotics are I9E mediated with the exception of polymyxin B and vancomycin, which directly release histamine from mast cells and basophils. Penicillin is the most common drug but other antibiotics including sulphonamides, cephalosporins and tetracyclines, as well as diuretics, tranquilizers, analgesics, muscle relaxants and anti hypertensives may be responsible. Morphine, codeine, doxorubicin, certain muscle relaxants like d-tubocurarine, and ionic radiocontrast dyes all cause mast cell degranulation. Urticaria and angioedema due to aspirin and other cyclooxygenase inhibitors is probably due to an imbalance between prostaglandin and leukotriene production. Urticaria manifests as severely pruritic circumscribed raised, oedematous and erythematous wheals widely scattered on the body. It may accompany systemic anaphylaxis or serum sickness. Urticaria lesions rarely persist for more than 24 hours[45],[46],[47]. Angioedema involving edema of the deep dermis or subcutaneous and submucosal areas is less commonly seen than urticaria as an adverse drug reaction with the exception of ACE inhibitors in which angioedema is more frequent during initial weeks of therapy[48]. 4. Vasculitis: It is characterized by inflammation and necrosis of small vessel walls, having multiple etiologies and drugs cause about 10 percent of cases of acute cutaneous vasculitis. It usually develops 7-21 days after a new drug is begun and is clinically characterized by palpable purpura predominantly of the lower extremities. The other less common manifestations include erythematous macules, haemorrhagic vesicles, papules, wheals, blisters, ecchymoses and large palpable nodules. It may involve other organs including kidneys, liver, joints, CNS and pericardium. Histologically there is swelling of endothelial cells, fibrinoid necrosis, neutrophilic infiltrate within and around the blood vessel and nuclear dust[49],[50],[51],[52]. The direct immunoflourescence is more often positive with deposits of IgM and C3 and fibrin in and around the capillaries[4]. Drugs most often implicated in causing vasculitis are allopurinol, penicillin. aminopenicillins, sulphonamides, thiazides, pyrazolones, hydantoin, propylthiouracil, streptomycin, phenothiazine. aminosalicylic acids, vitamins, tamoxifen and oral contraceptive pills[52]. 5. Serum sickness: It is a type 3 hypersensitivity reaction mediated by the depositions of immune complexes in small vessels, activation of complement and recruitment of granulocytes. Serum sickness in its usual form is characterised by fever, urticaria (lasting for more than 24 hours), angioedema, arthralgia and/or arthritis and lymphadenopathy. About half the cases of serum sickness, have visceral involvement. In serum sickness C3 and C4 complement levels are markedly decreased. It may be produced by drugs like penicillin, streptomycin, sulphonamides, thiouracil, diphenyil hydantoin and aminosalicylic acid[18],[53],[54],[55]. 6. Hypersensitivity syndrome: It is a severe idiosyncratic reaction characterized by skin rash and fever, often associated with hepatitis, arthralgia, lymphadenopathy or haematological abnormalities. It usually develops two to six weeks after the drug is first administered. The drugs associated with this syndrome include antiepileptic agents, dapsone, allopurinol, gold and sorbinil. Recovery is usually total but rash and hepatitis may persist for weeks. Treatment with steroids has been widely advocated but controlled studies are lacking[4]. 7. Erythema Multiforme/Stevens Johnson Syndrome/ Toxic Epidermal Necrolysis: Originally it was widely accepted that EM minor, EM major, Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were all part of a single “EM spectrum”[56]. But recently a consensus clinical classification was proposed, based on the pattern of skin lesions and the extent of epidermal detachment". Accordingly. EM (minor or major) could be one disorder, which is mainly caused by herpes virus infection and sometimes by other infectious diseases, but rarely, if ever by drugs. On the other hand. SJS, TEN and overlap (SJS/TEN) are probably severe variants of a single disorder mainly if not exclusively caused by drugs[57],[58]. i. Diagnostic criteria for EM: * An acute self-limiting illness * Duration of episode less than four weeks * Symmetrically and acrally distributed, typical or raised atypical target lesions. * Absent or limited mucosal involvement. * Recurrent episodes. ii. Stevens Johnson Syndrome: It is a serious mucocutaneous illness with systemic symptoms and signs with significant mortality[59],[69], characterized by the presence of flat atypical target lesions or purpuric macules with blisters that are distributed mainly on the trunk or widespread and the epidermal detachment being less than ten percent of body surface area (BSA). Two or more mucosal sites can be involved [57],[58]. iii. Toxic Epidermal Necrolysis: It is a life threatening illness characterized by high fever and confluent erythema followed by necrolysis. The epidermal detachment is more than 30 per cent of BSA. Patients with this condition may also have flat atypical target lesions (TEN with spots). Rprelly extensive epidermal necrosis occurs without any discrete target lesion (TEN without Spots)[57]. iv. In the overlap category (SJS/TEN) the area of epidermal detachment, which is often much less than the area of erythema, is between 10 and 30% of the BSA[57]. Drug induced SJS and TEN typically begin one to three weeks after the initiation of therapy Drugs associated with SJS and TEN[10] Drugs commonly associated Other drugs Thioacetazone Allopurinol Isoniaid Barbiturates Diphenylhydantoin Chlorpromazine Carbamazepine Erythromycin Phenylbutazone Rifampicin Cotrimoxazole NSAIDs Ampicillin Salicylates Oxytetracycline Oxyphenbutazone Phenylbutazone Piroxicam Pyritinol Diltiazam 8. Exfoliative Dermatitis: It may follow exanthematous eruptions or may develop as erythema and exudation in the flexures, rapidly generalizing. It is a serious condition and can be life threatening in elderly patients. It takes 4 of 6 weeks to subside even after withdrawal of drugs. The most frequently encountered drugs include sulfonamides, antimalarials, penicillin, INK thioacetazone and a variety of homeopathic preparations. Recently incriminated drugs are Captopril, Cefoxitin and Cimetidine[71],[72],[73]. 9. Pseudolymphomatous eruptions: The pseudolymphoma syndrome is associated with a number of anticonvulsant drugs and is characterized by fever, generalized rash, lymphadenopathy, hepatosplenomegaly, abnormal liver function tests, arthralgia, eosinophilia and dyscrasias. This condition usually responds to drug withdrawal[71],[72],[73],[74],[75],[76],[77]. Common drugs: Phenytoin, Mepheloin, Trimethadione and Phenobarbitone 10. Miscellaneous: a) Acneiform eruptions may be caused by steroids, ACTH, INH, Iodides, Bromides, dantrolene, danazol, quinidine, lithium and azathioprine. Lesions usually are monomorphic and comedones are absent [80],[81],[82],[83],[84],[85]. b) Lichenoid drug reactions (LDE): skin eruptions caused by certain drugs and compounds can be identical or similar to lichen planus. An LDE may have eczematous papules and generalized eczematous skin reactions with marked desquamation. The lesions are symmetrical, larger, and psoriasiform and often have a photo distribution. Mucosae are less commonly involved[86],[87],[88],[98]. Inducers of LDE, gold salts, antimalarials, diuretics, calcium channel blockers, heavy metals etc. c) Drug induced pigmentation results from increased melanin synthesis, increased lipofuscin synthesis, cutaneous deposition of drug related material or most commonly as a result of post inflammatory hyperpigmentation[99],[100],[101]. Drugs causing pigmentation: oral contraceptives, minocycline, antimalarials (chloroquine and mepacrine), chlorpromazine, clofazimine, gold and lead. d) Other reactions include photosensitivity, pruritus, hypertrichosis, photoonycholysis, bullous eruptions, alopecia, erythema nodosum, allergic eczematous dermatitis, systemic eczematous "contact type" dermatitis and pityriasis rosea like eruptions. Drug reactions in children and adolescents: The frequency of drug rash is low in the younger age group, probably because of less cumulative drug exposure, rapid dissipation of IgE compared to adults and poorly developed immunopathologic mechanisms like impaired T cell reactivation, diminished production of lymphokines, decreased chemotactic activity of macrophages and less functional competence of NK cells. The frequency of adverse cutaneous reactions in hospitalised children is 2 to 3 %, The common drug reaction patterns include maculopapular rash, fixed drug eruption and erythema multiforme and the commonly implicated drugs are antibiotics, antiepileptics drugs, antiemetics, bronchodilators, vaccines, antipyretic, analgesics and drugs used for preanaesthetic medication[16],[102],[103],[104],[105],[106],[107].
First Step: History and Physical Examination: * Temporal correlation with the drug * Incubation period (interval between the introduction of the drug and the onset of reaction) * Clinical pattern of the eruption * Any improvement on drug withdrawal * Any reaction on re-administration of the drug Second Step: In vivo Testing i) Rechallenge (Test Dosing): A positive rechallenge is generally accepted as strong evidence for causality. Reexposure should not be performed after a serious reaction. If a reaction fags to recur on rechallenge. it may be due to the fact that the previous reaction was a result of drug interaction[108]. ii) Patch Testing: It is a well-known method of rechallenging the skin in conditions when cell mediated immunity is suspected viz-maculopapular eruptions[109], FDE[110], exfoliative dermatitis[111] and lichenoid dermatitis[112]. iii) Dechallenge: Most adverse reactions to drugs should remit with dechallenge i.e. withdrawal of the drugs[108]. Third Step: In Vitro Testing Immunoassays such as radioallergosorbent lest (RAST) and Enzyme linked Immunosorbent Assays (ELISA) are in varying stages of development for the detection of IgE to aminoglycosides, penicillin, sulfonamides, ACTH etc. Other tests include Lymphocyte Transformation Test (LTT), Macrophage Migration Inhibition Factor Test (MIF), Lymphocyte Toxicity Assay (LTA), Basophil Degranulation Test, Histamine Release Test, Haemagglutination Assays 108 and flowcytometry. But unfortunately most in vitro tests 3 are unreliable for routine clinical use and are suitable only for immunologic research.
Basic principles: * Stop the offending drug or all drugs * Assess the type of rash and percentage involvement * Symptomatic treatment (antihistamines) for minor reactions * Steroids for major reactions like SJS, TEN and exfoliative dermatitis. Short courses of steroids have been advocated in severe maculopapular reactions, erythema multiforme and Stevens Johnson or overlap syndromes especially early in the disease (within 48 hours of the onset of the disease) Though the role of steroids in TEN is controversial[113], their restricted use in preexfoliative cases, slowly evolving cases of those in which the necrolysis has started on newly regenerated skin, has been found beneficial. The rationale for the use of steroids is based on the concept that TEN is due to a delayed hypersensitivity reaction or antibody dependent cytotoxicity and also their inhibitory action against the secretion of Tumour necrosis factor. * Anti-viral therapy in case of HSV induced EM[114] * Monitoring of vitals * Fluid and electrolyte maintenance Desensitization: when no alternative drug is available, it is possible to induce a state of antigen specific mast cell unresponsiveness in patients with Type 1 IgE mediated reactions especially to penicillin.
The severity of cutaneous adverse drug reactions is variable with TEN and SJS having a fatality rate of 30-40 percent. Severe drug reactions like SJS and TEN need to be identified early for the prompt treatment. High index of suspicion is required for early diagnosis and appropriate management.
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