Vasculitis and Thrombophlebitis

Practitioners may find it helpful to think of primary systemic vasculitides based on the predominant size of the involved vessels, as suggested by the Chapel Hill Classification.[1, 2] See the image below.

Preferred sites of vascular involvement by selected vasculitides.

However, an overlap of vessel sizes affected within the diseases is noted, and the phenotype and pattern of organ involvement in vasculitis seems to be independent of vessel size. For example, Kawasaki disease is characterized by a mucocutaneous syndrome and coronary artery inflammation, whereas polyarteritis nodosa (PAN), another medium-vessel vasculitis, manifests with nodular skin lesions, neuropathy, and hypertension.

As such, the classification of childhood vasculitides incorporates both vessel size and organ manifestations. This classification was proposed at a consensus conference in 2005 and was endorsed by Paediatric Rheumatology European Society (PRES) and the European League against Rheumatism (EULAR). These criteria represent a modification and adaptation of existing American College of Rheumatology and Chapel Hill criteria for vasculitis in adults.

The predominantly large vessel vasculitis is Takayasu arteritis.

Predominantly medium-sized vessel vasculitis includes the following:

• Childhood polyarteritis nodosa

• Cutaneous polyarteritis

• Kawasaki disease

• Primary vasculitis of the CNS, angiography-positive primary angiitis of the CNS (PACNS)

Predominantly small vessel vasculitis is divided into granulomatous and nongranulomatous. Granulomatous includes the following:

• Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis)

• Churg-Strauss syndrome

Nongranulomatous includes the following:

• Microscopic polyangiitis

• Henoch-Schönlein purpura

• Isolated cutaneous leukocytoclastic vasculitis

• Hypocomplementemic urticarial vasculitis

• Primary vasculitis of the CNS, angiography-negative, small vessel PACNS

Other vasculitides includes the following:

• Behçet disease

• Antiglomerular basement membrane (GBM) antibody disease

• Vasculitis secondary to infection (including hepatitis B associated polyarteritis nodosa), malignancies, and drugs, including hypersensitivity vasculitis

• Vasculitis associated with connective tissue diseases

• Cogan syndrome

• Unclassified

Large-vessel vasculitides

Note that the main large vessel vasculitis that affects children is Takayasu arteritis, and that temporal arteritis is not seen in the pediatric population. Takayasu arteritis is characterized by transmural inflammation and evidence of intramural giant cells. It involves the aorta and its major branches. Characteristic clinical features are caused by stenotic large vessels and subsequently decreased blood supply to the organ systems. Classically, children present with claudication, absent peripheral pulses, blood pressure abnormalities, strokes, and features of internal organ ischemia. A literature review by Duarte et al found an estimated prevalence of stroke/transient ischemic attack in patients with Takayasu arteritis of almost 16%.[3]

Classification criteria for Takayasu arteritis includes angiographic abnormalities (conventional, CT, or MRI) of the aorta or its main branches (mandatory criterion), plus at least one of the following features:

• Decreased peripheral artery pulse and/or claudication of extremities

• Blood pressure difference of more than 10 mm Hg

• Bruits over aorta and/or its major branches

• Hypertension (related to childhood normative data)

Medium-vessel vasculitides

The most common childhood medium-vessel vasculitis is Kawasaki disease. It is a necrotizing vasculitis that has a predilection for the coronary arteries. Classic features include prolonged fever, mucocutaneous changes and lymphadenopathy. Other manifestations may include irritability, arthritis, and abdominal pain.

Classification criteria for Kawasaki disease include a fever persisting for at least five days (mandatory criterion) plus 4 of the following 5 features:

• Changes in peripheral extremities or perineal area

• Polymorphous exanthema

• Bilateral conjunctival injection

• Changes of lips and oral cavity (injection of oral and pharyngeal mucosa)

• Cervical lymphadenopathy

Childhood polyarteritis nodosa is a necrotizing vasculitis of medium-sized arteries and is recognized in distinct systemic and cutaneous forms.

Systemic polyarteritis nodosa involves all organ systems and the presentation widely varies.[4] Features include vasculitic skin lesions, hypertension, neuropathy, and myalgia. Note that renal involvement does not manifest as glomerulonephritis, as occurs with small-vessel disease. Unlike in adults, angiographic or biopsy evidence of vasculitis is required to make this diagnosis.

Classification criteria for childhood polyarteritis nodosa include a systemic illness characterized by the presence of either a biopsy finding that reveals small and mid-size artery necrotizing vasculitis or angiographic abnormalities (aneurysms or occlusions), plus at least 2 of the following:

• Skin involvement (eg, livedo reticularis, tender subcutaneous nodules, other vasculitic lesions)

• Myalgia or muscle tenderness

• Systemic hypertension, relative to childhood normative data

• Mononeuropathy or polyneuropathy

• Abnormal urine analysis and/or impaired renal function (glomerular filtration rate of < 50% normal for age)

• Testicular pain or tenderness

• Signs or symptoms suggesting vasculitis of any other major organ system (GI, cardiac, pulmonary, CNS)

Cutaneous polyarteritis nodosa is characterized by the presence of subcutaneous nodular, painful, nonpurpuric lesions with or without livedo reticularis and absence of systemic involvement. However, more than half of patients also have myalgia, arthralgia, and nonerosive arthritis. Cutaneous polyarteritis nodosa has been associated with serological or microbiological evidence of streptococcal infection in 40% of patients.[4]

Childhood PACNS is defined by clinical evidence of a newly-acquired focal or diffuse neurologic deficit plus angiographic or histologic evidence of CNS vasculitis, in the absence of a systemic condition associated with these findings. Two clinically and radiologically distinct types of childhood PACNS are noted: large-medium vessel (angiography-positive) and small vessel (angiography-negative). These have different clinical presentations (see Primary CNS Vasculitis of Childhood).

Small-vessel vasculitides

Henoch-Schönlein purpura is the most common vasculitis in children, and is associated with immunoglobulin A (IgA) immune deposition in small vessels. Presenting features include palpable purpura, abdominal pain (which may be associated with GI hemorrhage and/or intussusception), arthritis, and evidence of glomerulonephritis (hematuria, proteinuria).

Classification criteria for Henoch-Schönlein purpura include palpable purpura (mandatory criterion) in the presence of at least one of following 4 features:

• Diffuse abdominal pain

• Any biopsy finding that reveals predominant lgA deposition

• Arthritis or arthralgia (arthritis is acute in any joint)

• Renal involvement (any hematuria, proteinuria)

Antineutrophil cytoplasmic antibody (ANCA) positive small-vessel vasculitides are also seen in the pediatric population. Granulomatosis with polyangiitis (GPA) (formerly known as Wegener granulomatosis) is a granulomatous vasculitis that most commonly involves the sinopulmonary system but can involve any organ system. Presenting features may include purpuric rash, recurrent sinusitis, epistaxis, shortness of breath, and/or hemoptysis from alveolar hemorrhage. It is also commonly associated with a necrotizing glomerulonephritis that may cause significant renal impairment.[5] Patients with Wegener granulomatosis have a positive ANCA finding in 90% of cases, most frequently in a cytoplasmic pattern (c-ANCA), with antibodies against proteinase 3 (anti-PR3).[6]

Classification criteria for GPA include 3 of the following 6 features:

• Abnormal urinalysis findings (hematuria and/or significant proteinuria)

• Granulomatous inflammation on biopsy (If a kidney biopsy is done it characteristically shows necrotizing pauci-immune glomerulonephritis.)

• Nasal sinus inflammation

• Subglottic, tracheal, or endobronchial stenosis

• Abnormal chest radiography or CT findings

• PR3 ANCA or c-ANCA staining

Microscopic polyangiitis (MPA) is a necrotizing vasculitis associated with glomerulonephritis and pulmonary capillaritis. Presenting features include purpuric rash, proteinuria and/or hematuria, hemoptysis, CNS involvement, and arthralgias.[7] MPA is associated with ANCA, most commonly with a perinuclear pattern (p-ANCA) and antibodies against myeloperoxidase (anti-MPO).

Churg-Strauss syndrome (CSS) is an eosinophilic granulomatous vasculitis characterized predominantly by pulmonary involvement. Patients typically have a previous history of asthma, allergic rhinitis, and/or sinusitis. A characteristic feature is the finding of nonfixed pulmonary infiltrates. Eosinophilic infiltration results in multiorgan involvement, including neuropathy and cardiovascular disease (pericarditis).[8] ANCA positivity is seen in approximately 40% of patients, usually with an “atypical” or “indeterminate” pattern.

Isolated cutaneous leukocytoclastic vasculitis can be either primary (rarely) or secondary to various medications, infections, or collagen vascular disease.

Hypocomplementemic urticarial vasculitis is a cutaneous vasculitis that may result from primary hypocomplementemia or as part of a disease associated with low complement levels (eg, systemic lupus erythematosus).

Other vasculitides

Behcet disease involves vessels of all sizes. The diagnosis is made clinically in patients with recurrent oral ulcers who also have recurrent genital ulcers, uveitis, various skin lesions, and/or a positive pathergy test.

Anti-GBM antibody disease/Goodpasture syndrome is a type of vasculitis caused by deposition of anti-GBM antibodies in small vessels of lungs and kidneys. Goodpasture syndrome clinically manifests with rapidly progressive glomerulonephritis and/or pulmonary hemorrhage (pulmonary renal syndrome).

Thrombophlebitis refers to inflammation of a vein associated with the formation of a blood clot. This may arise due to an interaction of endothelial injury, stasis of blood, and a hypercoagulable state. Risk factors include intravenous catheter placement, immobilization, malignancy, inherited prothrombotic condition (eg, factor V Leiden, antithrombin III deficiency), antiphospholipid antibody syndrome, and Behçet disease. One study found vascular involvement in 14% of patients with Behçet disease, most commonly manifesting as superficial vein thrombophlebitis or deep vein thrombosis.[9]

Vessel inflammation occurs by various mechanisms in this heterogenous group of diseases. The histopathological pattern of inflammation is a characteristic feature of the vasculitis subtypes.

Lymphocytic/giant cell-mediated vasculitis

Takayasu arteritis and temporal arteritis (in adults) both involve large elastic arteries and share a similar histopathology. This form of vasculitis is T-cell dependent, and CD4+ T cells are the main players in the process. Dendritic cells within the arterial adventitia recruit and stimulate the CD4+ cells, which then activate the monocytes and macrophages that mediate oxidative injury of the vessel wall. Vascular lesions are characterized by a panarteritis with mononuclear infiltration of all layers of the arterial wall. Typically, activated T cells and macrophages are arranged in granulomas, and multinucleated giant cells are present. Often, the intimal layer is hyperplastic, leading to concentric occlusion of the lumen. Also, the end stage of giant-cell aortitis may be complicated by the formation and rupture of aneurysms.[10]

Necrotizing vasculitis

Kawasaki disease and polyarteritis nodosa are examples of necrotizing vasculitis. Possible etiologies in the case of Kawasaki disease include infectious agents and/or superantigen-mediated activation of lymphocytes. The inciting factors in polyarteritis nodosa are less well understood; however, in developing countries, it has been associated with hepatitis B or C. Pathologically, segmental transmural inflammation of muscular arteries is noted. Nodule (vascular narrowing) and aneurysm formation result from panmural fibrinoid necrosis. Note that aneurysmal dilatation of the arterial wall is a common feature of necrotizing vasculitis. Typically, immunofluorescence for immunoglobulin or complement deposition is negative.[11]

Antibody-mediated vasculitides

A review by Jennette and Falk discusses the scientific evidence showing that ANCA immunoglobulin Gs (IgGs) are involved in the pathogenesis of small vessel vasculitides such as GPA and MPA.[12]

ANCA antibodies are directed towards cytoplasmic proteins within neutrophils and monocytes (eg, PR3, MPO), which may also be expressed at the cell surface, particularly on stimulated cells. In vitro studies have shown that ANCA IgGs can directly activate neutrophils and monocytes by both Fc receptor engagement and direct Fab2 binding to antigen. These activated cells interact with endothelial cells via adhesion molecules and release inflammatory mediators, such as toxic granule enzymes and reactive oxygen metabolites that cause apoptosis and necrosis. In addition, anti-MPO IgG may activate MPO itself triggering an oxidative burst and resulting in severe endothelial damage. ANCA-activated neutrophils may release factors that activate the alternative complement pathway, which initiates an amplification loop that mediates the severe necrotizing inflammation of ANCA disease.[12]

In vivo studies also support this pathogenesis; for example, injection of mice with anti-MPO antibodies results in the development of necrotizing and crescentic glomerulonephritis and pulmonary capillaritis.[13]

A study that sought to assess clinical and B cell biomarkers to predict relapse after rituximab in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) using retreatment on clinical relapse strategy found that naïve B-lymphopenia may be a biomarker of disease activity in AAV.[14, 15]

Antibody deposition

Henoch-Schönlein purpura is generally characterized by the deposition of IgA antibodies in affected tissues. Histopathologically, the typical finding on skin biopsy is leukocytoclastic vasculitis, with perivascular accumulation of neutrophils and mononuclear cells. Immunofluorescence demonstrates IgA, C3, and fibrin in the walls of affected vessels, including the postcapillary venules within the dermis, and the endothelial and mesangial cells of the kidney. Elevated serum IgA and circulating IgA-containing immune complexes may be present in some patients. One study showed that galactose deficiency of O-linked glycans in the hinge region of IgA1 has been associated with Henoch-Schönlein purpura.[16]

In anti-GBM antibody disease, circulating antibodies bind to type IV collagen within the glomerular basement membrane. Immunofluorescence study of renal biopsies demonstrates linear deposition of IgG along the glomerular basement membrane. Pulmonary hemorrhage occurs when these antibodies have access to the alveolar basement membrane.

Secondary vasculitis

Infectious causes include the following:

• Tuberculosis

• Streptococcus

• Mycoplasma infections

• Syphilis

• HIV Infection

• Herpes simplex

• Varicella

• Epstein-Barr virus (EBV)

• Cytomegalovirus (CMV)

• Parvovirus B19

• Hepatitis B and C

• Candida albicans

Systemic rheumatic disease causes include the following:

• Systemic lupus erythematosus

• Sjogren syndrome

• Sarcoidosis

• Juvenile dermatomyositis

Inflammatory bowel disease is a cause.

Lemierre syndrome is an anaerobic suppurative thrombophlebitis of the internal jugular vein and is most commonly a complication of pharyngeal, dental, or mastoidal infection.

Hypocomplementemic urticarial vasculitis is also a cause.

Malignancy causes include the following:

• Leukemia

• Lymphoma

• Bronchopulmonary blastoma, angioblastoma (both rare)

Hypersensitivity vasculitis (leukocytoclastic vasculitis) and drug-induced ANCA vasculitis (propylthiouracil, hydralazine) are also both noted.

United States statistics

Henoch-Schönlein purpura is the most common vasculitis in childhood with an incidence of approximately 1 in 5000 children annually.[17]

In North America, Kawasaki disease occurs in about approximately 20 per 100,000 children younger than 5 years.[18]

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is reported to occur in 0.03-3.2 per 100,000 children per year.[19]

The other vasculitides are quite rare in childhood.

International statistics

In Japan, the incidence of Kawasaki disease is 188 per 100,000 children per year.[18]

The global incidence of Henoch-Schönlein purpura is 10-20 cases per 100,000 children per year.[20]

Race-, sex-, and age-related demographics

Race

The vasculitides are seen in patients of all races and ethnicities, but some notable patterns of distribution are noted.

Kawasaki disease is most common in children of Japanese and other Asian descent.

Henoch-Schönlein purpura is more common in Whites.

Takayasu arteritis is more common in the Asian population.

Behçet disease is more common in Turkey, the Middle East and eastern Asia.

Sex

Henoch-Schönlein purpura has a male-to-female ratio of 2:1.

Kawasaki disease has a male-to-female ratio of 1.6:1.

Polyarteritis nodosa has a slight male preponderance.

Takayasu arteritis has a strong female preponderance.

Age

Henoch-Schönlein purpura has a peak age of onset at 3-10 years; 75% of patients are younger than 10 years.

Kawasaki disease has a mean age of onset 4.3 years; 80% of patients are younger than 5 years.[17]

Polyarteritis nodosa has a peak age of onset at 9-11 years.

Takayasu arteritis most commonly presents in the second and third decades of life; 20% are younger than 20 years.

Prognosis is related to the degree of end-organ involvement. Generally, ANCA-associated vasculitis is associated with a poorer prognosis

Recurrence rate in Kawasaki disease is approximately 2%. Patients with Kawasaki disease and large coronary aneurysms are at risk for multiple complications, including stenosis and obstruction, myocardial infarction, and dysrhythmias. Some experience with bypass grafting for revascularization has been reported very good success.[21, 22]  In 2014, the largest US study of longer-term cardiac outcomes after Kawasaki disease reported a low rate of adverse cardiovascular events through age 21 years.[23]

The recurrence rate in Henoch-Schönlein purpura is approximately 30%.

A cohort study by Batu et al found that fever and renal involvement were more common in patients with COVID-19–associated pediatric IgA vasculitis/Henoch-Schönlein purpura than in those who developed pediatric IgA vasculitis/Henoch-Schönlein purpura before the pandemic. In addition, patients with COVID‐19–associated vasculitis were less likely to recover without treatment or to achieve a complete recovery. Patients with multisystem inflammatory syndrome in children (MIS-C) were excluded from the study.[24]

Morbidity/mortality

Morbidity and mortality in systemic vasculitides has been reviewed by Phillip and Luqmani; however, it is mainly based on adult data.[25]

In Kawasaki disease, acute mortality is 0.12% (mainly cardiac-related deaths). With appropriate treatment, the rate of coronary aneurysm development is approximately 2-4%.

Henoch-Schönlein purpura is usually a self-limited condition. The long-term prognosis relies mainly on the severity of renal involvement. The overall risk of end-stage renal disease is 1-3%, but this risk can increase to 20% if the patient presents with significant nephritis or nephrotic syndrome.[26]  In adults with Henoch-Schönlein purpura, a higher rate of renal impairment is noted, and the 5-year survival rate is only approximately 75%.

Takaysu arteritis is associated with a 10-year survival rate of approximately 87%.

Polyarteritis nodosa and Churg-Strauss syndrome are associated with a 5-year survival rate of 75-80%.

Microscopic polyangiitis is associated with a 5 year survival rate of 45-75%.

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is associated with significant morbidity and mortality. Approximately 11% of patients require mechanical ventilation and/or require dialysis.[19]  Survival is approximately 75% at 5 years in adults; survival data are not reported in pediatric patients.

Long-term data in childhood PACNS are lacking, but early recognition and treatment have been associated with good recovery.[27]

Complications

Complications may include the following:

• Destruction of paranasal sinuses

• Subglottic stenosis requiring tracheostomy

• Life-threatening pulmonary hemorrhage

• Renal insufficiency requiring dialysis or transplant

• Digital gangrene with autoamputation

• Stroke

• Myocardial infarction

• Sepsis

• Morbidity associated with immunosuppressive medications

• Death

Patients receiving corticosteroids should be advised of possible side effects, including weight gain, sleep disturbance, hirsutism, glucose intolerance, and hypertension.

Patients receiving immunosuppressive agents should be instructed to seek medical attention with any sign of infection.

Patients taking methotrexate should avoid alcohol and other hepatotoxic substances.

Discussion of adequate birth control measures with patients of childbearing age is necessary if they are treated with teratogenic medications (eg, methotrexate, warfarin).

As vasculitides are systemic processes, a comprehensive history and full review of systems is necessary.

Possible triggers include the following:

• Recent infections (upper respiratory tract infections, especially streptococcal; tuberculosis [TB])

• Vaccinations - Eg, an Italian study found evidence that the measles-mumps-rubella (MMR) vaccine increases the risk of Henoch-Schönlein purpura (odds ratio = 3.4)[28]

• New medications

Presenting features include the following:

• Constitutional symptoms - Fever, weight loss, fatigue, malaise (these occur in 90-100% of patients with granulomatosis with polyangiitis [GPA], formerly Wegener granulomatosis) and microscopic polyangiitis [MPA].[19, 7]

• Skin – Nodules, which may be painful, erythematous, or ulcerated; purpura; petechiae; papulopustular lesions; erythema nodosum; livedo reticularis; Raynaud phenomenon; lower extremity swelling

• Recurrent oral and/or genital ulcerations that heal with scarring

• Nasal/sinus – Allergic rhinitis, nasal congestion, recurrent epistaxis, sinus pain, tearing

• Pulmonary – Chronic cough, hemoptysis, shortness of breath, stridor, wheezing, chest pain

• Musculoskeletal – Joint pain or swelling, myalgias, calf pain

• Renal – Hematuria, hypertension

• GI tract – Abdominal pain, hematochezia, vomiting, nausea

• Genitourinary – Testicular swelling and/or pain

• Vascular – extremity claudication, blood pressure difference between limbs, pre-syncope/fainting spells

• Neurological – Headache, seizure, focal neurological deficits (eg, stroke, cranial nerve palsy, vision loss, fine motor deficits, movement abnormalities), diffuse neurological deficits (eg, cognitive decline, poor school performance), mononeuropathy or polyneuropathy (eg, numbness, paresthesias, hand/foot drop, weakness), visual/auditory hallucinations, fluctuating/decreased level of consciousness/encephalopathy

Past medical history may include the following:

• Recurrent sinusitis and pneumonias

• Asthma and allergic rhinitis precede development of Churg-Strauss syndrome

Family history may include an increased risk of Kawasaki disease in siblings.

Clinical features common in Henoch-Schönlein purpura include the following:

• Palpable purpuric rash (must be present)

• Diffuse abdominal pain

• Arthritis (acute, any joint) or arthralgia

• Hematuria and/or proteinuria

• Lower limb swelling may be seen

Clinical features common in Kawasaki disease include the following:

• Fever, at least 5 days in duration, unresponsive to antibiotic therapy

• Polymorphous exanthem (nonvesicular)

• Perineal desquamation

• Changes in peripheral extremities (erythema and/or edema)

• Cervical lymphadenopathy, usually unilateral, larger than 1.5 cm

• Bilateral, non-purulent, conjunctivitis

• Changes of lips and oral cavity - Injection of oral and pharyngeal mucosa, fissured lips

• Irritability, arthralgia/arthritis

General

Vital sign measurements should include 4-limb blood pressure measurement to look for a difference of more than 10 mm Hg between limbs.

Head and Neck

Funduscopy and ophthalmologic assessment for conjunctivitis, uveitis, scleritis and/or retinal vasculitis, and optic neuritis is indicated. Orbital inflammation (lid edema/erythema, proptosis) may be seen in granulomatosis with polyangiitis and microscopic polyangiitis.[29]

Inspection of nasal cavity for bleeding, ulceration, and septal perforation is indicated.

Other findings may include the following:

• Nasal bridge swelling, pain or saddle-nose deformity (See the image below.)

  Patient with Wegener granulomatosis and saddle-nose deformity.

• Paranasal sinus tenderness

• Cervical lymphadenopathy

• Oral ulcers seen in Behçet disease

• Otitis, mastoiditis, hearing loss

Respiratory

The following may be noted:

• Increased work of breathing, tachypnea, hypoxia

• Decreased breath sounds

• Stridor, wheeze

• Blood-tinged sputum

Cardiovascular

The following may be noted:

• Pulselessness, inequality of pulses

• Bruits over major arteries

• Increased capillary refill time

• Abnormal heart sounds, including gallop rhythm, muffled heart sounds, rub

Abdominal and genitourinary

Findings may include the following:

• Abdominal tenderness (focal or diffuse)

• Hepatomegaly, splenomegaly

• Blood on rectal examination

• Genital ulcers or scars in Behçet syndrome

• Testicular pain and/or swelling

Dermatologic

All patients with Henoch-Schönlein purpura have palpable purpuric rash, typically over buttocks and lower extremities.

Dermatologic manifestations of Kawasaki disease include polymorphous exanthem and red/swollen extremities.

Patients with polyarteritis nodosa have deep red tender subcutaneous nodules that can become ischemic and necrotic (see the images below).

Tender erythematous nodules in cutaneous polyarteritis nodosa (PAN).

Nodules on sole of foot in cutaneous polyarteritis nodosa (PAN).

Necrotic lesions of polyarteritis nodosa (PAN).

Livedo reticularis may also be seen in childhood polyarteritis nodosa.

Musculoskeletal

These findings may include the following:

• Arthritis (joint swelling, effusions, decreased range of motion and/or stress pain)

• Muscle tenderness

Neurologic

These findings may include the following:

• Peripheral neuropathy, paresthesia

• Mononeuritis multiplex

• Cranial nerve palsies, vision loss, visual field defects

• Altered level of consciousness

• Focal neurological deficits, including stroke

• Diffuse neurological deficits

• Hallucinations, bizarre behavior

Investigations must be performed to detect signs of inflammation, to determine the type and extent of organ involvement, to test for vasculitis-specific autoantibodies, and to rule out secondary causes. Note that the degree of inflammation often differs between diseases and among individual patients.

General laboratory tests

CBC count and differential may reveal normochromic, normocytic anemia; leukocytosis; thrombocytosis consistent with inflammatory process; and eosinophilia in Churg-Strauss syndrome.

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be elevated, but these findings are not sensitive or specific.

C3 and C4 levels are usually elevated, except in hypocomplementemic urticarial vasculitis.

Albumin levels may be low due to chronic inflammation, third spacing, or vascular leakage.

von Willebrand factor antigen (factor VIII-related antigen) may be elevated.

Organ-specific tests

BUN, creatinine, liver enzyme levels may be abnormal, depending on involvement.

Urine studies for hematuria and/or proteinuria are indicated.

Lumbar puncture may reveal pleocytosis, elevated protein levels, and/or elevated opening pressure in childhood primary angiitis of the CNS (PACNS)

Autoantibody tests

The initial test for antineutrophil cytoplasmic antibody (ANCA) is indirect immunofluorescence to detect staining pattern, either cytoplasmic or perinuclear.

If positive results are noted, test for reactivity to proteinase 3 (PR3) and myeloperoxidase (MPO) by enzyme-linked immunoassay (ELISA)

ANCA positivity is noted in approximately 90% of pediatric patients with granulomatosis with polyangiitis (GPA) (formerly Wegener granulomatosis), 79% of who are cytoplasmic.[6]

PR3-ANCA and MPO-ANCA positivity have a high sensitivity and specificity for the diagnosis of GPA and microscopic polyangiitis (MPA), respectively.

The association of Churg-Strauss syndrome and ANCA positivity is approximately 40%.

Note that an atypical ANCA finding is nonspecific and may be seen in other inflammatory conditions such as infection and inflammatory bowel disease.

Anti-glomerular basement membrane (GBM) antibody testing is indicated for pulmonary renal syndromes.

Other autoantibodies such as anti-nuclear antibody (ANA) and rheumatoid factor (RF) are rarely positive

Infectious work-up (as indicated)

See the list below:

• Bacterial - Mycoplasma PCR and serology, antistreptolysin O test (ASOT), syphilis serology, Mantoux skin test

• Viral - Serology for hepatitis B and C, parvovirus B19, HIV, herpes simplex virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella

• Fungal culture

Thrombophilia investigations

Antiphospholipid antibody syndrome studies include the following:[30]

• Prolonged activated partial thromboplastin time (aPTT), which does not correct with mixing

• Screening for lupus anticoagulant

• Anticardiolipin antibody by ELISA

• Anti-β2-microglobulin-1 antibody by ELISA

Classification criteria for pediatric antiphospholipid antibody syndrome includes the following clinical criteria for vascular thrombosis: One or more clinical episodes of arterial, venous, or small-vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (ie, unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.

The laboratory criteria include the following:

• Anticardiolipin antibody of immunoglobulin G (IgG) and/or immunoglobulin M (IgM) isotype in serum or plasma - Must be present in medium or high titre (ie, >40 GPL or MPL, or >99th percentile) on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA

• Anti-β2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma - Must be present in titre >99th percentile, on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA

• Lupus anticoagulant in plasma - Must be present on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis

Pediatric antiphospholipid syndrome is considered to be present if the clinical criterion and at least I of the laboratory criteria are met.

Other thrombophilia work-up includes protein C, protein S, antithrombin III, factor V Leiden mutation, homocysteine, prothrombin gene mutation (G20210A), and methylene tetrahydrofolate reductase (MTHFR) mutation.

Imaging is essential for evaluation of blood vessels and of end-organ damage. In particular, vascular imaging is often imperative for diagnosis and follow-up of the disease. Information regarding both luminal blood flow and vessel wall changes is important. Conventional angiography generally provides information about blood flow, clot formation, and collateral blood flow; whereas CT and/or magnetic resonance (MR) angiography provide visualization of vessel wall thickness and fragility, aneurysm formation, and overall disease activity.

Chest radiography

This is indicated to screen for pulmonary involvement in granulomatosis with polyangiitis (formerly Wegener granulomatosis), Churg-Strauss syndrome, microscopic polyangiitis, Takayasu arteritis (TA), and Behçet syndrome.

A characteristic of CSS is fluctuating infiltrates (see the image below).

Chest radiography in Churg-Strauss syndrome (CSS) with pulmonary infiltrates.

CT scan of the sinuses

Turbinate mucosal thickening with associated sinusitis and possible erosive changes is seen in granulomatosis with polyangiitis (see the image below).

CT of sinuses in a patient with Wegener granulomatosis (WG) showing erosion and loss of sinus walls.

Orbital pseudotumors may be seen in granulomatosis with polyangiitis and microscopic polyangiitis.

CT scan of the chest

In granulomatosis with polyangiitis, nodules (may be cavitary and/or multifocal), ground-glass opacification, air-space opacification, mediastinal lymphadenopathy, and pleural thickening and effusion may be seen.[31]

In Churg-Strauss syndrome, nodules, ground-glass opacification, bronchial wall thickening or dilatation, consolidation, septal thickening, and tree-in-bud pattern may be seen (see the image below).[32]

CT chest in a patient with Churg-Strauss syndrome (CSS) showing multiple nodules.

In microscopic polyangiitis, patchy or confluent bilateral areas of consolidation may be seen, mainly in lower lobes.[33]

Echocardiography

Echocardiography is indicated to assess for coronary artery involvement, especially in Kawasaki disease (KD)

Head CT scan or MRI

These studies may reveal acute ischemia or hemorrhage in patients with CNS symptoms

In large or medium-vessel childhood PACNS, T2-hyperintense focal areas of acute ischemia in a vascular distribution is noted. Diffusion weighted imaging (DWI) findings are positive. Vessel wall enhances with gadolinium.

In small-vessel childhood PACNS, T2-fluid-attenuated inversion-recovery (FLAIR) hyperintensities that do not conform to a vascular territory are noted. DWI findings are negative.

CT angiography, MR angiography, or conventional angiography plus MRI vessel wall imaging (gadolinium enhancement)

These studies are used to assess for large and/or medium vessel vasculitis.

Angiography (CT, MR, conventional) of the aorta and its main branches is indicated when investigating for Takayasu arteritis.

• The European Union League Against Rheumatism (EULAR) recommends MRI as a first imaging test for Takayasu arteritis and not conventional angiography. Only in cases that involve vascular intervention (eg, percutaneous transluminal balloon angioplasty or stenting) is conventional angiography recommended. ^{[34, 35]}

Head MR angiography is diagnostic in large/medium vessel childhood PACNS.

Vascular imaging in polyarteritis nodosa (PAN) must be done with conventional angiography because medium-sized vessels are involved (site depends on clinical features); findings include “beading” of vessels caused by alternating areas of vascular narrowing and dilatation.

Consider angiography in Behçet disease (site depends on clinical features).

CT/MR venography is indicated if venous thrombosis is suspected in antiphospholipid antibody syndrome, Behçet disease, and polyarteritis nodosa.

Ultrasonography with Doppler

This is used to identify thromboses in deep venous system, renal vessels, and transcranial vessels.

Positron emission tomography (PET) scan

This can detect subtle evidence of inflammation to identify potential sites of vasculitis.

Other tests include the following:

• Pulmonary function tests – Both obstructive and restrictive patterns seen in pulmonary vasculitis

• Electrocardiography – To identify signs of myocarditis or pericarditis

• Nerve conduction studies – In patients with peripheral nerve involvement

• Electroencephalogram – In patients with CNS involvement

• Bronchoscopy/lavage – May be required in patients with lung involvement

Tissue biopsy may be necessary to confirm a diagnosis of vasculitis in systemic and cutaneous polyarteritis nodosa (PAN), ANCA vasculitides, childhood PACNS, and infrequently in Henoch-Schönlein purpura.

• Henoch-Schönlein purpura - Skin and/or renal biopsy

• Polyarteritis nodosa - Skin biopsy

• ANCA-vasculitides - Sinus, renal, lung, and/or skin biopsy

• Childhood PACNS - Lesional brain biopsy often needed in small-vessel CNS vasculitis

Histologic findings include the following:

• Takayasu arteritis: Inflammatory infiltrate is composed of T cells. Macrophages are arranged into granulomas with giant cells. Concentric thickening of all layers of the artery wall (intima, media and adventitia) is noted.

• Polyarteritis nodosa: Acute and segmental necrotizing vasculitis of medium-sized arteries is seen with an inflammatory infiltrate composed of neutrophils and eosinophils within the vessel walls and extravasation of erythrocytes and fibrin.

• Churg-Strauss syndrome: In the lung, extravascular microgranulomas filled with eosinophils and intramural eosinophilic infiltrate are noted.

• Granulomatosis with polyangiitis (GPA) (formerly Wegener granulomatosis): In the lung, granulomatous inflammation with mononuclear infiltrate including T cells, macrophages/histiocytes, and giant cells are noted.

• GPA and microscopic polyangiitis: Renal histologic findings include "pauci-immune" (ie, little immune deposition on immunofluorescence) necrotizing glomerulonephritis with large circumferential crescents, segmental loss of basement membrane, and tubulointerstitial inflammation.

• Henoch-Schönlein purpura: Immunofluorescence demonstrates deposition of IgA, C3, and fibrin in the walls of affected blood vessels within the dermis and the endothelial and mesangial cells of the kidney. Skin biopsy reveals features of leukocytoclastic vasculitis with infiltrate of neutrophils and mononuclear cells.

• Childhood PACNS: Segmental nongranulomatous intramural infiltration of predominantly T lymphocytes involves small arteries, arterioles, capillaries, and/or venules. Surrounding reactive changes may include gliosis, calcification, and pallor of myelin staining.

The management of children with Kawasaki disease involves hospital admission and treatment with intravenous immunoglobulin (IVIG) and high-dose aspirin in the acute phase of the illness.[36] Subsequently, daily low-dose aspirin is given for 6-8 weeks until follow-up echocardiography. IVIG-resistant disease may be treated with methylprednisolone and/or other immunosuppressive therapies (see Kawasaki Disease “Treatment of IVIG-Resistant Disease”). Guidelines from the American College of Rheumatology and the Vasculitis Foundation conditionally recommend the use of adjunctive glucocorticoids with IVIG as initial therapy for patients with acute Kawasaki disease who are at high risk for IVIG resistance or the development of coronary artery aneurysms.[37]

The management of children with Henoch-Schönlein purpura is primarily symptomatic, and most patients do not require hospital admission. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be given for joint pain or swelling. Corticosteroids may be considered in selected patients (ie, those with severe GI symptoms),[38] but is an area of controversy in the literature.[39] Clinically significant nephritis is typically treated with steroids and other immunosuppressive therapies.

Patients with chronic vasculitides should be managed by a multidisciplinary group of specialists (eg, rheumatologists, cardiologists, nephrologists) and require long-term follow-up for monitoring of relapses, disease activity, end-organ damage and morbidity associated with therapy.

Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet's disease.[40]

No therapeutic trials have looked at management of vasculitis in the pediatric population, and practice has been based on adult guidelines, which have been summarized.[41, 42, 43] These recommendations provide general guidance that should be modified based on the features of each individual’s illness.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis

In general, adult patients with ANCA vasculitis are categorized according to different levels of severity to assist treatment decisions, as proposed by the European Vasculitis Study (EUVAS) group.[41]

Table 1. EUVAS disease categorization of ANCA-associated vasculitis (Open Table in a new window)

Induction therapy

Optimal induction therapy for patients with generalized disease (renal or other major organ involvement) is a subject of intensive study. Initial guidelines suggested a combination of cyclophosphamide and high-dose glucocorticoids. However, there have been 3 randomized controlled trials investigating the use of rituximab as an induction agent in adults with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).[44, 45, 46] These studies have shown that rituximab is likely as effective as cyclophosphamide in inducing remission.

The most recent treatment recommendations[43] suggest that either regimen be considered and that rituximab may be preferred when cyclophosphamide avoidance is desired (eg, due to toxicity). Some evidence suggests that granulomatous manifestations (eg, orbital granulomas) may not respond to rituximab as well as vasculitic manifestations.[47] With either regimen, high-dose prednisone (1 mg/kg) should be maintained for 1 month. When rapid effect is needed, intravenous (IV) pulsed methylprednisolone may be used in addition to the oral prednisone.

A study by van Daalen et al reported that rituximab treatment for ANCA-associated vasculitis had lower malignancy risk than in cyclophosphamide treatment and that rituximab was not associated with an increased malignancy risk compared with the general population.[48]

Local guidelines for the prevention of glucocorticoid-induced osteoporosis should be followed in all patients. Cyclophosphamide use should be limited to 3-6 months because of potential for long-term toxicity. However, no consensus about whether pulse IV cyclophosphamide is superior to daily oral therapy. All patients who receive cyclophosphamide should also receive prophylaxis against Pneumocystis jiroveci (trimethoprim-sulfamethoxazole or pentamidine), especially those with GPA.

For patients with mild-to-moderate or limited disease, methotrexate can be used as a less toxic alternative for induction. However, there is some evidence that induction with methotrexate may be associated with a higher risk of relapse.[49]

Plasma exchange is recommended as adjunctive therapy for patients with rapidly progressive severe renal disease.

Maintenance therapy

Evidence suggests that once remission is achieved with either a cyclophosphamide- or rituximab-based regimen, maintenance therapy is required to prevent relapse. One alternative is to use either methotrexate or azathioprine. A recent study has also suggested the use of biannual rituximab as maintenance therapy.[50] The use of low-dose glucocorticoids (10 mg/d of prednisone) is also recommended. Maintenance therapy should be continued for at least 18-24 months, and early cessation is associated with an increased risk of relapse.

Refractory or relapsing disease

The RAVE trial,[44] a randomized, controlled, double-blinded study of cyclophosphamide versus rituximab in ANCA vasculitis, included a planned subgroup analysis of patients with refractory or relapsing disease. The findings demonstrated that rituximab was particularly effective in this population. Several other small series also report the effectiveness of rituximab in patients with refractory or relapsing disease. Other options for refractory or relapsing disease include IVIG, mycophenolate mofetil, infliximab, 15-deoxyspergualin, and antithymocyte globulin.[41]

Systemic polyarteritis nodosa

Patients with severe disease should receive a combination of cyclophosphamide and glucocorticoids. However, a selected group of patients with mild polyarteritis nodosa may be successfully treated with glucocorticoids alone.

Cutaneous polyarteritis nodosa

Some patients respond to NSAIDs alone; however, most require treatment with prednisone. Steroid-sparing agents may be needed (eg, methotrexate, mycophenolate mofetil, colchicine, IVIG). Penicillin prophylaxis may prevent disease exacerbations in patients with evidence of triggering streptococcal infections.[5]

Large vessel vasculitis

A paucity of large controlled trials in the management of large-vessel vasculitis is noted, even in adult patients. Treatment recommendations are based on the EUVAS guidelines.[42]

Induction therapy usually involves high-dose glucocorticoid (prednisone, 1 mg/kg/d). The initial high dose should be maintained for a month and then gradually tapered. Azathioprine or methotrexate have been used as adjuncts to steroid therapy in patients with Takayasu arteritis to improve disease control and to facilitate reduction of the steroid dose. Cyclophosphamide has been used in adults with Takayasu arteritis resistant to glucocorticoids. In addition, tumor necrosis factor (TNF)-α inhibitors (eg, infliximab, etanercept) have been tried with encouraging results, including in a small study of 4 children.[51]

Primary CNS vasculitis

Initiate treatment with high-dose steroids and monthly IV cyclophosphamide for 6 months, followed by maintenance with mycophenolate mofetil or azathioprine for 18 months. Anti-thrombotic therapy (heparin followed by antiplatelet) may be added for large-vessel disease.[27] See Behcet Syndrome and Anti-GBM Antibody Disease for specific treatment of these conditions.

Thrombophlebitis/hypercoagulable state

Anticoagulation is indicated for any patient with a thrombotic episode and an underlying hypercoagulable state. This usually involves initial treatment with heparin with subsequent transition to warfarin.

Refer to Antiphospholipid Antibody Syndrome for details on treatment. Generally, anticoagulant prophylaxis is not indicated in the absence of a thrombotic event. No studies in the optimal management of pediatric patients with antiphospholipid antibody syndrome have been done. The adult literature suggests that patients with documented venous or arterial thrombotic events should be managed with warfarin.[52]

With involvement of the aorta and renal arteries, angioplasty and stenting of stenotic vessels has been used to improve flow (eg, in Takayasu arteritis). A significant proportion of vessels may develop restenosis, but good response to repeat procedure is noted.[53] In addition, reconstructive surgery with graft implantation may be required. Note that vascular procedures must be done during periods of inactive disease.

Patients with granulomatosis with polyangiitis (formerly Wegener granulomatosis) may develop subglottic stenosis; these lesions can be amenable to endoscopic management with local corticosteroid injection and/or mitomycin-C application.[54] Note that in granulomatosis with polyangiitis, repeated procedures are often necessary, and some patients may require tracheostomy insertion.

Consultations may include the folllowing:

• Pediatric rheumatologist

• Pediatric nephrologist (if renal involvement)

• Pediatric cardiologist (if large vessel involvement)

• Pediatric otolaryngologist (for upper respiratory tract involvement)

• Pediatric hematologist (for thrombophilic disorders)

• Pediatric neurologist (for CNS involvement)

• Vascular surgeon or interventional radiologist, as indicated

Diet

Therapy with prednisone requires adherence to low-salt and low-fat diet with extra calcium and vitamin D.

A low-salt diet is indicated if the patient is hypertensive.

Activity

No limitations are indicated unless anticoagulants are used (then avoid contact sports).

Class Summary

These agents have potent immunosuppressive activity with rapid onset of action.

Prednisone (Deltasone, Sterapred)

Used to control acute symptoms and laboratory evidence of inflammation. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Class Summary

IVIG is used as first-line therapy for Kawasaki disease; it decreases risk of coronary artery aneurysms.

Immune globulin, intravenous (Sandoglobulin, Gamimune, Gamunex, Gammar-P)

Multiple mechanisms. May absorb superantigens or toxins in Kawasaki disease. May saturate available Fc receptors. May block cytokines, cytokine receptors, or both. May absorb complement activation products. May down-regulate immunoglobulin synthesis. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade. May increase CSF IgG (10%).

Class Summary

These agents help control inflammatory signs and symptoms.

Azathioprine (Imuran)

Imidazolyl derivative of 6-mercaptopurine. Many of biological effects are similar to those of parent compound. Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or mercaptopurine is detectable in urine 8 h after taken. Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. Mechanism whereby azathioprine affects autoimmune diseases is unknown. Works primarily on T cells. Suppresses hypersensitivities of cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses. Works very slowly; may require 6-12 mo of trial prior to effect. As many as 10% of patients may have idiosyncratic reaction disallowing use. Do not allow WBC count to drop below 3000/mL or lymphocyte count to drop below 1000/mL. Available in tablet form for PO administration or in 100-mg vials for IV injection

Cyclophosphamide (Cytoxan)

Cyclic polypeptide that suppresses some humoral activity. Chemically related to nitrogen mustards. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. Interaction of phosphoramide mustard with DNA considered cytotoxic. When used in autoimmune diseases, mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking. In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T-cell functions.

Methotrexate (Rheumatrex, Folex)

Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction. Effects may also be mediated by adenosine via the inhibition of aminoimidazole carboxamide ribonucleotide (AICAR) transformylase, leading to increased release of adenosine. Adjust dose gradually to attain satisfactory response.

Mycophenolate mofetil (CellCept); Mycophenolic acid (MyFortic)

Inhibits inosine monophosphate dehydrogenase and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.

Two formulations are available and are not interchangeable. The original formulation, mycophenolate mofetil (MMF, Cellcept) is a prodrug that once hydrolyzed in vivo, releases the active moiety mycophenolic acid. A newer formulation, mycophenolic acid (MPA, Myfortic) is an enteric-coated product that delivers the active moiety.

Class Summary

Blocks the process by which activated neutrophils adhere to endothelium and stimulate lysis of endothelial cells in the presence of TNF-alpha.

Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas.

Class Summary

May consider these agents for conditions refractory to other treatments.

Rituximab (Rituxan)

Chimeric IgG1-kappa monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The Fab domain binds to CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).

Class Summary

These agents provide immediate and long-term treatment of vascular thrombosis.

Heparin

Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.

Provide as continuous heparin infusion to maintain aPTT at 1.5 times the control.

Enoxaparin (Lovenox)

Low molecular weight heparin. Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.

Advantages include intermittent dosing and decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing.

Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K–dependent coagulation factors.

Class Summary

Prophylaxis for P jiroveci with cyclophosphamide therapy.

Trimethoprim-sulfamethoxazole (Bactrim, Septra)

As P jiroveci prophylaxis for patients taking cyclophosphamide. Dihydrofolate reductase inhibitor in combination with sulfonamide.

Close follow-up of patients with systemic vasculitis by a multidisciplinary team is extremely important for monitoring progression of disease, response to therapy, and complications.

Patients with Henoch-Schönlein purpura should have periodic checks of urinalysis as long as 6 months after the acute illness to screen for delayed-onset nephritis.[26]

Patients with Kawasaki disease should have follow-up with echocardiogram at 6-8 weeks after acute illness. Most centers are also doing follow-up echocardiogram at 1 year.

Patients receiving cyclophosphamide should have close monitoring of CBC count for cytopenias.

Patients receiving rituximab should have regular monitoring of immunoglobulin levels and CD19+ lymphocyte count.

For patients with elevated antineutrophil cytoplasmic antibody (ANCA), titers may normalize during periods of disease control and increase with disease activity. Serial ANCA titers have been used to measure disease activity, with limited success. An acute rise in ANCA titer suggests clinical activity; persistent high titers are less helpful in identifying patients with active disease.

Transfer to tertiary care center is indicated for patients with the following:

• Kawasaki disease complicated by myocarditis, shocklike syndrome, and refractory disease

• Henoch-Schönlein purpura complicated by significant renal impairment and CNS involvement

• Patient who is suspected to have Takayasu arteritis (TA), polyarteritis nodosa, antineutrophil cytoplasmic antibody-associated vasculitis, Behçet disease, childhood primary angiitis of the CNS (PACNS)

• Significant organ involvement or compromise (ie, renal, CNS, cardiac)

Primary prevention of systemic vasculitis is not usually possible.

One must maintain a high index of suspicion for this group of diseases because early diagnosis and appropriate aggressive treatment is essential.

Prevention of renal disease in Henoch-Schönlein purpura has been an area of controversy in the literature. Treatment with corticosteroids may prevent progression of renal disease; however, a true benefit has not been proven.[39]

Prophylaxis for P jiroveci with trimethoprim-sulfamethoxazole is indicated for patients being treated with cyclophosphamide.

All patients receiving prednisone should have monitoring of bone mineral density and should ensure good intake of calcium and vitamin D.

Secondary thromboprophylaxis indicated for patients with thrombotic event and hypercoagulable state/antiphospholipid antibody syndrome.