Rudolph's Pediatrics, 22nd Ed.

CHAPTER 203. Vasculitides

Karyl S. Barron

Vasculitis, defined as inflammation of blood vessels, is a feature of many rheumatic and nonrheumatic diseases of childhood. This chapter addresses only those diseases in which vasculitis plays a central role in both pathogenesis and clinical presentation. Criteria used for a diagnosis of vasculitis in adults are often problematic when applied to children. Recently a consensus was reached on a new international classification of childhood vasculitis and these criteria will be used in this chapter.1 Classification of vasculitis is based on the size of the blood vessels involved or the pathology of the lesions (Table 203-1). This chapter will be limited to the more commonly seen vasculitides of childhood.

Table 203-1. Proposed Classification of Childhood Vasculitis (International Consensus Conference, Vienna 2005)

I. Predominantly large vessel vasculitis

Takayasu arteritis

II. Predominantly medium-sized vessel vasculitis

Childhood polyarteritis nodosa

Cutaneous polyarteritis

Kawasaki disease

III. Predominantly small vessel vasculitis

A. Granulomatous

Wegener granulomatosis

Churg-Strauss syndrome

B. Nongranulomatous

Microscopic polyangiitis

Henoch-Schönlein purpura

Isolated cutaneous leukocytoclastic vasculitis

Hypocomplementemic urticarial vasculitis

IV. Other Vasculitides

Behçet disease

Vasculitis secondary to infection (including hepatitis B-associated PAN), malignancy and drugs including hypersensitivity vasculitis

Isolated vasculitis of the CNS

Cogan syndrome



Henoch-Schönlein purpura (HSP) is an acute leukocytoclastic vasculitis, mainly affecting the small vessels of the skin, joints, gastrointestinal tract, and kidneys (Table 203-2). HSP is the most common form of systemic vasculitis in childhood with an incidence of about 10 cases per 100,000 a year. The main features of the disease include nonthrombocytopenic palpable purpura (present in 100% of affected children), arthritis or arthralgias (75–85%), colicky abdominal pain with or without gastrointestinal hemorrhage (60–85%), and renal involvement (10–50%). The diagnostic criteria are shown in Table 203-2. Although it can occur at any age, HSP is overwhelmingly a disease of childhood. The mean age of patients is 6 years; 75% of patients are younger than age 8 and 90% are less than 10 years of age. The clinical features of HSP may be atypical at the extremes of age. The severity tends to be milder in infants under 2 years of age and worse in adults. The disease is more common in males, although sex differences are not seen in patients older than age 16.2 HSP has a seasonal pattern, with peaks in winter and spring. It is an IgA-mediated leukocytoclastic vasculitis, characterized by neutrophil infiltration and fibrinoid necrosis in the vessel walls of arterioles, capillaries, and postcapillary venules, with deposition of IgG, IgA, and C3.3

Table 203-2. Classification Criteria for Henoch-Schönlein Purpura

Palpable purpura (mandatory criterion) in the presence of at least 1 of the following 4 features:

Diffuse abdominal pain

Any biopsy showing predominant IgA deposition

Arthritis* or arthralgia

Renal involvement (any hematuria and/or proteinuria)

*Acute, any joint


The etiology of the disease is unknown. HSP often follows a respiratory infection. A wide variety of pathogens, drugs, and other environmental exposures have been associated with HSP including bacterial infections, viral infections, drugs, vaccines, food additives, and insect bites. Of all of the pathogens linked to HSP, group A β hemolytic Streptococcus has been studied the most. Thus, a substantial minority of patients has concomitant or recent streptococcal infection, but most cases have no direct link to streptococcal infection.


The onset of HSP may be acute or subacute, with clinical features of the disease most commonly developing in an additive manner over a short time span. Skin lesions, present in all patients, are the initial manifestation in about 50% of patients. The typical rash begins as small wheals or erythematous maculopapules that evolve into petechial or purpuric lesions, more prominent on dependent and pressure-bearing areas (Fig. 203-1). Although usually located over the lower extremities or buttocks, the rash may involve upper extremities, trunk, and face.4 In young children, HSP might present as edema and purpura involving the face and ears. Skin lesions tend to occur in crops and last from 5 days to 4 weeks. Angioedema of the scalp, perineal area, and extremities may precede the rash.

Arthritis is the second most common feature of HSP, occurring in roughly 75% of patients and most often affecting knees and ankles. In about 25% of patients, arthritis/arthralgias of large joints are the initial symptom of HSP; this nonspecific finding confounds the diagnosis until the appearance of skin rash 24 to 48 hours later. Because joint swelling is often periarticular, there may be no true joint effusion despite significant pain on motion. Joint symptoms typically resolve spontaneously after a few days without residual deformity, but may recur with new exacerbations of HSP.

Gastrointestinal (GI) involvement occurs in 50% to 75% of patients. The most common complaint is colicky abdominal pain, frequently associated with vomiting. Pain may be severe enough to mimic an acute abdomen and may precede the rash in as much as 10% to 15% of patients. GI bleeding is usually occult, but 30% of patients have grossly bloody or melanotic stools. Upper gastrointestinal series show nonspecific changes such as thickening of the bowel wall, “thumb printing,” and filling defects. Ultrasound studies are abnormal in up to 80% of patients with GI involvement, including increased echogenicity and thickening of the wall of the second portion of the duodenum and/or hydrops of the gallbladder. Endoscopy may reveal lesions with similar appearance to the palpable purpura seen in the skin. These finding are not present in HSP patients without GI complaints. Intussusception has been reported in 1% to 5% of patients and is usually ileoileal. Other uncommon GI complications include perforation or bowel infarct.

Renal involvement is discussed in more detail in Chapter 472. It occurs in 40% to 50% of patients with HSP and is most commonly limited to transient urinary abnormalities such as microscopic hematuria or hematuria plus mild proteinuria. Unlike arthritis and GI involvement, nephritis rarely, if ever, precedes the onset of purpura. About 75% to 90% of patients with nephritis develop urinary abnormalities within 4 weeks, but these may occur up to 3 months after the onset of symptoms. Urinalysis should be done each week while the disease is active, then monthly for the next 3 months. If all analyses are normal, nephritis is unlikely to occur. If at anytime there is evidence of nephritis, long-term monitoring of urinalyses, protein excretion, renal function, and blood pressure is warranted until the urinary abnormalities resolve. Renal histopathology shows lesions indistinguishable from those of IgA nephropathy (Berger disease). Prognosis for those patients with renal involvement is excellent: Only 1% to 2% with severe renal involvement will have residual nephropathy, with less than 1% progressing to end-stage renal disease. An age of more than 7 years at onset, persistent purpura for more than 1 month, and decreased factor XIII are significant risk factors for progression of renal involvement.

Less common manifestations of HSP include acute scrotal swelling secondary to vasculitis and hemorrhage of the scrotal vessels, pancreatitis, pulmonary hemorrhage, encephalopathy, anterior uveitis, myositis, hemiparesis, and convulsions.

FIGURE 203-1. Classical palpable purpura on the lower legs of a patient with Henoch-Schonlein purpura. Source: (Source: From Wolff K, Johnson RA. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill, 2009, p. 400.)


The diagnosis of HSP is made on clinical grounds because laboratory tests are not diagnostic. Elevations of acute phase reactants and white blood cell count are frequent. Platelet count and coagulation studies are normal. Serum levels of IgA are frequently elevated. Hemoglobin may be depressed in the context of severe bleeding. Ultrasonography is the preferred imaging technique to rule out intussusception, because barium enema may miss an ileoileal intussusception, which is common in HSP.


Treatment is supportive. Most children may be managed as outpatients with appropriate analgesia and hydration. Development of GI and renal complications may be monitored by assessing stool guaiac test, blood pressure, and urine dipsticks as an outpatient, unless severe intestinal or renal involvement necessitates hospital admission. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used to manage severe joint pain, although they should be avoided in the setting of significant renal disease. Prednisone in a dosage of 1 to 2 mg/kg/day is helpful in the management of painful edema and scrotal swelling, and is sometimes used in children with severe abdominal pain, although its efficacy has not been proven.5 Treatment of HSP nephritis remains controversial. Therapies used include intravenous pulses of methylprednisolone, cyclophosphamide, and azathioprine, alone or in different combination, as well as plasmapheresis as discussed in Chapter 472. HSP is a self-limited disease that usually lasts 1 to 2 weeks. The disease has a tendency to recur within an initial 6-week period but exacerbations may occur as late as 2 years after onset. The prognosis of the disease is excellent. HSP morbidity is determined in most cases by GI complications during the acute phase and by renal involvement in the long term.


Kawasaki disease (KD) is an acute febrile illness of childhood and is the primary cause of acquired heart disease in children in the United States and Japan. The course of the disease is divided into three phases. The acute phaseencompasses a febrile period of 1 to 2 weeks and is characterized by fever to 104°F or higher; injection of the bulbar conjunctiva with sparing of the limbus; mouth and lip changes without oral ulcerations or exudates; rash; reddening of the palms and soles and/or swelling of the hands and feet; and cervical lymphadenopathy. During this phase up to 30% of patients develop arthralgias or arthritis, usually polyarticular, involving knees, ankles, and hands. Arthritis is self-limited, resolving in 3 weeks, although it may persist for as long as 3 months. The subacute phase typically begins about 10 to 25 days after the onset of fever and lasts until all signs of clinical activity subside. Around the second to third week of illness patients can develop pauciarthritis involving hips, knees, or ankles. Arthritis in this phase is also self-limited. The convalescent phase begins during the third or fourth week of illness, when clinical signs disappear, and continues until all parameters of inflammation normalize, usually 6 to 8 weeks after onset. Kawasaki disease is discussed in detail in Chapter 488.


Polyarteritis nodosa (PAN) is a necrotizing vasculitis associated with aneurysmal nodules along the walls of medium-sized arteries. The disease is rare in childhood. Mean age of presentation recorded in most series is 9 years.6 When the disease occurs in childhood there is a male predominance (1.6–2.5:1). The exact cause and pathogenesis of PAN in children is unknown. In general, vasculitis is thought to occur when a susceptible host encounters an environmental trigger, typically an infection that cannot be handled appropriately. An association with hepatitis B infection (HBV) has been described in adults and occasionally in children. Streptococci infection has also been associated with PAN. Mutations in the Mediterranean fever (MEFV) gene are also noted to be susceptibility factors for development of PAN in some children.7


The main features of the disease are constitutional symptoms (fever, malaise, anorexia, and fatigue) that are present in almost 100% of affected children, together with skin rash, abdominal pain, and musculoskeletal involvement, which is reported in as many as 80% of patients. Cutaneous manifestations include erythematous rashes, maculopapular purpuric lesions (similar to those of HSP), painful skin nodules, livedo reticularis, cutaneous ulcers, and, rarely, digital infarction or gangrene. Arthralgia, arthritis, myalgia, and myositis are common as well. Renal involvement manifesting as hematuria, proteinuria, hypertension, or rapidly progressive glomerulonephritis may be present in up to 60% of patients. Gastrointestinal disease (bleeding, ulcerations) and neurologic involvement (mononeuritis multiplex, peripheral neuropathy, hemiparesis, encephalopathy, stroke) are less frequent. Orchitis is a classical symptom of PAN, although it is less frequently seen in patients without concomitant HBV infection.

A subset of the disease is cutaneous PAN, characterized by crops of painful skin nodules and livedo reticularis, and sometimes nonspecific musculoskeletal findings such as myalgia and arthralgia. There is often a history of preceding upper respiratory infection, often Streptococcus. Constitutional symptoms are not present and acute phase reactants are often normal. Skin biopsy reveals necrotizing vasculitis. The condition is treated with oral corticosteroids and has a favorable prognosis; however relapses are common. Every child with a diagnosis of cutaneous PAN should be followed closely for systemic symptoms. Constitutional symptoms should prompt consideration of immunosuppressive treatment. Penicillin prophylaxis may be needed to prevent recurrences when streptococcal infections are implicated.


Diagnosis of PAN is often difficult because of the variability of presenting complaints. There are no specific laboratory tests. Acute phase reactants are elevated, and anemia, polymorpho-nuclear leukocytosis, and thrombocytosis are common. Other laboratory abnormalities depend on specific organ involvement. The diagnosis is based primarily on the presence of either a biopsy showing small and midsize artery necrotizing vasculitis or angiographic abnormalities in addition to skin involvement, muscle involvement, hypertension, neuropathy, renal involvement, testicular pain or tenderness, or signs or symptoms suggesting vasculitis of any other major organ system (Table 203-3).

Table 203-3. Classification Criteria for Childhood Polyarteritis Nodosa

A systemic illness characterized by the presence of either a biopsy showing small and midsize artery necrotizing vasculitis OR angiographic abnormalities* (aneurysm or occlusion) (mandatory criteria), plus at least 2 of the following:

Skin involvement (livedo reticularis, tender subcutaneous nodules, other vasculitis lesions)

Myalgia or muscle tenderness

Systemic hypertension, relative to childhood normative data

Mononeuropathy of polyneuropathy

Abnormal urine analysis and/or impaired renal function**

Testicular pain or tenderness

Signs or symptoms suggesting vasculitis of any other major organ system (gastrointestinal, cardiac, pulmonary, or central nervous system)

*Should include conventional angiography if magnetic resonance angiography is negative.

**Glomerular filtration rate of less than 50% normal for age.


Treatment consists of corticosteroids, anti-platelet agents, and a cytotoxic agent, usually cyclophosphamide. Cyclophosphamide is usually administered orally for 2 to 3 months at 2 mg/kg/day to induce remission. Pulsed intravenous cyclophosphamide may have an advantage over the oral route in reducing the total cumulative dose and potential side effects, but it may not be as effective as the daily oral regimen in aggressive disease for the prevention of relapses. Maintenance therapy is usually with oral azathioprine at a dose of 2 mg/kg/day, with low-dose, alternate-day prednisone and anti-platelet agents. If remission with this regimen is not maintained then cyclosporine or mycophenolate mofetil may prove useful, although the published evidence for use of these agents in this context is lacking.

Relapses occur in up to 20% of patients. The overall prognosis of this disease has improved during the past decades primarily because of earlier diagnosis and rapid initiation of more effective treatments.


Microscopic polyangiitis (MPA) is a necrotizing pauci-immune vasculitis affecting predominantly small vessels. Rapidly progressive necrotizing glomerulonephritis is very common. Pulmonary capillaritis with resultant pulmonary hemorrhage often occurs, in the absence of granulomatous lesions of the respiratory tract. MPA is rare in children. Patients frequently have perinuclear staining antineutrophil cytoplasmic antibodies (p-ANCA) targeted against myeloperoxidase (MPO). The disease has a worse prognosis than does PAN, with a 5-year survival rate of 60% to 65%. Patients require aggressive therapy with corticosteroid, immunosuppressive drugs, and possibly plasmapheresis. Relapses are common.8


Wegener granulomatosis (WG) is a necrotizing granulomatous vasculitis of small to mediumsized vessels characterized by the triad of paranasal sinus involvement, pulmonary infiltration, and pauci-immune glomerulonephritis (Table 203-4). The disease is uncommon in children. Prior to adulthood WG usually presents during adolescence and affects females more often than males. The indolent nature of the disease may delay the diagnosis for months, although presentation is acute in some patients.


At onset, clinical features are similar to those seen in polyarteritis nodosa (fever, rash, weight loss, arthralgia). There are, however, particular features that might point to the diagnosis including upper airway illness such as persistent cough, nasal stuffiness, mucosal ulceration, sinusitis, epistaxis, hoarseness, or earache. Nasal (saddle nose) deformity owing to damage to the nasal cartilage and subglottic stenosis (SGS) are more common in children than in adults. SGS is the result of granulomatous involvement of the trachea. A high proportion of patients with SGS require surgical intervention to maintain airway patency. Overall, nasal, sinus, tracheal (including tracheal stenosis), and ear abnormalities are seen in 91% of patients with childhood onset disease.9 Lung disease occurs in 74% of children. Lower respiratory tract symptoms include cough, dyspnea, and hemoptysis. Nodular pulmonary infiltrates are often visible on radiographs at presentation and may masquerade as infection. Renal involvement is uncommon at presentation, although up to 70% of children develop pauci-immune glomerulonephritis during the evolution of the disease. The renal disease may take the form of an aggressive crescentic glomerulonephritis and is discussed in more detail in Chapter 472. Ocular abnormalities, including conjunctivitis, dacryocystitis, scleritis, episcleritis, and proptosis, may be present in 10% to 15% of children at disease onset. Other manifestations of WG include arthritis, present in one third of the children at presentation and two thirds of the children at follow-up; cutaneous disease including palpable purpura, skin ulceration, and subcutaneous nodules; pericarditis; and neurologic involvement.

Table 203-4. Classification Criteria for Wegener Granulomatosis

Three of the following 6 features should be present:

Abnormal urinalysis*

Granulomatous inflammation on biopsy**

Nasal sinus inflammation

Subglottic, tracheal, or endobronchial stenosis

Abnormal chest X-ray or CT

PR3 ANCA or c-ANCA staining

*Hematuria and/or significant proteinuria.

**If a kidney biopsy is done it characteristically shows necrotizing pauci-immune glomerulonephritis.


The diagnosis of WG has been greatly facilitated by its association with the presence of cytoplasmic staining of antineutrophil cytoplasmic antibodies (c-ANCA). The target of these antibodies is the cytoplasmic protein proteinase 3 (PR3). Chest computed tomography (CT) may reveal multifocal infiltrates with or without small peripheral nodules. Urinalysis characteristically demonstrates proteinuria, microscopic hematuria, and red blood cell casts in up to 50% of patients. Gross hematuria is uncommon. Confirmation of the disease is established by the detection of granulomatous inflammation on biopsy of upper airway, lung, kidney, or skin.


The disease was uniformly fatal in children before the use of a combination of glucocorticoids and cytotoxic agents. Treatment with steroids in combination with cyclophosphamide has induced remission in more than 90% of patients. Cyclophosphamide (2 mg/kg/day) with prednisone at a dose of 1 mg/kg/day for 4 weeks and then tapered to an alternate-day regimen is recommended to induce remission. The median time to remission using this regimen is usually 3 months, whereas steroids can usually be discontinued after 6 to 8 months. When remission is achieved, the cyclophosphamide is switched to methotrexate or azathioprine, which is then continued for at least 2 years in an attempt to limit relapses.16 For non–life-threatening disease, therapy may be initiated with glucocorticoids and methotrexate. For patients with pulmonary hemorrhage, intensive care management may be required. The utility of plasmapheresis in these situations is unknown but it is frequently used in an attempt to stabilize the patient. Treatment-related morbidity includes cystitis and infertility. Relapses of disease requiring retreatment occur in approximately half of the WG patients.


Takayasu arteritis (TA), also known as pulseless disease, is characterized by granulomatous vasculitis of large vessels leading to stenosis and aneurysms. It is rare in children younger than age 16. The underlying pathology is a segmental arteritis of the aorta and its major branches, which can cause weak or absent pulses in the upper extremities. It is most common in young women, particularly those of Japanese origin. Hypertension is the most common complaint, followed by headache. However fever, back pain, claudication, or visual complaints may also be presenting manifestations. TA may present as coarctation of the aorta or congestive heart failure in association with features of systemic vasculitis such as fever and constitutional symptoms. Ischemic manifestations such as visual disturbances, neurologic deficits, or claudication are frequently present in adults, but uncommon in children.11 A triphasic pattern of disease has been described. Phase I is the prepulseless period with nonspecific systemic complaints such as fever, night sweats, anorexia, arthralgia/arthritis, and weight loss. In Phase II there is vessel inflammation. The final phase is the fibrotic state where bruits and significant ischemia become prominent. Not all patients go through all phases and some may present with a mixture of symptoms. Classification criteria to aid the diagnosis of TA are listed in Table 203-5. There is an association between TA and Mycobacterium tuberculosis in some geographical areas. Laboratory abnormalities are nonspecific, including anemia and elevation of acute phase reactants. ANCAs are seldom found. Chest radiographs may demonstrate cardiomegaly or an irregular contour of the aortic arch and descending aorta. There may be areas of calcification or widening associated with prestenotic dilatation. Arteriography may reveal multiple sites of segmental involvement of the aorta and major branches. MR angiography, CT, and ultrasonography may document early inflammatory changes occurring before the development of obstructive lesions.

Table 203-5. Classification Criteria for Takayasu Arteritis

Angiographic abnormalities (conventional, CT, or MRI) of the aorta or its main branches (mandatory criterion), plus at least 1 of the following 4 features:

Decreased peripheral artery pulse(s) and/or claudication of extremities

Blood pressure difference >10 mm Hg

Bruits over aorta and/or its major branches

Hypertension (related to childhood normative data

High-dose glucocorticoids (1–2 mg/kg/day) constitute the initial treatment, although as many as 40% to 50% of patients require the addition of cyclophosphamide or methotrexate because of persistent disease activity.12Antiplatelet agents can be added to the therapy in patients with transient neurologic deficits. Aggressive treatment of hypertension is critical. Surgery is of value in the management of stenotic lesions that do not regress after medical therapy.


Behçet disease (BD) is a vasculitis affecting arteries and venules characterized by the clinical triad of painful recurrent oral and genital ulcers and inflammatory eye disease. The disease is uncommon in children, with most cases reported from the eastern Mediterranean or the Far East. The cause of BD is unknown.


The most common clinical feature of the disease is recurrent oral ulceration, which usually occurs at disease onset and may persist for much of the course of the disease. The ulcers occur in painful crops on the lips, tongue, palate, and elsewhere in the gastrointestinal tract (Fig. 203-2); persist for 3 to 10 days; and heal without scarring. Skin lesions may be in the form of erythema nodosum, papulopustular (acneiform) lesions, folliculitis, pustules, ulcers, or purpura.13 Pathergy, noted by the appearance of a pustule or papule surrounded by erythema 24 to 48 hours after a needle prick, is highly characteristic but not pathognomonic of the syndrome. Genital ulcers usually occur after oral ulcers and in contrast may scar with healing. The spectrum of eye lesions includes posterior uveitis, papilledema, and optic atrophy. Hypopyon may occur and severe uveitis may lead to blindness. Four neurologic syndromes are recognized in patients with BD: encephalomyelitis, aseptic meningitis, benign intracranial hypertension, and organic psychiatric disturbances. Arthritis commonly affects the knees, ankles, wrists, and elbows and does not usually result in erosions or joint destruction. Arthralgia is also common. Less common manifestations of the disease include venous or arterial thrombosis or gastrointestinal involvement. Vascular complications may occur in the form of arterial aneurysm or thrombosis of veins or arteries.

FIGURE 203-2. Behçet disease. Extensive aphthae involving the lips and tongue. (Source: From Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw-Hill, p. 646.)


The diagnosis is based on the criteria of the international study group for BD, which requires recurrent oral ulceration and at least two of the following: recurrent genital ulceration, eye lesions, skin lesions, and positive pathergy test. There is often a delay in making the diagnosis; therefore, children who satisfy only some of the criteria should be followed closely. Boys and girls are affected with equal frequency, in contrast to adults, where men are affected almost twice as often as women.

There are no controlled studies evaluating treatment of BD in children. Recommendations are based on adult experience. For oral and genital ulcers, mouth washes with sucralfate suspension, or topical and/or oral corticosteroids may be helpful. During the acute stage of ulceration, a short course of oral prednisone helps to provide fast relief of the symptoms. Long-term colchicine is effective in controlling the frequency and severity of oral and genital ulceration. For severe lesions, thalidomide may be useful, but the risk of peripheral neuropathy and its contraindication during pregnancy limits its usefulness. For erythema nodosum and arthralgia or arthritis, nonsteroidal anti-inflammatory drugs and colchicine are usually sufficient. Eye disease should be followed by an experienced ophthalmologist. For central nervous system disease and vasculitis, corticosteroid and immunosuppressive agents such as cyclophosphamide are indicated in regimens such as those used for other vasculitides. Sulfasalazine has been reported to be of benefit in gastrointestinal disease. BD tends to run a very long and relapsing course. Young age of onset and male sex are both indicators of a prolonged disease course. Mortality because of the disease is 3%, usually secondary to central nervous system involvement, large-vessel thrombosis, or GI perforation.