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Properties of a drug that increase the risk of a drug-induced hypersensitivity reaction are:

1) molecular weight >4,000 Da (e.g., insulin, erythropoietin); 2) presence of foreign proteins or large polypeptides of nonhuman origin (streptokinase, beef or pork insulin, chimeric/murine-derived monoclonal antibodies); or 3) the ability of the parent drug or its active metabolite to bind to a carrier protein and form a complete antigen (penicillins and sulfonamides).[4]







Drugs can also cause hair and nail changes, affect the mucous membranes, or cause itching without outward skin changes.[1]

Drug-induced skin disorders are often classified as either acute or chronic.

Acute diseases include erythematous eruptions; urticaria, angioedema, and anaphylaxis; fixeddrug eruptions; hypersensitivity syndrome; Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN); warfarin-induced skin necrosis; vasculitis; serum sickness–like reaction; acute generalized exanthematous pustulosis (AGEP); and photosensitivity.

Chronic disorders include drug-induced lupus, drug-induced acne, and pigmentary changes.

Erythematous Reactions

This eruption is considered a type IV delayed cellmediated hypersensitivity reaction. The eruption typically occurs 4 to 14 days after the causative drug is initiated; however, the reaction may occur 1 to 2 days after discontinuation of the drug.[1,5]Upon a second exposure, the eruption may occur more rapidly.

Lesions are symmetric erythematous macules or papules, which may be pruritic and usually develop on the trunk or upper extremities before progressing and becoming more confluent.[5,6] Patients may experience a low-grade fever; however, mucous membranes are not typically involved.

Drugs that are more likely to cause this type of eruption include penicillins, cephalosporins, sulfonamides, anticonvulsants, and allopurinol (Table 1).[5,6] Primary treatment involves discontinuing the causative agent; however, if the drug is required for essential therapy, consideration may be given to continuation of the agent unless symptoms associated with the eruption suggest a more serious reaction. Topical corticosteroids, systemic corticosteroids, or antipruritic agents may also be considered. The eruption generally resolves within 7 to 14 days after the causative agent is discontinued.[6] The rash should be monitored for the first 48 hours to ensure that more severe complications/reactions are not occurring.[5] Differential diagnoses for patients presenting with this eruption include viral eruptions (e.g., Epstein-Barr virus, herpesvirus type 6), eruptions from a bacterial toxin, acute graft-versus-host disease, and Kawasaki disease.[5]

Urticaria, Angioedema, and Anaphylaxis

Urticaria (hives) is a common, acute, transient reaction sometimes referred to as the cutaneous expression of anaphylaxis.[5,6] It is characterized by pruritic monomorphic erythematous and edematous papules and plaques.[1,5,6] The onset of symptoms is rapid, sometimes within minutes, and the papules and plaques last from a few hours to 24 hours. New lesions, however, may continually develop. In contrast, angioedema is defined by involvement of dermal and subcutaneous tissues and is described as pale or pink swelling that affects the face, buccal mucosa, tongue, larynx, and pharynx. Anaphylaxis may complicate urticaria and angioedema and may involve additional body systems, leading to shock and death. Urticaria, angioedema, and anaphylaxis are a consequence of either an immunoglobulin E (IgE)–mediated type 1 hypersensitivity reaction or an anaphylactoid mechanism involving histamine or other inflammatory mediators. Management of this reaction consists of discontinuing the causative agent. Histamine receptor (H1) blockers, systemic corticosteroids, and epinephrine may also be required acutely.

Many drugs have been implicated in causing urticaria and/or angioedema (Table 1).[1,4–6] Examples of anaphylactoid reactions include responses to radiocontrast media, opiate-induced urticaria, and vancomycin-induced red man syndrome.

Fixed-drug Eruptions

These eruptions present as pruritic, red, raised lesions that may blister or develop into plaques.[1,6] A burning or stinging sensation may also be noted.[6] Lesions typically develop in minutes to days of drug initiation and typically resolve within days; however, hyperpigmentation may remain for months.[1,5] The lesions may develop anywhere on the body and may include the mucous membranes.[1] When the causative agent (Table 1) is readministered, the lesions recur in the same area as the primary eruption.[1,6] Removal of the offending drug is the primary treatment.[1] The mechanism for this eruption is unknown.[1,5,6]

Drug Hypersensitivity Syndrome

This syndrome, also known as drug rash with eosinophilia and systemic symptoms (DRESS), is a severe exanthematous eruption with fever, lymphadenopathy, and multi-organ involvement.[5,6] DRESS occurs more frequently in persons of African descent and may be fatal if not appropriately treated. Rash and fever are usually the first symptoms. The face, upper trunk, and extremities are originally involved, with inclusion of facial edema.[6] Severe hepatitis is responsible for many of the fatalities associated with this syndrome. Predominant eosinophilia is common, and aminotransferase, alkaline phosphatase, and/or bilirubin levels are elevated in approximately 50% of patients.[5] DRESS typically occurs 1 to 6 weeks after introduction of the causative agent.[5,6]

Drugs commonly associated with DRESS are listed in Table 1.[5,6] The incidence of the syndrome is estimated to be between 1 in 1,000 and 1 in 10,000 for patients exposed to anticonvulsants.[5] Early discontinuation of the offending drug is critical but may not lead to a complete recovery. Treatment may include topical corticosteroids for skin symptoms and systemic corticosteroids when the heart and lungs are affected. A relapse of the rash and hepatitis may occur when corticosteroids are tapered. The rash and visceral involvement may remain for several weeks after removal of the offending drug.[5]

Stevens-johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

SJS and TEN are rare, life-threatening syndromes.[5–7] The eruptions are drug-induced approximately 70% of the time.[5] The incidence of SJS is estimated to be 1 to 7.1 cases per million person-years, while the incidence of TEN is thought to be 0.4 to 1.2 cases per million person-years.[5,7,8] The risk is greatest in those patients infected with HIV.

In much of the literature, SJS and TEN are considered a spectrum of drug-induced skin disorders.[5,7,8]The definitions of the two syndromes have evolved over the years. The percentage of skin detachment determines the classification. Less than 10% of body surface area (BSA) with skin detachment is classified as SJS, while 10% to 30% of affected BSA is referred to as SJS/TEN overlap, and greater than 30% of affected BSA is classified as TEN.

The exact mechanisms are not understood; however, early lesion immunopathologic patterns infer a cell-mediated cytotoxic reaction to epidermal cells.[5] A genetic propensity for SJS and TEN may exist, as documented by a strong association between the human leukocyte antigen HLA-B*1502 allele and carbamazepine-induced SJS, and between the HLA-B*5801 allele and allopurinolinduced SJS in the Han Chinese population.[5,7]

Symptoms are very acute, and begin within 4 weeks of drug exposure.[5,6] Symptoms have also been documented to occur days after drug withdrawal. The eruption occurs even more rapidly when the causative agent is rechallenged. Initial symptoms include a prodromal phase of fever, sore throat, and stinging eyes.[5–7] The skin blisters and mucous erosions occur 1 to 2 days later, with extensive epidermal detachment and sloughing. The rash may cover the entire body. Initially, the lesions are irregularly shaped, erythematous, purpuric macules that progressively coalesce. Patients exhibit a positive Nikolsky's sign and flaccid blisters form. Necrotic epidermis detachment occurs. The mucous membranes (buccal, ocular, nasal, and genital) are affected in at least 85% of patients.[5,8] Additionally, epithelium of the gastrointestinal and respiratory tracts may be involved. Patients may also have increased hepatic enzymes and leukopenia; however, the syndromes are not typically associated with eosinophilia. A marked loss of fluids, a drop in blood pressure, electrolyte disturbances, and infection may occur.[6] SJS is fatal in 5% to 10% of patients and TEN is fatal in >30% of patients.[5,7]Discontinuation of the causative agent is vital. Treatment is symptomatic and supportive.[5–8] No other treatments are universally accepted, as the use of corticosteroids and other therapies is controversial.[5–7]

Over 100 drugs have been implicated as a cause of SJS or TEN.[3,5,6,9] The more commonly associated agents are provided in Table 1.[3,5–7,9]

Warfarin-induced Skin Necrosis

Warfarin tissue necrosis is a rare but serious disorder that may occur 3 to 5 days after the initiation of warfarin.[5] Red, painful plaques form that develop into necrosis, hemorrhagic blisters, and ulcers. Necrosis occurs in approximately 1 in 10,000 patients exposed to warfarin. Patients are at increased risk if a hereditary deficit in protein C is present, due to the hypercoagulable state during initiation of therapy. The mainstay of treatment is typically supportive. Warfarin should be discontinued and vitamin K, heparin, and monoclonal antibody–purified protein C concentrate administered.

Drug-induced Vasculitis (DIV)

This is defined as any case of inflammatory vasculitis caused by a specific drug.[10] The exact mechanism is unknown.[5,10] Patients may present with palpable purpuric lesions or a maculopapular rash. Ulcers, nodules, hemorrhagic blisters, or Raynaud's disease may also be present, and additional organ systems may be involved.[5] DIV may occur 7 to 21 days after initial drug exposure; however, the interval may be variable.[5,11] Withdrawal of the causative agent (Table 1) may lead to rapid resolution. For more severe cases, corticosteroids or immunosuppressive drugs may be required.[10] Drugs from almost every class have been associated with DIV.

Serum Sickness-like Reactions

These reactions present with fever, an urticarial rash, arthralgias, and lymphadenopathy.[5,6] The reaction occurs 1 to 3 weeks post initial drug exposure. Immune complexes, vasculitis, and renal lesions are not present. It is estimated that 1 in 2,000 children exposed to cefaclor may experience this reaction.[5] Additionally, minocycline, penicillins, and propranolol have been documented to induce a serum sickness–like reaction (Table 1). The causative agent should be discontinued. Systemic corticosteroids may be required for treatment over 5 days for severe symptoms.[4]

Acute Generalized Exanthematous Pustulosis (AGEP)

AGEP is a rare, acute, pustular eruption.[1,5,6,12] While the etiology may be viral or a reaction to mercury, greater than 90% of cases are drug induced.[1,5] AGEP is characterized by a fever and diffuse erythema. Burning and itching accompany the eruption. Patients may experience facial edema, swelling of the hands, and mucous membrane involvement. Small and mostly nonfollicular pustules develop. The eruption may last 1 to 2 weeks and is followed by superficial desquamation. Drugs frequently associated with AGEP are included in Table 1. Treatment consists of drug withdrawal, topical corticosteroids, and occasionally a systemic antipruritic agent or brief use of systemic corticosteroids.


This is an adverse cutaneous reaction triggered by doses of sunlight that are normally harmless. It may be idiopathic or result from either endogenous photosensitizers or exogenous causes, such as drugs.[5,13–16] Photosensitivity reactions may manifest as either a photoallergic or phototoxic reaction. Some drugs are capable of producing both types of reactions.

Phototoxic reactions are common and often predictable.[5,13,16] Drugs that induce a phototoxic reaction absorb ultraviolet A (UVA) light; no immunologic mechanisms are involved.[5,6,14,15] Phototoxicity is characterized by rapid onset of a burning sensation.[14,15] Clinically, patients present with an exaggerated sunburn, followed by hyperpigmentation.[5,13] This reaction occurs only on sun-exposed skin. Less common clinical forms of the reaction are photo-onycholysis (phototoxicity involving the nails) and pseudoporphyria (a bullous photosensitivity disorder). Photoallergy is less common than phototoxicity and is a result of cell-mediated hypersensitivity.[5,6,13,14] Photoallergy occurs from UVA transformation of drugs into allergens.[6] This reaction may involve exposed skin and skin that is not exposed to the sun.[5,6,13,14] Unlike the more immediate phototoxic reaction, photoallergy may not present until 24 to 72 hours post sun exposure. A photoallergy clinically appears as an acute, subacute, or chronic dermatitis.[13]

Many drugs have been documented to cause photosensitivity reactions (Table 1). Treatment includes discontinuation of the causative agent and avoidance of sun exposure.[5,6] Topical corticosteroids and systemic antipruritic therapies may be utilized in some circumstances. The use of sunscreens that block both UVA and UVB is important; however, in some patients sunscreen is the causative agent.Continue Reading


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Withdraw the drug.



Complications of Injecting Drug Use

  • Local problems—Abscess (Figures 240-2 
    Image not available.

    A 32-year-old woman with type 1 diabetes developed large abscesses all over her body secondary to injection of cocaine and heroin. Her back shows the large scars remaining after the healing of these abscesses. (Courtesy of ­Richard P. Usatine, MD.)

    and 240-3; Abscess), cellulitis, septic thrombophlebitis, local induration, necrotizing fasciitis, gas gangrene, pyomyositis, mycotic aneurysm, compartmental syndromes, and foreign bodies (e.g., broken needle parts) in local areas.2
    • IDUs are at higher risk of getting methicillin-resistant Staphylococcus aureus(MRSA) skin infections that the patient may think are spider bites (Figure 240-4).
    • Some IDUs give up trying to inject into their veins and put the cocaine directly into the skin. This causes local skin necrosis that produces round atrophic scars (Figure 240-5).
  • IDUs are at risk for contracting systemic infections, including HIV and hepatitis B or hepatitis C.
    • Injecting drug users are at risk of endocarditis, osteomyelitis (Figures 240-6and 240-7), and an abscess of the epidural region. These infections can lead to long hospitalizations for intravenous antibiotics. The endocarditis that occurs in IDUs involves the right-sided heart valves (see Chapter 50, Bacterial Endocarditis).2 They are also at risk of septic emboli to the lungs, group A β-hemolytic streptococcal septicemia, septic arthritis, and candidal and other fungal infections.


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A 75-year-old triathlete complains of gradually worsening vision over the past year. It seems to be involving near and far vision. The patient has never required corrective lenses and has no significant medical history other than diet-controlled hypertension. He takes no regular medications. Physical examination is normal except for bilateral visual acuity of 20/100. There are no focal visual field defects and no redness of the eyes or eyelids. Which of the following is the most likely diagnosis?

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The correct answer is A. You answered A.

Age-related macular degeneration is a major cause of painless, gradual bilateral central visual loss. It occurs as nonexudative (dry) or exudative (wet) forms. Recent genetic data have shown an association with the alternative complement pathway gene for complement factor H. The mechanism link for that association is unknown. The nonexudative form is associated with retinal drusen that leads to retinal atrophy. Treatment with vitamin C, vitamin E, beta-carotene, and zinc may retard the visual loss. Exudative macular degeneration, which is less common, is caused by neovascular proliferation and leakage of choroidal blood vessels. Acute visual loss may occur because of bleeding. Exudative macular degeneration may be treated with intraocular injection of a vascular endothelial growth factor antagonist (bevacizumab or ranibizumab). Blepharitis is inflammation of the eyelids usually related to acne rosacea, seborrheic dermatitis, or staphylococcal infection. Diabetic retinopathy, now a leading cause of blindness in the United States, causes gradual bilateral visual loss in patients with long-standing diabetes. Retinal detachment is usually unilateral and causes visual loss and an afferent pupillary defect.


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A 42-year-old African-American man has been diagnosed with hypertension for the past 10 years and treated with medication. One morning, he is found unresponsive by his wife. He is taken to the emergency department and pronounced dead by the physician. An autopsy revealed cardiac hypertrophy and a narrowing of the aorta just distal to the ligamentum arteriosum, with dilation of the intercostal artery's ostia. How could the death have possibly been prevented?



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