Key points

Introduction

Childhood vasculitis is a complex and fascinating area in pediatric rheumatology that has experienced an unprecedented surge in research, leading to new knowledge over the past several years. Vasculitis is defined as the presence of inflammatory cell infiltration in blood vessel walls, usually with multisystemic involvement. Some forms of vasculitis have an abrupt onset, whereas others are very insidious leading to delayed diagnosis. Some vascular lesions can cause aneurysm formation, whereas others can cause stenosis or occlusion, resulting in ischemia, infarction, hemorrhage, and organ failure.

Vasculitis is difficult to classify and the most acceptable childhood vasculitis classification defines the type of vasculitis according to the size of the vessel affected.

The pathogenic mechanisms of the different forms of vasculitis include presence of circulating immune complexes, disturbance in humoral immune response manifested by the presence of antibodies, antineutrophil cytoplasmic autoantibodies (ANCA), and antiendothelial cells; antibodies against antigens in vessel walls; and disturbance in cellular immune response with T-cell reactivity. Complement, cytokines, cell adhesion molecules, chemokines, growth factors, and neutrophils are involved in the immunologic processes of the systemic vasculitis. Host susceptibility and environmental triggers play a role in these diseases.

Clinical features suggesting vasculitis include constitutional symptoms, such as fever, weight loss, fatigue, skin lesions, neurologic manifestations, arthralgia, arthritis, myalgia, myositis, serositis, arterial hypertension, and lung and renal involvement with infiltration and hemorrhage. High acute-phase reactants, anemia, leukocytosis with eosinophilia, antibodies, such as antineutrophil cytoplasmic antibodies, and altered urinary sediment are common laboratory features in vasculitis. Because of the nonspecific features, some forms of vasculitis are not recognized and their prevalence might be underestimated.

Diagnosis can be difficult, evaluating disease activity is problematic, and outcome in some cases can be poor.

The most frequent forms of vasculitis in childhood are the small-size vasculitides, of which Henoch-Schoenlein Purpura (HSP) and other leucocytoclastic vasculitis are the best examples, followed by Kawasaki disease, a midsize vasculitis, and Takayasu arteritis, a large-size vasculitis, both of which are topics in this article. Other forms of vasculitis include midsize vasculitis, such as polyarteritis nodosa (PAN), small-size vasculitis, subdivided into granulomatous disease (granulomatosis with polyangiitis [GPA] or Wegener granulomatosis and eosinophilic granulomatosis with polyangiitis [EGPA], or Churg-Strauss syndrome) and nongranulomatous disease (microscopic polyangiitis [MPA]) and vasculitis affecting various-sized vessels like Behçet disease.

HSP is an IgA immune complex–mediated vasculitis that affects small vessels, with the main characteristics of purpuric rash, followed by arthralgia/arthritis, abdominal pain, and nephritis. The typical histopathologic feature in the acute inflammatory lesions is perivascular accumulation of neutrophils, known as leucocytoclastic vasculitis. HSP is often a self-limited condition that involves skin, joint, and gut, but approximately 40% of patients develop nephritis within 4 to 6 weeks after the skin involvement, and depending on severity may lead to poor disease outcome. Disturbance in the immune system, including elevations in serum levels of immunoglobulin (Ig)A1 and IgA1-containing circulating immune complexes have been detected in patients with HSP. Although the pathogenetic mechanisms are still not fully delineated, several studies suggest that galactose-deficient IgA1 (Gd-IgA1), which is increased in patients with HSP with nephritis, is recognized by antiglycan antibodies, leading to the formation of the circulating immune complexes and their mesangial deposition, resulting in renal injury. Furthermore, serum levels of alpha–smooth muscle actin and C-Met were found to be higher in patients with HSP than those in the immunoglobulin-A nephropathy and healthy control groups and correlated with blood urea nitrogen levels, serum creatinine levels, hematuria, and proteinuria and may be associated with disease severity.

Polyarteritis nodosa (PAN) is a chronic vasculitis that rarely occurs in childhood, although in some studies it appears to be the third-most common form of vasculitis after HSP and KD. It is a necrotizing form of vasculitis associated with aneurysmal nodules along the walls of the medium-sized muscular vessels, which can be divided into systemic PAN, involving the skin and the gastrointestinal, renal, and central nervous systems, and in cutaneous PAN, a form limited to the skin. The main clinical features of systemic PAN are malaise, fever, weight loss, skin lesions, myalgia, arthropathy, abdominal pain, and testicular involvement, which are often associated with hypertension, proteinuria, and hematuria, secondary to renal artery involvement. Neurologic features, such as focal defects, mononeuritis multiplex, and psychosis may be present. The skin lesions are variable and may range from erythematous rash to necrotic lesions with peripheral gangrene, but livedo reticularis and nodules overlying affected arteries are characteristic features of this disease. Cutaneous PAN is characterized by the presence of painful subcutaneous nodules with or without other lesions, and no systemic involvement, except for myalgia, arthralgia, and nonerosive arthritis. In this type of PAN, serologic or microbiological evidence of streptococcal infection is common. There is controversy as to whether this is a separate entity or part of the systemic PAN spectrum. High acute-phase reactants are usually present in the active phase of both types. Positive hepatitis B serology is an unusual association with PAN in children. In a single-center retrospective study, gastrointestinal involvement was associated with increased risk of relapse, whereas longer time to induce remission and an increased cumulative cyclophosphamide dose were associated with lower risk of relapse. To make a diagnosis for patients whose symptoms suggest cutaneous PAN, a skin biopsy demonstrating necrotizing nongranulomatous medium-sized and small-sized vessel vasculitis is necessary. Patients with symptoms of systemic PAN require an angiogram, which typically shows aneurysms or stenoses/occlusions in medium-sized arteries or a biopsy of the affected organ. Although prognosis has dramatically improved, PAN remains a life-threatening form of systemic vasculitis and late morbidity can occur years after childhood onset from chronic vascular injury.

ANCAs are a heterogeneous group of autoantibodies associated with certain forms of vasculitis characterized by necrotizing inflammation with a paucity of immunoglobulin in the vessel wall detectable by immunohistologic methods. The genesis of the ANCA autoimmune response is a multifactorial process that includes genetic predisposition, environmental factors, an initiating antigen, and failure of T-cell regulation. ANCAs activate primed neutrophils and monocytes by binding to certain antigens expressed on the surface of neutrophils. ANCA-associated vasculitis (AAV) predominantly affects small vessels in any organ of the body, and most patients with AAV have systemic disease that can be classified on the basis of clinical and pathologic features as MPA, GPA, or EGPA. GPA is the most frequent AAV in childhood, characterized by the hallmark triad of granulomatous inflammation of upper and lower respiratory tracts and necrotizing pauci-immune glomerulonephritis. In a cohort of 117 children with GPA and other ANCA-associated vasculitides, most children presented with GPA and the most frequent clinical features were constitutional; ear, nose, and throat; pulmonary; and renal involvement. Almost all patients present with cytoplasmic immunofluorescence staining pattern and positive antiproteinase 3 (PR-3). The diagnosis is based on the combination of pulmonary and renal vasculitis, presence of serologic markers, especially antibodies to PR-3, and characteristic histopathologic findings, like pauci-immune granulomatous inflammation of predominantly small-vessel or pauci-immune glomerulonephritis. At onset, nonspecific complaints of fever, malaise, and weight loss are very common. Prognosis depends in part on the stage of disease at diagnosis and at least 50% of patients relapse within 5 years despite treatment. EGPA, a rare disease in children, is characterized by a nonvasculitic prodrome of asthma and eosinophilic inflammation, such as eosinophilic pneumonia, followed by small-vessel vasculitis and glomerulonephritis. Peripheral eosinophilia is typical and most commonly antimyeloperoxidase ANCA is found in a minority of patients. This diagnosis is suspected in patients with chronic asthma, fever, and eosinophilia and is confirmed by skin, renal, or lung biopsy showing eosinophilic infiltration of granuloma and vasculitis.

MPA is a pauci-immune necrotizing vasculitis that predominantly affects small vessels and is characterized by pulmonary alveolar capillaritis and glomerulonephritis, seen in almost all patients. Other manifestations, such as purpuric rash, arthralgia/arthritis, and abdominal pain, are also common in pediatric patients. Most patients have antimyeloperoxidase ANCA. To make a diagnosis of MPA, GPA or EGPA should be ruled out.

Introduction

Childhood vasculitis is a complex and fascinating area in pediatric rheumatology that has experienced an unprecedented surge in research, leading to new knowledge over the past several years. Vasculitis is defined as the presence of inflammatory cell infiltration in blood vessel walls, usually with multisystemic involvement. Some forms of vasculitis have an abrupt onset, whereas others are very insidious leading to delayed diagnosis. Some vascular lesions can cause aneurysm formation, whereas others can cause stenosis or occlusion, resulting in ischemia, infarction, hemorrhage, and organ failure.

Vasculitis is difficult to classify and the most acceptable childhood vasculitis classification defines the type of vasculitis according to the size of the vessel affected.

The pathogenic mechanisms of the different forms of vasculitis include presence of circulating immune complexes, disturbance in humoral immune response manifested by the presence of antibodies, antineutrophil cytoplasmic autoantibodies (ANCA), and antiendothelial cells; antibodies against antigens in vessel walls; and disturbance in cellular immune response with T-cell reactivity. Complement, cytokines, cell adhesion molecules, chemokines, growth factors, and neutrophils are involved in the immunologic processes of the systemic vasculitis. Host susceptibility and environmental triggers play a role in these diseases.

Clinical features suggesting vasculitis include constitutional symptoms, such as fever, weight loss, fatigue, skin lesions, neurologic manifestations, arthralgia, arthritis, myalgia, myositis, serositis, arterial hypertension, and lung and renal involvement with infiltration and hemorrhage. High acute-phase reactants, anemia, leukocytosis with eosinophilia, antibodies, such as antineutrophil cytoplasmic antibodies, and altered urinary sediment are common laboratory features in vasculitis. Because of the nonspecific features, some forms of vasculitis are not recognized and their prevalence might be underestimated.

Diagnosis can be difficult, evaluating disease activity is problematic, and outcome in some cases can be poor.

The most frequent forms of vasculitis in childhood are the small-size vasculitides, of which Henoch-Schoenlein Purpura (HSP) and other leucocytoclastic vasculitis are the best examples, followed by Kawasaki disease, a midsize vasculitis, and Takayasu arteritis, a large-size vasculitis, both of which are topics in this article. Other forms of vasculitis include midsize vasculitis, such as polyarteritis nodosa (PAN), small-size vasculitis, subdivided into granulomatous disease (granulomatosis with polyangiitis [GPA] or Wegener granulomatosis and eosinophilic granulomatosis with polyangiitis [EGPA], or Churg-Strauss syndrome) and nongranulomatous disease (microscopic polyangiitis [MPA]) and vasculitis affecting various-sized vessels like Behçet disease.

HSP is an IgA immune complex–mediated vasculitis that affects small vessels, with the main characteristics of purpuric rash, followed by arthralgia/arthritis, abdominal pain, and nephritis. The typical histopathologic feature in the acute inflammatory lesions is perivascular accumulation of neutrophils, known as leucocytoclastic vasculitis. HSP is often a self-limited condition that involves skin, joint, and gut, but approximately 40% of patients develop nephritis within 4 to 6 weeks after the skin involvement, and depending on severity may lead to poor disease outcome. Disturbance in the immune system, including elevations in serum levels of immunoglobulin (Ig)A1 and IgA1-containing circulating immune complexes have been detected in patients with HSP. Although the pathogenetic mechanisms are still not fully delineated, several studies suggest that galactose-deficient IgA1 (Gd-IgA1), which is increased in patients with HSP with nephritis, is recognized by antiglycan antibodies, leading to the formation of the circulating immune complexes and their mesangial deposition, resulting in renal injury. Furthermore, serum levels of alpha–smooth muscle actin and C-Met were found to be higher in patients with HSP than those in the immunoglobulin-A nephropathy and healthy control groups and correlated with blood urea nitrogen levels, serum creatinine levels, hematuria, and proteinuria and may be associated with disease severity.

Polyarteritis nodosa (PAN) is a chronic vasculitis that rarely occurs in childhood, although in some studies it appears to be the third-most common form of vasculitis after HSP and KD. It is a necrotizing form of vasculitis associated with aneurysmal nodules along the walls of the medium-sized muscular vessels, which can be divided into systemic PAN, involving the skin and the gastrointestinal, renal, and central nervous systems, and in cutaneous PAN, a form limited to the skin. The main clinical features of systemic PAN are malaise, fever, weight loss, skin lesions, myalgia, arthropathy, abdominal pain, and testicular involvement, which are often associated with hypertension, proteinuria, and hematuria, secondary to renal artery involvement. Neurologic features, such as focal defects, mononeuritis multiplex, and psychosis may be present. The skin lesions are variable and may range from erythematous rash to necrotic lesions with peripheral gangrene, but livedo reticularis and nodules overlying affected arteries are characteristic features of this disease. Cutaneous PAN is characterized by the presence of painful subcutaneous nodules with or without other lesions, and no systemic involvement, except for myalgia, arthralgia, and nonerosive arthritis. In this type of PAN, serologic or microbiological evidence of streptococcal infection is common. There is controversy as to whether this is a separate entity or part of the systemic PAN spectrum. High acute-phase reactants are usually present in the active phase of both types. Positive hepatitis B serology is an unusual association with PAN in children. In a single-center retrospective study, gastrointestinal involvement was associated with increased risk of relapse, whereas longer time to induce remission and an increased cumulative cyclophosphamide dose were associated with lower risk of relapse. To make a diagnosis for patients whose symptoms suggest cutaneous PAN, a skin biopsy demonstrating necrotizing nongranulomatous medium-sized and small-sized vessel vasculitis is necessary. Patients with symptoms of systemic PAN require an angiogram, which typically shows aneurysms or stenoses/occlusions in medium-sized arteries or a biopsy of the affected organ. Although prognosis has dramatically improved, PAN remains a life-threatening form of systemic vasculitis and late morbidity can occur years after childhood onset from chronic vascular injury.

ANCAs are a heterogeneous group of autoantibodies associated with certain forms of vasculitis characterized by necrotizing inflammation with a paucity of immunoglobulin in the vessel wall detectable by immunohistologic methods. The genesis of the ANCA autoimmune response is a multifactorial process that includes genetic predisposition, environmental factors, an initiating antigen, and failure of T-cell regulation. ANCAs activate primed neutrophils and monocytes by binding to certain antigens expressed on the surface of neutrophils. ANCA-associated vasculitis (AAV) predominantly affects small vessels in any organ of the body, and most patients with AAV have systemic disease that can be classified on the basis of clinical and pathologic features as MPA, GPA, or EGPA. GPA is the most frequent AAV in childhood, characterized by the hallmark triad of granulomatous inflammation of upper and lower respiratory tracts and necrotizing pauci-immune glomerulonephritis. In a cohort of 117 children with GPA and other ANCA-associated vasculitides, most children presented with GPA and the most frequent clinical features were constitutional; ear, nose, and throat; pulmonary; and renal involvement. Almost all patients present with cytoplasmic immunofluorescence staining pattern and positive antiproteinase 3 (PR-3). The diagnosis is based on the combination of pulmonary and renal vasculitis, presence of serologic markers, especially antibodies to PR-3, and characteristic histopathologic findings, like pauci-immune granulomatous inflammation of predominantly small-vessel or pauci-immune glomerulonephritis. At onset, nonspecific complaints of fever, malaise, and weight loss are very common. Prognosis depends in part on the stage of disease at diagnosis and at least 50% of patients relapse within 5 years despite treatment. EGPA, a rare disease in children, is characterized by a nonvasculitic prodrome of asthma and eosinophilic inflammation, such as eosinophilic pneumonia, followed by small-vessel vasculitis and glomerulonephritis. Peripheral eosinophilia is typical and most commonly antimyeloperoxidase ANCA is found in a minority of patients. This diagnosis is suspected in patients with chronic asthma, fever, and eosinophilia and is confirmed by skin, renal, or lung biopsy showing eosinophilic infiltration of granuloma and vasculitis.

MPA is a pauci-immune necrotizing vasculitis that predominantly affects small vessels and is characterized by pulmonary alveolar capillaritis and glomerulonephritis, seen in almost all patients. Other manifestations, such as purpuric rash, arthralgia/arthritis, and abdominal pain, are also common in pediatric patients. Most patients have antimyeloperoxidase ANCA. To make a diagnosis of MPA, GPA or EGPA should be ruled out.

Kawasaki disease

Kawasaki disease (KD) is a necrotizing arteritis that affects small-size and medium-size arteries. KD is the second-most common systemic vasculitis in childhood and is an important cause of acquired heart disease. The disease is acute and self-limiting and occurs most commonly in children younger than 5 (peak incidence between 6 and 12 months), in males, and individuals of Asian descent.

Clinical Presentation

Generally, the onset of KD is acute and can be divided into 3 phases: acute (febrile, 10 days), subacute (2–4 weeks, ending with the normalization of platelet counts), and chronic or convalescent (months).

The fever is usually high, persistent, and lasts for at least 5 days. The fever does not respond to antibiotics but may respond partially to antipyretics. If untreated, the febrile phase lasts 5 to 20 days, averaging 10 days, followed by a spontaneous resolution even in the absence of specific treatment.

A skin rash usually accompanies the fever throughout the acute phase of the disease. The rash is polymorphic, nonitchy, and can vary over time. Typically, the rash is localized to the trunk but can also involve the extremities and perineum. The rash can be scarlatiform, macular, papular, multiform, or purpuric. The lesions in the extremities include red purpuric erythema on the palms and soles, usually accompanied by painful soft tissue swelling of the dorsum of the hands and feet. The typical peeling (“glove finger”) starts at the fingertips and toes and spreads across the entire palm or sole and can also occur in the perineum ( Fig. 1 ). Such changes are more evident after 15 days and can last for weeks.

Typical peeling (“glove finger”).

The mucosal changes occur during the febrile period and include labial and oropharyngeal erythema, sometimes with strawberry tongue ( Fig. 2 ). The most common changes are red, shiny, swollen, and cracked lips. Nonpurulent bilateral conjunctivitis is also quite characteristic ( Fig. 3 ). Nail changes (Beau lines) can occur 1 to 2 days after the fever onset.

Labial erythema and strawberry tongue.

Nonpurulent bilateral conjunctivitis.

Cervical lymphadenopathy, usually unilateral and greater than 1.5 cm in diameter, is the least characteristic and most infrequent clinical manifestation ( Fig. 4 ).

Cervical unilateral lymphadenopathy.

Compromised cardiac function is the most serious manifestation of KD and is the main cause of mortality and morbidity. Congestive heart failure may occur secondary to myocarditis or myocardial infarction, in addition to pericarditis, endocarditis, or arrhythmias. Aneurysms or coronary artery ectasia are often clinically silent and can be diagnosed years after the acute phase of the disease when the patient presents with myocardial infarction or sudden death. Arterial thrombosis with vessel occlusion can also occur. The coronary aneurysms require echocardiography or angiography for diagnosis. Brachial, axillary, iliac, femoral, and renal artery aneurysms can be observed by angiography.

In addition to these findings, symptoms of KD can include the following: arthralgia/arthritis, aseptic meningitis, facial nerve paralysis, irritability, sensorineural hearing loss, otitis media, interstitial pneumonitis, gastroenteritis, hydropic gallbladder, dysuria and urethritis, Raynaud phenomenon, peripheral gangrene, anterior uveitis, and abdominal pain. Changes in the Bacillus Calmette–Guérin (BCG) vaccine scar with local induration are suggestive of the disease. Younger children tend to exhibit atypical presentations and develop aneurysms more frequently.