Signs and symptoms
Generalized Reaction
Anaphylaxis and anaphylactoid reactions to drugs and other therapeutic agents have the same signs and symptoms of reactions as other agents that frequently cause allergic reactions (e.g., insect stings, foods, natural rubber latex). Reactions range in severity from mild pruritus, skin erythema and urticaria/angioedema to more generalized and systemic reactions of laryngeal edema, rhinitis/conjunctivitis, asthma, shock, and possibly death. immunoglobulin E sensitization is involved with the following drug reactions: P-lactam antibiotics, insulins, protamine, blood products, chymopapain, monoclonal antibodies, vaccines, natural rubber latex used in drug-delivery systems, ethylene oxide used to clean dialysis agents, or neuromuscular agents used in anesthesia induction. Anaphylactoid reactions may occur to sulfa radiocontrast media, ASA, nonsteroidal anti-inflammatory drugs, local/general anesthetics, angiotensin-converting enzyme-IN, vancomy-cin, chemotherapeutic agents, protamine, and monoclonal antibodies and blood products.
Other generalized allergic-like drug reactions include serum sickness, in which the symptoms begin 7-21 d into drug therapy. These drug-induced serum sicknesslike reactions are characterized by fever, malaise, urticaria, arthralgia, and lymphadenopathy. Reactions occur not only to blood products, but to β-lactam antibiotics, sulfonamides, thiouracil, cholecystographic dyes, hydantoin, aspirin, and streptomycin as well as to other agents.
Urticaria and Drug Reactions
• Severe urticaria may be a manifestation of cutaneous (mild) anaphylaxis/or anaphylactoid reactions.
• Urticaria is suggestive, but not diagnostic, of an allergic etiology.
• Urticaria may be caused by other factors, such as viral infections.
• A drug-induced skin rash that does not include urticaria does not rule out immunological involvement.
Isolated drug fever typically occurs between day 7 and 10 of therapy and may occur with many drugs, especially antibiotics and blood products. Drug-induced lupus erythe-matosus (DLE) is usually characterized by mild fever, malaise, and arthralgias. Butterfly rashes on the face, renal and central nervous system involvement, and Raynaud’s phenomenon are less common in the drug form than in the idiopathic systemic form of the disease (SLE). The drugs usually involved with this condition include procainamide, hydralazine, isoniazid, chlorpromazine, and hydantoin. The signs and symptoms usually improve or decrease with discontinuation of the specific drug involved. Drug-induced vasculitis may occur with hydralazine, antithyroid medications, or penicillamine. The anticonvulsant drug hypersensitivity syndrome is characterized by fever, facial edema, maculopapular rash, and generalized lymphadenopathy. This syndrome may be induced by phenytoin, carbamazepine, and phenobarbitol.
Skin Reactions
Isolated skin lesions in reaction to drugs are the most common adverse symptoms of drug reactions. Almost any type of manifestation can occur. However, a maculopapular/morbilliform rash is the most frequent, followed by urticaria in allergic or allergic-like reactions. Usually, drug reactions are symmetrical and begin in the extremities in the ambulatory patient or on the back in bedridden patients. The ampi-cillin/amoxicillin rash typically occurs on the knees and elbows first before spreading over the body. Urticaria/angioedema occurs with all types of reactions, including drug allergy, drug intolerance, and infections. A fixed drug eruption is a rare localized patch of eczema that reappears at the same site with repetitive drug treatment. Many drugs can be involved, but the reaction is more commonly associated with phenobarbital or antibiotic treatments.
Phototoxic (sunburn) rash may occur with short-term sun exposure while patient are taking drugs such as doxycycline or chlorpromazine. Prolonged sun exposure may produce aphotoallergic (urticarial or eczema) rash in individuals taking drugs such as griseof-ulvin, psoralens, and sulfonamides.
Erythema multiform consists of target-like rashes, usually without associated oral mucosal involvement are frequently caused by viral infections and are self-limited. When Erythema multiform (plus other rash types) includes involvement of two or more mucosal surfaces, a diagnosis of Erythema multiform major or Stevens-Johnson syndrome is made. Toxic epidermal necrolysis, also known as Lyell’s disease, is a severe extension of Stevens-Johnson syndrome
Febrile Mucocutaneous Reactions
• Includes Stevens-Johnson syndrome and toxic epidermal necrolysis
• Syndrome consists of fever, erythema multiforme rash and ulceration of two or more mucous membranes, plus with Toxic epidermal necrolysis, skin sloughing
• Stevens-Johnson syndrome and Toxic epidermal necrolysis are frequently drug associated; however, these reactions may be precipitated by viral infections and other unknown events
• If drug-associated, repeat exposure to the same drug is contraindicated
and is characterized by systemic symptoms and extensive denudation. Drugs are the usual cause of Stevens-Johnson syndrome and Toxic epidermal necrolysis and include antibiotics (e.g., sulfanomides and β-lactums) and antiseizure medications. Infections, including mycoplasm and viral, have been implemented in Stevens-Johnson syndrome. Although an exact mechanism for Stevens-Johnson syndrome and Toxic epidermal necrolysis is not known, it has been proposed that those reactions resemble a graft-vs-host reaction and may involve production of CD95 (FAS) apoptotic ligand, which leads to cell death.
Any drugs that have been implicated in Erythema multiform major (Stevens-Johnson syndrome and Toxic epidermal necrolysis) should be strictly avoided, since re-exposure may be associated with a more serious reaction.
Severe skin and systemic reactions to antiseizure medications can occur. These are termed either drug hypersensitivity syndromes or drug reactions associated with eosinophyillia and systemic symptoms (DRESS). These reactions can be differentiated from Toxic epidermal necrolysis by having less (or no) mucous membrane involvement, no skin loss, and the presence of eosinophils (and atypical lymphocytes) in the complete blood count plus systemic organ involvement (e.g., heart, lung, liver, kidney).
Signs and Symptoms of Other Organ-Specific Reactions
Type II immune reactions to drugs such as β-lactam antibiotics may result in a hemolytic anemia, usually 7 d after beginning therapy. Quinine, quinidine, and heparin have been involved in immune thrombocytopenic-type reactions. Hepatitis has been shown to occur with several drugs, including sulfonamides, phenytoin, and halothane. Methicillin as well as sulfonamides have been involved in producing interstitial nephritis in rare patients. Phenytoin and gold have been involved in reactions characterized by systemic eosinophilia and pneumonitis. The Churg-Strauss syndrome, a systemic eosinophilic granu-lomatosis and vasculitic process involving asthmatics, has been reported in increasing numbers of patients receiving leukotriene antagonists, glucocorticosteroids, and macrolide antibiotics, although there may be no causal relationship.
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