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P.K.’s family and medical history are classic for atopic dermatitis. His family

history is significant for asthma, allergic rhinitis, and atopic dermatitis. He had his

initial outbreak at the age of 1 month and then experienced seasonal allergic rhinitis

after his dermatitis went into remission. His skin examination reveals findings of both

acute and chronic atopic dermatitis, with typical lesion location and description.

p. 818

p. 819

Product Selection

CASE 39-5, QUESTION 2: P.K. received a prescription for halcinonide 0.25% cream, 30 g, to be applied at

bedtime to nonfacial areas and mometasone furoate cream 0.1%, 30 g, twice daily to the facial lesions. Based

on pertinent biopharmaceutic considerations, why is this prescription appropriate for P.K.?

Results from P.K.’s treatment regimen might be improved by providing more

frequent (twice daily) application or a more potent preparation to control inflamed

lesions. Once any weeping is stopped, a less potent preparation in the ointment form

should be used for maintenance and the number of applications may be reduced.

Because of the reservoir effect, control can be maintained in many cases with

intermittent regimens such as once daily, every other day, or every third day use of

topical corticosteroids. In addition, intermittent regimens can involve alternating

corticosteroids and agents such as topical pimecrolimus or tacrolimus to maintain

control and minimize adverse effects of either agent.

Because the calcineurin inhibitors are as potent as mid-potency topical

corticosteroids without causing atrophy, telangiectasias, or striae, many

dermatologists would use either tacrolimus or pimecrolimus on the face in preference

to mometasone.

22

Topical Antibiotics with Corticosteroids

CASE 39-5, QUESTION 3: P.K.’s atopic dermatitis presentation is complicated with areas of erythematous,

honey-colored, crusted lesions on his arm, and leg. Can a corticosteroid and an antibiotic preparation be used

together? What are the risks associated with topical antibiotics?

It is determined that P.K. has impetigo superimposed on his atopic dermatitis.

Because impetigo can be treated with topical antibiotics such as mupirocin,

combination therapy with a corticosteroid–antibiotic preparation would appear to be

a logical choice. Although mupirocin may be an appropriate alternative for some

topical dermatologic infections, the current over-the-counter topical antibiotics

(bacitracin, neomycin, and polymyxin) are ineffective for most dermatologic

infections and are indicated only for the prophylaxis of skin infections. In addition,

because staphylococcal toxins act as superantigens, eliciting the production of IgE,

thus worsening the atopic dermatitis, almost all clinicians treat atopic dermatitisassociated impetigo with oral antibiotics such as dicloxacillin, macrolides, or

cephalexin, in combination with topical corticosteroids for the atopic dermatitis.

22

Oral antibiotics reduce the bacterial counts faster and have a lower incidence of

recurrent impetigo compared with topical agents. In areas in which community

methicillin-resistant Staphylococcus aureus rates are high, more effective antibiotic

therapy might be indicated as an alternative. P.K. would most likely benefit from a

treatment course of an oral antibiotic plus a topical corticosteroid preparation.

P.K. is prone to repeated infections and atopic dermatitis flares because his skin is

colonized with staphylococci. Many dermatologists upon clearance of the impetigo

would initiate dilute bleach baths. These consist of 5- to 10-minute baths twice a

week, made by adding 120 cc (1/2 cup) of household bleach (6%) to a full bathtub

(approximately 40 gallons) to create a 0.005% solution. Because of the variety of tub

sizes, the amount of bleach should be adjusted to the size of the bathtub and the

amount of water in the tub.

23

Pruritus

CASE 39-5, QUESTION 4: As stated in Case 39-5, Question 1, one of P.K.’s complaints is pruritus. What

could you recommend for relief of pruritus?

As previously noted, pruritus (itching) is the most common cutaneous symptom in

atopic dermatitis.

21 Scratching, which can damage or fatigue receptor nerve endings,

is the most common method of relieving pruritus. Topically applied local anesthetics

or antihistamines could also be effective in dulling the sensation. However, this

approach is often disappointing, probably because the intact epidermis poorly

absorbs the salt forms of these drugs. In addition, low concentrations are used in

many over-the-counter preparations. If adequate concentrations of local anesthetics

are used (lidocaine 3%–4%), pruritus or pain may be reduced for up to 45 minutes.

These agents are most useful for relieving pruritus or pain for short periods (e.g.,

when trying to go to sleep at night).

21 A serious drawback to the use of topical

benzocaine and antihistamine preparations is their propensity to induce allergic

contact dermatitis.

24

P.K. could also try cold water or ice cubes, which effectively relieve pruritus via

vasoconstriction, as do products containing aluminum acetate (Burow solution),

tannic acid, or calamine. A cool bath may be useful for the relief of pruritus from

dermatologic lesions if they are widespread.

Moisturizing mixtures such as Eucerin, Nivea, Lubriderm, or even simply mineral

or baby oil are useful in the treatment of pruritus caused by dry skin in patients with

atopic dermatitis. Bathing should be restricted to avoid washing away normal body

oils, the drying effect of water, the irritant effect of alkaline soaps, and the trauma of

toweling.

6

Topical corticosteroid applications can be very effective if dermatologic lesions

exist. They reduce inflammation, which helps soothe the affected area.

Systemic antihistamines are effective antipruritic agents, although their major

beneficial effect may be attributable to sedation. The newer, nonsedating

antihistamines are notably ineffective at relieving itch, with the exception of

cetirizine.

25 There is disagreement over which antihistamine or antiserotonin agents

are most effective for treatment of pruritus.

21,25,26 Oral hydroxyzine is a commonly

used antihistamine; doses of 10 to 25 mg 3 to 4 times a day are commonly used. Oral

cyproheptadine is another option. There is little evidence that antihistamines are

effective in treating non–histamine-mediated pruritus, except that their inherent

sedative effect may be somewhat beneficial in all pruritic conditions. Doxepin, a

tricyclic antidepressant with potent H1

-blocking properties, is valuable as a secondline antihistamine topically or systemically if others fail.

27 Because P.K.’s pruritus is

worse at night, as is typical with atopic dermatitis, the use of any of the three H1

-

blockers mentioned at bedtime would be appropriate.

22

Nondrug Recommendations for Atopic Dermatitis

CASE 39-5, QUESTION 5: In addition to prescriptions for topical corticosteroids, a systemic antibiotic

(cephalexin 500 mg 4 times daily for 10 days), and an oral antihistamine (hydroxyzine 25 mg, one to two tablets

by mouth at bedtime as needed), what nondrug interventions should be suggested for P.K.?

The general goals of therapy for atopic dermatitis are to decrease pruritus,

suppress inflammation, and moisturize the skin. The nondrug recommendations shown

in Table 39-10 are useful adjuncts and mainstays for use between disease flares for

patients such as P.K. with atopic dermatitis or any other irritant dermatitis. Often

careful attention to nonpharmacologic measures can markedly reduce the incidence of

disease flare. Because even nonlesional skin in patients with atopic dermatitis has

reduced moisture, the use of emollients should include all skin surfaces.

28

p. 819

p. 820

Table 39-10

Nondrug Recommendations for Patients with Atopic Dermatitis or Other

Irritant Dermatoses28

Clothing should be soft and light. Cotton or corduroy is preferred. Wools and coarse, heavy synthetics should be

avoided.

Heat should be avoided because it often makes eczema worse. The environment should be well ventilated, cool,

and low in humidity (30%–50%). Rapid changes in ambient temperature should be avoided.

Bathing should be kept to a minimum (no longer than 5 minutes), and the patient should use a nonirritating soap

(e.g., Basis soap). A colloid bath or the use of appropriate amounts of bath oil may be useful.

The skin should be kept moist with frequent applications of emollients (e.g., Lubriderm, Nivea, Aquaphor,

Eucerin, or petrolatum).

Primary irritants such as paints, cleansers, solvents, and chemicalsprays should be avoided.

P.K. should be warned to avoid people with active herpes simplex infections

because severe disseminated infections can occur.

Tachyphylaxis and Calcineurin Inhibitors

Clinicians commonly misdiagnose tachyphylaxis due to corticosteroids. Failure of

topical corticosteroids to clear difficult atopic dermatitis after an initial improvement

may give the false impression of tachyphylaxis, when the actual problem is a primary

failure of the treatment.

29 This could be caused by either inappropriate application

technique by the patient or the choice of a product with inadequate potency.

Tachyphylaxis can occur within 1 week of therapy, but generally takes several weeks

to a month to occur.

29 To treat this problem, patients should discontinue the

corticosteroid for a week and restart at an appropriate dose. Alternatively, patients

may be switched to topical tacrolimus or pimecrolimus.

Topical tacrolimus or pimecrolimus is an effective alternative to moderatepotency topical corticosteroids and is safe for use in children.

22,23,27

In addition to

inhibitory effect on cytokine production, calcineurin inhibitors result in decreased

immunologic response to antigens. Transient burning, erythema, and pruritus are the

most common adverse effects. Neither pimecrolimus nor tacrolimus causes skin

atrophy, making them attractive alternatives for patients with lesions on the face and

the neck. Issues regarding the long-term safety of these products have led the U.S.

Food and Drug Administration to place a black-box warning in the manufacturer’s

literature regarding a potential increased cancer risk.

22

ALLERGIC CONTACT DERMATITIS: POISON

IVY, POISON OAK, OR POISON SUMAC

Contact dermatitis is an inflammation of the skin that occurs when a substance comes

in direct contact with the epidermal surface. The most common form is irritant

contact dermatitis caused solvents or other chemicals that irritate the skin resulting

red, painful lesions, for example, dish pan hands, diaper dermatitis. Allergic contact

dermatitis is a type IV delayed hypersensitivity reaction controlled by allergenspecific T cells. The resulting dermatitis is pruritic and many times vesicular in

nature.

1–6

Poison ivy (Rhus) dermatitis is a major cause of allergic contact dermatitis in the

United States, exceeding all other causes combined. Other allergens include latex,

leather, nickel, and laundry detergents. It is estimated that 50% to 95% of the

population is sensitive to the plants to some degree. The severity of the condition

varies from mild discomfort to an extremely painful, debilitating condition. Rhus

dermatitis is caused by sensitization to an allergic substance in the leaves, stems, and

roots of poison ivy, poison oak, and poison sumac plants. All three plants contain the

same sensitizing oleoresin, urushiol oil, which contains pentadecacatechol, the actual

sensitizing agent. Therefore, the dermatitis caused by the three different plants is

identical.

Direct contact with the plant is unnecessary for the rash to occur. Highly sensitive

persons may develop severe dermatitis merely from exposure to Rhus oleoresin

carried by pollen or by smoke from burning leaves. The oleoresin may remain active

for months on clothing, shoes, tools, and sporting equipment. Once the toxic

substance is exposed to the skin, it can be spread by the hands to other areas of the

body (e.g., genitals or eyes) or to people who may come into close contact with the

exposed person. Although washing with soap and water may not prevent the

dermatitis, even if it is done within 15 minutes of exposure, it will prevent spread of

the oleoresin to other parts of the body.

Sensitive individuals should be instructed to avoid contact with the offending

plant. If contact is inevitable, every effort should be made to shield exposed areas of

the skin with appropriate clothing.

Exposed individuals should bathe or shower as soon as they come in from

outdoors and should wash their clothes. Nonprescription topical cleansers (Tecnu,

Zanfel, Mean Green Hand Scrub) claim to remove urushiol oil embedded in the skin

through the action of microfine scrubbing beads and surfactants, thus possibly

preventing the rash or limiting spread. They are applied to exposed areas of the skin,

followed by vigorous scrubbing, and rinsed off after application.

After an initial incubation period of 5 to 21 days, a patient would be expected to

react to the oleoresin in 12 to 48 hours after re-exposure. A mild exposure to these

plants in a sensitized person results in a typical erythematous, vesicular, linear, and

sometimes, oozing rash after 2 to 3 days; complete clearing occurs in 1 to 3 weeks.

If a large area is exposed, lesions appear within 6 to 12 hours and may appear

blistered and eroded; in some cases, ulcers may appear. Healing occurs more slowly,

often requiring 2 to 3 weeks for complete resolution. The following factors

contribute to the development of poison ivy, poison oak, or poison sumac dermatitis:

the concentration of the oleoresin to which the skin is exposed, area of exposure (i.e.,

the thickness of the stratum corneum), duration of exposure, site of exposure, genetic

factors, and immune tolerance. It is important to determine the areas of the body that

are affected. If the eyes, genital areas, mouth, respiratory tract, or more than 15% of

the body is affected, the patient should receive a course of systemic corticosteroids.

See Case 39-6 below.

Treatment

CASE 39-6

QUESTION 1: K.P., a 27-year-old woman, has recently returned from an outing in the woods. She now has

vesicular eruptions that appear in a linear pattern on one arm and hand. She believes that she has had a poison

oak reaction and requests therapy. What should be recommended at this point? What should be recommended

if the condition becomes more severe?

p. 820

p. 821

Weeping lesions should be treated with aqueous vehicles (e.g., Burow solution or

saline) as outlined in the beginning of this chapter. Lesions that are not wet or

weeping should be treated with calamine lotion applied 2 to 4 times daily. The zinc

oxide in calamine lotion may act as a mild astringent, although some people find this

preparation to be unacceptable because of its pink color, which can stain clothes.

Alternatively, a topical corticosteroid appropriate for the body part affected could be

used. If K.P.’s poison oak reaction becomes more severe, additional treatment with

prednisone 1 mg/kg/day for at least 2 or 3 weeks will be required; such therapy

should be withdrawn slowly (1–2 weeks) to prevent recurrence of the lesions.

SYSTEMIC THERAPY

CASE 39-7

QUESTION 1: Z.T., a 19-year-old man, has just returned from a fishing trip and now has an erythematous,

linear, dry eruption on his leg and arm, and a generalized eruption on his hands and face. He has been in areas

that have dense poison ivy growth, and he may have burned some in the campfire. Z.T. has washed himself and

his clothes thoroughly. How should he be treated?

The fact that Z.T.’s facial rash is not linear (as one would expect if he had just

contacted the plant) suggests that he may have contacted the smoke of a burning

poison ivy plant. This can be quite serious because the oleoresin can be carried in

smoke and, if inhaled, can cause vesiculation of lung tissue leading to severe

respiratory problems. Z.T. should be observed for signs of respiratory difficulties

and should be treated with a course of systemic corticosteroids.

RELAPSE

CASE 39-7, QUESTION 2: Z.T.’s physician prescribed oral prednisone for his rash. He was instructed to

take 80 mg/day for 14 days and to decrease the dose by 5 mg/day each day thereafter. Calamine lotion (3 times

daily to affected areas) also was prescribed. After 12 days, Z.T. complains that the lesions seem to be getting

worse. The lesions had cleared after 8 days of treatment, and he began rapidly tapering the prednisone at that

time. Why is he experiencing a relapse?

Two weeks is the minimum course of treatment when systemic corticosteroids are

used for severe cases of poison ivy, poison oak, or poison sumac. The oleoresin

remains fixed in the skin, and if the systemic corticosteroid is withdrawn too soon,

the lesions return. This is probably the most common reason for treatment failure

with systemic corticosteroids. Alternatively, systemic corticosteroids can be

discontinued before 2 weeks of treatment and a moderate-potency topical

corticosteroid preparation can be started 24 hours before discontinuation of systemic

corticosteroids and continued for 7 to 10 days to prevent relapse.

DRUG ERUPTIONS

Clinically recognizable adverse drug reactions are manifested on the skin more often

than any other organ or organ system.

30–33 An estimated 1% to 5% of hospitalized

patients experience a drug eruption.

31 Outpatient statistics are more difficult to

obtain, but are probably within the same range.

Many of the common dermatologic reactions that can be induced by drugs have

other causes as well, so a complete workup must include other nondrug etiologies.

Viral, fungal, and bacterial infections, as well as certain systemic diseases and

foods, have been identified as causes for common reactions such as urticaria,

erythema multiforme, and erythema nodosum. The diagnosis of drug eruptions is best

made by identifying the type of lesions observed and associating the lesions with

specific drug therapy. The most important diagnostic criterion is an accurate

assessment of the skin lesions. With this critical information, the clinician can then

refer to a drug information source to associate any current or past drug therapy with

the specific lesions observed (see Chapter 32, Drug Hypersensitivity Reactions).

Acneiform Eruptions

Acneiform eruptions appear very much like common acne. They may be distinguished

from acne by their sudden occurrence, the absence of comedones, uniform

appearance (i.e., all at the same stage of development), and the fact that they may

occur on any part of the body. Cysts and scarring are rarely associated with druginduced acne. Eruptions can also occur during any period of the patient’s life; thus,

drug-induced acne should be suspected when the lesions appear in persons outside

the typical age bracket for acne. Drugs implicated include adrenocorticotropic

hormone, anabolic steroids, azathioprine, danazol, glucocorticoids, iodides,

bromides, lithium, gefitinib, erlotinib. lapatinib, and oral contraceptives. For patients

with acne vulgaris, these drugs may worsen existing lesions (see Chapter 40, Acne).

Photosensitivity Reactions

Photosensitivity eruptions require the presence of both a drug (or chemical) and a

light source of appropriate wavelength. These eruptions are divided into two

subtypes: phototoxic and photoallergic. Phototoxic reactions, the most common druginduced photodermatosis, manifest themselves as an exaggerated sunburn or

increased sensitivity to sunburn. The ultraviolet A (UVA) light source alters the drug

to a toxic form, resulting in tissue damage independent of any allergic response, and

occurs in everyone who gets high enough skin levels of the offending drug. This

eruption can occur on first exposure to a drug, is dose-related, and will continue as

long as the skin concentration of the drug exceeds the threshold level for the reaction

to occur. Photoallergic reactions, which are very uncommon, may appear as a variety

of lesions, including urticaria, bullae, and eczema. UVA light alters the drug so it

becomes an antigen or acts as a hapten. Photoallergic eruptions require previous

contact with the offending drug, are not dose related, exhibit cross-sensitivity with

chemically related compounds, and are secondary to the use of topical agents.

Unfortunately, outside light through a window and fluorescent lighting permit passage

of or can emit UVA light. In addition, until recently there were inadequate topical

preparations that provide protection against UVA light. Avobenzone, although

covering much of the UVA spectrum, is photolabile, losing 60% of its effectiveness

in less than 1 hour. However, many products now solve that problem by adding

agents such as octocrylene, which stabilize avobenzone’s photolability, and are

usually labeled “stabilized UVA protection.” New products containing ecamsule

appear to offer an advance in protection against lower spectrum UVA rays. Most

phototoxic and photoallergic reactions occur fairly soon after exposure to light.

Implicated drugs are numerous, including among others, antibiotics (tetracyclines,

fluoroquinolones, and sulfonamides), antidepressants (tricyclics), antihypertensives

(hydrochlorothiazide, β-blockers), hypoglycemics (sulfonylureas), nonsteroidal antiinflammatory drugs, sunscreens (p-aminobenzoic acid [PABA]),

p. 821

p. 822

oral contraceptives, and antipsychotics (phenothiazines) (see Chapter 42,

Photosensitivity, Photoaging, and Burns Injuries).

Allergic Contact Dermatitis

Topical administration of a sensitizing agent produces localized papulovesicular

lesions. These lesions are limited only to areas that are exposed to the topical

product. Neomycin, benzocaine, and diphenhydramine are well-known topical

sensitizers (Table 39-11).

34–36 Systemic administration of a drug to a patient

previously sensitized to the drug by topical application can provoke widespread

dermatitis. Implicated systemically or topically administered drugs that reactivate

allergic contact dermatitis include procaine or benzocaine, radiographic contrast

media or iodine, and streptomycin and gentamicin or neomycin, among others.

Erythema Multiforme

As the name implies, erythema multiforme (EM) eruptions take on a varied spectrum

of morphologic forms, ranging from the mildest with tiny maculovesicular lesions to

more severe forms such as SJS and toxic epidermal necrolysis syndrome (TENS)

with extensive bullous lesions and routine involvement of mucous membranes.

Although all forms have been reported to have oral lesions, they are much more

severe in SJS and TENS, in which genital, nasal, and ocular mucosae can also be

involved. Target lesions are usually present in all forms of the disorder, which

characteristically are erythematous, iris-shaped papules, and vesiculobullous lesions

typically involving the extremities, especially the palms and soles in EM and the

torso in SJS and TENS. The lesions take on the appearance of a circular target with a

bull’s-eye in the middle, thus the term target lesion. Questions have recently been

raised about the shared pathologic nature of these forms of EM.

37 EM in its mildest

forms, EM minor and EM major, is more common in children and young adults, and

is self-limited in nature with only transient hypopigmentation or hyperpigmentation as

complications. Sometimes malaise, a low-grade fever, and itching or burning may

accompany this type of eruption. Etiologic factors associated with EM include drugs,

mycoplasma and herpes infections, radiation therapy, foods, and sometimes

neoplasms. Allopurinol, barbiturates, phenothiazine, and sulfonamides are the drugs

most often implicated in EM eruptions.

Table 39-11

Frequent Contact Sensitizers

Substance Found In

Ammonia Soaps, chemicals, hair dyes

Antihistamines Topical anti-itch creams and ointments

Balsam of Peru Cosmetics

Benzyl alcohol Medications, cosmetics

“Caine” anesthetics Medications (e.g., over-the-counter benzocaine

products)

Carba Rubber

Chromium Jewelry

Epoxy resin Glue

Ethylenediamine Stabilizer in topical products (e.g., aminophylline)

Formaldehyde Shoes, clothing, soaps, insulations

Mercaptobenzothiazole Rubber

Naphthyl Rubber

Neomycin Topical medications (e.g., Neosporin)

Nickelsulfate Jewelry, fasteners

Paraben Preservative in many topical products

Paraphenylenediamine Hair dyes, leather

Potassium dichromate Shoes, leather

Thiomersal Preservatives, contact lens products

Thiram Rubber products

Turpentine Paint products

Wool alcohols Lanolin-containing products, clothes

Stevens–Johnson Syndrome

SJS is probably the most common type of severe drug eruption. The syndrome is

usually a moderate mucocutaneous and systemic reaction. Blisters and atypical target

lesions involve less than 10% of body surface area, with some epidermal

detachment, which can cause scarring in some cases.

With more extensive involvement, clinical findings are almost indistinguishable

from TENS. The skin can become hemorrhagic, and pneumonia and joint pains may

occur. Serious ocular involvement is common and can culminate in partial or

complete blindness. Besides drugs, this syndrome has been associated with

infections, pregnancy, foods, deep radiographic therapy, and neoplasms. Mortality is

estimated to be in the range of 5% to 18%. The duration of the syndrome is usually 4

to 6 weeks. The long-acting sulfonamides are most often implicated. Allopurinol,

carbamazepine, fluoroquinolones, hydantoin, phenylbutazone, piroxicam, and other

sulfa derivatives such as sulfonylureas are also possible causative agents.

Toxic Epidermal Necrolysis Syndrome

Epidermal necrolysis, a severe, life-threatening mucocutaneous and systemic

reaction, may be preceded by a prodrome characterized by malaise, lethargy, fever,

and occasionally throat or mucous membrane soreness. Epidermal changes follow

and consist of erythema and massive bullae formations that easily rupture and peel,

giving the skin a scalded appearance.

Hairy parts of the body are usually not affected, but mucous membrane

involvement is common. Blisters cover more than 30% of body surface area, with

extensive epidermal detachment that can result in scarring. Mortality in TENS

patients is roughly 30%, often within 8 days after bullae appear. The usual cause of

death is infection complicated by massive fluid and electrolyte loss, similar to

patients with extensive burns. Although the skin takes on a grave appearance, healing

occurs within 2 weeks in approximately 70% of patients, with some potential for

scarring. In addition to drugs, certain bacterial infections and foods are believed to

cause this type of eruption. Most causes of TENS in children are owing to infection

(e.g., S. aureus). A higher incidence of this type of drug eruption appears to occur in

HIV-positive patients. Drugs most frequently implicated include allopurinol,

aminopenicillins, carbamazepine, hydantoin, phenylbutazone, piroxicam, and sulfa

drugs.

Erythema Nodosum

Erythema nodosum eruptions appear as red, indurated, inflammatory nodules on the

shins and knees.V

p. 822

p. 823

In addition to the unusual distribution, the lesions are tender when palpated.

Occasionally, these lesions are accompanied by mild constitutional symptoms, but

there is usually no mucous membrane involvement. Etiologic factors associated with

the development of erythema nodosum include drugs, female sex, rheumatic fever,

sarcoidosis, leprosy, certain bacterial infections (e.g., tuberculosis), and systemic

fungal infections such as coccidioidomycosis. Usually, the lesions heal slowly over

the course of several weeks after the offending agent is removed. Oral contraceptives

are the most frequently implicated drug with this type of eruption. Other implicated

drugs include sulfonamides and penicillin.

Drug Hypersensitivity Syndrome

This severe systemic reaction is also known as anticonvulsant hypersensitivity

syndrome and as a drug reaction with eosinophilia and systemic symptoms (DRESS).

Symptoms begin with a high fever followed by widespread maculopapular–pustular

rash on the trunk, arms, and legs that may lead to exfoliative dermatitis with large

areas of skin sloughing. Hair and nails are sometimes lost. Eosinophilia occurs in

greater than 50% of cases, 30% have abnormal lymphocytosis, and 20% have

lymphadenopathy. Internal organ damage appears late in the syndrome with

elevations of liver function or renal function laboratory values. These may be

accompanied by other general systemic symptoms such as headache and malaise.

Secondary bacterial infections can occur. Approximately 10% of patients die, many

because of infection. If exfoliative dermatitis occurs, it can take weeks or months to

resolve, even after withdrawal of the offending agent. The most commonly implicated

drugs are sulfonamides, antimalarials, anticonvulsants, and penicillin. Although

rarely reported in the literature, its broad range of symptoms, confusing

nomenclature, and symptom overlap with other drug-related adverse effects may lead

to underdiagnosis and reporting.

Maculopapular Eruptions

Maculopapular eruptions are subdivided into two groups: scarlatiniform and

morbilliform. Most drug eruptions fall within one of these two groups. Scarlatiniform

eruptions are erythematous and usually involve extensive areas of the body. They are

differentiated from streptococcal-induced scarlet fever by the lack of other diagnostic

signs and laboratory studies. Morbilliform eruptions usually begin as discrete,

reddish-brown maculae that may coalesce to form a diffuse rash. These eruptions are

differentiated from measles by the lack of fever and other typical clinical signs. In

either type of maculopapular eruption, pruritus may or may not be present. Generally,

this type of eruption appears within 1 week after the causative drug (2 or more weeks

with penicillins) has been started and completely clears within 7 to 14 days after

stopping it. Morbilliform eruptions commonly are caused by ampicillin, amoxicillin,

and allopurinol.

Urticaria

Urticarial eruptions are immediate hypersensitivity reactions (IgE-mediated) and

usually appear as sharply circumscribed (raised), edematous, and erythematous

lesions (wheals) with an abrupt onset.

In most cases, individual lesions disappear within 24 hours. These are replaced

with new lesions elsewhere until the offending allergen is cleared from the body.

Urticarial lesions are associated with an intense itching, stinging, or prickling

sensation. Commonly called hives, urticarial eruptions are frequently associated with

certain drugs, foods, psychic upsets, and serum sickness. The most frequently

implicated drugs with this type of reaction are aspirin, penicillin, and blood

products. Patients who exhibit urticaria attributable to a drug are at increased risk of

anaphylaxis if re-exposed to the same medication in the future.

Angioneurotic Edema

Angioneurotic edema (also called angioedema) is a more severe form of urticaria in

which giant hives penetrate more deeply into surrounding tissues.

Lips, mouth, tongue, and eyelids are common locations. Extensive involvement of

the tongue, throat, or larynx can be fatal.

Angiotensin-converting enzyme inhibitors (ACEIs) are the most common drug

cause of angioedema. Patients taking ACEIs should be warned to look out for any

unusual swelling in the facial or oral area and, if present, should go immediately to

the nearest emergency room for treatment. Although it usually occurs within the first

several months of treatment, cases have been reported up to as long as 3 years after

initiation of ACEI therapy (see Chapter 14, Heart Failure and Chapter 32, Drug

Hypersensitivity Reactions).

CASE 39-8

QUESTION 1: D.Z., a 42-year-old man with a chronic seizure disorder and long-standing anxiety, was

recently given a prescription for penicillin V 250 mg 4 times daily for a group A, α-hemolytic streptococcalpositive pharyngitis. Chronic medications include carbamazepine 200 mg 3 times daily and clonazepam 2 mg 2

times daily. One week later, D.Z. presents with urticarial lesions on his chest and arms. Is this a typical time of

onset for a drug-induced dermatologic reaction? How should the drug eruption in D.Z. be managed?

Although most drug eruptions occur within 1 to 2 weeks after starting therapy, it

may take 3 to 4 weeks after an initial exposure to a medication for the reaction to

occur. Repeated exposure to the same offending agent can reduce the time of onset of

the reaction to a few days or even within hours of ingestion. Because D.Z. has been

taking clonazepam and carbamazepine chronically and penicillin for only 8 days, the

temporal relationship would logically lead to the conclusion that penicillin is a

highly probable cause. Almost all cases of urticaria are associated with extensive

eosinophilia; however, it is not specific for any particular antigen. However, before

labeling penicillin as the cause of his drug eruption, a thorough history to rule out

other common nondrug causes should be taken.

For D.Z., a different antibiotic (macrolide) should be substituted for penicillin (to

complete the 10-day course of therapy). The individual lesions should begin to clear

in 24 hours of eruption (if the penicillin is the cause of the urticaria). If the urticaria

does not begin to clear in a few days, another cause should be investigated.

Treatment is primarily supportive, and use of an oral antihistamine (e.g.,

diphenhydramine 25–50 mg 4 times daily) for several days would be recommended.

If the reaction is severe, a 1- to 2-week course of prednisone 40 to 60 mg/day will

control most symptoms within 48 hours.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

p. 823

p. 824

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