P e d i a t r i c Va s c u l i t i s

a,b,
Pamela F. Weiss, MD, MSCE *

KEYWORDS
 Vasculitis  Pediatrics  Review

Childhood vasculitis is a challenging and complex group of conditions that are multi-
system in nature and often require integrated care from multiple subspecialties,
including rheumatology, dermatology, cardiology, nephrology, neurology, and gastro-
enterology. Vasculitis is defined as the presence of inflammation in the blood vessel
wall. The site of vessel involvement, size of the affected vessels, extent of vascular
injury, and underlying pathology determine the disease phenotype and severity.
Vasculitis can be secondary to infection, malignancy, drug exposure, and other rheu-
matic conditions, such as systemic lupus erythematosus and juvenile dermatomyosi-
tis. This article explores the classification and general features of vasculitis, as well as
the clinical presentation, diagnostic evaluation, and therapeutic options for the most
common primary systemic vasculitides.

DIAGNOSIS

Making the diagnosis of vasculitis is often challenging, as presenting symptoms may

be subacute, nonspecific, and nondiagnostic. Fever, malaise, diffuse pain, and labo-
ratory evidence of elevated acute-phase reactants may be the only early symptoms to
suggest systemic inflammation. As vessel damage evolves, more specific clinical
features, such as a purpuric rash, evidence of organ involvement, such as glomerulo-
nephritis, or detection of certain antibodies, such as antineutrophil cytoplasmic anti-
bodies (ANCA), may heighten the suspicion of vasculitis. The presenting symptoms
can vary widely depending on the size and location of involved vasculature.
If vasculitis is suspected, then a thorough history and physical examination are
paramount. The history should include recent infections, drug exposure, and a detailed
family history. The physical examination should include a 4-extremity blood pressure
evaluation. Takayasu arteritis (TA) may present with a blood pressure difference of
greater than 10 mm Hg between arms, and hypertension is common with many of
the vasculitides. In addition, careful auscultation for bruits (carotid, axillary, aortic,

Disclosures: None.
a
Division of Rheumatology and Center for Pediatric Clinical Effectiveness, Children’s Hospital
of Philadelphia, 3401 Civic Center Boulevard, Colkett Translational Research Building, Philadel-
phia, PA 19104; b Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania,
Philadelphia, PA, USA
* Division of Rheumatology, The Children’s Hospital of Philadelphia, Room 1526, North
Campus, 3535 Market Street, Philadelphia, PA 19104.
E-mail address: [email protected]

Pediatr Clin N Am 59 (2012) 407–423

doi:10.1016/j.pcl.2012.03.013 pediatric.theclinics.com
0031-3955/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
408 Weiss

renal, and iliac vessels) and palpation of peripheral pulses is essential. Absent periph-
eral pulses may help identify areas of vessel involvement. A thorough skin examination
is also important; the presence of painful nodules, purpura, ulcerations, microinfarc-
tions, or livedo reticularis is common. A neurologic examination should evaluate for
peripheral neuropathy; polyarteritis nodosa (PAN) is associated with mononeuritis
multiplex. A fundoscopic examination and nailfold capillaroscopy are also helpful to
visualize small vessel abnormalities.
The laboratory evaluation for vasculitis should include a complete blood count and
acute phase reactants, such as the erythrocyte sedimentation rate and C-reactive
protein, which can be markedly elevated. Liver enzymes, blood urea nitrogen and
creatinine, and urinalysis will evaluate for hepatic and renal involvement. Specific anti-
body testing, such as antinuclear antibodies and ANCA, and complements should be
sent depending on the vasculitis being considered. When clinical suspicion is high,
imaging, such as computed tomography (CT) angiography, magnetic resonance
(MR) angiography, or conventional angiography may help detect blood vessel abnor-
malities. Imaging may demonstrate prototypical patterns of vessel involvement, such
as beading and aneurysms in PAN and TA, respectively. Typically, imaging is most
useful when there is suspicion for medium-vessel or large-vessel disease. The diag-
nostic gold standard for diagnosis, however, is tissue biopsy.

CLASSIFICATION

Primary vasculitis can be classified according to clinical manifestations, size of the

affected vessels, or histopathology, including the presence or absence of granuloma.
In 2005, the European League Against Rheumatism (EULAR) and the Pediatric Rheu-
matology European Society (PReS) developed the first pediatric-specific classification
of vasculitis (Box 1).1 This classification system is primarily based on size of affected
vessels and the presence or absence of granuloma.

EPIDEMIOLOGY AND PATHOGENESIS

The annual incidence of primary vasculitis in children and adolescents younger than
17 years is approximately 23 per 100,000.2 Primary vasculitis accounts for approxi-
mately 2% to 10% of all pediatric conditions evaluated in pediatric rheumatology
clinics.3–6 Of the primary vasculitides, Henoch Schönlein purpura (HSP) and Kawasaki
disease (KD) are the most common, accounting for 49% and 23% of all childhood
vasculitis, respectively.6 The prevalence of diseases may be different based on the
population studied. For example, the incidence of KD and Behçet’s disease is higher
in Asian and Turkish children, respectively, than in other ethnicities.
These ethnic differences in prevalence suggest that genetics and environment may
play an important role in disease susceptibility and pathogenesis. Other theories of
pathogenesis include humoral factors, as manifest by ANCA-associated vasculitides.
Abnormal regulation of immune complex formation may be contributory, as in HSP.
Impaired lymphocyte regulation, specifically T-regulatory cell dysfunction, may also
be involved. Antecedent infections, particularly streptococcal infections, have been
implicated in many of the vasculitides including HSP, granulomatosis with polyangiitis
(GPA), and PAN.
Henoch Schönlein Purpura
Etiology and epidemiology
HSP is a leukocytoclastic vasculitis that predominantly affects the small blood vessels.
It is also known as anaphylactoid purpura or purpura rheumatica. The EULAR/PReS
 Pediatric Vasculitis 409

Box 1
EULAR/PReS classification of pediatric vasculitis

Vasculitis category
Predominately large vessel
Takayasu arteritis
Predominately medium vessel
Childhood polyarteritis nodosa
Cutaneous polyarteritis
Kawasaki disease
Predominately small vessel
Granulomatous
Wegener granulomatosisa
Churg-Strauss syndrome
Nongranulomatous
Microscopic polyangiitis
Henoch-Schönlein purpura
Isolated cutaneous leucocytoclastic vasculitis
Hypocomplementemic urticarial vasculitis
Other
Behçet disease
Vasculitis secondary to infection, malignancy, drugs
Vasculitis associated with connective tissue disease
Isolated vasculitis of the central nervous system
Cogan syndrome
Unclassified
a
Granulomatosis with polyangiitis.
Adapted from Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria
for the classification of childhood vasculitides. Ann Rheum Dis 2006;65:936–41.

classification criteria are listed in Box 2.7 Among children younger than 17 years, the
annual incidence of HSP is approximately 20 per 100,000 and the peak age of onset
is between 4 and 6 years.2 Caucasians have the highest incidence and African Ameri-
cans have the lowest incidence. Unlike most vasculitides, males are affected more
commonly than females, with a ratio of approximately 2 to 1. Certain autoimmune
risk factors, such as complement deficiencies,8 and hereditary fever syndromes,9
such as Familial Mediterranean Fever syndrome, may predispose a child to HSP.
HSP is most prevalent during the winter and spring. This seasonal distribution supports
the hypothesis that an infectious agent triggers this condition.10 Group A b–hemolytic
streptococcus, Staphylococcus aureus, influenza, parainfluenza, Epstein-Barr virus,
adenovirus, parvovirus, and mycoplasma have all been reported as triggers for HSP.

Clinical presentation
The classic presentation of HSP includes lower-extremity purpura, arthritis, abdominal
pain, and renal disease. The purpuric rash is usually on dependent areas but may be
410 Weiss

Box 2
EULAR/PReS classification criteria for HSP

Purpura or petechiae with lower limb predominance and at least 1 of the following:
1. Arthritis or arthralgias
2. Abdominal pain
3. Histopathology demonstrating immunoglobulin A deposition
4. Renal involvement (hematuria or proteinuria)

Data from Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein
purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood
Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;
69:798–806.

seen on the arms, face, and ears (Fig. 1A). The purpura may be preceded by a
maculopapular or urticarial rash that usually disappears within 24 hours.11 The
rash may appear as bullae, necrotic lesions (see Fig. 1B), or deep bruising (see
Fig. 1C).

Fig. 1. Skin lesions of HSP: (A) classic lower extremity purpura, (B) necrotic lesions, (C) deep
bruising. (Courtesy of David D. Sherry, MD, Philadelphia, PA.)
 Pediatric Vasculitis 411

Arthritis affects three-quarters of children, and the most commonly affected joints
are the knees and ankles. The arthritis is usually oligoarticular, self-limited, and nonde-
structive. It is the presenting symptom in 15% of patients.12
The gastrointestinal (GI) manifestations of HSP affect 50% to 75% of children and
may include bleeding, intussusception, and abdominal pain. GI manifestations may
precede the purpura by up to 2 weeks in as many as 20% of children.11 Intestinal
bleeding, manifested as gross or occult blood per rectum, occurs in approximately
one-third of children. Intussusception occurs in 1% to 5% of children and is mostly
ileo-ileal in location.13
Renal disease affects 20% to 60% of children, and the most common manifestation
is microscopic hematuria with or without proteinuria. Renal disease rarely precedes
the onset of rash. Children may present with nephritic or nephrotic syndrome, or rarely
renal failure. Most children who develop renal disease do so within the first 6 weeks
and 97% within 6 months.14 In longitudinal studies of unselected patients, the risk
of chronic renal impairment and end-stage renal disease is 2% to 15% and less
than 1%, respectively.14,15
Unusual clinical manifestations of HSP may include edema of scrotum, eyes, or
hands; pulmonary hemorrhage; seizures; stroke; and mental status changes. The
mean duration of symptoms is 3 to 4 weeks and up to one-third of children have at
least 1 recurrence.16
HSP must be distinguished from other causes of purpura in childhood, including
acute hemorrhagic edema of infancy, immune thrombocytopenic purpura, acute
poststreptococcal glomerulonephritis, hemolytic-uremic syndrome, disseminated
intravascular coagulation, infections, and hypersensitivity vasculitis. Hypersensitivity
vasculitis is also known as cutaneous leukocytoclastic vasculitis and microscopic pol-
yarteritis. It typically affects the small vessels and is idiopathic or triggered by infection
or drug exposure. Clinical manifestations include urticaria, purpura, or a maculopapular
rash, arthralgias, hypocomplementemia, and elevated inflammatory markers (Fig. 2).

Treatment
Therapy for mild HSP cases is primarily supportive, with analgesics and nonsteroidal
anti-inflammatory drugs. Current literature, however, supports the notion that in the

Fig. 2. Hypersensitivity vasculitis. Hypersentivity vasculitis secondary to propylthiouracil

exposure. (Courtesy of David D. Sherry, MD, Philadelphia, PA.)
412 Weiss

hospital setting, early use of corticosteroids for HSP is associated with improved
outcomes, particularly GI comorbidities.17 In more severe hospitalized cases, pulse
methylprednisolone (30 mg/kg up to 1 g) may be warranted. The optimal dose and
duration of corticosteroids has not been well studied. In some cases, oral corticoste-
roid doses of 2 mg/kg per day may be adequate; however, too short a course of corti-
costeroids or a rapid tapering of corticosteroids may precipitate a flare of symptoms.
Corticosteroid treatment for mild cases of HSP remains controversial. A meta-analysis
of 15 studies of patients with HSP treated at diagnosis with corticosteroids versus
supportive care revealed that corticosteroid treatment significantly reduced the
mean resolution time of abdominal pain and reduced the odds of developing persis-
tent renal disease.18 In a 6-month prospective clinical trial of 223 children, prednisone
was effective in reducing the severity of abdominal and joint pain and in treating renal
disease19; however, in that same study, prophylaxis with prednisone did not prevent
the development of nephritis.19 In life-threatening cases or acute renal failure, plasma-
pheresis followed by a more potent immunosuppressive agent, such as cyclophos-
phamide, azathioprine, or cyclosporine, should be considered.
Kawasaki Disease
Etiology and epidemiology
KD is the second most common childhood vasculitis, accounting for 23% of all vascu-
litides.6 It affects primarily medium-sized blood vessels and is also known as mucocu-
taneous lymph node syndrome. The EULAR/PReS classification criteria for KD are
listed in Box 3. Fewer than 4 criteria are required if there are characteristic coronary
artery changes and fever7; 90% of cases occur in children younger than 5 years. In
the United States, the annual incidence in children younger than 5 years is 20 per
100,000.20 The incidence is higher among children who live in eastern Asia, at 100
per 100,000 in Japan21 and 69 per 100,000 in Taiwan.22 Similar to HSP, KD is more
common in boys. Children younger than 6 months are more likely to have atypical
features and to develop coronary aneurysms. The cause of KD remains unknown,
although bacterial and viral infections, superantigens, genetics, and humoral factors,
such as antiendothelial cell antibodies, ANCA, and circulating immune complexes may
be involved.
Clinical presentation
KD is a triphasic disease consisting of an acute febrile period that lasts up to 14 days,
a subacute phase of 2 to 4 weeks, and a convalescent phase that can last months to

Box 3
EULAR/PReS classification criteria for KD

Fever that persists for at least 5 days plus at least 4 of the following:
1. Bilateral conjunctival injection
2. Changes of the lips and oral cavity
3. Cervical lymphadenopathy
4. Polymorphous exanthem
5. Changes in the peripheral extremities or perineal area

Data from Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein
purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood
Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;
69:798–806.
 Pediatric Vasculitis 413

years. The acute period is characterized by a persistent and high (>38.5 C) fever. The
fever is typically minimally responsive to antipyretics. The fever is likely related to
elevated concentrations of proinflammatory cytokines, particularly interleukin-6 and
tumor necrosis factor alpha (TNF-a).23 Conjunctivitis affects 85% of children and is
bilateral, nonexudative, and limbic sparing. Other ocular symptoms include anterior
uveitis, keratitis, papilledema, vitreous opacities, and subconjunctival hemorrhages
(Fig. 3A).24 Oral mucosal changes may include dry and cracked lips and strawberry
tongue. Cervical adenopathy is the least common of the diagnostic criteria, detectable
in 25% of children.25 The adenopathy is usually unilateral and limited to the anterior
cervical chain (see Fig. 3B). Diffuse lymphadenopathy is unusual. The rash associated
with KD is typically nonpruritic, macular, or target lesions on the trunk and extremities.
A perineal rash that desquamates by the end of the first week is common. Early
extremity changes include diffuse erythema of the palms and soles and swelling of
the dorsum of the hands and feet (see Fig. 3C); these changes usually last for fewer
than 3 days. Sheetlike desquamation on the fingers and toes occurs toward the end
of the acute phase.
There are also many symptoms of KD that are not part of diagnostic criteria. GI
symptoms include diarrhea, vomiting, abdominal pain, and hydrops of the gallbladder.
Genitourinary symptoms include scrotal pain and swelling, dysuria, and sterile pyuria.
Arthritis affects up to 25% of children26 and the most commonly affected joints are the
knees, ankles, and hips. The arthritis can be oligoarticular or polyarticular and is
usually self-limited and nondestructive. Most children with KD are very irritable, likely
secondary to aseptic meningitis and headache.27
Cardiovascular disease during the acute phase may include valvulitis, myocarditis,
and pericarditis. Coronary dilation and aneurysms may be detected during the acute
phase, but most develop during the convalescent phase. Up to 10% of children who

Fig. 3. Kawasaki disease: (A) subconjunctival hemorrhage; (B) unilateral cervical lymphade-
nopathy; (C) pedal edema. (Courtesy of Jon M. Burnham, MD, MSCE, Philadelphia, PA.)
414 Weiss

develop coronary changes do not meet full criteria for KD.28 As many as 20% of
untreated children develop aneurysms. Treatment with intravenous immunoglobulin
(IVIG) reduces the incidence of aneurysms by approximately 80%.29 Children younger
than 12 months are at the highest risk for coronary aneurysms.
Several conditions can mimic KD, including infections (Epstein-Barr virus, adenovirus,
echovirus, measles), toxin-mediated illnesses (toxic shock syndrome, scarlet fever),
inflammatory conditions (systemic juvenile idiopathic arthritis, polyarteritis nodosa),
hypersensitivity reactions (mercury), and drug reactions (Stevens-Johnson syndrome).

Treatment
The goal of treatment in KD is to reduce inflammation and prevent the formation of
coronary aneurysms. The American Heart Association (AHA) recommends treatment
with high-dose aspirin (80–100 mg/kg per day) and IVIG (2 g/kg) within the first 10
days of disease.30 Once afebrile for 48 hours, the aspirin should be adjusted to an anti-
platelet dosage of 3 to 5 mg/kg per day. Although corticosteroids are the cornerstone
of therapy for most vasculitides, their use in KD for the primary treatment of KD is
controversial.31,32 Approximately 10% to 15% of patients fail to respond to initial
IVIG therapy; failure is defined as persistent fever or recurrence of fever within 36 hours
of IVIG therapy. Persistent or recurring fever is concerning because it likely indicates
ongoing inflammation and is associated with an increased risk of developing coronary
aneurysms.33 In a small multicenter randomized prospective trial of a second IVIG
infusion versus infliximab, an anti–TNF-a agent (5 mg/kg), for refractory KD, there
were no statistically significant differences between the 2 treatment groups in recur-
rence of fever, coronary artery outcomes, or laboratory markers of inflammation.34
Current AHA guidelines, however, recommend re-dosing IVIG at least once in the
event of IVIG failure.30 If 2 or more doses of IVIG are ineffective, then corticosteroid
pulse therapy (30 mg/kg for 1–3 doses) or treatment with infliximab (5 mg/kg) should
be considered.30 For uncomplicated KD, an echocardiogram should be performed at
diagnosis, at 2 weeks, and then again at 6 to 8 weeks to assess treatment efficacy for
the prevention of aneurysm formation.30

Polyarteritis Nodosa
PAN is the third most common childhood vasculitis. PAN is predominantly a medium-
sized vasculitis and accounts for 3% of all childhood vasculitides in the United States.6
Classification of childhood-onset PAN is listed in Box 4. Similar to HSP, several

Box 4
EULAR/PReS classification criteria for childhood PAN

Systemic inflammation with evidence of necrotizing vasculitis or angiographic abnormalities of

medium-sized or small-sized arteries plus 1 of the following:
1. Skin involvement (livedo reticularis, nodules, infarcts)
2. Myalgias
3. Hypertension
4. Peripheral neuropathy
5. Renal involvement (proteinuria, hematuria, or impaired function)

Data from Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein
purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood
Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;
69:798–806.
 Pediatric Vasculitis 415

reports suggest an association with familial mediterranean fever. Peak age of onset in
children is 9 years.35 In adults, PAN is classically associated with hepatitis B; however,
this association is less common in childhood. Childhood PAN is associated with fewer
relapses and improved survival compared with adult-onset disease.35
PAN can affect the vascular supply to any organ, although the lungs are typically
spared. Vascular insufficiency is most common to the skin, muscles, kidneys, and GI
tract. Involvement of the heart, and peripheral and central nervous systems are less
common. Children may have fever, malaise, weight loss, myalgias, and arthralgias at
presentation. Depending on the distribution of involved vessels, children may have
hypertension, ischemic heart disease, testicular pain, abdominal pain, hematuria, or
proteinuria. Neurologic involvement may include mononeuritis multiplex with both
sensory and motor deficits. Inflammation of the small arteries leads to vasculitic skin
rashes, including livedo reticularis, purpura, necrosis, and possibly digital gangrene
(see Fig. 4A and B). Painful subcutaneous nodules along affected vessels are also a char-
acteristic feature. Laboratory markers of systemic inflammation are usually elevated.
There have not been any randomized clinical trials to compare different induction or
maintenance therapies for childhood systemic PAN. Therefore, treatment is primarily
based on clinical experience and adult studies. Corticosteroids (1–2 mg/kg per day
with or without initial corticosteroid pulses of 30 mg/kg) are the cornerstone of therapy.
Additional therapy with cyclophosphamide (oral: 2 mg/kg per day, or IV: 750 mg/m2
monthly) may be warranted during the induction phase. In life-threatening or organ-
threatening situations, plasmapheresis is indicated. Maintenance agents include
azathioprine, methotrexate, IVIG, and mycophenolate mofetil. More recently, the effi-
cacies of biologic agents and rituximab have been explored.36
Cutaneous PAN is limited to the skin and musculoskeletal system. Characteristic
features include fever, painful subcutaneous nodules, purpura, livedo reticularis, myal-
gias, arthralgias, and nondestructive arthritis. The skin manifestations are usually
limited to the lower extremities. Cutaneous PAN is often associated with antecedent
streptococcal infection.37 Nonsteroidal anti-inflammatory drugs and corticosteroids
are the mainstay of therapy. In cases of persistent or relapsing disease, steroid-
sparing agents, such as methotrexate, colchicine, and IVIG have been used. Cuta-
neous PAN rarely evolves into systemic PAN.

Takayasu Arteritis
TA is a granulomatous vasculitis that predominantly affects the aorta and its major
branches. The EULAR/PReS consensus criteria for childhood TA are listed in

Fig. 4. Polyarteritis nodosa. Digital necrosis of toes (A) and fingers (B) from PAN. (Courtesy
of David D. Sherry, MD, Philadelphia, PA.)
416 Weiss

Box 5.7 Most children are diagnosed during adolescence, with a mean age of 13
years.38 It is more common in females than males (3:1).38 The most commonly
involved vessels in children are the aorta and renal, subclavian, and carotid arteries.38
Early diagnosis of TA in children is challenging, because the presenting symptoms
are usually nonspecific. The most common complaints at diagnosis are headache
(84%), dizziness (37%), abdominal pain (37%), claudication of the extremities
(32%), fever (26%), and weight loss (10%).38 Other early indicators of disease are night
sweats, back pain, myalgias, and arthralgias. Hypertension is present in approxi-
mately 90% of children at diagnosis.38 If left untreated, more specific disease manifes-
tations develop and are determined by the distribution of vessel involvement.
Involvement of the aortic arch or its major branches is associated with central nervous
system (CNS) symptoms, claudication, absent peripheral pulses, and cardiac mani-
festations. CNS involvement may include headache, ischemic strokes, cerebral aneu-
rysms, and seizures. Cardiac manifestations may include cardiomyopathy, congestive
heart disease, and valvular disease. Involvement of the mid-aorta is associated with
hypertension, abdominal pain, and lower extremity claudication.
Once TA is suspected, imaging often helps to confirm the diagnosis. The gold stan-
dard for TA imaging is angiography; however, it is invasive and cannot detect thick-
ened vessel walls, an early sign of inflammation. CT and MR angiograms are less
invasive than conventional angiography and can detect luminal diameter changes
(Fig. 5A) and vessel wall thickening (see Fig. 5B).39
Treatment of TA is challenging. Corticosteroids may induce remission in up to
60% of patients; however, half of these patients flare with tapering.40 There are anec-
dotal reports of treatment with methotrexate, azathioprine, and biologics, such as
infliximab. Cyclophosphamide should be considered for life-threatening or organ-
threatening cases.

Childhood Primary Central Nervous System Vasculitis

Previously healthy children with childhood primary central nervous system vasculitis
(cPACNS) may present with devastating subacute-onset or acute-onset neurologic
changes and psychiatric symptoms. If the disease is diagnosed early, the inflamma-
tion and neurologic damage may be reversible. The Calabrese criteria, designed for
adults, requires a new neurologic deficit plus angiographic or histologic evidence of

Box 5
EULAR/PReS classification criteria for childhood-onset TA

Characteristic angiographic abnormalities of the aorta or its main branches and pulmonary
arteries plus 1 of the following:
1. Absent peripheral pulses or claudication
2. Blood pressure discrepancy in any limb
3. Bruits
4. Hypertension
5. Elevated acute phase reactants

Data from Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein
purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood
Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;
69:798–806.
 Pediatric Vasculitis 417

Fig. 5. Takayasu arteritis. (A) Contrast-enhanced MR angiography demonstrating narrowed

right internal carotid and subclavian arteries. (B) Thoracoabdominal CT angiography
demonstrating thickening of the aortic wall.

CNS vasculitis.41 Two subtypes of cPACNS are recognized: (1) angiography-positive

cPACNS, which affects the medium and large vessels, and (2) angiography-negative
cPACNS, which primarily affects the small vessels. Children with angiography-positive
cPACNS typically present with focal neurologic symptoms, such as unilateral sensory
or motor deficits. Systemic inflammatory markers and cerebrospinal fluid (CSF) anal-
ysis may be normal.42 The classic MR imaging (MRI) finding is a focal area of acute
ischemia in a vascular distribution. Diagnosis is confirmed by conventional angiog-
raphy or MR angiography, which demonstrates large-sized or medium-sized vessel
stenosis, tortuosity, beading, or occlusion.
Angiography-positive cPACNS is further defined as progressive or nonprogressive,
based on the appearance of new lesions 3 months after diagnosis. Diffuse neurologic
symptoms, such as headaches, cognitive dysfunction, and behavioral issues, are
more common in progressive disease.43 Progressive disease also tends to be multi-
focal. The treatment of nonprogressive cPACNS is controversial but may include anti-
coagulation and corticosteroids. Corticosteroids may help prevent recurrence and
improve neurologic recovery.44 Treatment of progressive cPACNS includes 6 months
of induction therapy with cyclophosphamide (500–750 mg/m2 per month) and cortico-
steroids (2 mg/kg per day initially) followed by maintenance therapy with mycopheno-
late mofetil or azathioprine for 18 months.45
Angiography-negative cPACNS may present with systemic features, including
fever and malaise in addition to diffuse or focal neurologic symptoms.43 Systemic
inflammatory markers may be normal but CSF analysis typically reveals pleocytosis,
elevated protein, or increased opening pressure. MRI findings are usually multifocal
and may can be unilateral or bilateral and involve the gray or white matter.43 Lepto-
meningeal enhancement on imaging can help to distinguish this disease from demy-
elinating conditions. Conventional angiography, by definition, is negative. If cPACNS
is suspected, then a brain biopsy must be performed to confirm the diagnosis.
Typical histologic findings are a lymphocytic and nongranulomatous vasculitis.46,47
Treatment of angiography-negative cPACNS includes 6 months of induction therapy
with cyclophosphamide (500–750 mg/m2) and corticosteroids (2 mg/kg per day
initially) followed by maintenance therapy with mycophenolate mofetil or azathioprine
for 18 months.45,46
418 Weiss

ANCA-vasculitis
The ANCA-associated vasculitides (AAV) are a group of pediatric conditions classified
by small-vessel and medium-vessel inflammation, multiorgan system involvement,
and potentially life-threatening disease. They are associated with a high frequency
of disease-related and treatment-related morbidities. The 3 classic vasculitides in
the AAV group are GPA (formerly known as Wegener’s granulomatosis), microscopic
polyangiitis (MPA), and Churg-Strauss syndrome (CSS). In the acute phase of disease,
the major comorbid conditions may include pulmonary hemorrhage, respiratory
failure, rapidly progressive glomerular nephritis, and acute renal failure. Untreated
AAV follows a severe course, with near 100% mortality48 and a mean survival of 5
months.49 In addition, renal failure at presentation confers a high risk of end-stage
renal disease and death despite potent immunosuppressive therapy.50 Relapses are
very common and occur in up to 60% of patients.51,52 In comparison with adults, chil-
dren are more likely to have multiple organ involvement, renal involvement, and sub-
glottic stenosis.53,54
GPA primarily affects the upper and lower respiratory tracts and the kidneys. The
pediatric GPA classification criteria are listed in Box 6.7 The median age of diagnosis
in childhood-onset disease is 14 years.53 Constitutional symptoms, such as fever,
malaise, and weight loss are present in 90% of children at diagnosis.53 Eighty percent
have pulmonary manifestations that may include pulmonary hemorrhage, nodules,
infiltrates, pleurisy, oxygen dependency, and respiratory failure (Fig. 6A).53 Eighty
percent have upper respiratory disease that may include oral or nasal ulcerations,
nasal septum perforation (with subsequent saddle nose deformity), recurrent
epistaxis, sinusitis, mastoiditis, hearing loss, and subglottic stenosis (see Fig. 6B).53
Seventy-five percent have renal involvement that may include hematuria, proteinuria,
glomerulonephritis, and kidney failure.53 The renal disease is classically necrotizing
and pauci-immune on biopsy. Ninety percent of patients with GPA are ANCA positive,
and 80% to 90% of those patients are cytoplasmic-ANCA (c-ANCA)/pr3-positive.55
Biopsy of inflamed tissue is helpful to confirm the diagnosis.
MPA is a necrotizing, nongranulomatous, pauci-immune disease that affects the
small vessels. The most common features of MPA include pulmonary capillaritis
and necrotizing glomerulonephritis. Almost all children have constitutional symptoms,

Box 6
EULAR/PReS classification criteria for childhood-onset GPA

Diagnosis requires 3 of the following 6 criteria:

1. Histopathological evidence of granulomatous inflammation
2. Upper airway involvement
3. Laryngo-tracheo-bronchial involvement
4. Pulmonary involvement (by radiograph or CT)
5. ANCA positivity
6. Renal involvement (proteinuria, hematuria, red blood cell casts, necrotizing pauci-immune
glomerulonephritis)

Data from Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein
purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood
Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;
69:798–806.
 Pediatric Vasculitis 419

Fig. 6. Granulomatosis with polyangiitis. (A) Contrast-enhanced CT of the chest demon-

strating pulmonary nodules and infiltrates. (B) Contrast-enhanced CT of head showing
diffuse sinus disease.

such as fever, malaise, arthralgias, myalgias, and weight loss.56 One-third of children
present with renal failure, and nearly 100% have renal disease that may include hyper-
tension, hematuria, or proteinuria.56 Ischemic cerebral insults (30%) and necrotizing
vasculitic lesions of the skin (30%) are common.56 MPA is associated with a high titer
of c-ANCA or peri-nuclear ANCA.
CSS is a granulomatous vasculitis of small-sized and medium-sized vessels that
primarily affects individuals with severe asthma or allergies. Pediatric-specific criteria
for CSS do not exist. The American College of Rheumatology (ACR) disease criteria for
adult-onset disease are listed in Box 7. CSS usually has an insidious onset over years.
The most common features in children at diagnosis are asthma (91%), pulmonary infil-
trates (85%), sinusitis (77%), skin involvement (66%), cardiac disease (55%), GI symp-
toms (40%), peripheral neuropathy (39%), and kidney disease (16%).57 Vasculitic skin
rashes are also common. The renal disease is usually mild and rarely progresses.58
Twenty-five percent of children are ANCA-positive.
Treatment regimens for AAV depend on the specific type of vasculitis and the end-
organ manifestations. Almost all knowledge about the optimal treatment and
outcomes of children with AAV have been adapted from adult studies or come from
a small collection of case series. Standard induction therapy for adults with severe
systemic AAV includes corticosteroids and cyclophosphamide (oral or IV).59 This
regimen, however, is suboptimal, as there are not only significant treatment-related
toxicities, including serious infection, hemorrhagic cystitis, infertility, and malignancy,

Box 7
ACR classification criteria for adult-onset CSS

Diagnosis requires 4 of the following:

1. History of asthma
2. History of allergies (seasonal, foods, contact)
3. Peripheral eosinophilia greater than 10%
4. Mononeuropathy or polyneuropathy
5. Migratory pulmonary infiltrates
6. Paranasal sinus pain or radiographic opacification
7. Biopsy demonstrating extravascular eosinophils
420 Weiss

but, in addition, a high risk of relapse.51,52 Recent studies in adults, therefore, have
examined the role of biologic medications and plasmapheresis as adjunct therapy in
an effort to find strategies with comparable efficacy, lower toxicity, and fewer
relapses. Methotrexate and corticosteroids are used for induction in milder cases.
Maintenance therapy is typically with mycophenolate mofetil or azathioprine for 18
to 24 months. Infliximab (5 mg/kg twice a month), rituximab (375 mg/m2 per week
for 4 weeks), and IVIG (2 g/kg per month) are options for refractory disease.

SUMMARY

Pediatric vasculitis is a challenging and complex group of conditions. The site of

vessel involvement, size of the affected vessels, extent of vascular injury, and under-
lying pathology determine the disease phenotype and severity. The most common
vasculitides are HSP and KD. Almost all knowledge about the optimal treatment
and outcomes of children with vasculitis, with the exception of HSP and KD, have
been adapted from adult studies or come from a small collection of case series. Early
diagnosis, which requires a high level of clinical suspicion, may help to improve
outcomes. Pediatricians should consider vasculitis as part of the differential diagnosis
in children with evidence of systemic inflammation and multisystem disease that
cannot be otherwise explained.

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