Childhood vasculitis is a challenging and complex group of conditions that are multisystem in nature and often require integrated care from multiple subspecialties, including rheumatology, dermatology, cardiology, nephrology, neurology, and gastroenterology. Vasculitis is defined as the presence of inflammation in the blood vessel wall. The site of vessel involvement, size of the affected vessels, extent of vascular injury, and underlying pathology determine the disease phenotype and severity. This article explores the classification and general features of pediatric vasculitis, as well as the clinical presentation, diagnostic evaluation, and therapeutic options for the most common vasculitides.
Childhood vasculitis is a challenging and complex group of conditions that are multisystem in nature and often require integrated care from multiple subspecialties, including rheumatology, dermatology, cardiology, nephrology, neurology, and gastroenterology. Vasculitis is defined as the presence of inflammation in the blood vessel wall. The site of vessel involvement, size of the affected vessels, extent of vascular injury, and underlying pathology determine the disease phenotype and severity. Vasculitis can be secondary to infection, malignancy, drug exposure, and other rheumatic conditions, such as systemic lupus erythematosus and juvenile dermatomyositis. This article explores the classification and general features of vasculitis, as well as the clinical presentation, diagnostic evaluation, and therapeutic options for the most common primary systemic vasculitides.
Diagnosis
Making the diagnosis of vasculitis is often challenging, as presenting symptoms may be subacute, nonspecific, and nondiagnostic. Fever, malaise, diffuse pain, and laboratory evidence of elevated acute-phase reactants may be the only early symptoms to suggest systemic inflammation. As vessel damage evolves, more specific clinical features, such as a purpuric rash, evidence of organ involvement, such as glomerulonephritis, or detection of certain antibodies, such as antineutrophil cytoplasmic antibodies (ANCA), may heighten the suspicion of vasculitis. The presenting symptoms can vary widely depending on the size and location of involved vasculature.
If vasculitis is suspected, then a thorough history and physical examination are paramount. The history should include recent infections, drug exposure, and a detailed family history. The physical examination should include a 4-extremity blood pressure evaluation. Takayasu arteritis (TA) may present with a blood pressure difference of greater than 10 mm Hg between arms, and hypertension is common with many of the vasculitides. In addition, careful auscultation for bruits (carotid, axillary, aortic, renal, and iliac vessels) and palpation of peripheral pulses is essential. Absent peripheral pulses may help identify areas of vessel involvement. A thorough skin examination is also important; the presence of painful nodules, purpura, ulcerations, microinfarctions, or livedo reticularis is common. A neurologic examination should evaluate for peripheral neuropathy; polyarteritis nodosa (PAN) is associated with mononeuritis multiplex. A fundoscopic examination and nailfold capillaroscopy are also helpful to visualize small vessel abnormalities.
The laboratory evaluation for vasculitis should include a complete blood count and acute phase reactants, such as the erythrocyte sedimentation rate and C-reactive protein, which can be markedly elevated. Liver enzymes, blood urea nitrogen and creatinine, and urinalysis will evaluate for hepatic and renal involvement. Specific antibody testing, such as antinuclear antibodies and ANCA, and complements should be sent depending on the vasculitis being considered. When clinical suspicion is high, imaging, such as computed tomography (CT) angiography, magnetic resonance (MR) angiography, or conventional angiography may help detect blood vessel abnormalities. Imaging may demonstrate prototypical patterns of vessel involvement, such as beading and aneurysms in PAN and TA, respectively. Typically, imaging is most useful when there is suspicion for medium-vessel or large-vessel disease. The diagnostic gold standard for diagnosis, however, is tissue biopsy.
Classification
Primary vasculitis can be classified according to clinical manifestations, size of the affected vessels, or histopathology, including the presence or absence of granuloma. In 2005, the European League Against Rheumatism (EULAR) and the Pediatric Rheumatology European Society (PReS) developed the first pediatric-specific classification of vasculitis ( Box 1 ). This classification system is primarily based on size of affected vessels and the presence or absence of granuloma.
Vasculitis category
Predominately large vessel
Takayasu arteritis
Predominately medium vessel
Childhood polyarteritis nodosa
Cutaneous polyarteritis
Kawasaki disease
Predominately small vessel
Granulomatous
Wegener granulomatosis a
Churg-Strauss syndrome
Nongranulomatous
Microscopic polyangiitis
Henoch-Schönlein purpura
Isolated cutaneous leucocytoclastic vasculitis
Hypocomplementemic urticarial vasculitis
Other
Behçet disease
Vasculitis secondary to infection, malignancy, drugs
Vasculitis associated with connective tissue disease
Isolated vasculitis of the central nervous system
Cogan syndrome
Unclassified
a Granulomatosis with polyangiitis.
Classification
Primary vasculitis can be classified according to clinical manifestations, size of the affected vessels, or histopathology, including the presence or absence of granuloma. In 2005, the European League Against Rheumatism (EULAR) and the Pediatric Rheumatology European Society (PReS) developed the first pediatric-specific classification of vasculitis ( Box 1 ). This classification system is primarily based on size of affected vessels and the presence or absence of granuloma.
Vasculitis category
Predominately large vessel
Takayasu arteritis
Predominately medium vessel
Childhood polyarteritis nodosa
Cutaneous polyarteritis
Kawasaki disease
Predominately small vessel
Granulomatous
Wegener granulomatosis a
Churg-Strauss syndrome
Nongranulomatous
Microscopic polyangiitis
Henoch-Schönlein purpura
Isolated cutaneous leucocytoclastic vasculitis
Hypocomplementemic urticarial vasculitis
Other
Behçet disease
Vasculitis secondary to infection, malignancy, drugs
Vasculitis associated with connective tissue disease
Isolated vasculitis of the central nervous system
Cogan syndrome
Unclassified
a Granulomatosis with polyangiitis.
Epidemiology and pathogenesis
The annual incidence of primary vasculitis in children and adolescents younger than 17 years is approximately 23 per 100,000. Primary vasculitis accounts for approximately 2% to 10% of all pediatric conditions evaluated in pediatric rheumatology clinics. Of the primary vasculitides, Henoch Schönlein purpura (HSP) and Kawasaki disease (KD) are the most common, accounting for 49% and 23% of all childhood vasculitis, respectively. The prevalence of diseases may be different based on the population studied. For example, the incidence of KD and Behçet’s disease is higher in Asian and Turkish children, respectively, than in other ethnicities.
These ethnic differences in prevalence suggest that genetics and environment may play an important role in disease susceptibility and pathogenesis. Other theories of pathogenesis include humoral factors, as manifest by ANCA-associated vasculitides. Abnormal regulation of immune complex formation may be contributory, as in HSP. Impaired lymphocyte regulation, specifically T-regulatory cell dysfunction, may also be involved. Antecedent infections, particularly streptococcal infections, have been implicated in many of the vasculitides including HSP, granulomatosis with polyangiitis (GPA), and PAN.
Henoch Schönlein Purpura
Etiology and epidemiology
HSP is a leukocytoclastic vasculitis that predominantly affects the small blood vessels. It is also known as anaphylactoid purpura or purpura rheumatica. The EULAR/PReS classification criteria are listed in Box 2 . Among children younger than 17 years, the annual incidence of HSP is approximately 20 per 100,000 and the peak age of onset is between 4 and 6 years. Caucasians have the highest incidence and African Americans have the lowest incidence. Unlike most vasculitides, males are affected more commonly than females, with a ratio of approximately 2 to 1. Certain autoimmune risk factors, such as complement deficiencies, and hereditary fever syndromes, such as Familial Mediterranean Fever syndrome, may predispose a child to HSP. HSP is most prevalent during the winter and spring. This seasonal distribution supports the hypothesis that an infectious agent triggers this condition. Group A β–hemolytic streptococcus, Staphylococcus aureus, influenza, parainfluenza, Epstein-Barr virus, adenovirus, parvovirus, and mycoplasma have all been reported as triggers for HSP.
Purpura or petechiae with lower limb predominance and at least 1 of the following:
- 1.
Arthritis or arthralgias
- 2.
Abdominal pain
- 3.
Histopathology demonstrating immunoglobulin A deposition
- 4.
Renal involvement (hematuria or proteinuria)
Clinical presentation
The classic presentation of HSP includes lower-extremity purpura, arthritis, abdominal pain, and renal disease. The purpuric rash is usually on dependent areas but may be seen on the arms, face, and ears ( Fig. 1 A). The purpura may be preceded by a maculopapular or urticarial rash that usually disappears within 24 hours. The rash may appear as bullae, necrotic lesions (see Fig. 1 B), or deep bruising (see Fig. 1 C).
Arthritis affects three-quarters of children, and the most commonly affected joints are the knees and ankles. The arthritis is usually oligoarticular, self-limited, and nondestructive. It is the presenting symptom in 15% of patients.
The gastrointestinal (GI) manifestations of HSP affect 50% to 75% of children and may include bleeding, intussusception, and abdominal pain. GI manifestations may precede the purpura by up to 2 weeks in as many as 20% of children. Intestinal bleeding, manifested as gross or occult blood per rectum, occurs in approximately one-third of children. Intussusception occurs in 1% to 5% of children and is mostly ileo-ileal in location.
Renal disease affects 20% to 60% of children, and the most common manifestation is microscopic hematuria with or without proteinuria. Renal disease rarely precedes the onset of rash. Children may present with nephritic or nephrotic syndrome, or rarely renal failure. Most children who develop renal disease do so within the first 6 weeks and 97% within 6 months. In longitudinal studies of unselected patients, the risk of chronic renal impairment and end-stage renal disease is 2% to 15% and less than 1%, respectively.
Unusual clinical manifestations of HSP may include edema of scrotum, eyes, or hands; pulmonary hemorrhage; seizures; stroke; and mental status changes. The mean duration of symptoms is 3 to 4 weeks and up to one-third of children have at least 1 recurrence.
HSP must be distinguished from other causes of purpura in childhood, including acute hemorrhagic edema of infancy, immune thrombocytopenic purpura, acute poststreptococcal glomerulonephritis, hemolytic-uremic syndrome, disseminated intravascular coagulation, infections, and hypersensitivity vasculitis. Hypersensitivity vasculitis is also known as cutaneous leukocytoclastic vasculitis and microscopic polyarteritis. It typically affects the small vessels and is idiopathic or triggered by infection or drug exposure. Clinical manifestations include urticaria, purpura, or a maculopapular rash, arthralgias, hypocomplementemia, and elevated inflammatory markers ( Fig. 2 ).
Treatment
Therapy for mild HSP cases is primarily supportive, with analgesics and nonsteroidal anti-inflammatory drugs. Current literature, however, supports the notion that in the hospital setting, early use of corticosteroids for HSP is associated with improved outcomes, particularly GI comorbidities. In more severe hospitalized cases, pulse methylprednisolone (30 mg/kg up to 1 g) may be warranted. The optimal dose and duration of corticosteroids has not been well studied. In some cases, oral corticosteroid doses of 2 mg/kg per day may be adequate; however, too short a course of corticosteroids or a rapid tapering of corticosteroids may precipitate a flare of symptoms. Corticosteroid treatment for mild cases of HSP remains controversial. A meta-analysis of 15 studies of patients with HSP treated at diagnosis with corticosteroids versus supportive care revealed that corticosteroid treatment significantly reduced the mean resolution time of abdominal pain and reduced the odds of developing persistent renal disease. In a 6-month prospective clinical trial of 223 children, prednisone was effective in reducing the severity of abdominal and joint pain and in treating renal disease ; however, in that same study, prophylaxis with prednisone did not prevent the development of nephritis. In life-threatening cases or acute renal failure, plasmapheresis followed by a more potent immunosuppressive agent, such as cyclophosphamide, azathioprine, or cyclosporine, should be considered.
Kawasaki Disease
Etiology and epidemiology
KD is the second most common childhood vasculitis, accounting for 23% of all vasculitides. It affects primarily medium-sized blood vessels and is also known as mucocutaneous lymph node syndrome. The EULAR/PReS classification criteria for KD are listed in Box 3 . Fewer than 4 criteria are required if there are characteristic coronary artery changes and fever ; 90% of cases occur in children younger than 5 years. In the United States, the annual incidence in children younger than 5 years is 20 per 100,000. The incidence is higher among children who live in eastern Asia, at 100 per 100,000 in Japan and 69 per 100,000 in Taiwan. Similar to HSP, KD is more common in boys. Children younger than 6 months are more likely to have atypical features and to develop coronary aneurysms. The cause of KD remains unknown, although bacterial and viral infections, superantigens, genetics, and humoral factors, such as antiendothelial cell antibodies, ANCA, and circulating immune complexes may be involved.
Fever that persists for at least 5 days plus at least 4 of the following:
- 1.
Bilateral conjunctival injection
- 2.
Changes of the lips and oral cavity
- 3.
Cervical lymphadenopathy
- 4.
Polymorphous exanthem
- 5.
Changes in the peripheral extremities or perineal area
Clinical presentation
KD is a triphasic disease consisting of an acute febrile period that lasts up to 14 days, a subacute phase of 2 to 4 weeks, and a convalescent phase that can last months to years. The acute period is characterized by a persistent and high (>38.5° C) fever. The fever is typically minimally responsive to antipyretics. The fever is likely related to elevated concentrations of proinflammatory cytokines, particularly interleukin-6 and tumor necrosis factor alpha (TNF-α). Conjunctivitis affects 85% of children and is bilateral, nonexudative, and limbic sparing. Other ocular symptoms include anterior uveitis, keratitis, papilledema, vitreous opacities, and subconjunctival hemorrhages ( Fig. 3 A). Oral mucosal changes may include dry and cracked lips and strawberry tongue. Cervical adenopathy is the least common of the diagnostic criteria, detectable in 25% of children. The adenopathy is usually unilateral and limited to the anterior cervical chain (see Fig. 3 B). Diffuse lymphadenopathy is unusual. The rash associated with KD is typically nonpruritic, macular, or target lesions on the trunk and extremities. A perineal rash that desquamates by the end of the first week is common. Early extremity changes include diffuse erythema of the palms and soles and swelling of the dorsum of the hands and feet (see Fig. 3 C); these changes usually last for fewer than 3 days. Sheetlike desquamation on the fingers and toes occurs toward the end of the acute phase.
