Section O: Hypersensitivity Syndromes

PATIENT STORY

A 14-year-old boy presents to the emergency department with a 1-day history of fever associated with lip swelling and peeling (Figure 185-1A). Within 48 hours he developed involvement of his ocular (Figure 185-1B) and urethral mucosa along with an erythematous papular rash on his trunk that spread to his extremities. In Figure 185-1C, target lesions can be seen on his back. He was diagnosed with Stevens-Johnson syndrome and admitted to the hospital.

INTRODUCTION

Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are skin disorders thought to be types of hypersensitivity reactions (undesirable reactions produced by a normal immune system in a presensitized host) that occur in response to medication, infection, or illness. Both SJS and TEN are severe cutaneous reactions thought to describe the same disorder, differing only in severity (TEN more severe); however, there is debate as to whether these three fall into a spectrum of disease that includes EM.

SYNONYMS

• EM has also been called EM minor.

• SJS has been called EM major in the past but is now thought to be a distinct entity different from all types of EM.

• TEN is also known as Lyell syndrome.

EPIDEMIOLOGY

• The incidence of EM has been estimated to range from 1 in 1000 persons to 1 in 10,000 persons.¹ The true incidence is unknown.¹

• SJS and TEN are rare severe cutaneous reactions often caused by drugs. Reports of incidence vary from 1.2 to 6 per 1 million for SJS and from 0.4 to 1.2 per 1 million for TEN.^2-4

• EM is rare in children under age 3 years and adults over age 50 years: 20% of cases occur in children and adolescents.⁵

• With respect to EM, males are affected more often than females (3:2 to 2:1).⁵

ETIOLOGY AND PATHOPHYSIOLOGY

Numerous factors have been identified as causative agents for EM:

• Herpes simplex virus (HSV) I and HSV II are the most common causative agents, having been implicated in at least 60% of cases (Figure 185-2).^6,7 The virus has been found in circulating blood,⁸ as well as on skin biopsy of patients with EM minor.⁶

• Bacterial causes are numerous and include cat-scratch disease, chlamydial infections, hemolytic streptococci, legionellosis, Neisseria meningitidis, Mycoplasma pneumoniae, pneumococci, and rickettsial infections.⁵

• Other causes include foods and food preservatives, immunologic disorders, mechanical factors (e.g., tattooing), and malignancy.⁵ Some cases are thought to be related to medications (e.g., sulfa drugs), although no test reliably proves the link to a specific drug, and half of EM cases are considered idiopathic.⁵

For SJS and TEN, most cases are drug induced.

• Drugs most commonly known to cause SJS and TEN are sulfonamide antibiotics, allopurinol, NSAIDs, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine.⁹

• Mycoplasma pneumoniae has been identified as the most common infectious cause for SJS⁷; in 2013, an outbreak of 8 pediatric cases of SJS was reported at Children's Hospital Colorado associated with M. pneumoniae infection.¹⁰ Clinical presentation of cases of SJS following mycoplasma infection were different from non-associated SJS cases in having less extensive skin disease, an elevated erythrocyte sedimentation rate, and preceding respiratory symptoms.

Other less-common causative agents for EM, SJS, and TEN include:

• Infectious agents such as Mycobacterium tuberculosis, group A streptococci, hepatitis B, Epstein-Barr virus, Francisella tularensis, Yersinia, enteroviruses, Histoplasma, and Coccidioides.¹

• Neoplastic processes, such as leukemia and lymphoma.¹

• Antibiotics, such as penicillin, isoniazid, tetracyclines, cephalosporins, and quinolones.

• Anticonvulsants, such as phenobarbital and valproic acid.^1,7

• Other drugs including captopril, etoposide, aspirin, and allopurinol.

• Immunizations such as bacillus Calmette-Guérin, diphtheria-tetanus toxoid, hepatitis B, measles-mumps-rubella, and poliomyelitis.⁶

• Other agents or triggers including radiation therapy, sunlight, pregnancy, connective tissue disease, and menstruation.¹

Although the pathogenesis of EM, SJS, and TEN remains unknown, recent studies show that it may be as a result of a host-specific cell-mediated immune response to an antigenic stimulus that activates cytotoxic T cells and results in damage to keratinocytes.^6,9

• The epidermal detachment (skin peeling) seen in SJS and TEN appears to result from epidermal necrosis in the absence of substantial dermal inflammation.

RISK FACTORS

• Recent evidence shows individuals with certain human leukocyte antigen (HLA) alleles may be predisposed to developing SJS/TEN, and to SJS-associated ocular involvement, when taking certain drugs.^2,11 In addition, IKZF1 has been identified as a susceptibility gene for cold medicine–induced SJS/TEN with severe mucosal involvement in Japanese, Korean, and Indian subjects.¹²

• Certain diseases such as HIV/AIDS (Figure 185-3), malignancy, or autoimmune disease, also predispose individuals to SJS/TEN.^2,13

DIAGNOSIS

CLINICAL FEATURES

In these conditions, there is a rapid onset of skin lesions. EM is a disease in which patients present with the following lesions:

• Classic lesions begin as red macules and expand centrifugally to become target-like papules or plaques with an erythematous outer border and central clearing (iris or bull's-eye lesions) (Figures 185-4, 185-5, 185-6, 185-7). Target lesions, although characteristic, are not necessary to make the diagnosis. The center of the lesions should have some epidermal disruption, such as vesicles or erosions.

• Lesions can coalesce and form larger lesions up to 2 cm in diameter with centers that can become dusky purple or necrotic.

• Unlike urticarial lesions, the lesions of EM do not appear and fade; once they appear they remain fixed in place until healing occurs many days to weeks later.

• Patients are usually asymptomatic, although a burning sensation or pruritus may be present.

• Lesions typically resolve without any permanent sequelae within 2 weeks.

• Recurrent outbreaks are often associated with HSV infection (see Figure 185-2).^6,7

In both SJS and TEN, patients may have blisters that develop on dusky or purpuric macules. SJS is diagnosed when less than 10% of the body surface area is involved, SJS/TEN overlap when 10% to 30% is involved, and TEN when greater than 30% is involved.

• Lesions may become more widespread and rapidly progress to form areas of central necrosis, bullae, and areas of denudation (see Figure 185-1).

• Fever higher than 39°C (102.2°F) is often present.

• In addition to skin involvement, there is involvement of at least 2 mucosal surfaces, such as the eyes, oral cavity, upper airway, esophagus, GI tract, or the anogenital mucosa (see Figures 185-1 and 185-3).

• New lesions occur in crops and may take 4 to 6 weeks to heal.

• Large areas of epidermal detachment occur (Figures 185-8, 185-9, 185-10).

• Severe pain can occur from mucosal ulcerations, but skin tenderness is minimal.

• Skin erosions lead to increased insensible blood and fluid losses, as well as an increased risk of bacterial superinfection and sepsis.

• These patients are at high risk for ocular complications (e.g., conjunctivitis, lid-margin and conjunctival ulceration, corneal opacification) that may lead to blindness. Additional risks include bronchitis, pneumonitis, myocarditis, hepatitis, enterocolitis, polyarthritis, hematuria, and acute tubular necrosis.

TYPICAL DISTRIBUTION

• The distribution of the rash in EM can be widespread.

• The distal extremities, including the palms and soles, are most commonly involved.

• Extensor surfaces are favored.

• Oral lesions may be present, especially in SJS (see Figures 185-1 and 185-3).

• Severe lesions with exfoliation and extensive mucosal lesions occur in SJS and TEN (see Figures 185-8, 185-9, 185-10).

LABORATORY AND IMAGING

• There are no consistent laboratory findings with these conditions. The diagnosis is usually made based on clinical findings.

• Routine blood work may show leukocytosis, elevated liver transaminases, and an elevated erythrocyte sedimentation rate.

• In TEN, leukopenia may occur.

BIOPSY

• A cutaneous punch biopsy can be performed to confirm the diagnosis or to rule out other diseases.

• Histologic findings of EM will show a lymphocytic infiltrate at the dermal–epidermal junction. There is a characteristic vacuolization of the epidermal cells and necrotic keratinocytes within the epidermis.¹

DIFFERENTIAL DIAGNOSIS

• Bullous pemphigoid—Can be either subacute or acute with tense widespread blisters that can occur after persistent urticaria; mucosal involvement is rare. Significant pruritus can be present. As with EM, SJS, and TEN, bullous pemphigoid can occur after certain exposures such as UV radiation or certain drugs (Chapter 192, Bullous Pemphigoid).

• Urticaria—A skin reaction characterized by red wheals that are usually pruritic. Unlike EM, individual lesions rarely last more than 24 hours (Chapter 156, Urticaria and Angioedema).

• Kawasaki disease—Fever persists at least 5 days and there must be at least four of the five following features to diagnose complete (or classic) Kawasaki disease.¹⁴

  • Changes in extremities—Acute: erythema and edema of the hands and feet; or subacute: periungual desquamation (peeling of fingers and toes).

  • Rash: maculopapular, diffuse erythroderma, or erythema multiforme–like.

  • Bilateral bulbar conjunctival injection without exudate.

  • Changes in lips and oral cavity—Erythema, lips cracking, strawberry tongue (see Chapter 36, Scarlet Fever and Strawberry Tongue), and/or erythema of the oral and pharyngeal mucosae.

  • Cervical lymphadenopathy (>1.5 cm diameter), usually unilateral.

• Cutaneous vasculitis—Also caused by a hypersensitivity reaction, lesions are palpable papules or purpura. Blisters, hives, and necrotic ulcers can occur on the skin. Lesions are usually located on the legs, trunk, and buttocks (see Chapter 187, Vasculitis).

• Erythema annulare centrifugum—A hypersensitivity reaction caused by a variety of agents. Lesions look similar with erythematous papules of a few to several centimeters that enlarge and clear centrally and may be vesicular. Lesions tend to appear on the legs and thighs, but may occur on upper extremities, trunk, and face; palms and soles are spared (see Chapter 215, Erythema Annulare Centrifugum).

• Staphylococcal scalded skin syndrome—Rash may also follow a prodrome of malaise and fever but is macular, brightly erythematous, and initially involves the face, neck, axilla, and groin. Skin is markedly tender. Like SJS and TEN, large areas of the epidermis peel away. Unlike TEN, the site of the staphylococcal infection is usually extracutaneous (e.g., otitis media, pharyngitis) and not the skin lesions themselves (Chapter 122, Impetigo).

MANAGEMENT

FIRST LINE

EM:

• Treat the infectious cause if known (e.g., herpes or mycoplasma).

• Withdraw the suspected drug (new medication within 2 months of onset).⁵

• Treatment is mainly supportive. Symptomatic relief may be provided with topical emollients and eye lubricants, mouthwashes (e.g., xylocaine), systemic oral antihistamines, and acetaminophen. These do not, however, alter the course of the illness.

• The use of corticosteroids has not been well studied but is thought to prolong the course or increase the frequency of recurrences in HSV-associated cases.⁷

• Prophylactic acyclovir has been used to control recurrent HSV-associated EM with some success.⁷

SJS and TEN:

• Treatment is mainly supportive and may require intensive care or placement in a burn unit. Early diagnosis is imperative so that triggering agents can be discontinued.

• Oral lesions can be managed with mouthwashes and glycerin swabs.

• Skin lesions should be cleansed with saline or Burow solution (aluminum acetate in water).

• IV fluids should be given to replace insensible losses.

• Daily examinations for secondary infections should occur, and systemic antibiotics should be started as needed.

• Consultation with an ophthalmologist is important because of the high risk of ocular sequelae.

• Pharmacologic therapy is widely debated in the literature. Intravenous immunoglobulin (IVIG) at doses of 2 to 3 g/kg may help shorten the course and improve outcome if started early during the disease.¹⁵

• Systemic corticosteroids have been the mainstay of treatment for SJS/TEN. Authors of a meta-analysis found that glucocorticosteroids and cyclosporine were the most promising therapies, although steroids were of statistically significant survival benefit in only one analysis, and cyclosporine was of significant benefit only in a feasible analysis of individual patient data.¹⁶ In this review, IVIGs were not found to be helpful.

SECOND LINE

SJS and TEN:

• Agents that have been tried with limited success include thalidomide, tumor necrosis factor α inhibitors, cyclophosphamide, granulocyte colony-stimulating factors, and plasmapheresis.¹⁶

• A tear-exchangeable limbal contact lens was found to improve vision and quality of life in patients with ocular sequelae.¹⁷

PREVENTION

Screening populations known to carry HLA alleles prior to starting medications with higher risks for SJS/TEN has been suggested by some researchers² but, in one study, was not found to be cost effective.¹⁸

PROGNOSIS

• EM usually resolves spontaneously within 1 to 2 weeks.

• Recurrence of EM is common, especially when preceded by HSV infection.

• Prognosis is poorer for patients with SJS and TEN, especially if they are older, have a large percentage of body surface area involved, or have intestinal or pulmonary involvement.

• About one quarter of patients with TEN require ventilator assistance; in one study, the need for a ventilator was associated with a higher percentage of epidermal-detached body surface area (especially greater than 30%), serum bicarbonates less than 20 mmol/L, serum urea greater than 10 mmol/L, WBCs more than 12,000/mm³, and hemoglobin less than 8 g/dL, in addition to more extensive pulmonary infiltrates.¹⁹

• Mortality for SJS/TEN can be predicted based on the severity of illness score for TEN (SCORTEN).²⁰ One point is given for each of the following: serum blood urea nitrogen greater than 10 mmol/L; serum bicarbonate less than 20 mmol/L; serum glucose greater than 14 mmol/L; age older than 40 years; malignancy present; heart rate greater than 120 beats per minute; percentage of body surface area involved greater than 10%. Scores of 0 to 1 are associated with a mortality rate of 3.2%, whereas scores of 5 or higher are associated with a mortality rate of 90%.

• For patients with SJS, mortality rates have been reported of 5% to 10% and up to 30% for TEN.^9,21

FOLLOW-UP

• For uncomplicated cases, no specific follow-up is needed.

• For patients with EM major and any of the complications listed above, follow-up should be arranged with the appropriate specialist.

PATIENT EDUCATION

• If an offending drug is found to be the cause, it should be discontinued immediately.

• Patients with HSV-associated EM should be made aware of the risk of recurrence.

REFERENCES

PATIENT STORY

A young woman presented to the office with several days of overall malaise, fever, and sore throat. At the time of presentation she noted some painful bumps on her lower legs, and denied trauma (Figure 186-1). No history of recent cough or change in bowel habits has been reported. The patient had no chronic medical problems, took no medications, and had no known drug allergies. Her temperature was slightly elevated, but other vitals were normal. On examination, her oropharynx revealed tonsillar erythema and exudates. Bilateral lower extremities were spotted with slightly raised, tender, erythematous nodules that varied in size from 2 to 6 cm. Rapid strep test was positive, and she was diagnosed clinically with erythema nodosum (EN) secondary to group A β-hemolytic Streptococcus. She was treated with penicillin and nonsteroidal anti-inflammatory drugs (NSAIDs) and was advised temporary bed rest. She experienced complete resolution of the EN within 4 weeks.

INTRODUCTION

EN is a common inflammatory panniculitis characterized by ill-defined, erythematous patches with underlying tender, subcutaneous nodules. It is a reactive process caused by chronic inflammatory states, infections, medications, malignancies, and unknown factors.

SYNONYMS

Löfgren syndrome (with hilar adenopathy).

EPIDEMIOLOGY

• Erythema nodosum occurs in approximately 1 to 5 per 100,000 persons.¹ It is the most frequent type of septal panniculitis (inflammation of the septa of fat lobules in the subcutaneous tissue).²

• EN tends to occur more often in women, with a male-to-female ratio of 1:4.5 in the adult population, generally during the second and fourth decades of life (Figures 186-1, 186-2, 186-3).³

• In 1 study, an overall incidence of 54 million people worldwide was cited in patients older than 14 years of age.⁴

• In the childhood form, the female predilection is not seen.

ETIOLOGY AND PATHOPHYSIOLOGY

• Most EN is idiopathic (Figures 186-3 and 186-4). Although the exact percentage is unknown, 1 study estimated that 55% of EN is idiopathic.⁵ This may be influenced by the fact that EN may precede the underlying illness. The distribution of etiologic causes may be seasonal.⁶ Identifiable causes can be infectious, reactive, pharmacologic, or neoplastic.

• Histologic examination is most useful in defining EN. Defining characteristics of EN are a septal panniculitis without presence of vasculitis. That this pattern develops in certain areas of skin may be linked to local variations in temperature and efficient blood drainage.

• Septal panniculitis begins with polymorphonuclear cells infiltrating the septa of fat lobules in the subcutaneous tissue. It is thought that this is in response to existing immune complex deposition in these areas.⁷ This inflammatory change consists of edema and hemorrhage which is responsible for the nodularity, warmth, and erythema.

• The infiltrate progresses from predominantly polymorphonuclear cells, to lymphocytes, and then histiocytes where fibrosis occurs around the lobules. There may be some necrosis, although minimal as complete resolution without scarring is the typical course.

• The histopathologic hallmark of EN is the Miescher radial granuloma. This is a small, well-defined nodular aggregate of small histiocytes around a central stellate or banana-shaped cleft.

RISK FACTORS

• Group A β-hemolytic streptococcal pharyngitis has been linked to EN (see Figure 186-1). A retrospective study of 129 cases of EN over several decades reports that 28% had streptococcal infection.⁵

• Nonstreptococcal upper respiratory tract infections may also play a role.¹

• Historically, tuberculosis (TB) was a common underlying illness with EN, but TB is now a rare cause of EN in developed countries. There are reports of EN occurring in patients receiving the bacille Calmette-Guérin vaccination.⁸ In developed countries, sarcoidosis is more commonly found. One study estimates sarcoidosis as being the cause of 11% of EN cases (see Figure 186-2).^5,7

• EN occurs in 3% of all patients with coccidiomycosis⁹ and approximately 4% of patients with histoplasmosis.¹⁰

• EN is less frequently associated with other infections agents, including Yersinia gastroenteritis, Salmonella, Campylobacter, toxoplasmosis, syphilis, amebiasis, giardiasis, brucellosis, leprosy, Chlamydia, Mycoplasma, Brucella, hepatitis B (infection and vaccine), Epstein-Barr virus, and Bartonella.^4,11

• When the EN rash occurs with hilar adenopathy, the entity is called Löfgren syndrome. Löfgren syndrome in TB represents primary infection. A more common cause of Löfgren syndrome is sarcoidosis.⁷

• The literature reports that EN is seen in patients with inflammatory bowel diseases. It is usually prominent around the time of GI flare-ups, but may occur before a flare. Most sources report a greater association between Crohn disease and EN than between ulcerative colitis and EN. Other chronic diseases associated with EN include Behçet disease and Sweet syndrome.¹¹

• EN can be associated with pregnancy and oral contraceptive use.

• Besides oral contraceptives, medications implicated as causing EN are antibiotics including sulfonamides, penicillins, and bromides. However, the antibiotics may have been prescribed for the underlying infection that had caused EN.¹¹

• Lymphomas, acute myelogenous leukemia, carcinoid tumor, and pancreatic carcinoma are associated with EN and should be considered in cases of persistent or recurrent EN.^11,12

DIAGNOSIS

CLINICAL FEATURES

• The diagnosis is usually clinical.

• The lesions of EN are deep-seated nodules that may be more easily palpated than visualized.

• Lesions are initially firm, are round or oval, and are poorly demarcated.

• Lesions may be bright red, warm, and painful (see Figure 186-3).

• Lesions number from 1 to more than 10.5 and vary in size from 1 to 15 cm.

• Over their course, the lesions begin to flatten and change to a purplish color before eventually taking on the yellowish hue of a bruise.

• A characteristic of EN is the complete resolution of lesions with no ulceration or scarring.

• EN is associated with systemic occurrence of fever, malaise, and polyarthralgia sometime near eruption.

TYPICAL DISTRIBUTION

• Lesions appear on the anterior/lateral aspect of both lower extremities (see Figures 186-1, 186-2, 186-3).

• Although lesions may appear in other regions such as the arms, absence in the lower legs is unusual (see Figure 186-4).¹

• Sarcoidosis, in particular, may present with lesions on the ankles and knees (see Figure 186-2).

• Lesions may appear in dependent areas in bedridden patients.

LABORATORY TESTING

• Blood tests may help to identify the underlying cause. Typical tests include complete blood count, chemistries, liver function tests, and erythrocyte sedimentation rate. Erythrocyte sedimentation rate may be elevated.

• For suspected Streptococcus cases, rapid strep test or throat cultures are best during acute illness, whereas antistreptolysin O titers may be used in the convalescent phase.⁴

• In sarcoidosis, angiotensin-converting enzyme levels may be helpful but are not 100% sensitive.² A chest X-ray and/or skin biopsy of a suspected sarcoid lesion can help make this diagnosis (see Chapter 184, Sarcoidosis).

BIOPSY

• The diagnosis of EN is mostly made on physical examination. When the diagnosis is uncertain, a biopsy that includes subcutaneous fat is performed. This can be a deep punch biopsy or a deep incisional biopsy sent for standard histology.

DIFFERENTIAL DIAGNOSIS

• Cellulitis should be considered and not missed. These patients tend to have more fever and systemic symptoms. EN tends to appear in multiple locations, whereas cellulitis is usually in one localized area (see Chapter 126, Cellulitis).

• Nodular cutaneous and subcutaneous sarcoid is skin-colored or violaceous without epidermal involvement. The lack of surface involvement makes this resemble EN. Subcutaneous sarcoidosis may be seen in advanced systemic sarcoidosis that can also be the cause of EN. Skin biopsy is the best method to distinguish between these two conditions. Either way, treatment is directed toward the sarcoidosis (see Chapter 184, Sarcoidosis).

• Erythema induratum of Bazin is a lobular panniculitis that occurs on the posterior lower extremity of women with tendency of lesions to ulcerate with residual scarring.⁷ This condition is typically caused by TB and is more chronic in nature than EN.²

• Erythema nodosum leprosum may occur in patients with leprosy and probably represents an immune complex or hypersensitivity reaction (Figures 186-5 and 186-6). Erythema nodosum leprosum is typically seen as a type 2 reaction to standard leprosy therapy.¹³ It is more common in multibacillary lepromatous leprosy. Although the lesions often look like standard EN, the lesions may also ulcerate.

• An infectious panniculitis should also be considered in the differential, especially in immunocompromised patients. These lesions are often asymmetric, and the patient may be febrile. If suspected, a punch biopsy of a lesion should be sent for tissue culture (bacteria, fungus, and mycobacteria).

MANAGEMENT

• Look for and treat the underlying cause. There is limited evidence to guide treatment unless an underlying cause is found.

FIRST LINE

NONPHARMACOLOGIC

• Cool, wet compresses, elevation of the involved extremities, bed rest, gradient support stockings, or pressure bandages may help alleviate the pain.¹¹ SORⒸ

MEDICATIONS

• Treat the pain and discomfort of the nodules with NSAIDs and/or other analgesics.¹⁴ SORⒸ

SECOND LINE

MEDICATIONS

• The value of oral prednisone is controversial, and it should be avoided unless it is being used to treat the underlying cause (such as sarcoidosis) and if underlying infection, risk of bacterial dissemination or sepsis, and malignancy have been excluded.¹ SORⒸ

• Oral potassium iodide (Figure 186-7) is an old therapy that has led to resolution of EN in several small studies.^6,7 SORⒷ It is now available over the counter but is contraindicated in pregnancy. Potassium iodide can be mixed in orange juice to make it more palatable. It is available in many different concentrations, so it is important to pay close attention to the dosage.

• Colchicine, hydroxychloroquine, and dapsone have been used as well.^2,7 SORⒸ

• There are a few case reports of EN treated with penicillin, erythromycin, adalimumab, etanercept, infliximab, mycophenolate mofetil, cyclosporine, thalidomide, and extracorporeal monocyte granulocytapheresis.^1,15,16 SORⒸ

• There are a few case reports and one small study of minocycline and tetracycline leading to EN and erythema nodosum leprosum improvement.^17,18 SORⒸ

PREVENTION

• Good handwashing and general health measures may prevent respiratory infections that may predispose to EN.

PROGNOSIS

• EN is usually self-limited or resolves with treatment of the underlying disorder.

• Patients may continue to develop nodules for a few weeks.

• The course depends on the etiology but usually lasts only 6 weeks.

• Lesions completely resolve with no ulceration or scarring.

• Recurrences occur in 33% to 41% of cases, usually when the etiology is unknown.¹⁶

FOLLOW-UP

• Follow-up is needed to complete the work-up for an underlying cause and to make sure that the patient is responding to symptomatic treatment.

PATIENT EDUCATION

Reassure the patient that there is complete resolution in most cases within 3 to 6 weeks. Inform the patient that some EN outbreaks may persist for up to 12 weeks, and some cases are recurrent.⁶

REFERENCES

PATIENT STORY

A 21-year-old woman presented with a 3-day history of a painful purpuric rash on her lower extremities (Figures 187-1 and 187-2). The lesions had appeared suddenly, and the patient had experienced no prior similar episodes. The patient had been diagnosed with a case of pharyngitis earlier that week and was given a course of clindamycin. She had not experienced any nausea or vomiting, fever, abdominal cramping, or gross hematuria. Urine dipstick revealed blood in her urine, but no protein. The typical palpable purpura on the legs is consistent with Henoch-Schönlein purpura (HSP), also known as IgA vasculitis.

INTRODUCTION

Vasculitis refers to a group of disorders characterized by inflammation and damage in blood vessel walls. They may be limited to skin or may be a multisystem disorder. Cutaneous vasculitic diseases are classified according to the size (small vs. medium to large vessel) and type of blood vessel involved (venule, arteriole, artery, or vein). Small- and medium-size vessels are found in the dermis and deep reticular dermis, respectively. While the classifications have not changed, the nomenclature has in an effort to characterize lesions based on the pathologic findings and underlying disease process. The most notable changes during the Chapel Hill Consensus Conference of 2012 changed HSP to IgA vasculitis (IgAV), Wegener's granulomatosis to granulomatosis with polyangitis (GPA), and Churg-Strauss to eosinophilic granulomatosis with polyangitis (EGPA).¹ The clinical presentation varies with the intensity of the inflammation and the size and type of blood vessel involved.²

SYNONYMS

Hypersensitivity vasculitis is also known as leukocytoclastic vasculitis.

HSP (IgAV) is a type of leukocytoclastic vasculitis.

EPIDEMIOLOGY

• HSP (IgAV) (Figures 187-1, 187-2, 187-3) occurs mainly in children with an incidence of approximately 1 in 5000 children annually.³ It results from immunoglobulin (Ig) A–containing immune complexes in blood vessel walls in the skin, kidney, and GI tract. HSP (IgAV) is usually benign and self-limiting and tends to occur in the springtime. A streptococcal or viral upper respiratory infection often precedes the disease by 1 to 3 weeks. Prodromal symptoms include anorexia and fever. Most children with HSP (IgAV) also have joint pain and swelling with the knees and ankles being most commonly involved (Figure 187-3). In half of cases there are recurrences, typically in the first 3 months. Recurrences are more common in patients with nephritis and are milder than the original episode. To make the diagnosis of HSP (IgAV), establish the presence of 3 or more of the following⁴:

  • Palpable purpura

  • Bowel angina (pain)

  • GI bleeding

  • Hematuria

  • Onset ≤20 years

  • No new medications

• Some patients with systemic lupus erythematosus (SLE) (Figures 187-4 and 187-5), rheumatoid arthritis (RA), relapsing polychondritis, and other connective tissue disorders develop an associated necrotizing vasculitis. It most frequently involves the small muscular arteries, arterioles, and venules. The blood vessels can become blocked, leading to tissue necrosis (see Figures 187-4 and 187-5). The skin and internal organs may be involved.

• Leukocytoclastic vasculitis (Figures 187-6, 187-7, 187-8) is the most commonly seen form of small vessel vasculitis. Prodromal symptoms include fever, malaise, myalgia, and joint pain. The palpable purpura begins as asymptomatic localized areas of cutaneous hemorrhage that become palpable. Few or many discrete lesions are most commonly seen on the lower extremities but may occur on any dependent area. Small lesions itch and are painful, but nodules, ulcers, and bullae may be very painful. Lesions appear in crops, last for 1 to 4 weeks, and may heal with residual scarring and hyperpigmentation. Patients may experience 1 episode (drug reaction or viral infection) or multiple episodes (RA or SLE). The disease is usually self-limited and confined to the skin. To make the diagnosis, look for presence of 3 or more of the following⁵:

  • Age older than 16 years

  • Use of a possible offending drug in temporal relation to the symptoms

  • Palpable purpura

  • Maculopapular rash

  • Biopsy of a skin lesion showing neutrophils around an arteriole or venule

• Systemic manifestations of leukocytoclastic vasculitis may include kidney disease, heart, nervous system, GI tract, lungs, and joint involvement.

ETIOLOGY AND PATHOPHYSIOLOGY

• Vasculitis is defined as inflammation of the blood vessel wall. The mechanisms of vascular damage consist of a humoral response, immune complex deposition, or cell-mediated T-lymphocyte response with granuloma formation.⁶

• Vasculitis-induced injury to blood vessels may lead to increased vascular permeability, vessel weakening, aneurysm formation, hemorrhage, intimal proliferation, and thrombosis that result in obstruction and local ischemia.⁶

• Small-vessel vasculitis is initiated by hypersensitivity to various antigens (drugs, chemicals, microorganisms, and endogenous antigens), with formation of circulating immune complexes that are deposited in walls of postcapillary venules. The vessel-bound immune complexes activate complement, which attracts polymorphonuclear leukocytes. They damage the walls of small veins by release of lysosomal enzymes. This causes vessel necrosis and local hemorrhage.

• Small-vessel vasculitis most commonly affects the skin and rarely causes serious internal organ dysfunction, except when the kidney is involved. Small-vessel vasculitis is associated with leukocytoclastic vasculitis, HSP (IgAV), essential mixed cryoglobulinemia, connective tissue diseases or malignancies, serum sickness and serum sickness–like reactions, chronic urticaria, and acute hepatitis B or C infection.

• Hypersensitivity (leukocytoclastic) vasculitis causes acute inflammation and necrosis of venules in the dermis. The term leukocytoclastic vasculitis describes the histologic pattern produced when leukocytes fragment.

RISK FACTORS

• Viral infections.

• Autoimmune disorders.

• Drug hypersensitivity.

• Cocaine (adulterated with levamisole) (Figure 187-9) (see Chapter 251, Cocaine, for additional images and information).

DIAGNOSIS

• Initially, determining the extent of visceral organ involvement is more important than identifying the type of vasculitis, so that organs at risk of damage are not jeopardized by delayed or inadequate treatment. In addition to the dermatologic findings, the physical examination may be useful in determining if large vessels are involved. Examination findings of a blood pressure difference of greater than 10 mm Hg in the arms, auscultation of bruits, and diminished peripheral pulses may indicate large vessel involvement.⁷ It is critical to distinguish vasculitis occurring as a primary autoimmune disorder from vasculitis secondary to infection, drugs, malignancy, or connective tissue disease such as SLE or RA.⁶

CLINICAL FEATURES

• Small-vessel vasculitis is characterized by necrotizing inflammation of small blood vessels and may be identified by the finding of "palpable purpura." The lower extremities typically demonstrate "palpable purpura," varying in size from a few millimeters to several centimeters (Figures 187-2, 187-6, 187-7, and 187-10). In its early stages leukocytoclastic vasculitis may not be palpable.

• The clinical features of HSP (IgAV) include nonthrombocytopenic palpable purpura mainly on the lower extremities and buttocks (see Figures 187-1, 187-2, 187-3), GI symptoms, arthralgia, and nephritis.

TYPICAL DISTRIBUTION

• Cutaneous vasculitis is found most commonly on the legs but may be seen on the hands and abdomen (see Figures 187-3, 187-8, and 187-10).

LABORATORY TESTING

• Laboratory evaluation is geared to finding the antigenic source of the immunologic reaction. Consider throat culture, antistreptolysin-O titer, erythrocyte sedimentation rate, platelets, complete blood count (CBC), serum creatinine, urinalysis, antinuclear antibody, serum protein electrophoresis, circulating immune complexes, hepatitis B surface antigen, hepatitis C antibody, cryoglobulins, and rheumatoid factor. The erythrocyte sedimentation rate is almost always elevated during active vasculitis. Immunofluorescent studies are best done within the first 24 hours after a lesion forms. The most common immunoreactants present in and around blood vessels are IgM, C3, and fibrin. The presence of IgA in blood vessels of a child with vasculitis suggests the diagnosis of HSP (IgAV).

• Basic laboratory analysis to assess the degree and types of organs affected should include serum creatinine, creatinine kinase, liver function studies, hepatitis serologies, urinalysis, and possibly chest X-ray and ECG.

BIOPSY

• The clinical presentation is so characteristic that a biopsy is generally unnecessary. In doubtful cases, a punch biopsy should be taken from the center of an active (nonulcerated) lesion or, if necessary, from the edge of an ulcer (see Figure 187-4). A 4-mm punch biopsy from a well-developed purpuric lesion (ideally 3 days old—or within 1 to 7 days) is best sent in formalin for hematoxylin–eosin-stained analysis.⁸ If the specimen is to be sent for direct immunofluorescence to find out the type of antibodies present, the lesion should ideally be less than 24 hours old and sent in special Michelle media (or on a saline-soaked gauze in a sterile urine container to be transferred to the Michelle media in the lab).

DIFFERENTIAL DIAGNOSIS

• Pigmented purpuric dermatosis is a capillaritis characterized by extravasation of erythrocytes in the skin with marked hemosiderin deposition. It is not palpable. Schamberg disease is a type of pigmented purpuric dermatosis found most often on the lower legs in older persons (Figures 187-11 and 187-12). It is described as a cayenne pepper–like appearance. Lichen aureus is a localized pigmented purpuric dermatosis seen in younger persons that may occur on the leg or in other parts of the body (Figure 187-13). The color may be yellow brown or golden brown. There is also a pigmented purpuric dermatosis of the Majocchi type that has an annular appearance with prominent elevated erythematous borders that may have telangiectasias (Figure 187-14). A dermatoscope can help to visualize the red or pink dots that represent inflamed capillaries in these conditions.

• Meningococcemia that presents with purpura in severely ill patients with central nervous system symptoms (Figures 187-15 and 187-16).

• Rocky Mountain spotted fever is a rickettsial infection that presents with pink to bright red, discrete 1- to 5-mm macules that blanch with pressure and may be pruritic. The lesions start distally and spread to the soles and palms (Figure 187-17).

• Malignancies, such as cutaneous T-cell lymphoma (mycosis fungoides) (see Chapter 180, Cutaneous T-Cell Lymphoma).

• Stevens-Johnson syndrome and toxic epidermal necrolysis (see Chapter 185, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).

• Idiopathic thrombocytopenia purpura can be easily distinguished from vasculitis by measuring the platelet count. Also, the purpura is usually not palpable and the petechiae can be scattered all over the body (Figure 187-18).

• Wegener granulomatosis (GPA) is an unusual multisystem disease characterized by necrotizing granulomatous inflammation and vasculitis of the respiratory tract, kidneys, and skin.

• Churg-Strauss syndrome (EGPA) presents with a systemic vasculitis associated with asthma, transient pulmonary infiltrates, and hypereosinophilia.

• Cutaneous manifestations of cholesterol embolism, which are leg pain, livedo reticularis (blue-red mottling of the skin in a netlike pattern), and/or blue toes in the presence of good peripheral pulses.

MANAGEMENT

NONPHARMACOLOGIC

• The offending antigen should be identified and removed whenever possible. With a mild hypersensitivity vasculitis that is due to a drug, discontinuing the offending drug may be all the treatment that is necessary. SORⒸ

MEDICATIONS

• An antihistamine might be used for itching. SORⒸ

• Oral prednisone is used to treat visceral involvement and more severe cases of vasculitis of the skin. Short courses of prednisone (60 to 80 mg/day) are effective and should be tapered slowly. SORⒷ

• Colchicine (0.6 mg twice daily for 7 to 10 days) and dapsone (100 to 150 mg/day) may be used to inhibit neutrophil chemotaxis.⁹ SORⒷ They are tapered and discontinued when lesions resolve. Azathioprine, cyclophosphamide, and methotrexate have also been studied. SORⒸ

• In HSP (IgAV) and prolonged hypersensitivity vasculitis, treatment with nonsteroidal anti-inflammatory drugs is usually preferred. Treatment with corticosteroids may be of more benefit in patients with more severe disease such as more pronounced abdominal pain and renal involvement.¹⁰ SORⒷ Adding cyclophosphamide to the steroids may also be effective. SORⒸ Azathioprine also may be used.¹¹ In children with persistent proteinuria a trial of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be used; patients with rapidly progressive nephritis may benefit from plasmapheresis to prevent long-term renal dysfunction.¹² SORⒸ

REFER OR HOSPITALIZE

• Refer or hospitalize with significant internal organ involvement or prolonged disease course.

PROGNOSIS

• In leukocytoclastic (hypersensitivity) vasculitis, the cutaneous lesions usually resolve without sequelae. Visceral involvement (such as kidney and lung) most commonly occurs in HSP (IgAV), cryoglobulinemia and vasculitis associated with SLE.¹³ Extensive internal organ involvement should prompt an investigation for coexistent medium-size vessel disease and referral to a rheumatologist.

FOLLOW-UP

• Relapses may occur, especially when the precipitating factor is an autoimmune disease. Regular monitoring is necessary.

PATIENT EDUCATION

• Reassure patients and parents that most cases of acute cutaneous vasculitis resolve spontaneously.

REFERENCES