Indian J Pediatr (2010) 77:1165–1171 DOI 10.1007/s12098-010-0132-z SYMPOSIUM ON RHEUMATOLOGY Pediatric Vasculitides: A Generalists Approach Raju P. Khubchandani & V. Viswanathan Received: 16 July 2010 / Accepted: 26 July 2010 / Published online: 28 August 2010 # Dr. K C Chaudhuri Foundation 2010 Abstract Vasculitis is defined as the presence of inflammation in a blood vessel that may occur as a primary process or secondary to an underlying disease. Primary vasculitides are rare in children. These are defined by both the size of vessels involved and the type of inflammatory response. Clinical features consist of multi-organ involvement on a background of constitutional features reflecting the size and location of the blood vessels involved. Whilst some vasculitides are best diagnosed clinically, many forms require sophisticated imaging and other investigations (auto antibodies) to reveal the correct diagnosis. Prompt recognition and treatment is crucial as many of the vasculitides cause significant morbidity or mortality. Treatment options range from symptomatic therapy, immunosuppresive agents, intravenous immunoglobulin (IVIG) or biologic agents and are determined by the type of vasculitis, the severity of the inflammation, and the organ systems affected. Early detection and aggressive treatment is crucial for the best outcomes in the most severe forms of childhood vasculitis. Keywords Vasculitis . Classification . Approach . Management . ANCA R. P. Khubchandani (*) Pediatric Rheumatology Clinic, Department of Pediatrics, Jaslok Hospital and Research Centre, 31 Kailas Darshan, Nana Chowk, Mumbai 400007, India e-mail: [email protected] V. Viswanathan Pediatric Rheumatology Clinic, Department of Pediatrics, MGM’s New Bombay Hospital, Vashi, Navi, Mumbai, India 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. The term vasculopathy is broader and signifies abnormality of blood vessels occurring due to inflammation, degeneration or intimal proliferation. How Common is Vasculitis in Children? The group of disorders termed ‘vasculitides’ are rare in the paediatric age group with varied incidence. Based on various surveys, vasculitis in children appears to have an incidence of about 50 cases per 100,000 children per year. Only Henoch Schonlein purpura (HSP) and Kawasaki disease (KD) are more common in children than in adults, with each one affecting at least 10–20/100,000 pediatric patients per year. It should be noted that there is wide ranging prevalence rates of Kawasaki disease depending on race, with a reported prevalence of 75– 125 per 100,000 in Japanese children and 9 per 100,000 in Caucasian children of USA. Takayasu arteritis (TA) and anti neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), on the other hand, occur in approximately one child per million for each condition [1]. Systemic polyarteritis nodosa (PAN) is also rare in childhood with an estimated incidence of one per one million children [2]. How is Vasculitis Classified in Children? Although many vasculitides affect both adults and children, some such as KD occur almost exclusively in childhood. 1166 Indian J Pediatr (2010) 77:1165–1171 On the other hand, temporal arteritis does not occur in children. Other forms of vasculitis such as polyarteritis and Wegener’s granulomatosis (WG) have different clinical and prognostic characteristics in children. Thus, it has been found inappropriate to apply adult classification criteria to childhood vasculitis. In recognition of this, the European League of Associations for Rheumatology (EULAR) along with the Pediatric Rheumatology European Society (EULAR-PReS) conducted mail surveys and hosted a consensus conference and subsequently proposed a new classification for childhood vasculitis [3]. This schema uses vessel size for classification purposes as does the Chapel Hill consensus conference for adult vasculitides. 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. Lastly a group titled ‘other vasculitides’ has been included which contains diseases not fitting into one category, or fitting into more than one category or where an aetiological process has been defined. (Table 1) Table 1 New classification of childhood vasculitides • Predominantly large vessel vasculitis Takayasu arteritis • Predominantly medium sized vessel vasculitis Childhood polyarteritis nodosa Cutaneous polyarteritis (C-PAN) Kawasaki disease • Predominantly small vessel vasculitis (A) GRANULOMATOUS Wegener’s granulomatosis Churg-Strauss syndrome (CSS) (B) NON-GRANULOMATOUS Microscopic polyangiitis Henoch-Schonlein purpura Isolated cutaneous leucocytoclastic vasculitis Hypocomplementemic urticarial vasculitis • Other vasculitides Behcet disease Vasculitis secondary to infection (including hepatitis B associated polyarteritis nodosa), malignancies, drugs, including hypersensitivity vasculitis Vasculitis associated with connective tissue diseases lsolated vasculitis of the central nervous system Cogan syndrome When Should a Pediatrician Suspect Vasculitis in a Child? As a general rule, it would be appropriate to suspect vasculitis when confronted with multi-organ manifestations (Table 2) in the presence of constitutional features such as fever, weight loss, fatigue, myalgia with the presence of inflammatory markers such as anemia, leukocytosis, thrombocytosis and a raised erythrocyte sedimentation rate (ESR). Some forms of vasculitis involve only skin and typical skin changes will alert the pediatrician to the likelihood of vasculitis. Always, it should be remembered in children there may be secondary vasculitis and also conditions that may mimic vasculitis. (See below) What is the Initial Clinical Approach to a Child with Vasculitis? Some forms of childhood vasculitis are essentially clinical diagnoses. Entities such as KD and HSP, acute hemorrhagic edema of infancy (considered widely as an infantile form of HSP) are examples. In other situations if a detailed history and clinical examination suggests vasculitis, the next step is to categorize the dominant vessel size involved. This helps to prioritize the investigative process. Medium vessel involvement: Hypertension (renal vessels), abdominal pain (celiac axes), chest pain (coronaries), claudication (subclavian, femoral or iliac vessels), deep skin changes, gangrene (Fig. 1), focal deficits (cerebrovascular insufficiency/sudden blindness), orchitis (testicular) and neuropathy (vasa vasorum). Small vessel involvement (symptoms in richly vascularized organs): Purpura, superficial ulcers, mucosal ulcers, pulmonary and/or renal syndrome, ear-nosethroat disease and asthma. What is the Investigative Approach for a Child with Vasculitis with Regards to Radiology, Histopathology and Serology? Radiology Imaging techniques play a pivotal role in securing the diagnosis especially of medium and large vessel vasculitis. Digital Subtraction Angiography (DSA) Large vessel involvement: Absent pulses, bruits over aorta and vessels, hypertension, discrepant four limb blood pressure, congestive heart failure and cardiomyopathy. In large vessel vasculitis, conventional DSA is useful in demonstrating vessel stenoses (Fig. 2) or aneurysms and it Indian J Pediatr (2010) 77:1165–1171 Table 2 Multisystem manifestations of systemic vasculitis Organ/system involved Manifestation Skin and mucosa Oral / nasal ulcers Exanthema Livedo reticularis Purpura Panniculitis Nodules Edema Superficial ulcers Deep ulcers Gangrene Arthralgias / itis Myositis Hypertension 1167 tion exposure, complications at the arterial injection site and inability to delineate the arterial wall anatomy. MR Angiogram (MRA) Joints and Muscles Kidneys and Genitals GI Tract ENT Heart Brain and Nerves Eyes Lungs Hematuria Proteinuria Epidydymoorchitis Abdominal pain /colic GI bleed Gut infarction/ perforation Intussusception Epistaxis Nasal septal perforation Pan sinusitis /chronic ear discharge Sudden onset deafness, vertigo Subglottic stenosis Myocardial infarction, cardiomyopathy , Pericarditis, valvular incompetence, bruits, Absent pulses, Hypertension Discrepant blood pressure Claudication, Raynauds Stroke, meningo-encepahilitis,cranial nerve palsy, paraparesis, focal deficits, Mononeuritis multiplex Painful red eye Uveitis, keratoconjunctivitis Sudden blindness Fundoscopic abnormalities e.g. exudates hemorrhage Tracheal stenosis, Hemoptysis, pulmonary hypertension Nodules, cavities, infiltrates Asthma , serositis is the gold standard for the diagnosis of TA. It also has an important role in cases requiring surgical interventions such as angioplasty or stenting. The major limitations of DSA include invasiveness, high contrast load, high-dose radia- MR angiography can be useful in detection of early signs of large-vessel disease as for the DSA, and has the added advantage of potentially revealing evidence of ongoing large arterial wall inflammation. The only possible disadvantage is its relative insensitivity to slow flow or in-plane flow because of saturation of the MR imaging signal intensity, which can lead to overestimation of the severity of the stenosis or to a false diagnosis of vascular occlusion [4]. Computerised Tomography (CT) and Ultrasonography (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 [5]. USG provides a very good image of the carotid, axillary, brachial, and femoral arteries with a much higher resolution compared to CT or MRI. However, 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. Major advantages are non invasiveness, no radiation, wide availability and low cost. In addition, blood flow characteristics, wall elasticity, and plaques can be delineated. TA can be suspected by noting a long segment of diffuse, homogeneous, circumferential vessel wall thickening in the proximal common carotid artery, resulting in narrowing of the lumen or characteristic smooth, hyperechoic (bright) wall thickening which is known as “Macaroni phenomenon.” Furthermore, the stiffness of the Fig. 1 Gangrene of the toes in systemic PAN 1168 Indian J Pediatr (2010) 77:1165–1171 Fig. 2 Digital subtraction angiography demonstrating stenoses of a segment of the aorta and the left proximal renal artery involved arteries is increased which can be assessed by flow and spectral characteristics of the vessels [6]. 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. Hence in India where MRA, DSA and CTA may not be widely available, CDFI may have an important role. Lastly, 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 [7]. Since most imaging findings are not specific for any given condition, it is important to interpret the results of imaging in the broader clinical context. 2 D Echocardiogram In KD, this modality helps in detecting or excluding coronary artery aneurysms, intraluminal or mural thrombi, regurgitant cardiac valves, myocardial dysfunction, or pericardial effusion. Coronary angiography provides little information regarding microvascular coronary artery flow. [8]. Dobutamine stress echocardiography, Multi-slice spiral CT imaging and cardiac magnetic resonance angiography (CMRA) have been reported for non-invasive assessment of coronary arteries, but have limited resolution. Further establishment of sensitivity and specificity is required [9]. 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 and is usually completed under local anaesthesia. 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 [10]. 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 Histology Biopsy is the most definitive form of testing in vasculitides especially SVV. The choice of tissue is guided by the clinical setting using the most accessible involved organ or tissue. The biochemistry and serology laboratory play a relatively small role in the diagnosis of the various vasculitides. ANCA are present with a high specificity of up to 98% in the specific group of AAV. These are a group of mainly IgG antibodies Indian J Pediatr (2010) 77:1165–1171 against antigens in the cytoplasm of neutrophil granulocytes (the most common type of white blood cell) and monocytes. They are detected as a blood test in a number of autoimmune disorders, but are particularly associated with systemic vasculitis, the so called ANCA-associated vasculitides (AAV). Two staining patterns for ANCA are detected by ELISA. Cytoplasmic ANCA (C-ANCA) representing antibody to proteinase 3 is present in 90% of patients with active diffuse WG i.e., with high specificity. Perinuclear ANCA (P-ANCA) caused by antimyeloperoxidase antibody is suggestive of involvement of small to medium sized arteries in conditions such as microscopic polyangiitis. False positive ANCA are seen in various conditions. Although P-ANCA levels vary with activity of disease, with current level of evidence it is not recommended that P-ANCA be used for monitoring disease activity. Serology occasionally provides vital clues towards diagnosing certain types of vasculitides. Hypergammaglobulinemia due to ongoing immune activation is seen in systemic vasculitis. 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). The biochemistry and hematology laboratory are more helpful in monitoring organ function and disease activity. What Conditions Comprise the Differential Diagnoses of Primary Vasculitides? There are many disorders that may closely resemble the clinical, radiologic and/or pathologic features of the primary vasculitides. Infections, drugs and malignancies form major differential diagnoses. Many hereditary conditions may present in a similar manner to vasculitis. The common mimics of vasculitis are listed. (Table 3) 1169 How are Children with Vasculitis Managed? The management of vasculitis is dependent upon the diagnosis, the nature of symptoms and the extent of organ involvement [11]. From a quiet “wait and watch” or symptomatic therapy to the use of steroids alone or in combination with immunosuppresive agents such as cyclophosphamide or azathioprine, decisions are largely dependent on vessel size and which vascular bed is involved. KD is treated initially with IVIG (2 g/kg) and aspirin 20– 25 mgm q6h. When the acute stage has settled aspirin dose is reduced to antithrombotic doses (3–5 mg/kg/day for 6 weeks). Large vessel disease (TA) may be approached by a combination of drug therapy and invasive radiologic procedures such as dilatation or stenting. A summary of the principles of care of the common forms of vasculitis is provided. (Table 4) What is the Prognosis of the Various Vasculitides? Although systemic vasculitis is a potentially lifethreatening disorder, morbidity and mortality can be prevented if this disorder is recognized and treated early in its course. The highly individualised and varied prognosis depends not only on the type and extent of vessel involvement, but on the interval between disease onset and the start of treatment as well as the response to therapy. 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% [12]. KD has a good prognosis, with 1–2% acute mortality rate due to myocardial infarction, having been reduced Table 3 Vasculitis mimics Infections Inherited disorders Drugs /toxins Hypercoagulable states Malignancies Vasospastic disorders Multisystemic inflammatory disorder Miscellaneous Immunodeficiency disorders HIV, Hepatitis B virus, Hepatitis C virus, Hepatitis A virus, Mycobacterium, Herpes viruses, Infective endocarditis , Mycotic aneurysms, Protozoa Marfan’s syndrome, Ehlers Danlos syndrome type IV, Pseudoxanthoma elasticum, Neurofibromatosis type I, Fibromuscular dysplasia, Moyamoya disease Antibiotics (penicillins, aminopenicillins, sulfonamides), thiazides, warfarin/coumarin derivatives, NSAIDs, hydantoins Antiphospholipid antibody syndrome Leukemias, lymphomas Reversible cerebral vasoconstriction syndrome, Reversible posterior leukoencephalopathy syndrome Sarcoidosis Segmental arterial mediolysis, Cardiac myxoma, post radiation therapy Common variable immunodeficiency, HLA class 1 deficiency 1170 Indian J Pediatr (2010) 77:1165–1171 Table 4 Management principles of the common forms of childhood vasculitis Disease type Principles of care Comments Henoch Schonlein Purpura Symptomatic therapy with non steroidal antiinflammatory agents (NSAIDS)for most cases Kawasaki Disease IVIG+Aspirin Cutaneous PAN (C PAN ) PAN Steroids Steroids+iv pulse cyclophosphamide (monthly for 6 months) followed by low dose steroids+ azathioprine. Steroids+iv pulse cyclophosphamide (monthly for 6 months) followed by low dose steroids+ azathioprine. Steroids and Methotrexate Steroids selectively used for severe intestinal symptoms or alone/ in combination with immunosuppresives for severe renal involvement. Repeat doses of IVIG, Methylprednisolone or infliximab used for refractory cases Penicillin prophylaxis for post streptococcal cases Steroids alone may suffice for non renal, non neurologic disease. ANCA associated vasculitides TA 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. However, in that series, 30% of the patients were classified as having C- PAN, which typically has a more benign course than systemic PAN [2]. C-PAN has a good prognosis, albeit with recurrent relapses and remissions. Where evidence is present that streptococcal infections are frequent and possibly triggering the pathology, consideration should be given to the use of penicillin prophylaxis. 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. Damage to vital organs may have life-long consequences. 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. There is a relatively high mortality rate amongst children with AAV who do not receive treatment. IVIG in refractory cases. Selective role of methotrexate and cotrimoxazole in WG. Appropriate use of invasive radiologic procedures. or wholly clinical diagnosis, the rarer varieties can challenge one’s clinical acumen and be diagnosed only after extensive or invasive investigations. The clinical picture should give a clue to the choice of investigations with DSA or similar angiographic procedures being chosen for large/medium vessel disease and deep skin biopsies being helpful for medium and small vessel disease. Serology plays a small but distinct role in the identification of some vasculitides such as AAV. Treatment depends on the type of vasculitis. For some forms of vasculitis, such as KD, there are specific guidelines for treatment. For other vasculitides, the spectrum of care may range from supportive care with NSAIDs to immunosuppressive therapy with steroids alone or in combination with cyclophosphamide, azathioprine or other cytotoxic medications depending on the severity, the presence of organ involvement and which vascular bed is involved. Biologic agents are slowly becoming available as efficacy is being shown in some of the childhood vasculitides. These agents bring with them a promise of better control of the more severe forms of vasculitis in children. Contributions RPK was involved in conceptualising and designing the article. RPK and VV were involved in the review of literature and drafting the manuscript. Both authors read and approved the final manuscript. The authors certify that the article is original, is not under consideration by any other journal and has not been previously published. Role of Funding Source None. Conclusions Conflict of Interest None. The primary vasculitides are unusual conditions with some of them such as HSP and KD being seen almost exclusively and commonly in children. The classification of childhood vasculitis modifies and adapts from the adult classification into large medium and small vessel disease with the latter being subclassified into granulomatous and non-granulomatous varieties. While the commoner diseases such as HSP and KD are largely References 1. Rowley AH, Ozen S, Sundel RP, Saulsbury FT. A Clinician's Pearls and Myths in Rheumatology. London, Springer, 2009;219–29. 2. Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children. J Pediatr. 2004;145:517–22. Indian J Pediatr (2010) 77:1165–1171 3. Dillon MJ, Ozen S. A new international classification of childhood vasculitis. Pediatr Nephrol. 2006;21:1219–22. 4. Brogan PA, Davies R, Gordon I, Dillon MJ. Renal angiography in children with polyarteritis nodosa. Pediatr Nephrol. 2002;17:277–83. 5. 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