PEDIATRIC VASCULITIDES

What is Vasculitis?

The term vasculitis means inflammation of the wall of blood vessels.

Various sizes of blood vessels may be involved.

The inflammatory exudates may vary and be mononuclear, eosinophilic or neutrophilic.

How Common is Vasculitis in Children?

Vasculitis in children appears to have an incidence of about 50 cases per 100,000 children per year.

Henoch Schonlein purpura (HSP) and Kawasaki disease (KD) are more common in children (75– 125 per 100,000 in Japanese children and 9 per 100,000 in Caucasian children of USA.)

How is Vasculitis Classified in Children?

The aorta and its main branches are termed large vessels;

The first branches of the aorta e.g., renal, mesenteric, coronary vessels are regarded as mid-sized;

Arterioles, capillaries and venules are regarded as small-sized.

Small vessel vasculitis (SVV) is sub-categorized into granulomatous and non-granulomatous varieties.

New classification of childhood vasculitides

When Should a Pediatrician Suspect Vasculitisin a Child?

Large vessel involvement:

1. Absent pulses, 2. Bruits over aorta and vessels, 3. Hypertension,4. Discrepant four limb blood pressure, 5. Congestive heart failure.6. Cardiomyopathy.

Medium vessel involvement:

1. Hypertension (renal vessels).2. Abdominal pain (celiac axes), 3. Chest pain (coronaries),4. Claudication (subclavian, femoral or iliac

vessels),5. Deep skin changes, gangrene.6. Focal deficits (cerebrovascular

insufficiency/sudden blindness), 7. Orchitis (testicular) and 8. Neuropathy (vasa vasorum).

Gangrene of the toes in systemic PAN

Small vessel involvement (symptoms in richly vascularized organs):

1. Purpura, superficial ulcers, mucosal ulcers,

2. Pulmonary and/or renal syndrome.3. Ear-nose throat disease.4. Asthma.

What is the Investigative Approach for a Childwith Vasculitis with Regards to Radiology,Histopathology and Serology?

Radiology: Digital Subtraction Angiography (DSA) In large vessel vasculitis, conventional DSA is

useful in demonstrating vessel stenoses or aneurysms.

The major limitations of DSA 1. Invasiveness,2. High contrast load, 3. High-dose radiation exposure,4. Complications at the arterial injection site.5. Inability to delineate the arterial wall anatomy.

Digital subtraction angiography demonstrating stenoses of a segment of the aorta and the left proximal renal artery

MR Angiogram (MRA)

MR angiography :1. Detects of early signs of large-vessel disease, and2. It has the added advantage of potentially revealing

evidence of ongoing large arterial wall inflammation.

Disadvantage : 1. Its relative insensitivity to slow flow or in-plane flow

because of saturation of the MR imaging signal intensity.

2. This can lead to overestimation of the severity of the stenosis or to a false diagnosis of vascular occlusion .

Computerised Tomography (CT) and Ultrasonography(USG)

USG provides a very good image of the following compared to CT or MRI.

1. Carotid.2. Axillary.3. Brachial.4. Femoral arteries.

Major advantages are1. Non invasiveness,2. No radiation, 3. Wide availability and4. Low cost. 5. Blood flow characteristics, wall elasticity, and plaques can

be delineated.

Relative Disadvantages : The image of the subclavian, iliofemoral, renal, superior and inferior mesenteric arteries, the celiac trunk, and the abdominal aorta is moderate.

The assessment of thoracic aorta requires transesophageal USG.

CT, Electron beam tomography and CT angiogram (CTA) have been reported as useful tools for assessing the aorta and its main branches.

However, poor visualisation of the more distal branches and a high radiation exposure are possible disadvantages.

Studies comparing Color Doppler Flow Imaging (CDFI) with MRA and conventional angiography have shown a high degree of correlation in delineating the extent of stenosis in the carotids and subclavian vessels.

Positron emission tomography (PET) scanning with radioactive-labelled 18-fluorodeoxyglucose (FDG) has been shown to be useful in monitoring disease activity (by its extreme sensitivity to pick inflamed vessels) and response to treatment in preliminary studies.

2 D Echocardiogram

Helps in detecting or excluding coronary artery aneurysms, intraluminal or mural thrombi, regurgitant cardiac valves, myocardial dysfunction, or pericardial effusion.

Histology

The choice of tissue is guided by the clinical setting using the most accessible involved organ or tissue.

Various organs biopsied include the skin, lungs and kidney (pulmonary-renal syndrome), sural nerve, and muscle.

Skin is the most commonly biopsied area. A deep punch biopsy (to diagnose changes in

the deeper vessels at the dermal level) is ideal.

Cutaneous vasculitis is mostly characterized by involvement of the post-capillary venules with endothelial cell swelling, neutrophilic invasion of blood vessel walls, presence of disrupted neutrophils (leukocytoclasia), extravasation of red blood cells, and fibrinoid necrosis of the blood vessels walls.

These features are termed cutaneous necrotizing vasculitis (CNV), which refers to leukocytoclastic vasculitis affecting the small and medium vessels supplying nutrients to the skin .

Along with leukocytoclasia, the biopsy may reveal areas of panniculitis, particularly in PAN.

Samples should be subjected to immunofluorescence particularly for possible HSP (IgA deposits), ANCA associated vasculitis (pauci-immune necrotising vasculitis) or secondary vasculitis like SLE (immunoglobulins and complement deposits at the dermo-epidermal junction).

Renal biopsies are carried out if clinical features and urinalysis suggest renal involvement.

Various changes from focal to segmental glomerulonephritis can be seen.

Subepithelial deposits can be seen on electron microscopy

As the yield from tissues like sinuses, nose, ears, and trachea is low (<50%), invasive procedures such as open or thoracoscopic lung biopsies or renal biopsies are often used to diagnose Wegeners granulomatosis (WG).

Serology

ANCA are present with a high specificity of up to 98% in the specific group of AAV.

Two staining patterns for ANCA are detected by ELISA.

1. Cytoplasmic ANCA (C-ANCA) representing antibody to proteinase 3 is present in 90% of patients with active diffuse WG i.e., with high specificity.

2. Perinuclear ANCA (P-ANCA) caused by antimyeloperoxidase antibody is suggestive of involvement of small to medium sized arteries in conditions such as microscopic polyangiitis.

The presence of Von Willebrand factor antigen is a surrogate marker for SVV.

Elevated IgA levels may be found in 50–70% of HSP.

Anti-streptolysin O titres may be elevated with cutaneous polyarteritis (C- PAN).

Serology for Hepatitis B and C are relevant in cases of polyarteritis nodosa (PAN).

Differential Diagnoses

How are Children with Vasculitis Managed?

What is the Prognosis of the Various Vasculitides?

The majority of children with HSP make a full and uneventful recovery with no evidence of ongoing significant renal disease.

Mortality is around 1–2% with severe gastrointestinal or renal involvement.

Renal involvement is the most serious long-term complication of HSP and occurs in 5%.

KD has a good prognosis, with 1–2% acute mortality rate due to myocardial infarction, having been reduced further to less than 1% due to increasing awareness of clinicians and prompt treatment.

Ozen et al reported in a retrospective series of childhood PAN an improved outcome compared to that reported in adults with only one (1.1%) death and two (2.2%) patients with end-stage renal disease among 110 patients.

C-PAN has a good prognosis, albeit with recurrent relapses and remissions.

The AAV carry considerable disease-related morbidity and mortality mainly due to progressive renal failure or aggressive respiratory involvement.

For Churg-Strauss syndrome (CSS) in children, the most recent series reports mortality of 18%, attributable to disease rather than to therapy.

The risk of organ damage is related to the duration of active disease.

With proper treatment, clinical remission is often achieved within the first year.

The remission may be life-long, but long-term maintenance therapy is frequently required.

Periods of disease remission may be interrupted with relapses requiring more intensive therapy.