Palpable purpura over the left leg of a 10-year-old boy with IgAV/HSP
This patient is a typical example of a child with severe IgA vasculitis (IgAV; formerly Henoch-Schönlein purpura, HSP) involving the skin, gastrointestinal tract, and kidneys. He also has the common features of vasculitis: constitutional symptoms, skin features, organ involvement of the affected vessels (gastrointestinal small vessels in this case), and high acute-phase reactants.
The systemic vasculitides are heterogeneous, uncommon systemic diseases characterized by blood vessel inflammation that may cause tissue ischemia and injury as a result of vascular stenosis, occlusion, aneurysm, or rupture [1, 2]. Childhood vasculitis is a challenging group of multisystem conditions that often require integrated care from different subspecialties such as rheumatology, nephrology, cardiology, neurology, gastroenterology, and dermatology. This chapter explores the epidemiology and classification of pediatric vasculitis as well as the general clinical presentation and diagnostic approach to a child with suspected vasculitis.
The estimated incidence of pediatric vasculitis is approximately 50 cases per 100,000 children per year . Primary systemic vasculitides are more common in adults when compared to children. Many vasculitides affect both children and adults; however, the relative frequency of vasculitis subcategories tends to differ between children and adults. Giant cell arteritis and essential cryoglobulinemic vasculitis are exclusively seen in adults, while IgAV/HSP and Kawasaki disease (KD) are mainly childhood vasculitides .
The prevalence of IgAV/HSP is 13.5/100,000 children [5, 6] and KD is 135–200 cases per 100,000 children in Japan and 9–17/100,000 children for Caucasians . Thus, there are major geographical differences in the incidence of vasculitis. The estimated annual incidence for IgAV/HSP is much less in adults: 0.8–1.8/100,000 adults .
There is paucity of epidemiologic data from developing countries. However, studies revealed that KD and IgAV/HSP are the two most common vasculitic disorders of young children .
Classification criteria are intended to define homogeneous patient groups for research but not for diagnosing or differentiating vasculitis from mimicking conditions . On the other hand, diagnostic criteria are applied to the individual patients by a physician to make a diagnosis . There are no diagnostic criteria for the primary systemic vasculitides, as yet.
In 1990, the American College of Rheumatology (ACR) proposed classification criteria for adult patients with vasculitis [12, 13]. Subsequently, the Chapel Hill Consensus Conference (CHCC) was held in 1994 with the goal of constructing a nomenclature system for vasculitis providing names and definitions . These definitions were revised in 2012 (see below).
Children and adults differ in the disease course, relative frequency of vasculitis subcategories, and some clinical manifestations, as well as the prognostic characteristics of different vasculitides . Thus, it was widely agreed that 1990 ACR classification criteria were not suitable for children. Therefore in 2005, pediatric rheumatologists and nephrologists proposed a new preliminary classification criteria at a consensus conference held in Vienna under the auspices of the Pediatric Rheumatology European Society (PRES) for some of the most common vasculitides in childhood, namely, HSP (later to be termed IgAV), KD, Wegener’s granulomatosis (later to be termed granulomatous polyangiitis, GPA), polyarteritis nodosa (PAN), and Takayasu arteritis (TA) . With support from the European League Against Rheumatism (EULAR) and the Pediatric Rheumatology International Trials Organization (PRINTO), these criteria were validated and took the final form at 2008 Ankara Consensus Conference [16, 17]. These childhood vasculitis classification criteria were based on the vessel size and include categories such as predominantly large-, medium-, and small-vessel vasculitis (granulomatous and non-granulomatous) .
Since CHCC 1994, there have been substantial advances in our understanding of vasculitis and changes in medical terminology with the improving diagnostic technology. Thus, in 2012, a second international CHCC was held in order to redefine subcategories of vasculitis and add important new categories not included in CHCC 1994 such as variable vessel vasculitis and single-organ vasculitis  (Table 33.1).
Classification of vasculitis*
I. Large-vessel vasculitis:
Giant cell arteritis
II. Medium-vessel vasculitis:
III. Small-vessel vasculitis:
A. Immune complex small-vessel vasculitis:
Anti-glomerular basement membrane (anti-GBM) disease
IgA vasculitis (Henoch-Schönlein):
Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)
B. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis:
Granulomatosis with polyangiitis (Wegener’s)
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
IV. Variable vessel vasculitis:
V. Vasculitis associated with probable etiology:
Hepatitis C virus-associated cryoglobulinemic vasculitis
Hepatitis B virus-associated vasculitis
Drug-associated immune complex vasculitis
Drug-associated ANCA-associated vasculitis
VI. Vasculitis associated with systemic disease:
VII. Single-organ vasculitis:
Cutaneous leukocytoclastic angiitis
Primary central nervous system vasculitis
There are still no diagnostic criteria for primary systemic vasculitis. However, recently, the Diagnostic and Classification Criteria for Vasculitis Study (DCVAS) has been designed with the aim of revising classification criteria and developing diagnostic criteria .
CHCC 2012 definitions  and ACR 1990 [20–23] and Ankara 2008  classification criteria are provided in Table 33.2 for some of the most common vasculitides in childhood.
CHCC 2012 definitions
Ankara 2008 criteria
IgA vasculitis/Henoch-Schönlein purpura
Vasculitis, with IgA1-dominant immune deposits, affecting small vessels. Often involves the skin and gastrointestinal tract; frequently causes arthritis. Glomerulonephritis indistinguishable from IgA nephropathy may occur
≥2 of the following:
≤ 20 years of age at disease onset
Acute abdominal pain
Biopsy showing granulocytes in the wall of small arterioles/venules
Purpura or petechia (mandatory) with lower limb predominancea plus one of four:
Histopathology (predominant IgA deposit in a biopsy)
Arthritis or arthralgia
Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules and not associated with ANCA
≥3 of the following ten criteria:
Granulocyte or mixed leukocyte infiltrate in an arterial wall on biopsy
Diastolic blood pressure >90 mmHg
Mono- or polyneuropathy
Elevated blood urea nitrogen or creatinine
Hepatitis B reactants
Weight loss >4 kg
Histopathology or angiographic abnormalities (mandatory) plus one of five:
Granulomatous polyangiitis/Wegener’s granulomatosis
Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract and necrotizing vasculitis affecting predominantly small to medium vessels. Necrotizing glomerulonephritis is common
≥2 of the following:
Abnormal urinary sediment (red cell casts or >5 red blood cell per high-power field)
Abnormal findings on chest radiograph (nodules, cavities, or fixed infiltrates)
Oral ulcers or nasal discharge
Granulomatous inflammation on biopsy
At least three of six:
Histopathology (granulomatous inflammation)
Upper airway involvement
Pulmonary involvement (chest X-ray or CT showing the presence of nodules, cavities, or fixed infiltrates)
Arteritis, often granulomatous, predominantly affecting the aorta and/or its major branches. Onset usually in patients younger than 50 years of age
≥3 of the following:
Arteriographic evidence of narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal, upper, or lower extremities
Decrease brachial artery pulse
Claudication of an extremity
>10 mmHg difference in systolic blood pressure between arms
A bruit over subclavian arteries or the aorta
Age at disease onset ≤ 40 years
Angiography (conventional, CT, or MRI) of the aorta or its major branches and pulmonary arteries showing aneurysm/dilatation, narrowing, occlusion, or thickened arterial wall (mandatory) plus one of five:
Pulse deficit or claudication
Four limbs’ blood pressure discrepancy >10 mmHg
Hypertension (>95 percentile for height)
Elevated acute-phase reactants
CHCC 2012 vasculitis categories are summarized in Table 33.1. CHCC 2012 grouped vasculitis mainly according to the vessel size predominantly involved . However, it is stated that any size of the artery can be affected in any vasculitis. Behçet’s disease and Cogan’s syndrome are classified as variable vessel vasculitis that can potentially affect arteries of all size as well as veins. In CHCC 2012, with the improved understanding of etiopathogenesis and clinical features of vasculitis, most of the eponyms were replaced with more descriptive terms .
For example, we have learned much about the pathogenesis of IgAV/HSP in recent years: Glycosylation of IgA1 is important in facilitating the clearance of IgA1 molecules , and an abnormal glycosylation in IgAV/HSP leads to accumulation of IgA1-dominant immune deposits which activate the alternative complement pathway, recruit inflammatory cells, and cause damage in small vessels . This led to the replacement of the eponym Henoch-Schönlein with the descriptive term “IgA vasculitis” in CHCC 2012 .
CHCC 2012 also emphasized the significance of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of small-vessel vasculitis (SVV) . After the discovery of ANCA in 1982 , in vitro experiments, clinical observations, and animal models documented that ANCA can activate neutrophils and monocytes to mediate vasculitis [27, 28]. Thus, SVV has been divided into ANCA-associated vasculitis (AAV) and immune complex SVV in CHCC 2012, and it is stated that a prefix should be added indicating ANCA reactivity as all AAV patients are not ANCA positive . Also, a negative ANCA was included in the definition of PAN which is an important discriminating feature from microscopic polyangiitis (MPA) [18, 29].