Drug eruptions are common in the hospitalized patient. The majority of them are relatively benign. When suspecting a drug eruption a drug chart with medications and time courses is extremely helpful in identifying the causative medication. Any medication can cause a drug eruption but the most common offenders are antibiotics (aminopenicillins, cephalosporins, macrolides), sulfonamides, and anticonvulsants.
Morbilliform Drug Eruptions
Morbilliform eruptions are the most common type of drug eruptions and follow a benign course. They occur 7 to 12 days after the start of a new medication. The eruption may develop sooner on rechallenge.
The rash begins as erythematous macules on the trunk that soon generalizes symmetrically (Figure 47–6). The lesions then become more confluent and slightly raised. Morbilliform eruptions last 1 to 2 weeks and may be associated with a low grade fever.
Morbilliform drug eruption. Symmetric erythematous macules and papules on the trunk.
Workup and Differential Diagnosis
Morbilliform drug eruption is a clinical diagnosis. A high index of suspicion and recent initiation of culprit medications is often present. There may be a peripheral eosinophilia and mildly elevated white blood cell count. Most importantly, it needs to be watched for possible evolution to a more serious drug eruption such as acute generalized exanthematous pustulosis (AGEP), DRESS, SJS and TEN. Viral exanthems clinically mimic morbilliform eruptions. Skin biopsy is relatively nonspecific but findings such as eosinophils and the presence of interface changes is highly suggestive of a drug eruption.
Aside from discontinuing the medication no specific treatment is needed. Topical steroids may be used but will generally not hasten recovery.
Acute Generalized Exanthematous Pustulosis
Acute generalized exanthematous pustulosis (AGEP) is characterized by an acute onset of widespread pustules and erythema. The most common causes of AGEP are the beta-lactam antibiotics and macrolides. It can occur as early as 24 hours after exposure to a few days. Other important causes of AGEP include calcium channel blockers and antimalarials.
The rash begins as erythema, often edematous, usually starting on the face or intertriginous areas. Within days, widespread sterile nonfollicular pustules generalize (Figure 47–7) and are accompanied by high fever. The rash may be asymptomatic, mildly pruritic or burning. Although pustules mainly characterize the rash, blisters, targetoid lesions, and mucous membrane involvement may also occur. AGEP lasts 1 to 2 weeks and resolves with superficial desquamation.
Acute generalized exanthematous pustulosis. Nonfollicular pustules studding edematous erythematous plaques.
Workup and Differential Diagnosis
The initial presentation may resemble a morbilliform eruption but will be easily distinguished once the pustules appear. High fever is characteristic. There is often an elevated white count. There are generally no other lab abnormalities but mild renal dysfunction, mild hypocalcemia, and mild eosinophilia can occur. Eliciting a personal or family history of psoriasis is helpful since AGEP cannot be clinically distinguished from pustular psoriasis. A skin biopsy will distinguish between the two. A careful review of medications and time course will often reveal the causative drug. AGEP can be distinguished from DRESS by the lack of other organ involvement.
Aside from discontinuing the offending medication, treatment is supportive. Topical steroids (such as triamcinolone 0.1% cream) may be helpful if the rash is pruritic and antipyretics for fever.
Drug Reaction with Eosinophilia and Systemic Symptoms
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a drug eruption that involves at least one other organ system. The liver is the most commonly affected organ followed by the kidney. The underlying mechanism is most likely due to an impaired ability to detoxify certain drugs. DRESS occurs somewhat later than other drug eruptions at 2 to 6 weeks after starting the medication with a mean of 3 weeks.
DRESS was formally known as phenytoin hypersensitivity syndrome and the anticonvulsants are indeed the most common class of medications to cause DRESS. Other drugs include antibiotics (sulfonamides, minocycline, vancomycin), allopurinol, antiretrovirals, amlodipine, and nonsteroidal anti-inflammatory drugs (NSAIDs).
The rash often begins as a morbilliform eruption but often becomes more edematous and violaceous appearing as it evolves. The face, upper trunk, and upper extremities are most often affected. A hallmark of DRESS is facial edema. Blisters, pustules, purpuric lesions, and an exfoliative dermatitis are other clinical manifestations of DRESS. The mucous membranes can be involved. Fever and lymphadenopathy is almost always present.
Workup and Differential Diagnosis
Laboratory workup for DRESS includes a complete white blood cell count with differential to look for eosinophilia, liver function tests and creatinine. Elevated Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) is often present (70%) and can evolve to a fulminant hepatitis. Kidney involvement is less common (11%). Myocarditis, pneumonitis, and even neurologic symptoms can occur but are fortunately uncommon to rare.2,3 Skin biopsy is relatively nonspecific.
Discontinuing the offending medication is paramount. Depending on the degree of organ involvement, systemic steroids starting at a dose of atleast 1 mg/kg/d may be initiated and tapered slowly over at least a month. Few to several months may be needed. Some advocate the use of IVIG for severe DRESS. Antithyroid antibodies resulting in hypothyroidism can occur a few months after DRESS. A TSH should be checked 1 to 3 months afterward and periodically as indicated.
Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis
Stevens–Johnson syndrome (SJS) and TEN are rare, severe, potentially life-threatening drug reactions. The 2 conditions are best thought of as part of a clinical spectrum with SJS associated with milder disease with less than 10% affected body surface area (BSA), SJS-TEN overlap as intermediary disease with 10% to 30% affected BSA and TEN with greater than 30% affected BSA. They are clinically characterized by widespread skin detachment due to keratinocyte apoptosis.
SJS and TEN generally occur about 7 to 21 days after the medication is started. The most common culprits are sulfonamides (particularly trimethoprim-sulfamethoxazole), allopurinol, antibiotics, antiretrovirals, and NSAIDs. Certain risk factors have been identified and include certain Human Leukocyte Antigen types, decreased ability to detoxify drugs, and HIV infection. SJS has a mortality rate of up to 5% vs up to 30% in TEN.
Initial symptoms include fever, eye pain, and dysphagia. A rash appears a few days later and begins on the trunk and progresses to involve the face and upper extremities. The palms and soles are often involved. The rash initially looks morbilliform then becomes more dusky appearing and/or purpuric. There is mucosal involvement and often appears as hemorrhagic crusting of the lips (Figure 47–8) and painful erosions in the mouth. Patients will often have dysuria. The Nikolsky sign is positive. As the lesions evolve even further they take on a characteristic gray hue with subsequent detachment of the epidermis. This is seen as fragile bullae that break easily revealing raw dermis (Figure 47–9).
Stevens–Johnson syndrome. Hemorrhagic crusting of the lips.
Stevens–Johnson syndrome. Vesiculobullous lesions with surrounding erythema on the palm.
Toxic epidermal necrolysis. Sloughing of the skin revealing raw dermis.
Workup and Differential Diagnosis
There is no specific laboratory workup for SJS/TEN. There may be electrolyte imbalance due to impaired skin barrier function. Creatinine should be followed regularly to monitor renal function. The clinical presentation is characteristic but a skin biopsy is diagnostic revealing full thickness epidermal necrosis.
Several risk factors that predict worse prognosis have been identified. The SCORTEN represents this prognostic scoring system (Table 47–2).4,5,6 Important conditions that need to be distinguished are pemphigus vulgaris, SSSS, and erythema multiforme major.
Table 47–2SCORTEN. Risk factors to predict mortality risk in TEN. ||Download (.pdf) Table 47–2 SCORTEN. Risk factors to predict mortality risk in TEN.
|Risk Factor ||Point |
|Age > 40 years old ||1 |
|Malignancy ||1 |
|Heart rate > 120 beats/min ||1 |
|Serum BUN > 27 mg/dL ||1 |
|Detached skin > 20% body surface area ||1 |
|Serum bicarbonate > 20 mEq/L ||1 |
|Serum glucose > 250 mg/dL ||1 |
|Number of Risk Factors ||Mortality Risk |
|0-1 ||3.2% |
|2 ||12.1% |
|3 ||35.3% |
|4 ||58.3% |
|5 or more ||>90% |
Treatment of SJS/TEN is dependent on early diagnosis and immediate discontinuation of the offending medication. This reduces mortality by up to 30% per day for TEN. Next, supportive care and therapy (outlined below) is instituted. Supportive care is best undertaken in a burn unit familiar with the special needs of patients with SJS/TEN. Nutritional support is paramount. Many patients will require a nasogastric tube due to dysphagia.
Specific treatment is controversial and evolving but for uncom-plicated SJS, prednisone started at 1 mg/kg/d with a slow taper is often used. For SJS/TEN overlap and TEN, cyclosporine or IVIG is advocated. The author uses cyclopsporine starting at 3 mg/kg/day IV or PO in divided BID doses. The data for using cyclosporine is promising. Higher doses of IVIG are used than for autoimmune bullous diseases. We recommend starting IVIG at 1 gm/kg/d for 3 days for a total of 3 g/kg. IVIG is thought to work via inhibition of Fas-Fas ligand mediated keratinocyte death.
For eye involvement, ophthalmology should be consulted. Steroid, antibiotic, and lubricating eye drops are often needed. Long-term sequelae include scarring leading to vision loss. The patient needs to be monitored for infection. Death is mainly due to infection from the impaired skin barrier due to S. aureus and Pseudomonas aeruginosa.
Purpura is hemorrhage into the skin or mucous membranes. The differential diagnosis is extensive and a thorough review of these is outside the scope of this chapter. The two main morphological entities of interest are palpable purpura and retiform purpura. Palpable purpura generally presents as bright red and slightly raised lesions. Discussion will mainly be limited to leukocytoclastic vasculitis (LCV) as the leading clinical entity associated with palpable purpura.
Retiform purpura has a net-like pattern most easily seen at the edges of the lesion. This pattern is due to the pattern of occlusion of the affected vessels. This can be caused by infiltration of the vessel wall by organisms in immunocompromised patients, abnormal coagulation or embolic phenomenon.
Leukocytoclastic vasculitis (LCV) refers to inflammation of predominantly small vessels in the dermis. It is usually idiopathic (~50%) but it can sometimes be attributed to other causes (Table 47–3). It is mediated by the deposition of immune complexes in the vessels. These immune complexes ultimately lead to the release of proteolytic enzymes from neutrophils producing vessel wall inflammation or vasculitis.
Table 47–3Major causes of LCV. ||Download (.pdf) Table 47–3 Major causes of LCV.
|Cause ||Incidence ||Common Agent/Disease(s) |
|Idiopathic ||50% || |
|Infectious ||15%-20% || |
Group A beta-hemolytic streptococci
Upper respiratory infections
Hepatitis C > B (including vaccines)
Neisseria meningitidis (acute)
Disseminated fungal infections (immunocompromised patients)
|Inflammatory ||15%-20% || |
Autoimmune connective tissue diseases
Inflammatory bowel disease
|Medication ||10%-15% || |
Cocaine adulterated with levamisole
|Malignancy ||2%-5% || |
Plasma cell dyscrasias
LCV generally presents as palpable purpura, flat purpuric or petechial lesions, or as urticarial lesions (Figure 47–10). Atypical presentations include pustules and targetoid lesions. They occur 7 to 10 days after the triggering event and tend to favor the extremities and dependent areas. Lower extremity edema may be present. Lesions are usually asymptomatic but may be associated with mild pruritus or burning. Up to 50% of patients will also have mild systemic symptoms such as fevers, myalgias, arthralgias, and weight loss.
Leukocytoclastic vasculitis. Palpable purpura on the lower extremity.
Workup and Differential Diagnosis
When LCV is suspected clinically, laboratory workup should be directed at the suspected underlying cause. An initial screening workup could include a complete blood count with differential, ESR, C-reactive protein, blood and urine cultures, cryoglobulins, hepatitis B and C, ANA, C3, C4, ASO titer, and a chest X-ray. Anti-Neutrophil Cytoplasmic Antibodies (ANCAs), further imaging, and a malignancy workup can also be considered. A skin biopsy will confirm the histopathologic diagnosis of vasculitis. Direct immunofluorescence may also be useful.
The main concern will be the presence of a systemic vasculitis or the possibility of cryoglobulinemia. There is no associated vasculitis with Type I cryoglobulinemia since it is due to occlusion of vessels and presents with retiform purpura. It is usually caused by an underlying lymphoproliferative disorder. Types II and III cryoglobulinemia, also known as the mixed cryoglobulinemias, are due to a vasculitic process and presents as palpable purpura. It is usually due to underlying hepatitis C infection and less likely due to HIV, autoimmune disease, or an underlying lymphoproliferative disorder.
Most cases of LCV do not require treatment. Treatment should be directed at the underlying cause, if found. For mild, skin-limited disease, NSAIDs, and antihistamines may be used in addition to other supportive measures such as leg elevation and avoiding tight-fitting clothing. In more severe cases, one can consider a short course of systemic steroids starting at 1 mg/kg/d of oral prednisone. For systemic vasculitis, corticosteroids and other immunosuppressive therapies are the mainstay of treatment.
Calciphylaxis is a potentially fatal condition characterized by vessel calcification with necrosis of the skin and soft tissues. It primarily affects obese female patients with diabetes often in the setting of chronic renal failure. Its etiology is poorly understood.
Calciphylaxis begins with livedoid racemosa, a net-like, mottled discoloration of the skin. The lesions are fixed, unlike the temporary lesions of livedo reticularis. As the lesions progress they become more purpuric (retiform) and necrotic (Figure 47–11). The lesions are severely painful and are most common on the lower extremities. Fatty areas such as the abdomen, buttocks, and breasts are also often affected.
Calciphylaxis. Necrotic plaques on the lower extremity.
Workup and Differential Diagnosis
In the typical patient with diabetes and renal failure, the diagnosis is made easily. Laboratory workup should include serum calcium, phosphate, electrolytes, BUN, creatinine, PTH, and a coagulation factors including PT, aPTT, antithrombin III, proteins C and S, anticardiolipin, antiphospholipid. Other workup to consider is hepatitis C serologies, cryoglobulins, and ANCA to rule out an underlying vasculitis.
Skin biopsy should be taken from the area adjacent to necrosis, preferably an area with early erythema or purpura. An excisional biopsy will provide an adequate sample and should go deep to subcutaneous fat. Other considerations include warfarin necrosis and purpura fulminans.
Treatment is mainly directed at correcting calcium dysregulation. This is accomplished with low calcium dialysis, phosphate binders, and possible parathyroidectomy. Intravenous sodium thiosulfate is also commonly used with variable success. Almost all patients will require analgesia for the pain.
Careful wound management with gentle debridement is recommended. Hyperbaric oxygen therapy can be considered for very painful ulcers. Unfortunately, necrotic lesions are very resistant to treatment and often provide a nidus of infection leading to sepsis. This is the leading cause of death in these patients. Even with optimal treatment, the mortality approaches 40% to 80%.
Purpura fulminans is a severe, life-threatening condition due to 3 main etiologies: infection and DIC, postinfectious, and hereditary deficiency of protein C or S (neonatal). Of particular interest is the type caused by infection, usually due to bacterial sepsis but can also be caused by viruses. In the postinfectious kind, it is due to a transient deficiency of protein S due to consumptive processes. Mortality is high at 20% to 40%.
Purpura fulminans presents with an acute onset of large purpuric to ecchymotic areas mainly on the distal extremities and acral surfaces. Its appearance can be gangrenous. The lesions enlarge rapidly and may have overlying hemorrhagic bullae (Figure 47–12). They are quite painful. It is invariably accompanied by fever, chills, shock, and often with DIC.
Purpura fulminans. Necrotic plaque with bullae formation in the antecubital fossa.
Workup and Differential Diagnosis
Laboratory workup should include blood and urine cultures, complete white blood cell count with differential, DIC workup.
Few conditions present with a sudden onset of large purpuric lesions. Rocky Mountain spotted fever may present with a purpura fulminans-like picture. In the setting of a patient with known connective tissue disease, the catastrophic antiphospholipid antibody syndrome can be considered.
Treatment is mainly supportive but it should also be directed at the underlying cause, if found. Replacement therapy with fresh frozen plasma, platelets, protein, C, and/or antithrombin may be indicated. Heparin may be considered if the patient has a thrombotic process but needs to be used with caution. Surgical debridement of affected extremities may necessary and amputation may sometimes be necessary.
Other Critical Skin Conditions
Introduction—Erythroderma refers to generalized erythema and scaling. Erythroderma is most commonly due to generalization of a pre-existing skin disease (psoriasis, atopic dermatitis, pemphigus foliaceous), drug reactions, or cutaneous T-cell lymphoma (Sezary syndrome). In approximately 25% of cases, no underlying etiology is found. Erythroderma has serious systemic complications including hypothermia and fluid and electrolyte imbalances.7
Clinical Features—Patients present with generalized erythema and scaling of more than 90% of the BSA (Figure 47–13). It is pruritic. Palmoplantar keratoderma may be a clue to underlying pityriasis pilaris rubra. The nails may shed. Eruptive pale seborrheic keratosis may be seen.
Erythroderma. Confluent bright erythema.
Patients are often febrile with chills. Extracellular fluid shifts lead to pedal, pretibial, and facial edema. Increased blood flow through the skin and the loss of a functioning cutaneous barrier lead to extreme fluid loss and electrolyte abnormalities. Fluid loss leads to reflex tachycardia as well as disturbances in body temperature regulation (both hyperthermia and hypothermia may be seen). Patients with erythroderma may have secondary cutaneous infections, most commonly with staphylococcus aureus.
Workup and Differential Diagnosis—Increased ESR, anemia, and hypoalbuminemia are commonly seen in erythroderma. Electrolytes need to be monitored. Flow cytometry may be useful if Sezary syndrome is suspected.
A history of dermatologic conditions known to cause erythroderma is helpful as well as any recent new medication exposures. A skin biopsy of a primary skin lesion can often differentiate erythrodermic psoriasis, atopic dermatitis, pityriasis rubra pilaris, or bullous disease.8 However, in many cases a skin biopsy shows a nonspecific hypersensitivity reaction. Important conditions that need be distinguished include DRESS, SJS/TEN, and SSS.
Treatment—Supportive care and treatment of the underlying condition (if found) is the mainstay of treatment. Patients need to be monitored for fluid and electrolyte imbalances, temperature, secondary infections, and nutritional needs. Sedating antihistamines (hydroxyzine) can be used to relieve pruritus. Topical therapy can include wet dressings, low-potency corticosteroid ointments. Systemic corticosteroids at an initial dose of 1 to 2 mg/kg/d may be useful in idiopathic erythroderma and drug reactions. Psoriatic erythroderma is typically treated with cyclosporine, methotrexate, acitretin, or biologic agents. Systemic corticosteroids should not be used in psoriasis as they can cause generalized pustular psoriasis (GPP).
Generalized Pustular Psoriasis
Introduction—Generalized pustular psoriasis (GPP) is a rare, life-threatening form of psoriasis.9 Usually, patients have a history of stable plaque-type psoriasis that flares into rapidly progressive pustular disease. Know triggers that can lead to a pustular psoriasis include rapid tapering of systemic corticosteroids, hypocalcemia, infections, pregnancy, and irritation such as sunburn.
Clinical Features—GPP presents with erythema studded with pustules. Patients are often febrile and have chills. GPP appears commonly on the trunk, extremities, face, and can potentially arise on nail beds resulting in onycholysis, lakes of pus with subsequent nail shedding.10
Workup and Differential Diagnosis—Initial workup should include a complete white count with differential, electrolytes, ESR and blood cultures. Patients will often have lymphopenia with leukocytosis and an elevated ESR. A skin biopsy can be considered if the patient does not have a pre-existing diagnosis of psoriasis or if the diagnosis is not clear. GPP cannot be clinically distinguished from AGEP. A biopsy will distinguish between the two.
Treatment—Supportive care, including intravenous fluid and temperature regulation is paramount in treating GPP. Intravenous antibiotics may be needed if the patient becomes infected. Specific GPP treatment is with acitretin (considered first line) or cyclosporine and less likely methotrexate due to slower onset of action. It is important to avoid oral corticosteroids unless absolutely necessary, due to withdrawal and worsening of psoriasis.
Introduction—Pemphigus vulgaris (PV) is a life-threatening autoimmune skin blistering condition. It affects middle-aged adults. Patients frequently develop persistent oral mucosal and/or cutaneous erosions. Lesions may progress to evolve the entire cutaneous surface. The condition runs a relapsing and remitting course over the course over many years.
Clinical Features—PV presents with superficial erosions or flaccid bullae that usually present on the scalp or oral mucosa (Figure 47–14). The blister roof is very fragile and often no intact blisters are seen at first presentation. Erosions associated with a collarette of the remains of the prior blister are common. Lesions occur in a seborrheic distribution—involving the central face, chest, and back (Figure 47–15). Involvement of the oral mucosa is associated with significant pain with oral intake. Cutaneous lesions may become superinfected—most commonly with S. aureus. However, superficial infections with candida or herpes virus have been reported as well.
Pemphigus vulgaris. Oral erosions.
Pemphigus vulgaris. Eroded plaques.
Not uncommonly, patients will have a positive Nikolsky sign. This is a test of skin fragility—where firmly stroking the skin induces blister formation. This can be used as a test to determine adequate control of disease activity.
Workup and Differential Diagnosis—All patients must meet clinical, histologic, and immunologic criteria in order to establish the diagnosis. Clinically, the patients must present with a history of chronic mucocutaneous erosions that on exam are consistent with those typically seen in pemphigus. A biopsy for H&E must demonstrate subcorneal or suprabasal acantholysis. Lastly, either direct or indirect immunofluorescence or ELISA autoantibodies to skin antigens must be present. Serum antibodies against intraepidermal adhesion molecules (ie, desmoglein 1 and 3) are present.
Serum may be sent to specialty laboratory (eg, Beutner Laboratories at http://www.beutnerlabs.com) to establish and monitor pemphigus titers. This may distinguish pemphigus from other immunobullous diseases in the differential diagnosis such as paraneoplastic pemphigus and bullous pemphigoid.
Treatment—Prior to the onset of the use of systemic steroids in this condition—pemphigus was uniformly fatal. Treatment involves the use of systemic steroids in combination with a steroid sparing immunosuppressant agent such as mycophenolate mofetil. Steroids are slowly tapered over the course of months to years. In spite of this treatment regimen, a large cohort of patients may be inadequately controlled or develop complications related to treatment.
In recent years, the use of rituximab has shown significant promise.11,12 Rituximab is an anti-CD 20 antibody that targets pre-B cells for destruction. It removes B-cells destined to become pathogenic antibody producing plasma cells from the circulation. This is often used in combinations with high-dose IVIG. IVIG induces a rapid and selective decrease in pemphigus autoantibodies.13
The use of rituximab and IVIG earlier in the course of treatment is becoming increasingly commonplace. Well-designed studies regarding the use of these agents and the weight of their relative toxicities to conventional therapy are lacking.