Vasculitis

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11.5 Vasculitis

Evelyn Doyle

Essentials

1 The most common childhood vasculidites are Henoch–Schönlein purpura (HSP) and Kawasaki disease.
2 In HSP persistent renal disease occurs in a minority of children. Repeat urinalysis is recommended at intervals until resolution of symptoms, as nephritis may be delayed.
3 Kawasaki disease should be considered in all children with unexplained high fever for more than 5 days. All features may not be present simultaneously and a history of mucositis, cervical lymphadenopathy, conjunctivitis, rash and peripheral cutaneous manifestations should be specifically sought.
4 Vasculitis may occur secondary to a primary underlying disease, infections, drug reaction or malignancy and should be excluded.
5 Vasculitis should be considered in children with a non-specific febrile illness and exanthem without explanation that do not resolve as would be expected with a self-limited infectious illness.

Introduction

Childhood vasculitides are a group of disorders characterised by inflammation of blood vessels. Vasculitis is the common end point of several different disease processes and no one mechanism can explain the pathogenesis in this heterogeneous group of conditions. Distinguishing a primary vasculitis from a secondary underlying disease or from conditions that mimic vasculitis can be difficult. Most forms of vasculitis are rare in childhood. Henoch–Schönlein purpura (HSP) and Kawasaki disease (KD) are the two commonest childhood vasculitides.

Clinical presentation

The presentation varies widely according to the size of the affected blood vessel and the extent and nature of organ involvement. Constitutional symptoms are common to all vasculitides and include fever, weight loss, malaise, irritability and arthralgias. Skin manifestations are frequent and often give a clue to the size of the vessel involved; lesions are commonly purpuric but may be urticarial, ulcerative, vesicular or resemble erythema multiforme. In severe vasculitis, vessel destruction leads to tissue infarction, and can result in ischaemia and gangrene.

Classification

The primary vasculitic disorders can be divided according to the size of the vessel involved.

Small vessel vasculitis

HSP, Wegener’s granulomatosis and Churg–Strauss syndrome predominantly involve small vessels; the latter two conditions are extremely rare in childhood.

Henoch–Schönlein purpura

HSP is the commonest vasculitis in childhood. It is immune mediated, associated with IgA complex deposition in tissues, and though several infective agents, drugs and immunisation have been implicated, the cause is unknown.

Clinical presentation

HSP is characterised by palpable purpura which is mandatory for diagnosis with one or more of the following: diffuse abdominal pain, arthritis or arthralgia, renal involvement, or a tissue biopsy showing predominantly IgA deposition.

Skin lesions begin as maculopapules that initially blanch and develop to palpable purpura, which may include macules, papules, vesicles, bullae, nodules and urticaria. Lesions are symmetrical and maximal on lower limbs and buttocks and may be painful. Local angio-oedema of face, hands, feet, back, scrotum and perineum is common in younger children.

Arthritis occurs in up to 80%, with one or more joints involved, and resolves leaving no residual joint deformity. Large joints of the lower extremity are usually affected but upper extremity joints may also be involved.

Gastrointestinal symptoms are common and include colicky abdominal pain, vomiting and bloody diarrhoea. Over half of patients have occult blood in stools. Intussusception (usually ileoileal) is the most common serious gastrointestinal complication and results from oedema and haemorrhage in the bowel wall acting as a lead point. Ultrasound is recommended when suspected, as contrast enema will not detect ileoileal pathology.

Some children present with isolated abdominal symptoms or arthritis and the diagnosis may only become apparent when the rash develops days to weeks later. Nephritis occurs in about half and may be delayed for up to 4 or more weeks. Other serious though uncommon conditions can occur including orchitis cerebral involvement, including seizures.

Investigations

There is no diagnostic test for HSP; the diagnosis is clinical but may be difficult in the absence of rash. Blood pressure measurement, urinalysis and renal function assessment at presentation are required in all patients. Renal biopsy is reserved for patients with nephritis complicated by nephrotic syndrome, hypertension or renal failure. Throat swab, C3/C4 and ASOT may be useful in distinguishing poststreptococcal arthralgia from HSP where the clinical picture is not full-blown.

Prognosis

It is generally a self-limited condition but can recur in one-third of patients. Resolution of symptoms occurs over a period of weeks. A small percentage of children develop persistent renal disease, with about 0.1% developing serious renal disease. Those with isolated haematuria and proteinuria without renal insufficiency completely recover.

Management

Most children are managed as outpatients with supportive care. Non-steroidal anti-inflammatory drugs are effective but use with caution in renal impairment. Steroids are not routinely used as the majority of patients’ symptoms resolve spontaneously without sequelae, but may be considered in patients with severe renal or extrarenal symptoms. Steroids have not been found to prevent development of renal or gastrointestinal symptoms but may be effective in treating symptoms. Renal disease is the major concern long term and specialist consultation should be sought in severe disease. Follow up should involve blood pressure surveillance and urinalysis for 3 months as renal involvement can occur later even when initial urinalysis is normal.

Medium vessel vasculitis

This group includes Kawasaki disease and polyarteritis nodosa (PAN).

Kawasaki disease

KD is an acute systemic vasculitis of unknown aetiology affecting predominantly medium muscular arteries, with a predilection for coronary arteries. It is the second most common vasculitic disease of childhood after HSP. The disease frequency varies globally, with highest rates in Japan and in Japanese children born overseas. It predominantly affects children under the age of 5 but can occur at any age. Coronary artery aneurysms develop in ~15–25% of untreated children and may lead to ischaemic heart disease or sudden death.

Clinical presentation

Diagnosis of KD is based on clinical criteria and the ‘classic’ form presents with unexplained high fever lasting at least 5 days and four of the following five clinical features, or fever with coronary artery involvement and three other clinical findings. Some children may present with incomplete or ‘atypical’ Kawasaki disease: they have some but not enough features to meet classical criteria. In these children diagnosis can be difficult and consultation with an experienced physician should be sought.

Cervical adenopathy.
Bilateral non-suppurative conjunctival injection with perilimbal sparing.
Polymorphous rash (maculopapular, multiforme or scarlatiniform).
Peripheral cutaneous or perianal changes including erythema, swelling and induration. Desquamation may occur as a late sign, usually 2–3 weeks after the onset of illness, beginning in the periungal region.
Mucous membrane changes to lips and/or oral cavity (fissuring of the lips, pharyngitis and strawberry tongue).

Fever is typically high, >39 with minimal response to antipyretics, and usually persists for 1 to 2 weeks if untreated. Extreme irritability in a toddler with persisting fever of unknown origin should always prompt consideration of KD. Other associated findings are carditis (pericarditis, myocarditis, valvular involvement), aseptic meningitis, arthritis, sterile pyuria, uveitis, hepatitis and hydrops of the gall bladder.

Investigations

There is no diagnostic test for KD. In the acute stage, laboratory findings may include leucocytosis with left shift, anaemia, and thrombocytosis (in the second to third week). Mild hepatitis with raised transaminases and elevated conjugated bilirubin, and cerebrospinal fluid analysis may show a mononuclear pleocytosis with normal glucose and protein and sterile culture. Mild proteinuria and pyuria may also be present.

If atypical KD is suspected laboratory tests, though non-specific, may be useful. The diagnosis is unlikely if platelet count, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are normal after day 7 of illness. A moderate to marked elevation in CRP or ESR is almost universal in children with KD. Leucopenia, lymphocyte predominance, and low platelet count in the absence of disseminated intravascular coagulation are also suggestive of an alternative diagnosis.

Echocardiography for coronary aneurysms should be performed in all children. Screening has shown that a substantial number of children with KD and coronary artery abnormalities are not identified by the classic case definition.

Management

Combined therapy with aspirin and high dose intravenous immunoglobulin (IVIG) has been shown to reduce the rate of coronary artery aneurysm from ~25% to ~5% when administered in the first 10 days of illness. High-dose IVIG 2 g kg−1, is usually given as a single infusion. High-dose aspirin is given initially: doses varying from 30–100 mg kg−1 day−1 are used. Following defervescence, aspirin is given for its antiplatelet action in a dose of 2–5 mg kg−1 once daily.

Children who do not respond after the first dose of IVIG may respond to a second dose. A group of patients remain resistant to IVIG therapy and some novel therapies have been tried under specialist supervision. Follow up includes regular echocardiography, the duration of which will be determined by the degree of coronary artery involvement. Stress testing in adolescence is required if there has been cardiac involvement and angiography may be indicated. Long-term antiplatelet or anticoagulation therapy may be indicated.

Prognosis

In children without cardiac involvement recovery is usually complete though the long-term effects are largely unknown. Aneurysmal coronary artery dilatation occurs in ~25% of untreated KD, and half to two-thirds regress over time but stenosis in these vessels may progress independently of this. The worst prognosis occurs in large aneurysms (>8 mm), and risks include thrombosis, myocardial ischaemia and infarction; also late sequelae of KD may manifest in adulthood.

Polyarteritis nodosa

PAN is a necrotising vasculitis of unknown aetiology involving medium-sized muscular arteries. It is rare in childhood. PAN is a systemic illness with a wide spectrum of clinical presentations depending on the organs involved. Constitutional symptoms are common. Skin manifestations may resemble those of HSP or erythema multiforme or may be necrotic with peripheral gangrene. Other features include myalgia, ischaemic heart pain, nephritis and cerebral manifestations of stroke, visual loss and psychosis. Diagnosis relies on elevation of inflammatory markers (ESR and CRP) and biopsy showing characteristic histopathological changes or angiographic or magnetic resonance angiography evidence of aneurysm or occlusion in affected vessels. Antineutrophil cytoplasmic antibodies (ANCA) are present in some forms of PAN.

Large vessel vasculitis

Takayasu disease is a large vessel vasculitis of unknown aetiology involving the aorta and its main branches. It occurs 10 times more commonly in young women than men. Morbidity results from stenosis, ischaemia and aneurysmal dilatation of affected vessels. Presentation may be non-specific with constitutional symptoms or specific symptoms relating to inflammation of large vessels, including congestive heart failure, angina, myocardial infarction, stroke, limb claudication and renal artery hypertension may be found. In children, careful examination of pulses and blood pressures in all four extremities, with a search for asymmetry and bruits is essential. High-dose corticosteroids are first line therapy. In resistant or relapsing patients, cyclophosphamide and methotrexate have been used. Long-term immunosuppressive therapy is required in some patients.

Secondary vasculitis and vasculitis mimics

Vasculitis is seen secondary to a primary underlying disease, infections, drug reaction or malignancy. Vasculitis occurs in connective tissue disorders such as systemic lupus erythematosus and dermatomyositis. There is an increased association with vasculitis in patients with familial Mediterranean fever, with several patients described with PAN and HSP features.

Many infectious diseases have been associated with vasculitis, predominantly with cutaneous manifestations. Papulovesicular acrolocated syndrome (PALS or Gianotti–Crosti syndrome) is a vasculitis associated with multiple viral and other triggers, including hepatitis B antigenaemia, Epstein–Barr virus, cytomegalovirus, human immunodeficiency virus, rickettsial diseases and streptococcal infections. Multiple skin-coloured or red, flat-topped papules occur in an acral distribution with sparing of the trunk.

Hypersensitivity angiitis is a serum-sickness-like reaction in infants that includes a rash, arthropathy and fever. It commonly follows the use of penicillin or cephalosporins (particularly Ceclor). Skin manifestations include oedema of the dorsum of the hands and feet and a nodular, purpuric, urticarial or erythema-multiforme-like rash. Arthralgia and arthritis are common and respond to non-steroidal anti-inflammatory drugs, with short-term oral steroids reserved for the more severe cases. The condition is self limiting but recurs on re-exposure to the same agent.

Any process that causes occlusion of a blood vessel can mimic vasculitis. In subacute bacterial endocarditis, the clinical appearance resembles a primary vasculitic process but is secondary to septic emboli.

Controversies and future directions

Aspirin, though routinely used to treat Kawasaki disease, has not been shown to reduce the risk of coronary artery aneurysm in Kawasaki disease.
Steroid use in HSP is not routine and remains controversial but recent studies appear to show benefit in terms of resolution of symptoms and may be considered in patients with severe disease.
International collaboration to study rare disorders such as paediatric vasculitis may point toward new treatment approaches.

Acknowledgement

The contribution of Ruth Barker as author in the first edition is hereby acknowledged.

Further reading

Brogan P.A., Bose A., Burgner D., et al. Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research. Arch Dis Child. 2002;86:286-290.

Dillon M.J., Ozen S. A new international classification of childhood vasculitis. Pediatr Nephrol. 2006;21:1219-1222.

Newburger J.W., Takahashi M., Gerber M.A., et al. Diagnosis, treatment, and long term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114:1708-1733. [Published correction appears in Pediatrics 2005;115:1118]

Weiss P.F., Feinstein J.A., Luan X., et al. Effects of corticosteroid on Henoch–Schönlein purpura: a systematic review. Pediatrics. 2007;120:1079-1087.

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