A 20-year-old college student was seen for fatigue and an upper respiratory infection and started on amoxicillin for a sore throat. Six days later she broke out with a red rash all over her body (Figure 212-1). She went to see her family physician back home with the rash and lymphadenopathy. A monospot was drawn and found to be positive. This morbilliform rash (like measles) is typical of an amoxicillin drug eruption in a person with mononucleosis. Amoxicillin was stopped, and diphenhydramine was used for the itching.
Amoxicillin rash in a young woman with mononucleosis. This is a morbilliform eruption. (Reproduced with permission from Richard P. Usatine, MD.)
Cutaneous drug reactions are the visible skin manifestations of a drug hypersensitivity and can present in a wide myriad of dermatosis. This includes the most common manifestation as a morbilliform exanthem but also includes urticaria/angioedema, acneiform or pustular, fixed drug eruption, eruptions, and the Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum. The primary morphology often elucidates a typical time course for its occurrence which can help identify the culprit drug for discontinuation. One should also quickly identify the more serious life-threatening drug-induced conditions or severe cutaneous adverse reactions (SCARs).
Drug hypersensitivity may be defined as symptoms or signs initiated by a drug exposure at a dose normally tolerated by non-hypersensitive persons.1 An adverse drug reaction (ADR) is defined by the World Health Organization as a noxious and unintended response to a drug at doses and indications normally used for treatment. They can be a predictable side effect of the pharmacologic action of the drug, type A (80%), or as an idiosyncratic reaction, which occurs only in susceptible patients, type B (10%–15%).2 Cutaneous drug reactions range from mild skin eruptions (e.g., exanthem, urticaria, and angioedema) to SCARs, the latter category including acute generalized exanthematous pustulosis (AGEP); drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS); SJS; and TEN.3 Other serious adverse reactions include anticoagulant-induced skin necrosis, drug-induced vasculitis, and generalized fixed drug eruption. Features suggestive of a complicated or severe SCAR include fever, facial swelling, bullae or skin shedding, mucosal involvement, and systemic symptoms.4
Cutaneous adverse reactions, drug reactions, medication reactions, adverse effects to drugs, hypersensitivity reactions.
Cutaneous drug reactions are common complications of drug therapy occurring in 2% to 3% of hospitalized patients.5
One study found that 4% to 5% of all adverse drug reactions were manifested in the skin.5 Approximately 1 in 6 adverse drug reactions represents drug hypersensitivity and can be either allergic or non–immune-mediated (pseudoallergic) reactions.2
Maculopapular eruptions, also known as exanthematous drug eruptions, are the most frequent of all cutaneous drug reactions, representing 95% of skin reactions.6 They are often confused with viral exanthems. This occurs most commonly with aminopenicillins, sulfonamides, cephalosporins, anticonvulsants, and allopurinol (Figures 212-1 and 212-2).
Urticarial drug reactions are the second most common skin eruptions, representing approximately 5% of cutaneous drug reactions.6 This reaction can result from any drug but commonly occurs with aspirin, penicillin, sulfa, angiotensin-converting enzyme (ACE) inhibitors, aminoglycosides, and blood products. Urticaria results from immunoglobulin (Ig) E reactions within minutes to hours of drug administration (Figures 212-3 and 212-4).
Drug-induced hyperpigmentation occurs with antiarrhythmics (amiodarone), antibiotics (minocycline), nonsteroidal anti-inflammatory drugs (NSAIDs), and chemotherapy agents (doxorubicin) (Figure 212-5).
A lichenoid drug eruption can also lead to hyperpigmentation and requires drug identification and discontinuation for resolution (Figure 212-6).
Warfarin-induced skin necrosis (WISN) is a rare but serious side effect predominantly seen in obese women and presents in the first few days of warfarin treatment. Skin lesions with purpura and necrosis usually occur in areas containing subcutaneous fat. WISN is more common in those with hypercoagulable abnormalities, given large loading doses (Figure 212-7).
Heparin-induced skin necrosis can present similarly but occurs later, typically 5 to 10 days after starting unfractionated or even low-molecular-weight heparin products. The necrosis is frequently observed at the site of the heparin injections and often favors fat-rich areas such as the abdomen. It may be associated with a trend of falling platelet counts from heparin-induced thrombocytopenia (HIT) and can be confirmed when suspected by an enzyme-linked immunosorbent assay (ELISA) for anti-platelet factor 4 antibody detection.
Fixed drug eruptions (FDEs) can occur with many medications, including phenolphthalein, doxycycline, ibuprofen, sulfonamide antibiotics, and barbiturates. FDEs are more commonly observed in men but occur in women as well (Figures 212-8, 212-9, 212-10, 212-11, 212-12, 212-13, 212-14).
Erythema multiforme (EM) is most often due to a preceding herpes simplex virus (HSV) or Mycoplasma infection (Figure 212-15).
SJS is more often associated with medication reactions and drug-induced in its etiology (Figure 212-16). Incidence of SJS is estimated at 1.2 per 6 million people.3
DRESS (Figures 212-17 and 212-18) is also a severe adverse drug-induced reaction characterized by eosinophilia and systemic symptoms, often with a rash, liver involvement, fever, and lymphadenopathy. In a case series (N = 172), 44 drugs were associated with DRESS.7 The most common causes are aromatic anticonvulsants, especially phenytoin, carbamazepine, and phenobarbital, and sulfonamides like dapsone and sulfasalazine.8 Also referred to as DIHS (drug-induced hypersensitivity syndrome), this syndrome is estimated to occur in 1 per 1000 to 1 per 10,000 exposures to antiepileptic drugs.9
Maculopapular drug eruption in a 5-year-old boy with an upper respiratory infection started on amoxicillin for a questionable otitis media. Four days later he broke out with a red rash all over his face and body. This morbilliform rash (like measles) is typical of an amoxicillin drug eruption. (Reproduced with permission from Robert Tunks, MD.)
Urticarial drug eruption secondary to trimethoprim/sulfamethoxazole. This young girl had urticaria multiforme. (Reproduced with permission from Richard P. Usatine, MD.)
Giant urticarial eruption (urticaria multiforme) in the patient in Figure 212-3 with drug reaction to sulfa. (Reproduced with permission from Richard P. Usatine, MD.)
Facial hyperpigmentation secondary to doxorubicin. (Reproduced with permission from Richard P. Usatine, MD.)
Hyperpigmented lesions from a biopsy-confirmed lichenoid drug eruption. This 61-year-old Hispanic woman developed these lichenoid lesions after starting medications for tuberculosis. (Reproduced with permission from Richard P. Usatine, MD.)
Warfarin (Coumadin) necrosis with dark bullae on the arm of a woman just started on Coumadin. (Reproduced with permission from Eric Kraus, MD.)
Annular-appearing fixed drug eruption with a dusky center on the leg. (Reproduced with permission from Richard P. Usatine, MD.)
Disseminated (or generalized) fixed drug eruption in a 31-year-old man. He had similar-appearing lesions in the exact same initial locations of the chin and glans penis upon exposure to trimethoprim-sulfamethoxazole in the past. During this episode the lesions returned to the chin and penis and also involved the trunk and extremities. (Reproduced with permission from Bucher J, Rahnama-Moghadam S, Osswald S. Generalized rash follows ankle ulceration. J Fam Pract. 2016 Jul;65(7):489-91. Frontline Medical Communications, Inc.)
Fixed drug eruption to ibuprofen with violaceous and hyperpigmented macules and erosions on the penis. (Reproduced with permission from Richard P. Usatine, MD.)
Bullous fixed drug eruptions. Bullous fixed drug eruption on the glans penis, a common location for these fixed drug eruptions. (Reproduced with permission from Jeffrey Meffert, MD.)
Third episode of fixed drug eruption to doxycycline. Note how the finger lesion is similar to a target lesion in erythema multiforme. However, there is no central epithelial disruption in this target lesion. The patient also had lesions on the palm, lips, and palate. (Reproduced with permission from Richard P. Usatine, MD.)
Fixed drug eruption to hydrocodone seen on the scalp and neck of this 22-year-old man. (Reproduced with permission from Richard P. Usatine, MD.)
Erythema multiforme showing target lesions on the palms secondary to herpes simplex in a young woman. (Reproduced with permission from Richard P. Usatine, MD.)
Erythema multiforme major with 2 mucus membranes involved secondary to mycoplasma. (Reproduced with permission from Sahand Rahnama, MD.)
Stevens-Johnson syndrome secondary to a sulfa antibiotic. (Reproduced with permission from Eric Kraus, MD.)
Drug reaction with eosinophilia and systemic symptoms (DRESS). Erythroderma has persisted, but the patient is feeling better after treatment and discharge from the hospital. (Reproduced with permission from Richard P. Usatine, MD.)
Drug reaction with eosinophilia and systemic symptoms (DRESS) on the face with facial swelling and erythema. This 40-year-old woman developed DRESS as a reaction to a new phenytoin prescription. (Reproduced with permission from Robert T. Gilson, MD.)
ETIOLOGY AND PATHOPHYSIOLOGY
Two mechanisms are responsible for cutaneous drug reactions: immunologic, including all four types of hypersensitivity reactions, and, more commonly, nonimmunologic (pseudoallergic). Although the precise mechanism of immune stimulation is unknown, it may be triggered by drug-protein (hapten-carrier) complexes or through direct interaction with immune receptors (p-i concept).2 The mechanism for pseudoallergic reactions is pathogenetically poorly defined.2
Hypersensitivity to NSAIDs is a nonimmunologic reaction that can be immediate (within hours after exposure) or delayed (more than 24 hours after administration).1
WISN develops during the hypercoagulable state as a result of a more rapid fall in concentration of protein C compared to the other vitamin-K–dependent procoagulant factors. Hypercoagulable abnormalities such as familial or acquired deficiency of protein C or S and factor V Leiden mutations have been implicated in WISN (see Figure 212-7).
Specific mutations in genes that encode drug detoxification enzymes have been shown in those having a higher risk of DRESS (see Figures 212-17 and 212-18) and are felt to lead to accumulation of drug-reactive metabolites.8
SJS/TEN is most commonly associated with penicillins and sulfonamide antibiotics but can also occur with anticonvulsants, NSAIDs, and allopurinol. It is hypothesized that a specific human leukocyte antigen (HLA)-B molecule may present the drug or its metabolites to naïve CD8 cells, resulting in clonal expansion of CD8 cytotoxic lymphocytes and induction of cytotoxic effector responses, resulting in apoptosis of keratinocytes.10 This pathway is not likely to be specific to SJS.
Drug hypersensitivity reactions increase with the drug dose, duration, route of administration (topical < subcutaneous < intramuscular < oral < intravenous),11 immune activation of the individual, and immunogenetic predisposition; they are also more frequent in women.2 Multiple drug therapy may also increase risk.11
Patients with certain HLA types in certain ethnic groups can be at higher risk for cutaneous drug reactions: for example, HLA-B*5701 identifies a higher risk of hypersensitivity reactions to abacavir (an antiretroviral drug).2,7 Other associations with specific medications have been further identified and can be screened for when the predictive value is deemed significant.
Prior drug reaction may result in a faster recurrence on reexposure.11
Concomitant illness, especially viral infections and autoimmune disorders.11
CLINICAL FEATURES AND TYPICAL DISTRIBUTION (THE MOST COMMON AND IMPORTANT DRUG ERUPTIONS)
Maculopapular—These eruptions, red macules with papules, can occur any time after drug therapy is initiated (often 7 to 10 days) and last 1 to 2 weeks. The reaction usually starts on the upper trunk or head and neck then spreads symmetrically downward to limbs. The eruptions may become confluent in a symmetric, generalized distribution that often spares the face (see Figure 212-1). Mild desquamation is normal as the exanthematous eruption resolves.
Urticaria and angioedema—Urticarial reactions present as circumscribed areas of blanching with raised erythema and edema of the superficial dermis (see Figures 212-3 and 212-4). They may occur on any skin area and are usually transient, migratory, and pruritic. Angioedema represents a deeper reaction, with swelling usually around the lips and eyes (see Chapter 156, Urticaria and Angioedema).
Hyperpigmentation—Drug-induced hyperpigmentation presents in many ways. Amiodarone causes a dusky red coloration that turns blue-gray with time in photo-exposed areas. Minocycline can cause a blue-gray color in acne lesions, on the gingiva, and on the teeth. Phenytoin (Dilantin) and other hydantoins may cause melasma-like brown pigmentation on the face. Bleomycin can cause a streaking hyperpigmentation on the trunk and extremities. Doxorubicin (Adriamycin), as evident in the case above, can cause hyperpigmentation of the face and nails (see Figure 212-5).
NSAIDs—The cutaneous reactions to NSAID-associated drug hypersensitivity are urticaria, angioedema, or anaphylaxis.1 These reactions can be caused by a single NSAID or multiple NSAIDs. There is also an NSAID-exacerbated urticaria and angioedema that occurs in patients with chronic idiopathic urticaria.
Warfarin-induced skin necrosis—WISN presents with sudden onset of a painful localized skin lesion that is initially erythematous and/or hemorrhagic and that becomes bullous, culminating in gangrenous necrosis (see Figure 212-7). It develops more often in obese women in their 50s in areas with high subcutaneous fat content such as breasts, thighs, and buttocks. This is different from a warfarin bleed secondary to too much anticoagulation (Figure 212-19).
Cocaine-associated retiform purpura (Figure 251-8 in Chapter 251, Cocaine). Nonprescription medications and substances should also be inquired into when suspecting a drug-induced rash. In particular, cocaine use is associated with a particularly unique retiform (angulated) purpura with necrosis, often affecting the ears, nose, and face. It has been determined to be induced by the contaminant levamisole now estimated to be in 70% of the U.S. supply of cocaine. ANCA antibodies and associated leukopenia are often detected.
Fixed drug eruption—FDE presents with single or multiple sharply demarcated circular, violaceous or hyperpigmented plaques that may include central blisters (see Figures 212-8, 212-9, 212-10, 212-11, 212-12, 212-13, 212-14). The lesion(s) appear after drug exposure and reappear exactly at the same site and location each time the drug is taken, typically within 8 hours. As the site resolves, it leaves a round to oval area of macular dusky gray to reddish brown hyperpigmentation (Figure 212-20). Lesions can occur anywhere including the hands and feet, but also favor the lips and genitalia, commonly involving the penis (see Figures 212-10 and 212-11). Bullous FDEs occur when the lesion blisters and erodes, followed by desquamation and crusting (Figures 212-11 and 212-21).
Erythema multiforme—EM presents with typical target (3 distinct zones) of raised edematous papules distributed acrally (see Figures 212-14 and 212-15; see Chapter 185, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis). It is a more benign reaction, typically associated with HSV or less commonly Mycoplasma pneumoniae infections.
SJS—It presents with erythematous or pruritic macules, widespread blisters on the trunk and face, and erosions of two or more mucous membranes, most commonly oral and conjunctival (see Figure 212-16). Prodromal symptoms may include fever, influenza-like symptoms, and painful skin. Burning or painful skin can be a sign of increased severity. Atypical 2-zoned macular target lesions or widespread erythema, particularly in the upper chest and back, are potential early signs of both SJS and TEN.11 Epidermal detachment occurs and involves less than 10% of total body surface area.
Toxic epidermal necrolysis—TEN is on the more severe side of the SJS/TEN spectrum. SJS is diagnosed when less than 10% of the body surface area is involved, SJS/TEN overlap when 10% to 30% is involved, and TEN when more than 30% is involved. A positive Nikolsky sign is present and induced by tangential pressure of the finger on the affected skin causing epidermal detachment. SJS and TEN are distinct from EM in that these are severe drug reactions with significant morbidity. Ocular involvement and complications can have long-term sequelae. Mortality ranges from less than 5% for SJS to more than 90% for those with severe TEN.
Drugs most commonly known to cause SJS and TEN are sulfonamide antibiotics, aminopenicillins, allopurinol, NSAIDs, antiretroviral drugs (especially non-nucleoside reverse-transcriptase inhibitors [NNRTIs]), amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine (see Chapter 185, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).12
Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS)—Infiltrated, palpable lesions are potential heralds of this disorder.11 Central facial edema and erythema (see Figure 212-18) and a maculopapular rash are seen along with high fever, generalized lymphadenopathy, and arthralgias. There may also be peripheral eosinophilia, atypical lymphocytosis, and increased hepatic enzymes. The typical rash is morbilliform, and significant facial edema is often characteristic. DRESS can also cause an erythroderma (see Figure 212-17). There is usually a longer lag time between drug exposure and symptoms, typically 15 to 40 days. The most common drugs include anticonvulsants, β-lactam antibiotics, allopurinol, NSAIDs, antiretrovirals, and sulfonamide antibiotics.4 It may be more common in certain populations with susceptible alleles or genetics. Certain screening can be done for at-risk populations and specific medications (carbamazepine, allopurinol, abacavir). There is often internal organ involvement, which includes hepatitis, nephritis, pneumonitis, myocarditis, and others. It has a significant mortality of up to 10%, and the symptoms can persist for weeks to several months.13
Large bleed in the arm secondary to overcoagulation with warfarin. The large hematoma was surgically evacuated to prevent neurovascular compromise to the arm. (Reproduced with permission from Richard P. Usatine, MD.)
Fixed drug eruption with hyperpigmented patches in a Hispanic woman. Note how the patches are gray to brown with a velvet-like appearance. (Reproduced with permission from Richard P. Usatine, MD.)
Bullous fixed drug eruption with a dusky color and an annular pink border on the ankle. (Reproduced with permission from Richard P. Usatine, MD.)
LESS COMMON DRUG REACTIONS
Acute generalized exanthematous pustulosis (AGEP)—A type of drug eruption occurring within 1–4 days of drug initiation. Antibiotics, specifically β-lactams, are among the most common culprits.4 AGEP results in the sudden appearance of clusters of small pustules along with erythematous skin (Figure 212-22). The patients are often febrile, and the pustules are primarily nonfollicular and sterile on an erythematous base. Leukocytosis and eosinophilia are also typically present. Systemic treatment is not usually required, as it tends to resolve spontaneously following withdrawal of the offending medication, with mortality existing between 1% and 2%.4
Systemic drug-related intertriginous and flexural exanthema (SDRIFE)—This is a type of drug eruption that causes erythema around the buttocks and genitalia along with intertriginous and flexural areas. If the pattern of erythema creates red buttocks, then it may also be called the baboon syndrome (Figure 212-23).
Acute generalized exanthematous pustulosis (AGEP) caused by a drug eruption. The clusters of small pustules with erythematous skin are seen on the buttocks. In this case the pustules and erythema covered major portions of the back and buttocks. (Reproduced with permission from Robert T. Gilson, MD.)
Systemic drug-related intertriginous and flexural exanthema. Because the pattern of erythema creates red buttocks, it may also be called the baboon syndrome. (Reproduced with permission from Robert T. Gilson, MD.)
APPROACH TO A SUSPECTED CUTANEOUS DRUG REACTION
A drug-induced reaction should be considered in anyone taking medication who develops a sudden cutaneous eruption. In reviewing the history, obtain a full listing of all the patient's medications, including prescriptions and also over-the-counter medications or supplements, by any route—including topical, intermittent, or regular. Current and recent past medication history is important, as the reaction may be attributable to a medicine the patient stopped taking or took only intermittently. A historical timeline is critical in defining the interval between the time the drug was taken and the onset of the eruption, because many drug-related adverse reactions have a characteristic time interval. Fixed drug eruptions and AGEP occur often within days, whereas SJS/TEN occur within weeks, and DIHS and DRESS even longer after the offending medication was started.
The next step is the physical examination to define the morphology of the skin findings. There are a myriad presentations, and the exam findings will define the type of adverse drug reaction and subsequently help in determining the most likely offending medications known to cause that particular type of drug reaction. Once one has established the type of drug eruption, that pattern can help define the type of drugs most commonly associated or described to cause that type of eruption. The particular drug eruption pattern coupled with its characteristic time course can then help define the likely offending medication in the drug history timeline (Table 212-1).
TABLE 212-1Types of Drug Eruptions* ||Download (.pdf) TABLE 212-1 Types of Drug Eruptions*
|Drug Eruption Type ||Typical Time Interval ||Commonly Responsible Drugs |
|Exanthematous eruption ||4–14 days || |
|Urticaria ||Minutes to hours || |
X-ray contrast media
|Fixed drug eruption || |
First exposure: 1–2 weeks
Re-exposure: 1–2 days, usually within 24 hours
|Acute generalized exanthematous pustulosis (AGEP) ||<4 days || |
Calcium channel blockers
|Stevens–Johnson syndrome/toxic epidermal necrolysis ||7–21 days || |
|Drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS) ||15–40 days || |
Examination should include a full cutaneous exam, including the groin and genitalia, mucosal surfaces of the eyes and oropharynx, and palpation for adenopathy. The clinician should specifically assess for the presence of facial edema or swelling, pustular or bullous lesions, and areas of denuded epithelium or skin at risk by evidence of a positive Nikolsky sign. This sign is induced by pushing a finger tangentially over involved skin and is positive if the epidermis detaches or sloughs with that frictional traction. The presence of any of the following are cause for concern for a more severe cutaneous adverse reaction: mucous membrane erosions, blisters or Nikolsky sign, confluent erythema, angioedema and tongue swelling, palpable purpura, skin necrosis, lymphadenopathy, fever, or hypotension.14
The ultimate goal is to identify and discontinue the offending medication if possible. Common causes of exanthematous morbilliform drug eruptions include antibiotics such as aminopenicillins, sulfonamides, and cephalosporins, although there are numerous culprits reported for this most common eruption. The most common attributable medications for the most severe drug eruptions such as SJS/TEN are sulfonamides, anticonvulsants, allopurinol, lamotrigine, and NSAIDs.
The diagnosis of drug eruptions is usually made based on history and physical examination, and with mild asymptomatic eruptions this is sufficient.
Evaluation of suspected severe cutaneous drug reactions, however, should include a complete blood count (CBC) with differential (to assess for eosinophilia or atypical lymphocytes) and comprehensive serum chemistry panel to look for systemic involvement such as liver and kidney effects or other organs involved with DRESS. Urinalysis for protein or microscopic hematuria should also be included when vasculitis is suspected. Other serologies such as antinuclear antibodies (ANAs) can be considered with specific entities.
Laboratory tests in patients with DRESS/DIHS may show atypical lymphocytes, eosinophilia, lymphocytopenia, and thrombocytopenia; and liver abnormalities are often seen. Eosinophilia may be seen with both AGEP and DRESS, but its absence does not exclude a drug-induced cause.15
In more challenging cases or instances of SJS/TEN, a skin biopsy may be helpful to confirm the diagnosis. Immunofluorescence studies may be helpful for evaluation of bullous lesions.
Intradermal skin testing may be hazardous to patients, and patch tests are not useful.
Skin biopsies are usually not required for diagnosis of WISN, but may aid in the diagnosis.
An FDE may be diagnosed by "provoking" the appearance of the lesion with an oral rechallenge with the suspected drug; however, this can be dangerous in bullous cases. Repeat drug challenge would also not be safe with angioedema, anaphylaxis, and suspected cases of SJS/TEN. Drug desensitization or induction of drug tolerance can be considered if no suitable alternative agent exists.15
Viral exanthems look just like generalized maculopapular drug eruptions. Sometimes when a patient is given an antibiotic for an upper respiratory infection, the rash that ensues may be the viral exanthem rather than a drug eruption. The best way to avoid this confusion is only to use antibiotics when the evidence for bacterial infection is sufficient to justify the risk of a drug reaction.
Urticarial reactions present as transient migratory circumscribed areas of blanching-raised erythema and edema of the superficial dermis. Patients experience itching. Identifying urticaria is easy compared with finding the precipitating factors. If there is a temporal association with starting a new drug, it is best to stop the drug (in most cases) and see if the urticaria resolves. (See Chapter 156, Urticaria and Angioedema.)
EM presents with sudden onset of rapidly progressive, symmetric, and cutaneous lesions with centripetal spread. The patient may have a burning sensation in affected areas but usually has no pruritus. EM is most often caused by a reaction to an infection such as HSV or Mycoplasma pneumoniae (see Figures 212-14 and 212-15) but may be caused by a drug reaction. Careful history and physical examination can help differentiate between the possible causes (see Chapter 185, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).
SJS and TEN present with generalized cutaneous lesions with blisters, fever, malaise, arthralgias, headache, sore throat, nausea, vomiting, and diarrhea. The patient may also have difficulty in eating, drinking, or opening his or her mouth secondary to painful, often hemorrhagic crusted erosions of the oral mucous membranes (see Figure 212-16) and often have a mucopurulent conjunctivitis. Most cases of SJS or TEN are secondary to drug exposure, and it is the job of the clinician to investigate this cause and stop any suspicious medications. SJS and TEN can be life-threatening (see Chapter 185, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).
DRESS/DIHS (see Figures 212-17 and 212-18) can be distinguished by involvement of organs other than skin, including liver (hepatitis in 50% to 70%), kidney (nephritis in 10%), and, more rarely, pneumonitis, colitis, myocarditis, parotitis, meningitis, encephalitis, or pancreatitis; the pattern of organ involvement appears to depend on the drug trigger.8,9 Some of the sequelae from DRESS/DHIS are strongly related to herpesvirus reactivation.9 A recurrence of symptoms at the third week is common. Diagnostic criteria have been proposed to include all of the following: maculopapular rash developing more than 3 weeks after drug exposure, prolonged clinical symptoms after drug discontinuation, fever (>38°C [100.4°F]), liver abnormalities or other organ involvement, leukocyte abnormalities (atypical lymphocytosis, leukocytosis, eosinophilia), lymphadenopathy, and human herpesvirus-6 reactivation.8
Pityriasis rosea (PR) is a mysterious eruption of unknown etiology that could easily mimic a maculopapular drug eruption. Look and ask for the herald patch to help make the diagnosis of PR. In PR, look for the collarette scale and observe whether the eruption follows the skin lines (causing a Christmas-tree pattern on the back). These clinical features should help positively identify PR, as there are no laboratory tests that are specific to PR or most drug eruptions (see Chapter 159, Pityriasis Rosea).
Syphilis is the great imitator. Any generalized rash without a known etiology may be caused by secondary syphilis. A rapid plasma reagin (RPR) will always be positive in secondary syphilis and is easy to run (see Chapter 225, Syphilis).
Bullous pemphigoid and pemphigus vulgaris can resemble a bullous drug eruption. Biopsies are the best way to diagnose these bullous diseases. Their clinical pictures are described in detail in Chapters 192, Bullous Pemphigoid, and 193, Pemphigus.
Hematoma is a much more common complication of warfarin therapy and must be distinguished from WISN early to decrease permanent tissue damage; a high index of suspicion is needed, and a very elevated international normalized ratio (INR) will confirm that bleeding may be a result of overcoagulation (see Figure 212-19).
Discontinue the offending medication for all types of drug reactions whenever possible. Older patients with drug eruptions may be on multiple medications and may be very ill; however, efforts should be made to discontinue all nonessential medications.6
Hyperpigmentation—Stop the drug if possible. In the case of doxorubicin-induced skin hyperpigmentation, the doxorubicin may be continued if it is the best chemotherapy for a life-threatening malignancy (see Figure 212-5).
Local wound care, debridement, and skin grafting may need to be performed to repair resultant disfigurement from necrosis.
Treatment of the drug eruption depends on the specific type of reaction.
Urticarial/angioedema-type drug reactions are treated with antihistamines. If the angioedema is causing airway compromise, epinephrine (10 mcg/kg intramuscular) and other treatments will be necessary. Usually an H1-blocker is started. In some cases of urticaria/angioedema, an H2-blocker is added on for broader antihistamine effects (see Chapter 156, Urticaria and Angioedema).
Diphenhydramine (Benadryl)—Adult dosing is 25 to 50 mg orally every 4 to 6 hours (nonprescription). Hydroxyzine (Atarax)—Adults receive 25 mg orally every 6 hours. Pediatric dose is 0.5 to 1.0 mg/kg per day orally 4 times daily.
Nonsedating nonprescription antihistamines such as cetirizine (Zyrtec), fexofenadine (Allegra), or loratadine (Claritin) may help reduce the sedation of earlier generation antihistamines. An H2-blocker can be added if needed.
Exanthematous or maculopapular eruptions are treated with topical steroids such as triamcinolone, which may be used for symptomatic relief of pruritus.
FDEs are treated by discontinuing the drug and applying topical corticosteroids to the affected area.5
Oral steroids are first line therapy in DRESS/DHIS, and the course is typically more prolonged.16
REFERRAL OR HOSPITALIZATION
Patients with WISN, SJS, TEN, and DRESS/DIHS, are usually hospitalized and those with SJS/TEN ideally referred and managed in a burn center familiar with the intensive skin care needs for this condition ("acute skin failure"). The prognosis for those with TEN is more guarded, with scarring, blindness, and death possible.
WISN treatment is generally supportive, including discontinuing the warfarin, admission to the hospital, and administration of vitamin K and either protein C concentrate if available or fresh-frozen plasma.17,18
Many clinicians recommend resuming heparin therapy if needed for the patient's underlying pathology that prompted the use of initial anticoagulation therapy.17,18
SJS, TEN, DRESS/DIHS—Start with early diagnosis, rapid discontinuation of the culprit offending agent, admission to an intensive care unit (ICU) or burn unit, preferably where supportive therapy includes wound care, fluid and electrolyte management, nutritional support, temperature management, pain control, and monitoring or treatment of superinfections (see Chapter 185, Erythema Multiforme, Steven-Johnson Syndrome, and Toxic Epidermal Necrolysis).5,6 Eye involvement merits an ophthalmologic consult, and severe disease may benefit from amniotic membrane transplantation. which, if performed early in the disease course (within 7–10 days), may prevent blindness and scarring. The first-line treatment is controversial but may include intravenous immunoglobulin (IVIG), short-term systemic steroids, cyclosporine, and now tumor necrosis factor (TNF)-α inhibitors.
Patients are monitored for developing infection, but antibiotics are not used prophylactically and are started only when infection is suspected.5
DRESS/DIH requires longer courses of steroids with slow tapering over months (often for liver or renal involvement), and complications of delayed hypothyroidism must be monitored for. Liver transplant has been used in patients with DRESS.16
Avoid reexposure to the drug.
In the future, prevention may occur through screening for HLA associations and drug avoidance.1
Screening for HLA-B*1502 is advised by the U.S. FDA and Health Canada for patients of southeastern Asian ethnicity before carbamazepine therapy.1
Most cutaneous drug reactions resolve with discontinuation of the causative agent.
Mortality, however, is high at 5% for SJS and 30% to 50% for TEN.6,19 In a case series of patients with possible or probable DRESS, the case fatality rate was 5% (9 of 172).7
Studies show the occurrence of autoimmune diseases, including autoimmune thyroid disease, months to years after resolution of DIHS/DRESS, and thyroid function should be routinely screened for at least 2 years.8
Follow-up is most important when the case is severe or the diagnosis is uncertain. Clear-cut mild drug reactions may not need scheduled follow-up.
Continued surveillance for autoimmune disorders may be warranted in patients following DRESS/DHIS.
Most patients with drug eruptions recover fully without any complications. The patient should be warned that even after the responsible medication is stopped, the eruptions may clear slowly or even worsen at first; the patient should be advised that the reaction may not resolve for 1 to 2 weeks.
The patient should also be counseled that mild desquamation is normal as the exanthematous eruption resolves. Confirming the diagnosis of an FDE, especially for lesions presenting on the glans, may allay the patient's anxiety about the venereal origin of the disease.
The family should be counseled as to the genetic predisposition of some drug-induced eruptions.
If a severe ADR, the patient should be advised to enroll in a medical alert program and to wear a bracelet detailing the allergy.
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