Etiology and Pathogenesis

The underlying cause of vasculitis has yet to be elucidated; however, similar to many chronic diseases, there is likely a complex interplay of genetic and environmental factors. Some theories suggest that the inflammation is attributable to the involvement of humoral factors, as seen in the antineutrophil cytoplasmic antibodies (ANCA)–associated vasculitides. Others suggest abnormal regulation of immune complex formation is contributory, as in HSP. Lymphocyte involvement has also been implicated, specifically T-regulatory cell dysfunction. Additionally, antecedent infections, particularly streptococcal infections, have been suggested as a cause in many of the vasculitides such as HSP, Wegener’s granulomatosis, and polyarteritis nodosa (PAN).

Classification

Vasculitis can be classified based on the involvement of primarily large, medium, or small vessels (Figure 28-1). In addition, certain vasculitides have a predilection for arteries, veins, or both. The vasculitides can be further classified as granulomatous or nongranulomatous. The granulomatous diseases include Takayasu arteritis, Wegener’s granulomatosis, and Churg-Strauss syndrome (see Chapter 30). The nongranulomatous vasculitides include PAN, KD, microscopic polyangiitis, HSP, cutaneous leukocytoclastic vasculitis, and essential cryoglobulinemic vasculitis.

Figure 28-1 Distribution of specific vasculitis syndromes.

Clinical Presentation

Vasculitis often presents with vague symptoms and multiorgan involvement. Nonspecific systemic features may include prolonged fever without any clear source, hypertension, fatigue, malaise, weight loss, and rash. As a consequence, the diagnosis is often delayed and requires a high index of suspicion. Definitive diagnosis often relies on imaging (angiography) and tissue biopsy. The history should include questions about recent infections, medication exposures, and a detailed family history.

Certain patterns of clinical symptoms and organ involvement may be suggestive of a specific vasculitis (Box 28-1). For example, whereas palpable purpura, arthralgias, abdominal pain, and renal disease suggest HSP, persistent fever, conjunctivitis, cervical lymphadenopathy, extremity swelling, mucocutaneous changes, and rash suggest KD (see below). Microscopic polyangiitis is associated with high titers of pANCA (protoplasmic-staining antineutrophil cytoplasmic antibodies) and affects mainly the pulmonary and renal systems. Hypersensitivity vasculitis is a necrotizing vasculitis that presents with a papular rash that may be red or blistering and is often associated with infection or medication exposure. Hypocomplementemic urticarial vasculitis presents with urticarial skin lesions and low serum complement levels of C4 and C3. Behçet’s disease is a unique systemic vasculitis that affects both arteries and veins. The classic triad of Behçet’s disease includes oral ulcers, uveitis, and genital ulcers; however, any organ system can be affected.

PAN is a necrotizing vasculitis affecting the medium-sized arteries and can present with systemic disease or in a limited form that only involves the skin and joints. It occurs in school-aged children, and there is typically a history of a preceding upper respiratory infection or streptococcal pharyngitis. In unvaccinated children, hepatitis B can be causative. Symptoms include prolonged fevers, malaise, calf pain, testicular pain, and weight loss. Physical examination findings include painful nodules (particularly on the feet), livedo reticularis (see Figure 29-2), myalgias, and arthritis of large joints. In the systemic form, any organ system can be affected; thus, hypertension, renal abnormalities, gastrointestinal involvement, and coronary disease can be seen. Of the large vessel diseases, temporal arteritis is not seen in childhood. Takayasu arteritis, the third most common childhood vasculitis, preferentially affects the large branches of the aorta. Examination may reveal bruits, hypertension, and absent pulses.

Evaluation and Management

Henoch Schönlein Purpura

HSP is the most common vasculitis in childhood (Figure 28-2). It is a leukocytoclastic vasculitis (leukocytes infiltrate the vessel walls and cause necrosis) predominantly affecting the small blood vessels. The classic triad is described as nonthrombocytopenic palpable purpura, arthritis, and abdominal pain. The most feared long-term morbidity of HSP is chronic renal disease. It affects boys more often than girls and most cases occur in winter and spring. Although HSP can affect adults, the peak age of onset is between 3 and 15 years.

Figure 28-2 Signs and symptoms of Henoch-Schönlein purpura.

The pathophysiology of HSP is associated with immunoglobulin A (IgA) deposition; circulating IgA forms immune complexes and activates the alternative complement pathway. IgA is then deposited in affected organs and small vessels, resulting in inflammation. In more than 75% of cases, there is a history of preceding upper respiratory illness, and many organisms have been implicated, including group A Streptococcus. HSP has also been seen after administration of vaccines and medications.

There are proposed classification criteria to guide the diagnosis of pediatric HSP (Box 28-1). The purpuric rash has raised, nontender, nonpruritic, deep red to purple lesions that are most often found in dependent areas such as the buttocks and lower extremities (with most crops at the feet and ankle area). However, they can also be on the face, trunk, and upper extremities. Abdominal pain occurs in approximately two-thirds of patients. More severe gastrointestinal symptoms include gastrointestinal hemorrhage and intussusception. Rare gastrointestinal complications include pancreatitis and ulcerative colitis. Up to 25% of children may have abdominal symptoms of HSP before the onset of rash, making the diagnosis a challenge. Arthritis affects 50% to 80% of children with HSP. It usually affects large joints, such as the knee or ankle, but small joints can also be involved. It is often painful but not usually erosive. Fortunately, the arthritis of HSP is usually transient, lasting a few days to 1 week. Renal manifestations are seen in about one-third of patients with HSP. Symptoms range from microscopic hematuria or proteinuria to acute renal failure. Of the children who develop renal involvement, most do so within the first 3 months of disease.

Laboratory findings in HSP are typically nonspecific. Evaluation should include a CBC (thrombocytopenia indicates an alternative diagnosis), electrolytes (to assess for renal insufficiency), and a urinalysis (to check for blood or protein). Complement levels are normal, and ANA and ANCA are not found. Blood pressure is also important to monitor both at diagnosis and throughout the acute phase of illness. Renal biopsy may be warranted to determine the severity of renal disease.

The prognosis for patients with mild manifestations is very good. In general, nonsteroidal antiinflammatory drugs are used for the arthralgias of HSP. Corticosteroids have been shown to be useful in HSP with regards to abdominal and renal manifestations. Recurrences are seen in up to one-third of children, usually within 4 to 6 months of initial diagnosis, and more often in patients with renal involvement. Long-term morbidity usually depends on the severity of renal disease, with worse disease predicting worse outcome.

Kawasaki Disease

KD is the second most common vasculitis seen in children (Figure 28-3). It is considered an acute vasculitis of medium-sized arteries. The peak age of onset is 2 years old, with 80% to 90% of cases occurring in children younger than 5 years old. Unlike most vasculitides, it is more common in boys than girls (about 1.5 : 1), and it has a higher incidence in the Japanese and Korean populations. Although the cause of KD is unknown, studies have suggested a transmissible agent causing a dysfunctional immune response; however, a specific agent has yet to be discovered.

Figure 28-3 Clinical features of Kawasaki disease.

Diagnosis is based on clinical criteria (Table 28-2). The fever, which is usually greater than 38.5°C, must be present for more than 5 days. It is typically minimally responsive to antipyretic medications. The conjunctivitis is nonexudative and limbic sparing. In some cases, patients can develop anterior uveitis, so a slit-lamp examination may be helpful if the diagnosis is unclear. Oral mucous membrane changes occur with continued inflammation and may include dry, red, cracked lips, a “strawberry” tongue; and pharyngitis. Swelling or erythema of the hands and feet usually occurs late in the acute phase. During the convalescent phase, desquamation of the tips of the toes and fingers may be noticeable. A transient arthritis is noted in about one-third of patients and can involve large or small joints. The rash of KD is nonspecific and ranges from erythema at the perineal area or a morbilliform exanthem on the trunk or extremities. Vesicular or pustular lesions are not typical. The final criterion is lymphadenopathy, which is usually the least common finding of KD.

Table 28-2 Kawasaki Disease Diagnostic Criteria

The laboratory evaluation for KD should include a CBC (there is often marked thrombocytosis, sometimes >1 million platelets/microliter), inflammatory markers (ESR and CRP), complete metabolic panel, urinalysis (sterile pyuria can be seen), and tests to exclude infection (adenovirus and Epstein-Barr virus may be present in a similar fashion). Complement and ANA levels are usually normal.

When the diagnosis of KD is suspected based on the clinical examination, electrocardiography and echocardiography must be performed because coronary abnormalities are the major cause of morbidity and mortality in this disease. If an echocardiogram shows evidence of coronary aneurysm, a diagnosis of KD can be made even if the patient has fewer than four criteria. In fact, the population most at risk for coronary abnormalities is infants, who usually do not meet the criteria for classic KD. The echocardiogram is repeated 6 to 8 weeks after diagnosis to monitor the patient’s response to treatment.

After a diagnosis is made, treatment must be initiated because early intervention (within 10 days of onset of fever) has been shown to decrease the occurrence of coronary artery aneurysms by fivefold. Treatment consists of intravenous immunoglobulin (2 g/kg) and high-dose aspirin (80-100 mg/kg/d). Low-dose aspirin is started when the patient has been afebrile for 48 hours. Aspirin therapy is discontinued after inflammatory markers and platelet count have normalized unless there is evidence of coronary artery disease.

The overall outcome for KD is excellent in the majority of patients without cardiac involvement. Because of the monocyclic nature of the disease, most patients have a full recovery. Of patients who develop coronary artery abnormalities, lifelong cardiology monitoring is needed because of the increased risk of heart disease.

Future Directions

Vasculitis is a rare childhood condition but should be considered in any child with unexplained constitutional symptoms, significant inflammation, and multiorgan involvement. Newer biologic agents are promising, but large-scale studies of these agents have not been performed in children. Given the rarity of these conditions, large clinical trials are extremely challenging to conduct. Instead, the development of patient registries is likely the key to being able to study these diseases in children in a systemic fashion.