Medium-size-artery vasculitides do occur in childhood and manifest, in the main, as polyarteritis nodosa (PAN), cutaneous PAN and Kawasaki disease. Of these, PAN is the most serious, with high morbidity and not inconsequential mortality rates. New classification criteria for PAN have been validated that will have value in epidemiological studies and clinical trials. Renal involvement is common and recent therapeutic advances may result in improved treatment options. Cutaneous PAN is a milder disease characterised by periodic exacerbations and often associated with streptococcal infection. There is controversy as to whether this is a separate entity or part of the systemic PAN spectrum. Kawasaki disease is an acute self-limiting systemic vasculitis, the second commonest vasculitis in childhood and the commonest cause of childhood-acquired heart disease. Renal manifestations occur and include tubulointerstitial nephritis and renal failure. An infectious trigger and a genetic predisposition seem likely. Intravenous immunoglobulin (IV-Ig) and aspirin are effective therapeutically, but in resistant cases, either steroid or infliximab have a role. Greater understanding of the pathogenetic mechanisms involved in these three types of vasculitis and better long-term follow-up data will lead to improved therapy and prediction of prognosis.
KeywordsVasculitisPolyarteritis nodosaCutaneous polyarteritis nodosaKawasaki diseaseChild
Vasculitis can be defined as inflammation and necrosis of blood vessels. By common usage, the term predominantly refers to arterial disease, and this interpretation will be used in this educational review. Although more common in adults than in children, vasculitis does occur in childhood and may present as a primary disorder or be a feature of some other systemic disease. Various attempts at classification and nomenclature of vasculitides in both adults and children have been published [1–9]. Most have focussed on vessel size as a useful distinguishing feature, resulting in vasculitis being categorised as affecting large vessels, medium-size vessels and small vessels. The large-vessel category in childhood refers primarily to Takayasu disease; the medium-size-vessel category includes polyarteritis nodosa (PAN), Kawasaki disease (KD) and cutaneous polyarteritis nodosa (CPAN); the small-vessel category is usually subdivided into granulomatous disease [Wegener’s granulomatosis (WG) and Churg-Strauss syndrome] and nongranulomatous disorders [microscopic polyangiitis (MPA), the leukocytoclastic vasculitides such as Henoch-Schönlein purpura (HSP), isolated cutaneous leukocytoclastic vasculitis and hypocomplementemic urticarial vasculitis]. There are, in addition, vasculitides affecting various-sized vessels, including Behçet disease, vasculitis associated with infection, vasculitis secondary to connective tissue diseases, isolated vasculitis of the central nervous system, Cogan’s syndrome and others . This educational review focuses on medium-size-vessel vasculitis, specifically, PAN, KD and CPAN.
This is a necrotising vasculitis associated with aneurysmal nodules along the walls of medium-sized muscular arteries and is the condition classically described by Kussmaul and Maier in 1866 . Despite some overlap with smaller-vessel disease, PAN appears to be a distinct entity and, in adults in Europe and the United States, appears to have an estimated annual incidence of 2.0–9.0/million . Although comparatively rare in childhood, it is the most common form of systemic vasculitis after HSP and KD [12, 13]. However, the data are difficult to interpret, as the incidence in various reports differs widely depending on which criteria are used to classify patients as PAN . Peak age of onset in childhood is 7–11 years, with often a male preponderance.
Proposed classification of childhood vasculitis (adapted from Ozen et al.  with permission)
I. Predominantly large vessel vasculitis
II. Predominantly medium-sized-vessel vasculitis
Childhood systemic polyarteritis nodosa (PAN)
Kawasaki disease (KD)
III. Predominantly small-vessel vasculitis
Churg Strauss syndrome
Isolated cutaneous leukocyclastic vasculitis
Hypocomplementemic urticarial vasculitis
IV. Other vasculitides
Vasculitis secondary to infection (including hepatitis-B-associated PAN), malignancy and drugs, including hypersensitivity vasculitis
Vasculitis associated with connective tissue disease
Isolated vasculitis of the central nervous system
Criteria for classifying polyarteritis nodosa (PN) (adapted from Ozen et al.  with permission)
Histological evidence of necrotizing vasculitis in medium or small sized arteries or angiographic abnormalities (aneurysms, stenoses or occlusion) as a mandatory criterion, plus one out of the following five:
1 Skin involvement
2 Myalgia or muscle tenderness
4 Peripheral neuropathy
5 Renal involvement
It is, however, important to appreciate that classification criteria are not diagnostic criteria, and meeting classification criteria is not equivalent to making a diagnosis in an individual patient . A diagnosis is made by considering all clinical features in a patient, only some of which may be classification criteria . In this context, it has been considered that the establishment of diagnostic criteria for childhood PAN would also be of value, and although attempts have been made to do so , this is currently under review.
The main clinical features of PAN are malaise, fever, weight loss, skin rash, myalgia, abdominal pain and arthropathy [6, 18–25]. In addition, ischaemic heart and testicular pain; renal manifestations such as haematuria, proteinuria and hypertension [23, 26, 27]; neurologic features such as focal defects, hemiplegia, visual loss, mononeuritis multiplex; and organic psychosis [28–30] may be present. Skin lesions are variable, and may masquerade as those of HSP or multiform erythema but can also be necrotic and associated with peripheral gangrene [31, 32]. Lesions sometimes mimic pyoderma gangrenosum. Livido reticularis is also a characteristic feature, and occasionally subcutaneous nodules overlying affected arteries are present [31, 32]. Systemic involvement is variable, but the skin, the musculoskeletal system, the kidneys and the gastrointestinal tract are most prominently affected, with cardiac, neurological and respiratory manifestations occurring less frequently [9, 18, 19, 21–23, 33, 34]. In some patients, rupture of arterial aneurysms can cause retroperitoneal and peritoneal bleeding, with perirenal haematomata being a recognised manifestation of this phenomenon . This feature has been noted a number of times in Turkey where it has occurred in patients with the well-recognised association of PAN and familial Mediterranean fever [36, 37]. However, clinical manifestations (and investigation findings) can be very confusing, with certainly in the early phase and sometimes the late phase of the illness absence of conclusive diagnostic evidence .
Differential diagnosis includes other primary vasculitides (HSP, WG, MPA, KD); connective tissue diseases (juvenile rheumatoid arthritis, dermatomyositis, lupus, mixed connective tissue disease); sarcoidosis; Behçet’s disease, viral infections, subacute bacterial endocarditis and lymphoma and other malignancies.
Diagnostic laboratory and radiological investigation
Although not a routine investigative procedure, the recently developed measurements of circulating endothelial microparticles and circulating endothelial cells may prove helpful in demonstrating the presence of active vasculitic disease as well as throwing light on the mechanisms involved [56–62]. Furthermore, measurement of circulating endothelial progenitor cells may be helpful in pointing to evidence of a repair process being under way in the recovery phase of disease [61, 63]. However, this may not be so clear cut in children and further work is necessary to clarify their role [64, 65].
The aetiology of PAN remains unclear, but there are data to support roles for hepatitis B [40, 41] and reports of a higher frequency of exposure to parvovirus B19 and cytomegalovirus in PAN patients compared with control populations [66, 67]. HIV has also been implicated , and PAN-like illnesses have been reported in association with cancers and haematological malignancies . However, in childhood, associations between PAN and these infections or other conditions are rare. Evidence has emerged suggesting that bacterial superantigens may play a role in some cases . Occasional reports link PAN to immunisation, but the evidence is not convincing. It seems likely that the immunological processes involved are similar to those in other systemic vasculitides and include immune complexes, complement, possibly autoantibodies, cell adhesion molecules, cytokines, growth factors, chemokines, neutrophils and T cells [71, 72]. Recent evidence that rituximab can be successful therapeutically suggests that B cells also have a pathogenetic role . There may be genetically predisposing factors that may make individuals vulnerable to PAN and other vasculitides. An example of this is the link with familial Mediterranean fever [36, 37]. There are three reports of PAN occurring in siblings that add weight to this hypothesis, but there are no detailed genetic studies [73–75].
For many years, PAN treatment has involved administration of high-dose steroid with an additional cytotoxic agent, such as cyclophosphamide, to induce remission [76–82]. In most patients, it is appropriate to treat aggressively. However, in those presenting with mild disease, verging on CPAN, steroid alone is sometimes recommended. Cyclophosphamide might be given orally in a dose of 2 mg/kg per day for 2–3 months or by pulsed monthly intravenous injections for up to 6 months or for shorter periods in children if remission is achieved. Aspirin has also been prescribed empirically as an antiplatelet agent . Once remission is achieved, maintenance therapy with daily or alternate-day low-dose prednisolone and oral azathioprine is frequently used for up to 18 months . Other maintenance agents include methotrexate, mycophenolate mofetil and cyclosporin A . Adjunctive plasma exchange can be used in life-threatening situations [83, 84], and more recently, successful treatment with biologic agents such as infliximab or rituximab has been reported for those unresponsive to conventional therapy [24, 80–82, 85–88]. Treatment response can be assessed using a modified Birmingham Vasculitis Activity Score .
Cutaneous polyarteritis nodosa
CPAN is a form of vasculitis affecting small- and medium-sized vessels limited to the skin . It is characterised by the presence of fever; subcutaneous nodular, painful, nonpurpuric lesions with or without livedo reticularis occurring predominantly in the lower extremities; with no systemic involvement (except for myalgia, arthralgia and nonerosive arthritis) [94, 95]. It is well recognised in childhood, and there are a number of reports in the literature [40, 96–98]. In a recent international survey of childhood vasculitis, approximately one third of children identified as having PAN were categorised as CPAN . The clinical course is characterised by periodic exacerbations and remissions that may persist for many years and occasionally throughout childhood. Skin biopsy shows necrotizing nongranulomatous small- and medium-sized vessel vasculitis, tests for ANCA are usually negative and the condition is often associated with serological or microbiological evidence of streptococcal infection [99, 100]. Nonrecurring CPAN has been observed in neonates born to mothers with chronic CPAN [94, 101, 102]. There has been much discussion as to whether the condition should be classed as a separate entity or as a part of the spectrum of PAN . In the main, the condition remains localized to the skin [94, 103], although a proportion of cases appear to evolve into full-blown PAN, and clinicians need to be mindful of this possibility . The distinction is difficult, and patients with more extensive clinical involvement or lack of response to standard treatment may need to be further evaluated and possibly treated as if they had PAN . There are some investigators who feel that their data support the view that CPAN does not progress to PAN .
The condition may respond to nonsteroidal anti-inflammatory drugs [96, 107] but can achieve remission with moderate doses of oral steroids . When streptococcal infection is implicated, penicillin may be effective [100, 108]. Some clinicians recommend continuing prophylactic penicillin throughout childhood, as relapses are common and occur in up to 25% of cases in association with further streptococcal infections [100, 109]. When there is a lack of response to standard treatment or concerns about possible steroid toxicity, intravenous immunoglobulin (IV-Ig) has been successfully used . Some success has also been reported with methotrexate , colchicine and dapsone , cyclophosphamide , pentoxifylline  and chloroquine .
Many, but not all, patients experience a persistence of cutaneous lesions through childhood, but it is uncommon for the condition to progress to PAN . However, it is mandatory for such patients to remain under surveillance to detect any evidence of developing systemic disease that would be an indication for intensification of treatment along the lines of that required for PAN.
KD is an acute self-limiting systemic vasculitis predominantly affecting young children. Distribution is worldwide, with a male preponderance, an ethnic bias towards Asian children, seasonality and occasional epidemics [115–119]. It is the second commonest vasculitic illness of childhood (HSP being the commonest) and the commonest cause of acquired heart disease in children in the UK and USA [120–122]. The incidence in Japan is 138/100,000  in children younger than 5 years, whereas in the United States, it is 17.1  and in the UK 8.1 .
The principal clinical features are fever persisting for 5 days or more, peripheral extremity changes (reddening of the palms and soles, indurative oedema and subsequent desquamation), a polymorphous exanthema, bilateral conjunctival injection/congestion, lips and oral cavity changes (reddening/cracking of lips, strawberry tongue, oral and pharyngeal injection) and cervical lymphadenopathy (acute nonpurulent). For the diagnosis to be established according to the Diagnostic Guidelines of the Japan Kawasaki Disease Research Committee, five of six criteria should be present . The North American recommendations for the diagnosis are similar, except that fever is a mandatory criterion and four of the remaining five criteria are required to establish the diagnosis . If coronary artery aneurysms are present, fewer features may be necessary for diagnostic purposes . These diagnostic criteria, with minor modifications, were adopted as classification criteria for KD, but perineal desquamation was added to the criteria at the Vienna Consensus Conference on the Classification of Childhood Vasculitides  describing changes in extremities. Cardiovascular features are the most important manifestations of the condition, with widespread vasculitis affecting predominantly medium-size muscular arteries, especially the coronary arteries. Coronary artery involvement occurs in 15–25% of untreated cases, with additional cardiac features in a significant proportion of these, including pericardial effusion, electrocardiographic abnormalities, pericarditis, myocarditis, valvular incompetence, cardiac failure and myocardial infarction [128, 129]. Vascular damage to the major limb arteries, renal and other visceral vessels and the aorta can be demonstrated [129, 130]. Other systemic involvement can occur, including in the gastrointestinal tract , the hepatobiliary tract with hydrops of the gall bladder being well recognised , the respiratory tract , the central nervous system with seizures and meningeal features , deafness , arthropathy  and renal involvement. Renal manifestations include pyuria, proteinuria, tubular disturbances, tubulointerstitial nephritis and renal failure [137–147]. The mechanism of the renal impairment is unclear, and there is some evidence suggesting that IV-Ig used in treatment might play a part . Another clinical sign that may be relatively specific to KD is the development of erythema and induration at sites of Bacillus Calmette-Guérin (BCG) inoculations . The mechanism of this is thought to be cross-reactivity of T cells in KD between specific epitopes of mycobacterial and human heat-shock proteins .
Diagnostic laboratory and other investigations
Polymorphonuclear leukocytosis, thrombocythemia and increased ESR and CRP are characteristic findings in the acute phase of KD [116, 118]. Two-dimensional echocardiography is the means of identifying coronary artery involvement acutely and monitoring changes long term [116, 118]. Coronary angiography has a role, especially in the presence of giant coronary artery aneurysms or in circumstances when stenotic lesions are suspected, but provides little information about the microvasculature [118, 151]. Dobutamine stress echocardiography has a role in follow-up evaluation . Spiral CTA  and MRA  have been advocated, but the former is associated with significant radiation and the latter has limited resolution. Coronary arteriography has an important role for delineating detailed anatomical injury, particularly for children with giant coronary artery aneurysms (>8 mm), in which stenoses adjacent to the inlet/outlet of the aneurysms are a concern. It is important to note that coronary arteriography should be delayed until at least 6 months after disease onset, as there could be a risk of myocardial infarction if performed in children with ongoing severe coronary artery inflammation .
The aetiology of KD is unknown, but it is thought that some ubiquitous infectious agent produces an abnormal immunological response in a genetically susceptible individual, which results in the characteristic clinical picture. A number of polymorphisms have been identified that appear to be linked to disease susceptibility or the risk of coronary artery aneurysms [155, 156]. A genome-wide association study identified five genes with functional relationships to inflammation, apoptosis and cardiovascular pathology . In addition, another study has reported an association of the functional polymorphism of the inositol 1,4,5-triphosphate 3-kinase C (ITPKC) gene with immune activation of KD . ITPKC acts as a negative regulator of T-cell activation and may contribute to immune hyperreactivity in KD. Furthermore, there is some evidence that a bacterial toxin causes KD . This hypothesis is based on clinical and immunological similarities between KD and staphylococcal or streptococcal toxin-mediated illnesses and the recent observations that some children with KD seroconvert with IgM antibodies against a number of bacterial superantigens . However, an alternative view is that the immune response in KD is oligoclonal (as with conventional antigens) and that IgA plasma cells play a central role .
Treatment of KD with aspirin and IV-Ig has been shown to reduce the occurrence of coronary artery aneurysms [118, 161]. IV-Ig is recommended within 10 days of disease onset but is also appropriate for late presenters with active disease [116, 118]. IV-Ig resistance occurs in up to 20% of cases . In such circumstances, corticosteroids have been advocated, but there are conflicting data from various randomised controlled trials as to their effectiveness [162–166]. From these data it is suggestive that perhaps corticosteroids need to be given over a more protracted period to achieve benefit, as the major studies used a single IV dose of methylprednisolone. All studies have been complicated by the need to evaluate steroid treatment along with IV-Ig, as it has not been considered ethically appropriate to undertake a trial directly comparing steroid with IV-Ig. Anecdotally, however, there are reports of steroid being beneficial when IV-Ig has failed and also of the effective use of steroid in patients who have refused IV-Ig on the basis of being Jehovah’s Witnesses [116, 167, 168]. Additionally, there is some evidence that steroid given as pulsed methylprednisolone plus gammaglobulin may have a role as initial treatment in high-risk KD patients . More recently, there are reports of the beneficial effects of infliximab in the treatment of IV-Ig-resistant KD [169–171].
In the convalescent phase, if aneurysms persist, antiplatelet therapy in the form of low-dose aspirin should be continued long term until the aneurysms resolve . In the presence of giant aneurysms (>8 mm), warfarin is recommended in addition to aspirin . Some patients may require coronary angioplasty or a revascularisation procedure should ischemic symptoms arise or evidence of obstruction occur .
The outlook for KD patients is generally good. The acute mortality rate in Japan is 1.14 [172, 173]. Angiographic resolution 1–2 years after disease onset has been observed in 50–70% of vessels with coronary aneurysms . About 20% of patients who develop coronary artery aneurysms during the acute stage of the disease will develop coronary artery stenoses , and the risk is greater with large (giant) aneurysms . However, there are data suggesting that, despite seeming recovery, there are long-term cardiovascular sequelae that persist into adult life and that may have important implications. Impaired endothelial function in peripheral [176, 177] and coronary arteries  has been reported, as have increased carotid media thickness and arterial stiffness . Perhaps more important than these studies of novel surrogate markers for subclinical atherosclerosis is the long-term epidemiological data from Japan. In the seventh look at the long-term outcomes of a cohort of 6,576 patients with KD enrolled between 1982 and 2004, the mortality rate for patients without cardiac sequelae in the acute phase of the disease and for female patients with sequelae did not differ from the normal population . The mortality rate of male patients with cardiac sequelae was, however, 2.4 times higher than the normal population . Epidemiological studies from Japan also have demonstrated that late sequelae, especially in patients with large aneurysms, include myocardial ischaemia with a frequency of 3% within 4 years after the disease onset .
Vasculitis affecting medium-size vessels does occur in childhood. The distinction from other conditions is often difficult, especially in the context of PAN, although it is usually possible to categorise the disorders into clinical-pathological entities. Further studies are needed on the aetiopathogenetic mechanisms involved in the development of these vasculitides that might hopefully lead to more focussed therapeutic approaches. Although current treatment has made a major impact on disease activity control, there remains a need for more randomised controlled trials, especially using newer biologic agents, to establish their roles in therapy. Finally, more follow-up studies are needed to establish the long-term implications of developing these conditions in childhood.