Section 15. Hypersensitivity Reactions

A drug hypersensitivity reaction is an adverse, allergic response to an ingested or parenterally administered drug characterized by a cutaneous eruption.

There are several different immune mechanisms thought to play a role:

1. Type I: IgE-dependent drug reactions urticaria, angioedema, and anaphylaxis.

2. Type II: Cytotoxic drug-induced reactions petechiae from drug-induced thrombocytopenia.

3. Type III: Immune complex-mediated drug reactions vasculitis, serum sickness, urticaria.

4. Type IV: Delayed-type, cell-mediated drug reactions exanthematous, fixed drug eruptions, Steven–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

Exanthematous Drug Reaction

An exanthematous drug reaction is an adverse, allergic response to an ingested or parenterally administered drug characterized by a morbilliform cutaneous eruption that mimics a viral exanthem.

Insight

In the appropriate clinical setting, an exanthematous drug reaction, a viral exanthem, and acute graft-vs-host disease (GVHD) are both clinically and histologically indistinguishable.

Synonyms Morbilliform drug eruption, maculopapular drug eruption, drug rash.

Epidemiology

Age Children < adolescents < adults.

Gender F > M.

Incidence 1% of population on a systemic medication.

Etiology Drugs with high probability of reaction (10%–20%): penicillin and related antibiotics, carbamazepine, allopurinol, gold salts. Medium probability: sulfonamides (bacteriostatic, antidiabetic, diuretic), nitrofurantoin, hydantoin derivatives, isoniazid, chloramphenicol, erythromycin, streptomycin. Low probability (1% or less): pyrazolone derivatives, barbiturates, benzodiazepines, phenothiazines, tetracyclines.

Pathophysiology

Exanthematous drug hypersensitivity reactions are likely type IV, cell-mediated immune responses. Viral infections may increase the incidence (e.g., aminopenicillin causes a morbilliform rash in 100% of patients concurrently infected with EBV).

History

The exanthematous rash typically appears 7 to 14 days (peak incidence ninth day) after drug administration; however, skin lesions can appear anytime between day 1 though 21 after drug exposure. The rash starts on the trunk and spreads to the face and extremities. It can be quite pruritic and distressing. Fever and malaise may or may not be present.

Physical Examination

Skin Findings

Type of Lesion Macules, papules, plaques (Fig. 15-1).

Size 1 mm to 1 cm.

Color Pink/red to purple/brown.

Distribution of Lesions Trunk, spreads to face and extremities. Confluent in intertriginous areas (axilla, groin, inframammary area). Palms and soles may be involved.

Mucous Membranes ± Exanthem on buccal mucosa.

General Findings

± Fever

Differential Diagnosis

An exanthematous drug reaction can be confused with a viral exanthema, allergic contact dermatitis, pityriasis rosea, psoriasis, toxic shock syndrome, scarlet fever, acute GVHD, eczema, or secondary syphilis.

Laboratory Examnination

Dermatopathology Perivascular inflammation with scattered eosinophils.

Course and Prognosis

Exanthematous drug reactions can occur 1 to 21 days after drug exposure. With discontinuation of the drug, the rash begins to fade (often 2- to 3-day lag time after the drug is discontinued). The fiery red rash gradually fades to a dull purple and then desquamates. A rechallenge with the drug often elicits a faster, more severe response. Ten percent of patients sensitive to penicillins given cephalosporins will exhibit cross-drug sensitivity and develop an eruption. Patients sensitized to one sulfa-based drug (bacteriostatic, antidiabetic, diuretic) may cross-react with another category of that drug.

Management

Correct identification and discontinuation of the offending drug is needed. Symptomatic relief for pruritic skin lesions can be obtained with systemic antihistamines (diphenhydramine, hydroxyzine HCl, cetirizine HCl), oatmeal baths, emollients (hydrated petrolatum, Vaseline, moisturizers), and topical steroids. Severe cases may benefit from a limited course of systemic steroids (prednisone or methylprednisolone).

Prevention

The patient should be made aware of the possible drug allergen and cross-reactants. His or her medical chart should be labeled accordingly. For morbilliform eruptions, the drug can be readministered. In rare instances, it is even possible to “treat through” an exanthematous drug hypersensitivity rash in cases where the offending drug is critical and there are no appropriate non-cross-reacting alternative medications.

Urticaria is a transient allergic response characterized by edematous plaques (wheals) and/or deep dermal swelling (angioedema). In some cases, urticaria is accompanied by respiratory symptoms, vascular collapse, and/or shock (anaphylaxis).

Insight

The hallmark of urticaria is its transience. An individual lesion should not persist for more than 24 hours.

Synonyms Wheals, hives, nettle rash.

Epidemiology

Age Any age.

Gender F > M 2:1.

Incidence 5% of the population.

Etiology >50% of urticaria is idiopathic. Urticaria can results from immune (autoimmune, IgE-mediated, immune complex, or complement/kinin-dependent) or nonimmune (direct mast cell degranulators, vasoactive stimuli, ASA, NSAIDs, dietary pseudoallergens, ACE inhibitors) mechanisms.

Pathophysiology

The mast cell is the primary cell responsible for urticaria. IgE, opiates, C5a anaphylatoxin, stem cell factor, and some neuropeptides can cross-link or bind receptors on the surface of the mast cell leading to degranulation of its contents. The mast cell releases histamine and other proinflammatory mediators which bind to receptors on the postcapillary venules in the skin. This leads to vasodilation and plasma leakage clinically seen as wheals and/or angioedema.

History

In urticaria, wheals are transient skin lesions that come and go in <24 hours. Skin symptoms can include pruritus, flushing, or burning. In angioedema, deeper swelling of the dermis, subcutaneous, or submucosal tissue occurs and may persist for 3 to 4 days. Systemic symptoms can include respiratory symptoms, arthralgias, fatigue, abdominal pain, fever, and diarrhea.

Physical Examination

Skin Findings

Type Wheal: papule, plaque (Fig. 15-2).

Size 1 mm to 10 cm.

Shape Round, oval, annular, polycyclic.

Color Pink to red, with surrounding or central pallor (Fig. 15-3).

Distribution Typically generalized.

Angioedema Skin Findings

Type Diffuse swelling.

Color Pink-red.

Sites of Predilection Face (eyelids, lips, tongue).

General Findings

Malaise, fever, arthralgias, respiratory symptoms, hypotension, and shock.

Differential Diagnosis

The transient edematous plaques are diagnostic for urticaria, although often parents can mistake blisters or insect bites for urticaria. Urticaria also needs to be differentiated from dermatographism (present in 5% of the normal population), eczema, contact dermatitis, mastocytosis, erythema multiforme, and allergic vasculitis.

Laboratory Examinations

Dermatopathology Dermal or subcutaneous edema, vascular dilation, and mild perivascular infiltrate.

Course and Prognosis

Urticaria self-resolves in 1 year in 50% of cases. Up to 20% of cases can have a chronic relapsing course.

Management

Identification and elimination of any causative agent is most helpful. Drugs commonly implicated in urticaria include antibiotics (penicillins, sulfonamides), cardiac drugs (amiodarone, procainamide), immunotherapeutics (serum), chemotherapeutics (L-asparagine, bleomycin, cisplatin, daunorubicin, 5%-FU, procarbazine, thiotepa), ACE inhibitors (captopril, enalapril, lisinopril), Ca+ channel blockers (nifedipine, diltiazem, verapamil), histamine releasers (morphine, radiocontrast dye, muscle relaxants, salicylates, sympathomimetics, hypotensive agents, and antimicrobials). Foods that can cause urticaria include milk, eggs, wheat, shellfish, and nuts. Other forms include physical urticaria (dermatographism, cold; Fig. 15-4); solar, cholinergic, pressure, vibratory, and hereditary angioedema (autosomal dominantly inherited disorder caused by low levels of C1 inactivation or dysfunction inhibitor). In up to 50% of cases, the etiology is unclear and at times, urticaria can be precipitated by stress.

Treatment is primarily symptomatic with one or more antihistamines (chlorpheniramine, hydroxyzine, diphenhydramine, doxepin, acrivastine, cetirizine, loratadine, mizolastine, desloratadine, fexofenadine, levocetirizine, cimetidine, or ranitidine). Topical regimens include oatmeal baths, calamine or 1% menthol cream, and/or topical steroids.

More refractory cases may require systemic steroids (prednisone or methylprednisolone), but only short courses are recommended and rebound is possible. Epinephrine is the treatment of choice for anaphylaxis, and it can be reassuring for patients with urticaria to carry an epinephrine pen for self-administration during severe episodes if necessary.

Acute blistering reactions can be classified as follows:

1. Erythema multiforme (EM) is a reactive syndrome precipitated by infectious agents such as herpes simplex virus (HSV).

2. SJS and TEN are reactive syndromes along the same clinical spectrum for drug reactions.

EM Syndrome

EM is a reactive syndrome characterized by “target” lesions of the skin and mucous membranes most commonly precipitated by an infection (usually HSV).

Synonyms EM von Hebra.

Classification

EM Minor Mild, sudden onset of papules, some of which evolve into target lesions. No prodrome or mucosal involvement. Recurrences common.

EM Major EM associated with mucosal lesions and systemic symptoms. Historically made synonymous with SJS, which we now know is probably not the case.

Epidemiology

Age 50% of patients are older than 20 years of age. Rare under 2 years of age.

Gender M > F.

Incidence Uncommon.

Genetics HLA-DQw3, HLA-DRw53, HLA-Aw33.

Etiology Most common precipitants is HSV (>50%), reported association with other infections, drugs, or systemic disease.

Pathophysiology

Likely an aberrant immune response to select precipitants in certain predisposed individuals. Possible precipitants include infections (HSV >>> Mycoplasma pneumoniae, Histoplasma capsulatum, parapoxvirus, vaccinia, VZV, adenovirus, EBV, CMV, hepatitis virus, Coxsackie virus, parvovirus B19, HIV, Chlamydophila psittaci, salmonella, Mycobacterium tuberculosis, dermatophytes), rarely drugs (NSAIDs, sulfonamides, antiepileptics, antibiotics), or systemic disease (IBD, SLE, Behcet’s).

History

Skin lesions appear abruptly 3 to 14 days after precipitant (herpes labialis in >50%) and new lesions can continue to appear for up to 10 days. Fever, malaise, and mucous membrane involvement may also be present.

Physical Examination

Skin Lesions

Type Macules, papules, scale, vesicles, bullae.

Color Red ring, dusky purple center (Fig. 15-5).

Size 1 to 3 cm.

Shape Target or iris lesions are typical.

Distribution Upper body, extremities. Grouped on elbows, knees.

Sites of Predilection Upper extremities and face > palms, neck, trunk > legs.

Mucous Membranes Oral, ocular, and genital blistering and ulceration may be present.

Differential Diagnosis

EM can be confused with viral exanthems, bullous diseases, urticaria, secondary syphilis, psoriasis, fixed drug, subacute cutaneous LE, vasculitis, polymorphous light eruption, or pityriasis rosea. The “target lesions” are classic for EM, but may be confused with erythema annulare centrifugum, tinea corporis, or other annular eruptions.

Laboratory Examinations

Dermatopathology Interface dermatitis, spongiosis, exocytosis, vacuolar degeneration of the basal keratinocytes, dermal edema, perivascular mononuclear infiltrate.

Course and Prognosis

EM appears abruptly 3 to 14 days after insult (HSV, infection, drug, etc.); skin lesions fully evolve in 72 hours and persist for a week. Lesions can be pruritic or painful, systemic symptoms and mucosal involvement may be present. EM typically resolves after 2 weeks with no sequelae, but recurrences are common.

Management

For EM management, if a precipitant can be identified, it should be treated or removed. In recurrent EM cases secondary to HSV, daily prophylactic acyclovir, valacyclovir, or famciclovir may be necessary.

In most cases of EM, the rash will self-resolve in 5 to 15 days without treatment. Symptomatic relief for pruritic skin lesions can be obtained with systemic antihistamines (diphenhydramine, hydroxyzine HCl, cetirizine HCl), oatmeal baths, emollients (hydrated petrolatum, Vaseline, moisturizers), and topical steroids.

In severe EM, systemic steroids (prednisone, methylprednisolone) can be added. Open skin lesions can be treated with topical antibiotics and topical petrolatum-impregnated gauze if needed. Oral lesions can benefit from anesthetic rinses. Ocular lesions need topical treatment in conjunction with an ophthalmologist.

In severe refractory or recurrent EM cases, azathioprine, thalidomide, dapsone, cyclosporine, mycophenolate mofetil, or PUVA have had reported successes.

Steven–Johnson Syndrome and Toxic Epidermal Necrolysis

SJS and TEN are rare, severe cutaneous drug reactions characterized by tenderness of the skin/mucosa, followed by extensive exfoliation that is potentially life-threatening.

Synonym Lyell’s syndrome.

Classification

SJS and TEN are considered are two clinical ends along a spectrum of adverse drug reaction severity with:

• SJS: <10% skin sloughing.
• SJS/TEN overlap: 10% to 30% skin sloughing.
• TEN: >30% skin sloughing.

Epidemiology

Age Older children. More common in adults older than 40 years.

Gender SJS: M = F. TEN: F > M.

Incidence SJS: 6 per million, TEN: 1 per million.

Genetics Genetic susceptibility in HLA-B12, HLA-B*5801, HLA-B*1502, HLA-DQB1*1601.

Etiology SJS: Drugs (50%); TEN: Drugs (>95%) NSAIDs, antibiotics, anticonvulsants.

Pathophysiology

Pathogenesis is because of a host’s impaired capacity metabolize reactive drug metabolites. The metabolites then trigger and interaction between the death-receptor-ligand pair Fas-FasL causing extensive keratinocyte death (apoptosis), loss of cohesion, necrosis resulting in full-thickness epidermal necrolysis. Drugs implicated include NSAIDs (phenylbutazone, piroxicam), antibiotics (amithiozone, aminopenicillins) sulfa drugs (sulfadoxine, sulfadiazine, sulfasalazine, trimethoprim-sulfa-methoxazole), allopurinol, antiretrovirals, and antiepileptics (barbiturates, carbamazepine, phenytoin, and lamotrigine).

History

One to three weeks after drug exposure, SJS/TEN begins with fever, pain with swallowing and stinging eyes. Up to 3 days later, the skin lesions appear on the trunk spreading to the upper extremities and face. Skin turns dusky red before dermal–epidermal detachment with sheets of skin falling off leaving raw, red denuded area. Systemic symptoms include fever, malaise, myalgia, arthralgias, nausea and vomiting, diarrhea, and conjunctival burning.

Physical Examination

Skin Findings

Type Macules, papules, plaques, blisters, desquamation (Fig. 15-6).

Color Red/purple to gray.

Palpation Nikolsky sign: lateral mechanical pressure causes epidermal detachment.

Distribution Trunk spreading to upper extremities and face. Palms/soles can be involved.

Mucous Membranes (90%) Erosions on buccal, ocular, genital mucosae (Fig. 15-7).

General Findings

Fever, Lymphadenopathy (LAD)

Ocular (85%) Conjunctival hyperemia, keratitis, pseudomembrane formation, erosions.

Respiratory (25%) Epithelial damage, erosions.

Gastrointestinal Diarrhea, esophagitis.

Renal Tubular necrosis, renal failure.

Other Hepatitis, cytopenia.

Differential Diagnosis

SJS/TEN can be confused with EM, staphylococcal scalded skin syndrome (SSSS), severe acute GVHD, Kawasaki’s disease (KD), thermal burns, phototoxic eruptions, generalized fixed drug eruption, LE, or generalized erythroderma (from severe psoriasis, atopic dermatitis, mycosis fungiodes, etc.).

Laboratory Examinations

Dermatopathology Early: necrosis of the basal cell layer with subepidermal bullae formation. Late: full-thickness epidermal necrosis, sparse perivascular infiltrate. Analysis of frozen cryostat sections on “jelly roll” skin samples can expedite SJS/TEN diagnosis for more rapid clinical intervention.

Course and Prognosis

Course is similar to that of severe widespread thermal burns. Outcome is worse for in patients who are older, or have more extensive skin involvement. Mortality rate is 5% for SJS and 35% for TEN as is typically caused by sepsis (Staphylococcus aureus, Pseudomonas aeruginosa) or fluid and electrolyte imbalances.

Management

SJS/TEN management consists rapid diagnosis and of elimination of the causative agent. Patient best cared for in a burn or intensive care unit with IV fluid and electrolyte replenishment, temperature control, and vigilant wound care. Careful daily wound care (wash with isotonic sterile sodium chloride, mupirocin on orifices, Vaseline-impregnated gauze or silicone dressings, antibiotic eye drops to cornea) with minimal manipulation can lead to regrowth of epidermis in 1 to 3 weeks. Pressure points and perioral areas heal more slowly.

The use of systemic steroids for SJS/TEN management is controversial. High-dose IV immunoglobulins may be of some benefit if administered early. Cyclosporine, cyclophosphamide, plasmapheresis, N-acetyl-cysteine have had anecdotal successes.

Prevention

Those who do recover from TEN need to be aware of their drug sensitivity and possible cross-reactants. Reexposure to the offending agent can lead to a faster, more severe TEN episode, thus drugs should not be readministered and the patient should wear a medical alert bracelet.

A fixed drug eruption (FDE) is a recurrent cutaneous reaction to an ingested drug characterized by the formation of a fixed plaque, bulla, or erosion at the same site, hours after the offending drug is ingested.

Epidemiology

Age Any age.

Gender M = F.

Incidence Uncommon.

Etiology The drugs most commonly implicated are phenolphthalein, antimicrobial agents (tetracycline, minocycline, sulfonamides, trimethoprim-sulfamethoxazole, metronidazole), nystatin, anti-inflammatory agents (salicylates, NSAIDs, naproxen, acetaminophen, dipyrone, dimenhydrinate, phenylbutazone, phenacetin), psychoactive agents (barbiturates, carbamazepine), quinine and quinidine. The foods most commonly implicated are peas, beans, and lentils.

History

A FDE will first present as an erythematous plaque that occurs 1 to 2 weeks after exposure to the offending agent. With subsequent exposures, the violaceous plaque recurs within 24 hours recurs at the same site. The patient typically reports seeing the lesion at seemingly random intervals. Careful history will usually elicit the sporadic use of an over-the-counter or PRN medication that is causing the recurrent rash (i.e., ibuprofen, aspirin, eye drops, laxatives, etc.).

Physical Examination

Skin Findings

Type Macule, plaque, bullae, erosion.

Shape Round to oval. (Fig. 15-8)

Color Red, purple, brown.

Size 0.5 to 20 cm in diameter.

Number Solitary lesion. With repeated attacks, multiple lesions may occur.

Sites of Predilection Lips, hands, face, feet, genitalia.

Differential Diagnosis

FDE can be confused with recurrent herpetic lesions, arthropod bite, other drug reactions, a contact dermatitis, or other eczematous processes.

Laboratory Examinations

Dermatopathology Perivascular and interstitial dermal lymphohistiocytic infiltrate, at times with eosinophils and/or subepidermal vesicles and bullae with overlying epidermal necrosis. Between outbreaks, the site shows marked pigmentary incontinence with melanin in macrophages in upper dermis.

Course and Prognosis

The cutaneous lesions of FDE resolve within a few weeks of withdrawing the offending agent. The rash recurs within hours following ingestion of a single dose of the drug.

Management

The management for a FDE is to identify and withhold the offending drug. The hyperpigmented postinflammatory changes will slowly resolve with time.

Serum sickness is an allergic reaction characterized by urticaria, malaise, fever, lymphadenopathy, splenomegaly, and arthralgias. It originally was seen most in treatment with horse or rabbit antiserum; it is now seen with drugs or vaccinations.

Epidemiology

Age Any age.

Gender M = F.

Incidence Uncommon.

Etiology Immune-mediated reaction.

Pathophysiology

Serum sickness is mediated by circulating antigen-antibody complexes (type III-Arthus reaction), in which IgG is the predominant immunoglobulin.

History

Urticarial rash and low-grade fever, usually 7 to 21 days following administration of offending agent, or earlier in individuals previously sensitized to the agent.

Physical Examination

Skin Findings

Type Wheals, edema (Fig. 15-9).

Color Pink, red.

Shape Round, oval, and polycyclic.

Arrangement Scattered, discrete lesions or dense, confluent areas.

Distribution Trunk, extremities, face. Mucous membranes may be involved.

General Findings

LAD (often in epitrochlear region).

Musculoskeletal (50%) arthralgia, polyarthritis.

Neurologic Peripheral neuritis, radiculitis, optic neuritis, cerebral edema.

Renal Glomerulonephritis.

Differential Diagnosis

Serum sickness can be confused with urticaria, angioedema, urticarial vasculitis, a viral exanthem, toxic epidermal necrolysis, or subacute bacterial endocarditis.

Laboratory Examinations

Dermatopathology Engorged blood vessels with edema and perivascular inflammation.

Hematology ± Eosinophilia, elevated ESR, hypocomplementemia.

Course and Prognosis

Serum sickness has a self-limited course, progression may continue for a while, and then disappear within 2 to 3 weeks. Most cases resolve with no permanent sequelae. In rare instances, coronary artery vasculitis or neuropathy may persist.

Management

Symptomatic treatment of serum sickness includes analgesics and one or more antihistamines (chlorpheniramine, hydroxyzine, diphenhydramine, doxepin, acrivastine, cetirizine, loratadine, mizolastine, desloratadine, fexofenadine, levocetirizine, cimetidine, or ranitidine). Antihistamines should be continued for 1 to 2 weeks beyond clinical clearance to avoid recurrences or relapses and may need to be tapered slowly over several months.

Although their efficacy has not been proven, systemic steroids (prednisone, prednisolone) are used if common measures fail to comfort patient. More refractory cases may require systemic steroids (prednisone or methylprednisolone), but only short courses are recommended and rebound is possible. For anaphylactic or life-threatening situations (individuals with facial edema or respiratory symptoms), subcutaneous epinephrine is effective.

Erythema annulare centrifugum (EAC) is a cutaneous eruption characterized by migratory erythematous annular lesions with raised borders and central clearing. The etiology of EAC is unknown but it has been speculated that it occurs as a hypersensitivity reaction to an underlying infectious, inflammatory, or neoplastic process.

Synonyms Erythema perstans, gyrate erythema, palpable migrating erythema.

Epidemiology

Age Any age.

Gender M = F.

Genetics Rare AD case reports.

Etiology Likely hypersensitivity reaction to drugs (diuretics, NSAIDs, antimalarials, gold), foods, infections (dermatophytes, Candida albicans, Penicillium, poxvirus, EBV, molluscum contagiosum, parasites, P. pubis), blood dyscrasias, immunologic disorders (neonatal lupus, Sjögren’s syndrome, autoimmune endocrinopathies, hypereosinophilic syndrome), liver disease, hyperthyroidism, or neoplasms (lymphomas, leukemias).

History

Rash appears and spreads centrifugally over a period of 1 to 2 weeks. It is typically asymptomatic or mildly pruritic and can recur for months to years depending upon its etiologic process.

Physical Examination

Skin Findings

Type Papules, plaques, scale.

Size 1 to 10 cm.

Color Pink, red, purple

Number Solitary or multiple.

Shape Oval, circinate, semiannular, targetlike, polycyclic (Fig. 15-10).

Distribution Trunk, buttocks, thighs, and lower legs. Rarely palms, soles, mucous membranes.

Differential Diagnosis

The differential diagnosis of EAC is other annular rashes include pityriasis rosea, erythema multiforme, erythema marginatum, erythema chronicum migrans, dermatophyte infections, urticaria, urticarial vasculitis, granuloma annulare, sarcoidosis, psoriasis, and annular LE.

Laboratory Examinations

Dermatopathology Skin biopsy shows parakeratosis and focal infiltration of lymphocytes around dermal blood vessels and adnexal structures in a “coat–sleeve” pattern. There is minimal papillary edema and mild spongiosis.

Course and Prognosis

The duration of EAC is extremely variable; new lesions may continue to form for months or even years, appearing in successive forms.

Management

The treatment of EAC depends on the etiology and eradication of the causative agent is curative. Even in the absence of an identifiable cause, empiric treatment with antibiotics or antifungals may be helpful. Pruritic symptoms of EAC can be treated with antihistamines (chlorpheniramine, hydroxyzine, diphenhydramine, doxepin, acrivastine, cetirizine, loratadine). Topical regimens include antipruritics (calamine or 1% menthol cream) and/or topical steroids. Improvement with topical tacrolimus and topical calcipotriol have been reported.

Systemic steroids (prednisone, prednisolone) may suppress EAC but the disorder frequently recurs after cessation. Anecdotally, systemic metronidazole and subcutaneous α-interferon have had some success.

GVHD is an immune disorder caused by the response of histoincompatible, immunocompetent donor cells against the tissues of an immunoincompetent host.

Classification

Acute GVHD:

1. 1. Maculopapular eruption involving <25% of body surface, bili 2 to 3 mg/100 mL, diarrhea 500 to 1000 mL/d.

   2. Maculopapular eruption involving 25% to 50% of body surface, bili 3 to 6 mg/100 mL, diarrhea 1000 to 1500 mL/d.

   3. Erythroderma, bili 6 to 15 mg/100 mL, diarrhea 1500 to 2000 mL/d.

   4. Bulla formation, bili >15 mg/100 mL, diarrhea >2000 mL/d ± ileus.

Chronic GVHD:

1. 1. Lichenoid.

   2. Sclerodermoid.

Epidemiology

Age Any age, increased risk with older donor or recipient.

Gender Increased risk with F donor/M recipient.

Incidence Acute: 25% to 50%, Chronic: 50% of allogeneic PBSCT or BMT recipients.

Etiology Immune-mediated reaction in the graft-recipient from immunocompetent donor cells.

Pathophysiology

GVHD is an immunologic reaction induced by a graft of allogeneic lymphoid cells into a recipient with antigens not present in the donor. It is one of the major complications of allogeneic bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) with clinical manifestations in the skin, liver (cholestatic hepatitis), and/or GI tract (diarrhea). Severity of GVHD is related to histocompatibility match between donor and recipient and preparatory regimen used.

History

• Acute GVHD: Rash and pruritus occur 14 to 21 days (<3 months) after BMT or PBSCT.
• Chronic GVHD: Rash appears later than 40 days (average: 4 months) post-BMT or PBSCT, either evolving from acute GVHD or arising de novo.

Physical Examination

Skin Findings (Acute GVHD)

Type Maculopapular, papules, bullae.

Color Red.

Distribution Acral: palms, soles, pinna (Fig. 15-11), cheeks, neck, upper back, or generalized (Fig. 15-12).

General Findings (Acute GVHD)

High fever, hepatitis, jaundice, diarrhea, serositis, pulmonary insufficiency.

Skin Findings (Chronic GVHD)

Type Papules, plaques (Fig. 15-13), ulcers.

Color Purple, hypopigmented.

Palpation Sclerotic.

Distribution Dorsal hands, forearms. Sclerosis on trunk, buttocks, hips, thighs.

General Findings (Chronic GVID)

Hair loss; anhidrosis, oral LP-like lesions; erosive stomatitis, oral and ocular siccalike syndrome; esophagitis, serositis, fasciitis, bronchiolitis obliterans, chronic liver disease; wasting.

Differential Diagnosis

Acute GVHD can be confused with an exanthematous drug reaction, viral exanthem, or TEN. Chronic GVHD can be confused with lichen planus, lichenoid drug reaction, PLC, scleroderma, or poikiloderma.

Laboratory Examinations

Dermatopathology

• Acute GVHD: Basal cell vacuolization and necrosis of individual keratinocytes with a mild perivenular mononuclear cell infiltrate. A position of lymphocytes to necrotic keratinocytes can be seen and vacuoles coalesce forming subepidermal clefts and/or complete dermoepidermal separation.
• Chronic GVHD: Hyperkeratosis, mild hypergranulosis, mild acanthosis, moderate basal vacuolization, bandlike lymphocytic infiltrate next to the epidermis, melanin incontinence, loss of hair follicles, entrapment of sweat glands, and dense dermal sclerosis.

Course and Prognosis

• Acute GVHD: Profoundly decreases survival after PBSCT or BMT. Mild-to-moderate acute GVHD responds well to treatment. Severe GVHD patients are susceptible to infections (bacterial, fungal, or viral) and those with TEN-like skin changes have a very poor prognosis. Acute GVHD has mortality rate of 45% in BMT and PBSCT patients.
• Chronic GVHD: Sclerodermoid changes and tight skin and joint contractures may result in impaired mobility and ulcerations. There is also associated hair loss, xerostomia, and xerophthalmia resulting in corneal ulcers and blindness. GI disease leads to malabsorption. Mild chronic cutaneous GVHD may resolve spontaneously. Severe changes are usually permanent and debilitating. Chronic GVHD has an overall survival rate of 42% at 10 years owing to infections and immunosuppression.

Management

• Acute GVHD: The current strategy is to treat the BMT or PBSCT recipient with cyclosporine or tacrolimus in addition to methotrexate for 180 days posttransplant, followed by an immunosuppressive taper to prevent acute GVHD. If GVHD develops while on this regimen, systemic steroids are added. Other treatment possibilities include thalidomide, hydroxychloroquine, clofazimine, azathioprine, or mycophenolate mofetil.
• Chronic GVHD: Treatment for chronic GVHD is difficult and consists of systemic steroids alone or in combination with cyclosporine or tacrolimus. Other treatment possibilities include PUVA, photopheresis, etretinate, acitretin, infliximab, daclizumab.

Erythema nodosum (EN) is a cell-mediated, hypersensitivity reaction characterized by tender red nodules on the pretibial area.

Insight

EN is sometimes mistaken for multifocal cellulitis.

Synonyms Erythema contusiformis, EN migrans.

Epidemiology

Age Any age. Most commonly seen in patients aging from 15 to 30 years.

Gender F > M, 3:1.

Incidence Uncommon.

Season Spring and fall prevalence.

Etiology Up to 40% or more cases are idiopathic. Other possible triggers include infections (streptococcus, mycoplasma, tuberculosis, coccidioidomycosis, histoplasmosis, leprosy, leishmaniasis, cat scratch disease, mycobacterium marinum, yersinia, lymphogranuloma venereum, hepatitis B, brucellosis, meningococcus, gonococcus, pertussis, syphilis, Chlamydia, blastomycosis, HIV), drugs (estrogens, birth control pills, sulfonamides, penicillin, bromides, iodides, phenytoin, pregnancy) or other diseases (sarcoidosis, Crohn’s, ulcerative colitis, Behcet’s, Sweet’s, regional ileitis), or internal malignancy.

Pathophysiology

EN represents a delayed-type hypersensitivity reaction to a variety of different stimuli.

History

Skin lesions appear over a few days as warm tender red nodules on the pretibial area. The skin lesions slowly heal over 3 to 6 weeks but can recur, especially with recurrent infection. Associated arthralgias (50%), fever, and malaise may be present.

Physical Examination

Skin Findings

Type Nodules (Fig. 15-14).

Color Bright to deep red followed by purple to brown.

Size 1 to 5 cm.

Shape Round, oval.

Distribution Pretibial area > thighs/forearms > trunk, neck, face.

General Findings

Fever

Musculoskeletal Arthritis, myalgias.

Differential Diagnosis

The differential diagnosis includes ecchymoses, cellulitis, erysipelas, deep fungal infections, insect bites, thrombophlebitis, erythema induratum, and other panniculitides.

Laboratory Examinations

Dermatopathology Septal panniculitis in the dermis, subcutaneous fat, perivascularly in the septum, and adjacent fat.

Course and Prognosis

Most cases of EN resolve spontaneously in 3 to 6 weeks, especially with rest and leg elevation. Ultimately, the course depends upon the underlying etiology and elimination of the precipitant when possible (i.e., discontinue drug, treat infection, etc.). Recurrences are also dependent on etiology and recurrent EN in children is primarily seen with recurrent streptococcal infection.

Management

Identification and elimination of the etiologic agent is most helpful. Recommended work-up for an etiologic agent includes a careful drug history, throat culture to rule out streptococcus, chest x-ray to rule out sarcoidosis, tuberculin test to rule out primary tuberculosis, or other tests as deemed necessary by history.

Symptomatic treatment of the skin lesions includes bed rest, leg elevation, and compressive bandages, salicylates, and other NSAIDs (indomethacin, naproxen). Intralesional or systemic steroids can be used only if the etiologic agent is known (and infectious agents have been excluded). Other possible treatments include potassium iodide, colchicines, hydrochloroquine, cyclosporin A, and thalidomide. NSAIDs should be avoided in patients with IBD since these can flare the bowel symptoms.

Cold panniculitis is characterized by erythematous plaques or nodules that appear on exposure to the cold.

Synonym Popsicle panniculitis.

Epidemiology

Age Infants, small children.

Gender M = F.

Etiology Cold (weather, ice, popsicles) causes the fat to solidify with resultant plaque or nodule formation. Also seen on the lateral thighs of female equestrians.

Pathophysiology

Cold panniculitis occurs when the body fat solidifies and then liquifies on rewarming, with resulting inflammatory changes. The higher prevalence in infants and children is thought to be related to the fact that the subcutaneous fat in young children solidifies more easily than it does in adults.

History

Erythematous plaques or nodules develop on the exposed area hours after exposure to the cold. The areas may be painful or asymptomatic.

Physical Examination

Skin Findings

Type Plaques, nodules.

Color Pink to red.

Shape Round to oval.

Distribution Bilateral cheeks (Fig. 15-15), chin, lateral thighs.

Differential Diagnosis

The differential diagnosis for cold panniculitis includes other forms of panniculitis, cellulitis, erysipelas, insect bites, or ecchymoses.

Laboratory Examinations

Dermatopathology Nonspecific inflammation septa and lobules of the deep dermis and subcutaneous fat.

Course and Prognosis

Cold panniculitis lesions can appear 5 minutes to 3 days after cold exposure, and regress over weeks to months with postinflammatory pigmentation changes that can persist for up to 1 year.

Management

Cold panniculitis self-resolves with cold avoidance and treatment is unnecessary.

Sweet’s Syndrome

Sweet’s syndrome (SS) is a rare, recurrent skin disease characterized by painful papules, plaques, and nodules on the limbs, face, and trunk, accompanied by fever and leukocytosis.

Insight

In the initial stage, SS may present as vesiculating papules; varicella must be excluded at this stage.

Synonym Acute, febrile, neutrophilic dermatosis.

Epidemiology

Age Infants, children, adults aging from 30 to 60 years.

Gender F > M. 4:1.

Incidence Rare.

Etiology 50% idiopathic. Possible hypersensitivity reaction to infection. In adults, SS can be seen as an immunologic response to IBD, drugs, autoimmune disorders, pregnancy, or malignancy (particularly AML).

Pathophysiology

SS is thought to represent a hypersensitivity reaction to an infection (Streptococcal, Yersinia, atypical mycobacteria, CMV, hepatitis, HIV, BCG vaccination), malignancy (acute myeloid leukemia, transient myeloid proliferation, GU carcinoma, breast carcinoma, colon carcinoma), autoimmune disease (Behcet’s, autoimmune thyroiditis, sarcoidosis, dermatomyositis, SLE, rheumatoid arthritis, relapsing polychondritis, Sjogren’s), IBD (ulcerative colitis), or drug (G-CSF, furosemide, hydralazine, minocycline, and trimethoprim-sulfamethoxazole) .

History

In cases of SS, upper respiratory tract infection or flulike symptoms with high fevers precede the skin lesions by 1 to 3 weeks. Then, there is a sudden appearance of tender and painful papules and plaques on the face, neck, and limbs (usually spares torso), associated with a leukocytosis and polyarthritis.

Physical Examination

Skin Findings

Type Papules, nodules, bullae (Fig. 15-16).

Color Red, bluish-red.

Size 1 to 2 cm.

Palpation Lesions are tender.

Shape Annular or arcuate.

Arrangement Single lesion or multiple lesions, asymmetrically distributed.

Distribution Face, neck, and extremities. Spares torso.

General Findings

Fever (80%)

Musculoskeletal (30%) arthralgias, arthritis, myalgias.

Ocular (50%) conjunctivitis, episcleritis, limbal nodules, iridocyclitis.

Other Neutrophilic alveolitis, multifocal sterile osteomyelitis (SAPHO syndrome), glomerulonephritis, hepatitis, myositis, meningitis, encephalitis, pancreatitis, gastritis.

Differential Diagnosis

The differential diagnosis of SS includes erythema multiforme, erythema nodosum, prevesicular herpes simplex infection, preulcerative pyoderma gangrenosum, bowel-bypass syndrome, urticaria, serum sickness, other vasculitides, SLE, and panniculitis.

Laboratory Examinations

Dermatopathology Edema and a dense, perivascular infiltration with polymorphonuclear leukocytes in the upper and mid-dermis without vasculitis.

Hematology Leukocytosis (>10000/ mm3), increased ESR, C-reactive protein, α2-globulin fraction.

Course and Prognosis

Untreated, SS lesions enlarge over a period of days or weeks, and eventually resolve without scarring after 1 to 12 months. The skin lesions exhibit an excellent response to systemic steroids, usually resolving in days. Recurrences are seen in 50% of patients, often in previously involved sites, especially in patients with associated hematologic disorders.

Management

If an infection is identified, proper antimicrobial therapy is necessary.

Both the skin lesions and systemic symptoms of SS respond dramatically to steroids (prednisone or prednisolone). Solitary lesions can be treated with topical steroids, and/or topical calcineurin inhibitors. Other effective SS treatments include potassium iodide, clofazimine, colchicine, indomethacin, naproxen, sulindac, cyclosporine, thalidomide, α-interferon, and dapsone.

Pyoderma Gangrenosum

Pyoderma gangrenosum (PG) is a rapidly evolving, chronic, and severely debilitating skin disease characterized by painful ulcers with undermined borders and a purulent necrotic base. It occurs most commonly in association with systemic disease, especially inflammatory bowel disease or myeloproliferative disorders.

Synonyms Phagedenisme geometrique.

Classification

1. 1. Ulcerative: Classic PG associated with IBD or arthritis.

   2. Bullous: Atypical or bullous PG associated with AML, myelodysplasia, and myeloproliferative disorders (CML).

   3. Pustular: Sterile pustular eruption ±PG associated with IBD.

   4. Superficial granulomatous: Localized vegetative lesion following trauma (surgery).

Epidemiology

Age Infants, children, adults aging from 20 to 50 years.

Gender F > M.

Incidence Rare.

Etiology Idiopathic (25%–50%), immunologic abnormality suspected.

History

Acute onset with painful hemorrhagic pustule or nodule either de novo or following minimal trauma (pathergy), typically on the lower legs.

Pathophysiology

An underlying immunologic abnormality in patients is suspected since PG is often associated illnesses with such as large bowel disease and small bowel disease, arthritis, paraproteinemia, multiple myeloma, leukemia, active chronic hepatitis, and Behçet’s syndrome.

Physical Examination

Skin Findings

Type Papule, pustule, nodule, ulcer with undermined borders (Fig. 15-17).

Size 1 to 10 cm.

Color Red or purple.

Shape Irregular or serpiginous.

Arrangement Usually solitary. May form in clusters that coalesce.

Distribution Lower extremities > genitals/ buttocks > abdomen > face.

Mucous Membranes Rarely, aphthae; ulcers of oral mucosa and conjunctivae.

General Findings

Fever

Gastrointestinal (30%) ulcerative colitis or Crohn’s syndrome.

Musculoskeletal (20%) arthritis.

Hematologic (25%) AML, CML, hairy cell leukemia, myelodysplasia, monoclonal gammopathy.

Differential Diagnosis

The differential diagnosis of PG includes furuncle, carbuncle, cellulitis, panniculitis, gangrene, ecthyma gangrenosum, atypical mycobacterial infection, clostridial infection, deep mycoses, amebiasis, bromoderma, pemphigus vegetans, stasis ulcers, and Wegener’s granulomatosis.

Laboratory Examination

Dermatopathology Nonspecific, nondiagnostic. Neutrophilic inflammation, engorgement, and thrombosis of the small and medium vessels. Necrosis, hemorrhage may be present.

Course and Prognosis

Untreated, PG may last months to years. Lesions undergo necrosis and ulceration can expose underlying tendons or muscles. Ulceration may extend rapidly within a few days, or slowly and new ulcers may appear as older lesions resolve. Reepithelialization begins at the margins of the lesion and the lesions heal with atrophic scars.

Management

PG is best managed by identification and treatment of any associated underlying disease. For cutaneous lesions, management consists of decreasing inflammation, reducing pain, and promoting healing.

Topical regimens for mild disease include gentle cleansing (0.25% acetic acid soaks, whirlpool baths), wet dressings with potassium permanganate, silver sulfadiazine cream, cromolyn sodium solution, nicotine patch, topical or intralesional steroids, or tacrolimus.

For moderate disease or severe disease, oral steroids (prednisone, prednisolone) are the most effective. Systemic cyclosporine or tacrolimus can be used for PG refractory to steroids. Other treatment modalities include oral antibiotics, colchicine, infliximab, dapsone, clofazimine, potassium iodide, thalidomide, methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, chlorambucil, IVIG, and plasmapheresis.

Surgical debridement and excision of the ulcers should be avoided because PG is subject to pathergy in 20% of cases.

Sarcoidosis is a chronic granulomatous inflammatory process of unknown etiology that affects the skin, eye, lungs, and reticuloendothelial system.

Synonyms Lofgren’s syndrome—erythema nodosum, hilar adenopathy, fever, arthritis, Heerfordt’s syndrome—parotid gland enlargement, uveitis, fever, cranial nerve palsy, Darier–Roussy disease—subcutaneous sarcoidosis.

Special Types

1. 1. Lupus pernio: Soft, violaceous plaques on the nose, cheek, and earlobes, associated with pulmonary sarcoidosis (75%).

   2. Scar sarcoidosis: Purple nodules occurring in an old scar.

Epidemiology

Age Uncommon in children. Adults: Aging between 25–35 years and 45–65 years.

Gender M = F.

Incidence African American women: 107 per 100000. Sweden 64 per 100000. United Kingdom 20 per 100000.

Race African Americans > Caucasians.

Geography United States: Southeast states, the “sarcoid belt.”

Seasonal Increased in winter and spring.

Genetics Familial cases reported. HLA-1, HLA-B8, HLA-DR3 associations. Polymorphism for gene encoding angiotensin-converting enzyme (ACE).

Etiology Multifactorial with host response/delayed hypersensitivity and abnormal immunoregulation all playing a role.

Pathophysiology

An autoimmune or infectious trigger leads to granuloma formation in susceptible hosts with hyperactivity of their cell-mediated immune system.

History

Children with sarcoidosis develop asymptomatic eczematous or infiltrated plaques and pustules. They tend to have polyarthritis, uveitis, and not as many pulmonary symptoms. Older children and adolescent symptoms resemble the adult form of sarcoidosis with fever, cough, weight loss, abdominal pain, adenopathy, lung disease, hypergammaglobulinemia, and hypercalcemia.

Physical Examination

Skin Lesions

Type Maculopapules, plaques.

Size 0.5 to 1 cm.

Color Red-brown to purple.

Palpation Blanching with glass slide (diascopy) reveals “apple-jelly” yellowish-brown color.

Shape Annular, polycyclic, serpiginous.

Distribution Face (Fig. 15-18), lips neck, upper trunk extremities.

General Findings

Fever LAD (90%) bilateral hilar adenopathy on chest x-ray.

Musculoskeletal Arthralgias.

Gastrointestinal Abdominal pain.

Pulmonary (90%) alveolitis, granulomatous infiltration, bronchiolectasis.

Ocular Uveitis and iritis.

Other Parotid gland enlargement, facial nerve paralysis, and CNS involvement is rare.

Differential Diagnosis

The differential diagnosis of sarcoid includes infections with granulomatous inflammation (leprosy, tuberculosis), lupus erythematosus, foreign body reactions, granulomation mycosis fungoides, granulomatous rosacea, granuloma annulare, necrobiosis lipoidica, rheumatoid nodule, and interstitial granulomatous dermatitis.

Laboratory Examinations

Dermatopathology Superficial and deep noncaseating epithelioid granulomas without surrounding lymphocytic inflammation (“naked” tubercles). Multinucleated giant cells with nuclei in a peripheral arc with eosinophilic “asteroid bodies” or basophilic “Schaumann bodies.”

Blood Chemistry Increase in serum ACE (60%), hypergammaglobulinemia, hypercalcemia.

Course and Prognosis

Sarcoidosis in children tends to regress completely over several years. Mortality is less than 5%.

Management

Mild Disease Topical corticosteroids under plastic dressings, intralesional steroids, or systemic corticosteroids (prednisone, methylprednisolone) help skin lesions.

Moderate-to-Severe Disease Systemic corticosteroids (prednisone, methylprednisolone) helps skin, ocular disease, active pulmonary disease, cardiac arrhythmia, CNS involvement, facial palsy, and hypercalcemia. Other drugs include hydroxychloroquine, oxyphenbutazone, chloroquine, potassium-p-aminobenzoate, azathioprine, chlorambucil, methotrexate, thalidomide, isotretinoin, minocycline, allopurinol, infliximab, adalimumab, and etanercept.

Cutaneous vasculitis represents a specific pattern of inflammation which can affect small medium or large vessels of the arterial or venous system. Small vessel disease occurs in capillaries, arterioles, and postcapillary venules as seen in Henoch–Schonlein purpura (HSP) and urticarial vasculitis. Medium-sized vessel disease affects arteries and veins within the dermis or subcutis as seen in polyarteritis nodosa. Large vessel disease occurs in named arteries and the aorta as seen in KD.

Henoch-Schönlein Purpura

HSP is a cutaneous small vessel vasculitis of children characterized by a diffuse vasculitis of the skin, joints, GI tract, CNS, and kidneys following an upper respiratory infection.

Synonym Anaphylactoid purpura, purpura rheumatica, cutaneous small vessel vasculitis secondary to circulating IgA complexes.

Epidemiology

Age 3 to 10 years.

Gender M = F. Intussusception in M > F.

Incidence 180 cases per million.

Seasonal Prevalence Winter.

Etiology IgA-mediated hypersensitivity reaction to an upper respiratory tract infection (sometimes β-hemolytic streptococci).

Pathophysiology

HSP vasculitis is caused by deposition of immune complexes of lgA class in the capillaries, pre- and postcapillary venules of the upper dermis, GI tract, glomeruli, and synovial membrane, lungs, and CNS. The immune complex deposition results in complement activation and vascular damage.

History

HSP presents as acute-onset purpura, joint pain, and abdominal symptoms, 1 to 2 weeks after an upper respiratory tract infection. Renal involvement may or may not occur.

Physical Examination

Skin Findings

Type Macules (petechiae), patches (ecchymoses), papules (palpable purpura) (Fig. 15-19).

Size 2 to 10 mm.

Color Red, purple, brown.

Shape Annular, oval, arciform.

Arrangement Discrete or confluent.

Distribution Lower extremities, buttocks.

General Findings

Fever (40%).

Gastrointestinal Abdominal pain (85%), vomiting, GI bleeding, intussusception (2%).

Musculoskeletal Swelling of the ankles and knees.

Renal Gross or microscopic hematuria, proteinuria.

Differential Diagnosis

The differential diagnosis for HSP includes acute rheumatic fever, disseminated intravascular coagulation, meningococcal septicemia, Rocky Mountain spotted fever, pigmented purpuric dermatoses, and other small vessel vascular reactions to drugs, neoplasms, inflammatory disorders, autoimmune disorders, and infections.

Laboratory Examinations

Dermatopathology Leukocytoclastic vasculitis with fibrinoid degeneration of small dermal vessel walls, perivascular and intramural infiltrate of neutrophils and/or lymphocytes, nuclear dust, and RBC extravasation with deposits of hemosiderin.

Immunofluorescence Deposition of IgA, C3, and fibrin.

Urinalysis Hematuria, proteinuria, red cell casts.

Hematology Leukocytosis, anemia, thrombocytosis, elevated sedimentation rate.

Other ALSO may be positive, throat culture may be positive, stools may be guaiac positive, complement may be reduced or normal.

Course and Prognosis

HSP is self-limited and typically resolves over the course of weeks to months. Recurrent attacks may occur (5%–10%). Younger children tend to have a milder disease course of shorter duration with less GI and renal involvement and reduced recurrence rate. Up to 5% of patients with HSP-associated nephritis will progress to ESRD. Mortality is estimated to be less than 1% to 3%, usually because of renal or GI complications.

Management

The skin and systemic symptoms of HSP are usually self-limited, thus treatment consists of bedrest and supportive care. Antibiotics may be given if an upper respiratory infection is suspected. Systemic steroids may be useful for complicated noninfectious cases of HSP with GI, renal, CNS, or pulmonary manifestations. Factor XIII concentrate may benefit some patients with severe abdominal pain and low factor XIII.

Renal vasculitis is the only potential chronic problem in a patient with HSP. Corticosteroids, cyclophosphamide, or azathioprine may be used to treat severe renal involvement. IVIg, plasmapheresis, and aminocaproic acid have anecdotal effectiveness.

Urticarial Vasculitis

Urticarial vasculitis is a multisystem disease characterized by cutaneous lesions resembling urticaria and biopsy findings of a leukocytoclastic vasculitis, accompanied by varying degrees of arthritis, arthralgia, angioedema, uveitis, myositis, abdominal or chest pain.

Synonym Hypocomplementemic vasculitis, usually lupuslike syndrome, chronic urticaria as a manifestation of venulitis.

Insight

While purpura is the classical sine qua non of vasculitis, in urticarial vasculitis, especially early lesions, there may be deep dusky areas that are not truly purpuric clinically.

Epidemiology

Age 30 to 50 years. Rare in children.

Gender F > M.

Incidence 10% of urticarial cases.

Etiology Immune complex disorder or nonspecific reaction pattern to different etiologic agents.

Pathophysiology

Thought to be an immune complex disease, similar to cutaneous vasculitis with deposition of antigen-antibody complexes in cutaneous blood vessel walls leading to complement activation and neutrophil chemotaxis. Collagenase and elastase released from neutrophils cause vessel wall and cell destruction. It can be associated with autoimmune connective tissue diseases (Sjogren’s syndrome, SLE), infections (HBV, HCV, EBV), medications (KI, fluoxetine), hematologic disorders (IgM or IgM monoclonal gammopathies), and malignancies (multiple myeloma, colon, and renal cell carcinoma).

History

Recurrent papules, plaques, or wheals that last more than 24 hours with itching, burning, or stinging ± arthritis, or other constitutional symptoms.

Physical Examination

Skin Findings

Type of Lesion Macules, plaques, wheals.

Color Early: pink, red; late: purple, yellow-green, brown.

Distribution Trunk, proximal extremities (Fig. 15-20).

Palpation Blanch when pressed, but purpura remains.

General Examination

Fever (15%) LAD: (5%)

Musculoskeletal Arthralgias ± arthritis (70%).

Gastrointestinal Nausea, abdominal pain (30%).

Pulmonary Cough, dyspnea, hemoptysis.

CNS Pseudotumor cerebri (10%).

Renal Diffuse glomerulonephritis (20%).

Ocular Conjunctivitis, episcleritis, iritis, uveitis (10%).

Differential Diagnosis

Urticarial vasculitis may be confused with urticaria, serum sickness, erythema multiforme, angioedema, SLE, and other vasculitides.

Laboratory Examinations

Dermatopathology Early: leukocytoclastic vasculitis with perivascular infiltrate consisting primarily of neutrophils; leukocytoclasis; fibrinoid deposition in and around vessel walls; endothelial cell swelling; and extravasation of RBCs.

Other Hypocomplementemia (70%), circulating immune complexes, elevated sedimentation rate, microhematuria/proteinuria (10%).

Course and Prognosis

Urticarial vasculitis has a chronic (months to years) but benign course. Episodes recur over periods ranging from months to years. Systemic disease occurs in 50% of the hypocomplementemic patients.

Management

First-line treatment includes H1-blockers (diphenhydramine, hydroxyzine HCl, cetirizine HCl), H2-blockers (cimetidine, ranitidine hydrochloride), and NSAIDs (ibuprofen, indomethacin, naproxen). Second-line treatment would be systemic steroids (prednisone, prednisolone). Systemic colchicine, dapsone, hydrochloroquine, mycophenolate mofetil, and pentoxifylline have reported successes. Rituximab may be helpful for hypocomplementemic urticarial vasculitis.

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a multisystem, necrotizing vasculitis of predominantly medium-sized arteries with cutaneous and systemic variants. Pediatric cases are typically more severe and life-threatening than the adult cases.

Synonym Periarteritis nodosa, panarteritis nodosa.

Epidemiology

Age Pediatric PAN: In children younger than 2 years. Adult PAN: Occurring from 40 to 60 years of age.

Gender Pediatric PAN: M = F. Adult PAN: M > F.

Incidence 16 cases per million.

Etiology Hypersensitivity reaction from infection or inflammatory disease that leads to IgM, C3 deposition in affected vessel walls.

Pathophysiology

Necrotizing inflammation of medium-sized muscular arteries associated with infections (HBV, streptococcus, parvovirus B19, HIV), inflammatory conditions (inflammatory bowel disease, SLE, familial Mediterranean fever) and malignancies (hairy cell leukemia).

History

Pediatric PAN Febrile illness, cardiac arteritis leading to fatal coronary disease. Renal and CNS arteries are also diseased with severe sequelae. May be a severe form of KD.

Adult PAN Painful nodules, fever, arthritis, abdominal pain, hypertension, peripheral neuropathy, and myocardial infarction.

Physical Examination

Skin Findings (15%)

Type Macules, nodules, ulcers.

Pattern Livedo reticularis pattern (Fig. 15-21).

Size 0.5 to 2 cm.

Color Red, purple.

Distribution Lower legs > thighs > arms > trunk > head and neck > buttocks.

General Examination

Fever Weight loss >4 lbs.

Musculoskeletal Arthralgias, myalgias.

CNS Cerebrovascular accidents.

Neurological Motor/sensory involvement, mononeuritis multiplex, peripheral neuropathy.

Eye Hypertensive, ocular vasculitis, retinal artery aneurysm, optic disc edema, atrophy.

Renal Renovascular hypertension, renal failure.

Other Abdominal pain, congestive heart failure, orchitis in males.

Differential Diagnosis

The diagnosis of PAN is made by tissue biopsy findings (in skin, muscle, nerve, tissue) or detection of microaneurysms (in kidney or GI tract) by imaging such as magnetic resonance angiography. The differential diagnosis includes cryoglobulinemia vasculitis, autoimmune connective tissue disease, microscopic polyangiitis, Wegener’s granulomatosis, and Churg–Strauss syndrome.

Laboratory Examinations

Dermatopathology Segmental necrotizing vasculitis of medium-sized vessels with polymorphonuclear neutrophils infiltrating all layers of the vessel wall and perivascular areas. Fibrinoid necrosis of vessel wall occurs with occlusion of lumen, thrombosis, and infarction of tissues supplied by involved vessel.

Immunofluorescence Deposits of C3, IgM, and fibrin within vessel walls.

Arteriography Aneurysms in kidney, hepatic, and visceral vasculature.

Other Leukocytosis, eosinophilia, anemia, elevated ESR, elevated BUN/creatinine.

Course and Prognosis

Pediatric PAN has a chronic relapsing course with a poor prognosis and death related to cardiac failure. Untreated, adult PAN also has a very high morbidity and mortality characterized by fulminant deterioration or by relentless progression associated with intermittent acute exacerbations. Mortality results from renal failure, bowel perforation, cardiovascular failure, or intractable hypertension. Effective treatment reduces mortality to 50%.

Management

In pediatric PAN, management consists of aspirin or NSAIDs (indomethacin or naproxen), and IV γ-globulin. In adult PAN, systemic corticosteroids leads to remission in half the patients. More refractory cases can be treated with cyclophosphamide, sulfapyridine, methotrexate, plasma exchange, or pentoxifylline.

Idiopathic Thrombocytopenic

Purpura

Idiopathic thrombocytopenic purpura (ITP) is a common autoimmune disorder of childhood resulting in increased destruction of platelets.

Synonym Immune thrombocytopenic purpura, autoimmune thrombocytopenic purpura.

Classification

Acute ITP In children, follows infection, resolves in 2 months.

Chronic ITP In adults, persists longer than 6 months without a cause.

Epidemiology

Age Acute: 2 to 4 years of age. Chronic: 20 to 50 years.

Gender Acute: M = F. Chronic F > M 2:1

Incidence Acute: 50 per 1000000 annually. Chronic: 66 per 1000000 annually.

Etiology Increased platelet destruction thought to be autoimmune and frequently follows infection (varicella, rubella, rubeola, or URI) or immunizations.

Pathophysiology

Autoimmune destruction of platelets caused by antibodies against platelets.

History

Acute presentation of bleeding into the skin (from petechiae to ecchymoses) usually following a febrile illness.

Physical Examination

Skin Findings

Type of Lesion Petechial macules (Fig. 15-22), ecchymoses.

Size 1 mm to several centimeters.

Color Red, purple, dark brown.

Palpation Nonpalpable. Lesions do not blanch with pressure.

Distribution of Lesions Pressure points (face and neck from crying, under elastic socks).

Mucous Membranes Petechiae, gingival bleeding.

General Findings

CNS Intracranial hemorrhage (mortality 5% in adults, 1% in children).

Other Menometrorrhagia, menorrhagia, GI bleeding, retinal hemorrhages, palpable spleen.

Differential Diagnosis

The differential diagnosis for ITP includes telangiectasia, palpable purpura (vasculitis) purpura of scurvy, progressive pigmentary purpura (Schamberg’s disease), purpura following severe Valsalva maneuver (tussive, vomiting, and retching), traumatic purpura, factitial or iatrogenic purpura, and Gardner–Diamond syndrome (autoerythrocyte sensitization syndrome).

Laboratory Examination

Dermatopathology May be contraindicated because of postsurgical hemorrhage.

Hematology Thrombocytopenia (platelets below 50000/mm) coagulation studies are normal (PT, PTT, fibrin split products) and exclude a consumptive process.

Course and Prognosis

Acute ITP of childhood is a self-limited disorder. Up to 80% of cases resolve in 4 weeks; 90% resolve in 6 months. Rarely, thrombocytopenia can last for months with a prolonged risk of hemorrhage. Only 10% of children have a more chronic course (>6 months) but these cases usually self-resolve as well. Only 2% of severe childhood ITP cases have a 5-year mortality rate because of bleeding.

Older age and previous history of hemorrhage increases the risk of severe bleeding in adult, chronic ITP. Forty-eight percent of severe adult ITP cases have a 5-year mortality rate because of bleeding, particularly intracranial hemorrhage.

Management

Treatment is not usually needed given the high rate of spontaneous recovery in childhood acute ITP. Conservative management includes avoiding platelet inhibitors (i.e., aspirin), limiting strenuous physical activities (injury might lead to severe hemorrhage).

Persistent severe thrombocytopenia (platelets <20000/mm) may warrant treatment with IVIg, systemic steroids (prednisone, methylprednisolone), platelet transfusion (for platelets <10000/mm), or splenectomy for chronic cases.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a life-threatening disorder resulting from intravascular fibrin and the consumption of procoagulants and platelets, associated with a wide range of clinical circumstances (bacterial sepsis, massive trauma) characterized by intravascular coagulation (cutaneous infarctions and/or acral gangrene) and hemorrhage.

Synonyms Purpura fulminans, consumption coagulopathy, defibrination syndrome, coagulation-fibrinolytic syndrome.

Epidemiology

Age All ages. Purpura fulminans more common in children.

Gender M = F.

Incidence 18000 cases of DIC occurred in 1994.

Etiology Conditions associated with DIC include sepsis/severe infection, massive tissue destruction (neurotrauma, organ destruction, transplant rejection), malignancy (solid tumor or myeloproliferative), transfusion reaction, rheumatologic disease (lupus), obstetric complications (amniotic fluid embolism, abruptio placentae, HELLP syndrome, retained fetal products), vascular anomalies (Kasabach–Merritt syndrome, aneurysms).

Pathophysiology

DIC is caused by the activation of coagulation leading to intravascular fibrin deposition which clogs the blood supply to the end organs. Four mechanisms include increased thrombin production, anticoagulant suppression, impaired fibrinolysis, and inflammatory activation.

History

DIC typically has its onset 3 to 30 days after a resolving infection. Hemorrhagic lesions appear rapidly and systemic symptoms include fever, tachycardia, anemia, and prostration. The prognosis is grave but can be improved with therapy.

Physical Examination

Skin Findings

Type Ecchymoses (Fig. 15-23).

Color Red, deep purple to black.

Distribution Distal extremities; areas of pressure; lips, ears, nose, trunk.

General Findings

Fever ± shock (14%).

Bleeding (64%) epistaxis, gingival/mucosal bleeding.

CNS (2%) confusion/disorientation.

Cardiac Hypotension, tachycardia, circulatory collapse.

Pulmonary (16%) dyspnea/cough, ARDS.

Renal (25%) azotemia, renal failure.

Hepatic (19%).

Differential Diagnosis

The differential diagnosis of DIC includes other diffuse hemorrhagic entities such as coumarin or heparin necrosis, thrombocytopenic purpura-hemolytic uremic syndrome, or ITP.

Laboratory Examinations

Dermatopathology Occlusion of arterioles with fibrin thrombi and a dense polymorphonuclear infiltrate around the infarct with massive hemorrhage.

Hematologic Studies CBC: schistocytes (fragmented RBC) arising from RBC entrapment and damage within fibrin thrombi, seen on blood smear; thrombocytopenia. Coagulation studies: reduced plasma fibrinogen; elevated fibrin degradation products (D-dimer and FDPs); prolonged PT, PTT, and thrombin time.

Course and Prognosis

The mortality rate from DIC is high. Surviving patients require skin grafts or amputation for gangrenous tissue. Common complications include severe bleeding, thrombosis, tissue ischemia and necrosis, hemolysis, organ failure. Mortality without therapy is 90% and occurs within 48 to 72 hours. Prompt therapy can improve the prognosis and reduce mortality to as low as 18%.

Management

Treatment of DIC requires prompt recognition and appropriate antibiotics, clotting factors, ± platelet replacement, vitamin K replacement, and/or supportive care.

KD is an acute febrile illness of infants and children, characterized by cutaneous and mucosal erythema and edema with subsequent desquamation and cervical lymphadenitis. With appropriate treatment, subsequent development of coronary artery aneurysms can be avoided.

Insight

The cutaneous manifestations of KD may be protean; in any child with fever for more than 5 days, this entity merits consideration.

Synonyms Mucocutaneous lymph node syndrome, juvenile periarteritis nodosa.

Epidemiology

Age Older than 5 years (80%), older than 2.5 years (50%).

Gender M > F, 1.5:1.

Race Japanese > African American > white children.

Incidence 10 in 100000 annually.

Etiology Unknown. Probably infectious with winter and spring epidemics.

Genetics Possible genetic susceptibility, since it is much more prevalent in the Japanese population.

Pathophysiology

KD is thought to be an immunologic disorder triggered by an infectious or toxic agent. This can lead to a generalized aneurysm vasculitis.

History

Children present with fever >19.4°C for 5 days without infection plus four out of the following:

1. 1. Conjunctival injection without exudate.

   2. Changes on lips and mouth (strawberry tongue, pharyngeal erythema, chelilitis).

   3. Polymorphous generalized body rash.

   4. Hand/foot edema followed by desquamation.

   5. Cervical lymphadenopathy.

Constitutional symptoms include diarrhea, arthralgias, arthritis, tympanitis, and photophobia.

Physical Examination

Skin Findings

Type Macules, papules, vesicles, desquamation (Fig. 15-24).

Color Pink, red.

Distribution Lower abdomen, groin, perineum, buttocks, extremities, palms, soles.

Mucous Membranes Hyperemic conjunctiva, red, dry fissured lips, injected pharynx, “strawberry” appearance to the tongue (Fig. 15-25).

General Findings

Fever LAD (80%) >1.5-cm cervical node.

Musculoskeletal Arthritis and arthralgias (knees, hips, elbows).

Cardiac Pericardial tamponade, dysrhythmias, rubs, congestive heart failure, left ventricular dysfunction.

GI Diarrhea, vomiting, abdominal pain, jaundice, gallbladder swelling, paralytic ileus.

Neurologic Meningeal irritation, convulsions, facial palsy, paralysis of the extremities.

Other Cough, rhinorrhea, pyuria.

Differential Diagnosis

The differential diagnosis of KD includes scarlet fever, SJS, measles, juvenile rheumatoid arthritis, infectious mononucleosis, viral exanthems, leptospirosis, Rocky Mountain spotted fever, toxic shock syndrome, staphylococcal scalded skin syndrome, erythema multiforme, serum sickness, SLE, and Reiter’s syndrome.

Laboratory Examinations

Histology Nonspecific, perivascular infiltrates, edema, dilation of small vessels.

Hematology Leukocytosis with left shift, anemia, thrombocytosis, elevated ESR, increased LFTs.

Urinalysis Proteinuria, leukocytes.

Echocardiography Pericardial effusions, coronary aneurysms.

Course and Prognosis

The acute episode of KD self-resolves in the majority of children with no sequelae. In absence of treatment, 20% of patients will go on to develop cardiovascular complications; coronary artery aneurysms can occur 2 to 8 weeks after febrile episode. This can result in myocarditis, myocardial ischemia and infarction, pericarditis, peripheral vascular occlusion, small bowel obstruction, and stroke. Mortality rate is 1%.

Management

Treatment is directed at prevention of the cardiovascular complications and includes high-dose aspirin during the febrile period and high-dose IV γ-globulin.