Vasculitis in children: Incidence and classification

INTRODUCTION — Vasculitides are disorders defined by the presence of inflammation in a blood vessel wall (vasculitis). The inflammation may occur as a primary process or secondary to an underlying disease. Clinical symptoms vary widely depending upon the types and location of the vessels involved, the extent of inflammation, and subsequent vessel wall damage with associated hemodynamic changes.

The nomenclature and framework for classifying the primary vasculitides has been according to the size and type of the involved blood vessels, the clinical manifestations, and the pathologic changes found within the vessel walls [1,2] and, more recently, for subclassification, the prominence or paucity of immunoglobulins in the vessel walls, the serologic presence or absence of antineutrophil cytoplasmic antibodies (ANCA), and the presumed underlying disease pathogenesis [3].

The classification of the primary childhood vasculitides are reviewed here. The approach to the child with suspected vasculitis and an overview of the management of children with vasculitic disorders are presented separately. The classification and approach to vasculitides in adults are also discussed elsewhere. (See "Vasculitis in children: Evaluation overview" and "Vasculitis in children: Management overview" and "Overview of and approach to the vasculitides in adults".)

INCIDENCE — Vasculitis is rare in children, with a reported incidence ranging from 12 to 53 cases per 100,000 children under 17 years of age [4-6], although even the upper end of this range is probably still an underestimate since these data were based upon voluntary surveys of clinicians serving limited segments of the population. Worldwide, immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]) is the most common vasculitis, followed by Kawasaki disease. In Japan and other parts of Asia, however, Kawasaki disease is more common. Other rarer vasculitides in children include Takayasu arteritis (TAK; which occurs more frequently in children from the Far East and Africa [7,8]), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), primary angiitis of the central nervous system (PACNS), and polyarteritis nodosa (PAN) [9]. Eosinophilic GPA (formerly Churg-Strauss syndrome) is extremely rare in children, and temporal arteritis is not seen in pediatric patients [1]. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Epidemiology' and "Kawasaki disease: Epidemiology and etiology", section on 'Epidemiology'.)

CLASSIFICATION VERSUS DIAGNOSIS — Classification criteria were developed in order to facilitate and improve research efforts by defining consistent and homogeneous patient populations for clinical protocols and outcome studies. Classification criteria were not developed to diagnose disease in individual persons and have not been validated for clinical diagnosis [3]. In particular, failure to meet the classification criteria does not necessarily preclude a specific diagnosis.

Even though the diagnostic accuracy of classification criteria for specific vasculitides is low [10], the rarity of childhood vasculitides means that individual clinicians with limited or no previous exposure to particular conditions may use classification criteria to assist in the diagnosis of individual patients [9]. The gold standard for diagnosing childhood vasculitis is with either histopathology from tissue biopsy samples or by characteristic lesions detected by imaging studies. However, diagnosis is more often based upon syndrome recognition in certain vasculitides such as Kawasaki disease, immunoglobulin A vasculitis (IgAV), and granulomatosis with polyangiitis (GPA).

CLASSIFICATION SYSTEMS — The most widely used classification system has been the American College of Rheumatology (ACR) 1990 criteria derived from adult patient data [1], which was endorsed in 1994 by the Chapel Hill Consensus Conference (CHCC) [2]. With increasing knowledge since then, limitations of the ACR criteria for use in adult populations have been elucidated [11]. In addition, these criteria have performed poorly in pediatric populations [1,9,12,13], and they did not include immunoglobulin A vasculitis (IgAV) and Kawasaki disease.

A consensus-based framework for classifying pediatric vasculitis was proposed by the European Alliance of Associations for Rheumatology (then known as the European League Against Rheumatism)/Paediatric Rheumatology European Society (EULAR/PRES) in 2005 [14] and revised by EULAR/Paediatric Rheumatology International Trials Organisation (PRINTO)/PRES in 2008 (table 1). The framework also included specific pediatric classification criteria for IgAV, polyarteritis nodosum (PAN), granulomatosis with polyangiitis (GPA), and Takayasu arteritis (TAK) [15]. Because these criteria were adapted, in part, from the adult ACR criteria, they carried forward some of its limitations; however, they are the preferred and most commonly used criteria for children because they were based upon pediatric data.

Similar to the ACR criteria, the framework for the EULAR/PRINTO/PRES classification scheme is primarily based upon the size of the predominantly involved blood vessel, and small-vessel vasculitis (SVV) is subclassified into granulomatous and nongranulomatous types. Secondary vasculitis and types of vasculitis that are not easily categorized according to predominant vessel size are classified in the "other vasculitides" category.

A second Chapel Hill Consensus Conference held in 2012 (CHCC 2012) provides the most up-to-date nomenclature and broad framework for vasculitis classification along with specific disease definitions (table 2) [2,3]. Included in CHCC 2012 are additional categories of variable-vessel vasculitis and single-organ vasculitis. Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) and immune complex vasculitis are subcategories of SVV that reflect more recent knowledge of underlying pathogenic mechanisms [16] rather than the previous granulomatous and nongranulomatous subcategories. Monogenic vasculitis was not included in CHCC 2012, because knowledge of this primary etiology emerged subsequently. The CHCC does not provide disease-specific classification or diagnostic criteria, but, in the absence of such for specific diseases such as microscopic polyangiitis (MPA), the provided descriptions are often used to help define diseases. (See "Overview of and approach to the vasculitides in adults" and 'Monogenic vasculitis' below.)

CLASSIFICATION CRITERIA

Overview — Validated pediatric-specific classification criteria from 2008 (European Alliance of Associations for Rheumatology/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society [EULAR/PRINTO/PRES] criteria) are available for the most common pediatric primary vasculitides, namely immunoglobulin A vasculitis (IgAV), Takayasu arteritis (TAK), polyarteritis nodosa (PAN), and granulomatosis with polyangiitis (GPA) [15]. However, pediatric-specific criteria were not developed for some of the less common disorders.

Concurrently with the 2012 Chapel Hill Consensus Conference (CHCC 2012), an initiative called "Diagnostic and Classification Criteria in Vasculitis Study" (DCVAS) was established to collect data on adults with vasculitis and to use this to develop improved adult classification criteria. This has resulted in the endorsement and publication in 2022 of revised American College of Rheumatology (ACR)/EULAR criteria for the classification of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), which includes GPA [17], microscopic polyangiitis (MPA) [18], and eosinophilic granulomatosis with polyangiitis (EGPA) [19]. These criteria provide the first ever categorical criteria for classifying MPA, although the utility of these criteria in the pediatric population has yet to be evaluated. The adult classification criteria are discussed in greater detail separately. (See "Overview of and approach to the vasculitides in adults", section on 'Classification criteria'.)

Major primary vasculitides

IgA vasculitis (Henoch-Schönlein purpura) — IgAV (HSP), the most common childhood vasculitis, is an immune-mediated vasculitis associated with IgA deposition.

The EULAR/PRINTO/PRES criteria for IgAV (HSP) include a mandatory finding of purpura (commonly palpable and in crops) (picture 1) or petechiae (without thrombocytopenia) with lower limb predominance and one or more of the following [14,15]:

●Diffuse abdominal pain

●Arthritis or arthralgia

●Leukocytoclastic vasculitis or proliferative glomerulonephritis with predominant IgA deposition

●Kidney involvement (hematuria, red blood cell casts, or proteinuria)

A biopsy demonstrating IgA deposits is required in the case of purpura with an atypical distribution. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)

Kawasaki disease — Kawasaki disease is an acute, self-limited vasculitis that occurs predominately in infants and young children [20]. This disorder mainly affects medium-sized arteries.

The EULAR/PRINTO/PRES classification criteria for Kawasaki disease are not validated; however, they are almost identical to the American Heart Association (AHA) diagnostic criteria, which are the most widely used criteria for the diagnosis of this disorder. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Diagnosis'.)

The criteria for Kawasaki disease include a mandatory finding of fever for five or more days and at least four of the five following features [14]:

●Bilateral bulbar conjunctival injection (picture 2).

●Oral mucous membrane changes, including injected or fissured lips (picture 3), injected pharynx, or strawberry tongue (picture 4).

●Perineal or peripheral extremity changes, including erythema of palms or soles, edema of hands or feet (acute phase) (picture 5), and periungual or perineal desquamation (convalescent phase) (picture 6). Inclusion of perineal desquamation is a modification added by the EULAR/PRES classification to the AHA criteria.

●Polymorphous exanthema.

●Cervical lymphadenopathy (at least one lymph node >1.5 cm in diameter).

Patients with fever and fewer than four of the above criteria can also be diagnosed with Kawasaki disease if coronary artery abnormalities are detected either by two-dimensional echocardiography or coronary angiography.

In some cases, children who do not fulfill clinical criteria are diagnosed with incomplete or atypical Kawasaki disease. Alternatively, some patients who fulfill the criteria of Kawasaki disease may have other conditions, as is inevitable in any system based upon clinical manifestations. (See "Incomplete (atypical) Kawasaki disease" and "Kawasaki disease: Clinical features and diagnosis", section on 'Differential diagnosis'.)

Polyarteritis nodosa — PAN (also called macroscopic polyarteritis or classic PAN) is a systemic necrotizing vasculitis with aneurysm formation affecting small- and/or medium-sized arteries. It typically presents with systemic symptoms (eg, fever, malaise, and weight loss) and signs of multisystem involvement. Recessive loss-of-function pathogenic variants of the cat eye syndrome chromosome region, candidate 1 (CECR1) gene encoding the growth factor adenosine deaminase 2 (ADA2) can cause a PAN-like disease [21]. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and 'Monogenic vasculitis' below.)

The EULAR/PRINTO/PRES classification criteria for childhood PAN include a mandatory finding of abnormalities in a small- or medium-sized artery, either necrotizing vasculitis on biopsy (picture 7) or aneurysms, stenoses, or occlusions not due to fibromuscular dysplasia by angiography and at least one of the following five systemic features [14,15]:

●Skin involvement (livedo reticularis, tender subcutaneous nodules, superficial or deep skin infarctions)

●Myalgia or muscle tenderness

●Hypertension (see "Definition and diagnosis of hypertension in children and adolescents")

●Peripheral neuropathy (sensory peripheral neuropathy or motor mononeuritis multiplex)

●Kidney involvement (proteinuria, hematuria, or red blood cell casts, or glomerular filtration rate of less than 50 percent the normal value for age)

Cutaneous polyarteritis nodosa — The term "cutaneous polyarteritis nodosa" has frequently been used to describe patients that have a more limited disease presentation. EULAR/PRES in 2005 endorsed a description of cutaneous PAN as a distinct entity from systemic childhood PAN that involved the skin but with no other systemic involvement (except for myalgia, arthralgia, and nonerosive arthritis) [14,22-25]. There are no formal classification criteria for cutaneous PAN, and, in fact, many children with limited disease as described would fulfill classification criteria for childhood systemic PAN. In the absence of any specific criteria for cutaneous PAN, we consider cutaneous disease as part of the spectrum of childhood PAN.

Limited cutaneous disease was frequently associated with a preceding streptococcal infection [22]. However, such patients should no longer be diagnosed as PAN; the proper diagnostic term is "vasculitis associated with probable etiology." These changes in nomenclature of cutaneous vasculitis along with disease descriptions were described in a 2018 dermatologic addendum to the CHCC 2012 classification system [26].

Takayasu arteritis — TAK is a chronic, inflammatory, large-vessel vasculitis of unknown cause that primarily affects the aorta and its major branches (image 1 and image 2) [27]. Ongoing granulomatous inflammation leads to stenosis, thrombus, and aneurysm formation causing altered blood flow to major organs. (See "Clinical features and diagnosis of Takayasu arteritis".)

The EULAR/PRINTO/PRES criteria for TAK in children require a mandatory finding of angiographic abnormalities of the aorta or its main branches and pulmonary arteries (aneurysm/dilatation, narrowing, occlusion, or arterial wall thickening not due to fibromuscular dysplasia) and at least one of the following five features [14,15]:

●Pulse deficit (lost/decreased/unequal peripheral artery pulse[s]) and/or claudication induced by activity

●Systolic blood pressure difference >10 mmHg between any limbs

●Bruits or thrills over the aorta and/or its major branches

●Hypertension

●Elevated acute-phase reactants

Angiographic confirmation may be performed by conventional radiography, computed tomography (CT), or magnetic resonance imaging (MRI).

Granulomatosis with polyangiitis — GPA is a systemic vasculitis with granulomatous inflammation of small- and medium-sized arteries that typically affect the upper and lower respiratory tract and the kidneys [28]. It is usually associated with the presence of cytoplasmic antineutrophil cytoplasmic antibodies (cANCAs), generally with specificity for proteinase 3 (PR3) (picture 8). GPA is a rare disease in childhood, with an estimated annual incidence of less than one per one million children [29-31]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and 'Other childhood primary vasculitides' below.)

The EULAR/PRINTO/PRES classification criteria for GPA require three of the following six features [14,15]:

●Kidney involvement (hematuria, proteinuria, or red blood cell casts, or necrotizing pauci-immune glomerulonephritis)

●Upper airway involvement (chronic/recurrent purulent or bloody nasal discharge or crusting, recurrent epistaxis, nasal septum perforation/saddle nose deformity, or chronic/recurrent sinus inflammation)

●Laryngotracheobronchial stenosis

●Pulmonary involvement (chest radiograph, CT showing nodules, cavities, or fixed infiltrates)

●ANCA positivity (myeloperoxidase [MPO]/pANCA or PR3/cANCA staining)

●Granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area on biopsy

Other childhood primary vasculitides — Although the following primary vasculitides were included in the EULAR/PRES classification schema, classification criteria were not developed for these disorders [14].

●Microscopic polyangiitis (MPA)

●Eosinophilic GPA (EGPA; Churg-Strauss syndrome)

●Hypersensitivity vasculitis

●Behçet syndrome

●Primary angiitis of the central nervous system (PACNS)

GPA, MPA, and EGPA are collectively classified as the ANCA-associated vasculitides (AAV) in CHCC 2012. They also each involve predominantly small arteries. The most important reason for this collective classification is that the definitions and classification criteria for each of these disorders are not mutually exclusive. Thus, an individual patient could be classified as having two of these diseases or even PAN. To overcome this conundrum, algorithms have been developed for adults [32] and adapted for use in children [33,34] whereby disease definitions and criteria are applied to the individual patient in a stepwise approach. The definition and criteria for eosinophilic GPA are the most specific; therefore, they are applied first. If the patient does not fulfill criteria, then the remaining elements of different criteria are sequentially applied until the patient is classified.

Microscopic polyangiitis — MPA is a vasculitis that predominantly affects small vessels without granuloma formation. Compared with PAN (macroscopic polyarteritis), MPA has extensive glomerular involvement, usually manifesting as focal segmental glomerulonephritis. This disorder also often involves the pulmonary capillaries, resulting in pulmonary hemorrhage.

MPA is thought by some investigators to represent part of a clinical spectrum that includes GPA. The two disorders have similar nonpulmonary histologic abnormalities and are associated with the presence of ANCAs. However, most patients with microscopic polyangiitis have anti-MPO ANCA present in a perinuclear pattern, in contrast to patients with GPA who demonstrate a primarily PR3 ANCA staining with cytoplasmic distribution (picture 8 and picture 9). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

The 2022 ACR/EULAR criteria for MPA were developed together with GPA and EGPA to be mutually exclusive [17-19]. However, if ACR/EULAR criteria for MPA is applied to an individual patient concurrently with the EULAR/PRINTO/PRES criteria for GPA, the patient may fulfill criteria for both GPA and MPA. The utility of the ACR/EULAR criteria for MPA in pediatric patients remains to be determined.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) — Eosinophilic GPA (formerly called Churg-Strauss syndrome and also called allergic granulomatosis and angiitis) is a predominantly small-vessel vasculitis (SSV) that is accompanied by asthma and eosinophilia. ANCA directed against both PR3 and MPO may be seen [7,35]. It is generally considered an adult disease and is exceedingly rare in children. Published childhood cases are limited to single case reports or series that have been collectively reviewed [36]. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

Classification of this disorder has been based upon criteria developed by the ACR in 1990 [1], and criteria were proposed as part of the 2022 ACR/EULAR criteria [19]. (See "Overview of and approach to the vasculitides in adults", section on 'Classification criteria'.)

Hypersensitivity vasculitis — The term "hypersensitivity vasculitis" has been used to include several forms of vasculitis of small blood vessels, including IgAV, mixed cryoglobulinemia, allergic vasculitis, leukocytoclastic vasculitis, and serum sickness. However, the term is used most appropriately to refer to the vasculitis that occurs as a part of a hypersensitivity reaction to a known or suspected antigen. (See "Hypersensitivity vasculitis in children".)

The major feature of this disorder is vasculitis of the skin with palpable petechiae or purpura. Biopsy of the lesions demonstrates inflammation of the small blood vessels, usually with a predominant infiltration of leukocytes, hence its inclusion within the histopathologic classification framework of leukocytoclastic vasculitis.

Classification of this disorder is based upon criteria developed by the ACR and is discussed elsewhere. (See "Overview of and approach to the vasculitides in adults", section on 'Classification criteria'.)

Behçet syndrome — Behçet syndrome is a multisystem inflammatory disorder characterized by recurrent oral ulcers, genital ulcers, and ocular inflammation, which may involve the joints, skin, central nervous system (CNS), and gastrointestinal tract. It is a systemic vasculitis that can affect both the arteries and veins of almost any organ. There is no universal agreement about the definition of this syndrome. A number of classification systems have been proposed, which are discussed in greater detail separately. (See "Clinical manifestations and diagnosis of Behçet syndrome".)

Primary angiitis of the central nervous system — PACNS, also called isolated CNS vasculitis, is an inflammatory vasculitis that solely affects the CNS vessels in the absence of an overt systemic inflammatory process [37]. Identifiable systemic conditions, such as an infectious process, a systemic vasculitis, collagen vascular diseases, toxin/drug exposure, or malignancy, must be ruled out. (See "Childhood primary angiitis of the central nervous system: Angiography-positive subtype".)

Specific criteria for a diagnosis of PACNS have not yet been established for children; however, the proposed adult-based Calabrese criteria are frequently used [38], though several limitations have subsequently been identified [39]. A review based upon 62 children with PACNS vasculitis found that headache (80 percent) and focal neurologic deficits (78 percent) were the most common presenting complaints, followed by hemiparesis in 62 percent [40]. There are no reliable laboratory findings in children with primary CNS vasculitis, and diagnosis relies on a combination of clinical findings and tests including cerebrospinal fluid analysis, MRI of the brain, and/or angiography [41]. Small-vessel involvement may be missed on conventional angiography, and a brain biopsy may be required for diagnosis [42].

Secondary vasculitis — Vasculitis in children may be secondary to a wide range of disorders. These conditions seem to represent a heightened susceptibility to vascular inflammation because most people exposed to these triggers do not develop vasculitis [7]. Causes of secondary vasculitis include the following:

●Infectious causes including parvovirus B19, hepatitis B and C, human immunodeficiency virus (HIV), varicella, Rickettsia, bacteria, fungi, and mycobacteria

●Medications including some antibiotics, tumor necrosis factor (TNF) inhibitors, and antithyroid agents

●Systemic diseases including systemic lupus erythematosus (SLE), juvenile dermatomyositis, juvenile idiopathic arthritis, sarcoidosis, inflammatory bowel disease, and malignancy

Under the CHCC 2012 nomenclature system, secondary vasculitis is captured under "vasculitis associated with systemic disease" and "vasculitis associated with probable etiology" (table 2).

Monogenic vasculitis — Monogenic conditions that can present with vasculitis of the skin and other organs have been identified:

●Loss-of-function pathogenic variants in the gene encoding adenosine deaminase 2 (ADA2) can cause a disease that mimics PAN [21,43]. (See 'Polyarteritis nodosa' above and "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis", section on 'Pathogenesis'.)

●Pathogenic variants in TMEM173, the gene encoding the stimulator of interferon genes (STING), causes a disease called STING-associated vasculopathy with onset in infancy (SAVI) [44]. SAVI is characterized by early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation [44]. (See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)", section on 'STING-associated vasculopathy with onset in infancy (SAVI)'.)

●CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) can present with neutrophilic dermatosis that can mimic cutaneous vasculitis [45]. CANDLE has been linked to pathogenic variants in the proteasome pathway [46,47]. (See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)", section on 'CANDLE'.)

These disease entities have not yet been considered for incorporation into any formal classification schemes for either primary or secondary systemic vasculitis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY

●Definition – Vasculitides are disorders defined by the presence of inflammation in a blood vessel wall (vasculitis) due to a primary process or secondary to an underlying disease. (See 'Introduction' above.)

●Epidemiology – Vasculitis is rare in children, with reported annual incidences that range from 12 to 53 per 100,000 children under 17 years of age. (See 'Incidence' above.)

●Classification versus diagnosis – Classification systems have been developed to standardize the definitions of specific vasculitides to facilitate research efforts of these disorders. They were not developed to diagnose disease and have not been validated for clinical diagnosis. (See 'Classification versus diagnosis' above.)

●Classification systems – Classification systems and classification criteria for vasculitis in both children and adults are evolving as mechanistic pathways (eg, antineutrophil cytoplasmic antibody [ANCA] associated versus immune complex small-vessel vasculitis [SVV]) and genetic underpinnings (monogenic vasculitis) unfold. (See 'Classification systems' above.)

●Classification criteria – There are validated pediatric-specific classification criteria (European Alliance of Associations for Rheumatology [previously known as the European League Against Rheumatism]/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society [EULAR/PRINTO/PRES] criteria) for some of the pediatric primary vasculitides including immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]), childhood polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA), and Takayasu arteritis (TAK). (See 'Classification criteria' above.)