Abstract

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of rare, immune-mediated disorders that cause inflammation and necrosis of small blood vessels. In children, AAV is less common than in adults but often presents with severe, multi-organ involvement, including the kidneys, lungs, and upper respiratory tract. Early diagnosis and prompt treatment are crucial to prevent irreversible organ damage and improve long-term outcomes. Recent advances in immunology have led to improved understanding of the disease mechanisms and therapeutic strategies, including the use of corticosteroids and biologic agents such as rituximab. This review summarizes the epidemiology, pathogenesis, clinical features, diagnosis, treatment, and prognosis of ANCA-associated vasculitis in children.

Keywords: ANCA, vasculitis, children, autoimmune disease, glomerulonephritis, rituximab

Introduction

ANCA-associated vasculitis (AAV) refers to a group of autoimmune disorders characterized by inflammation and destruction of small to medium-sized blood vessels. The condition includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Although predominantly observed in adults, pediatric cases are increasingly recognized due to advances in diagnostic testing. I'm 3 (PR3) or myeloperoxidase (MPO), which play a central role in its pathogenesis.

Epidemiology

AAV in children is rare, with an estimated incidence of 0.5–1.0 per million per year. GPA is the most frequently reported subtype in pediatric populations. The disease shows a slight female predominance and typically affects children between 10 and 15 years of age. Genetic susceptibility and environmental triggers, such as infections or exposure to certain medications, are believed to contribute to disease onset.

Pathogenesis

The pathogenesis of AAV involves complex interactions between genetic, immunologic, and environmental factors. The presence of ANCA antibodies leads to activation of neutrophils, which subsequently release reactive oxygen species and proteolytic enzymes that damage vascular endothelium. Complement activation, particularly through the alternative pathway, further amplifies inflammation. T-cell and B-cell dysregulation also play key roles in disease perpetuation.

Clinical Manifestations

Children with AAV may present with nonspecific symptoms such as fever, malaise, and weight loss, followed by organ-specific manifestations.

Renal involvement often manifests as rapidly progressive glomerulonephritis with hematuria, proteinuria, and hypertension.

Respiratory symptoms include sinusitis, nasal crusting, cough, hemoptysis, or pulmonary infiltrates.

Cutaneous signs such as purpura and ulcers, and neurological involvement like peripheral neuropathy, may also occur.

Without timely treatment, AAV can lead to irreversible kidney failure and respiratory compromise.

Diagnosis

Diagnosis is based on clinical presentation, laboratory tests, and histopathology. 

Serologic detection of ANCA by immunofluorescence and enzyme-linked immunosorbent assay (ELISA) confirms the autoimmune nature of the disease

PR3-ANCA is commonly seen in GPA, while MPO-ANCA predominates in MPA. 

Imaging studies, such as chest CT, and renal or nasal biopsies help identify organ-specific involvement. Diagnostic criteria are based on the European League Against Rheumatism (EULAR) and Pediatric Rheumatology International Trials Organization (PRINTO) guidelines.Diagnosis of ANCA-Associated Vasculitis (AAV)

1. Clinical Evaluation

A detailed history and physical examination help identify the pattern of organ involvement:

Constitutional symptoms: Fever, fatigue, weight loss, malaise.

Organ-specific findings:

Kidney: Hematuria, proteinuria, renal impairment.

Lungs: Cough, hemoptysis, dyspnea.

ENT: Sinusitis, nasal crusting, hearing loss.

Skin: Purpura, ulcers.

Nerves: Peripheral neuropathy.

2. Laboratory Investigations

a) ANCA Testing

Indirect Immunofluorescence (IIF):

c-ANCA (cytoplasmic pattern) — most often due to anti-PR3 antibodies, common in Granulomatosis with Polyangiitis (GPA).

p-ANCA (perinuclear pattern) — due to anti-MPO antibodies, common in Microscopic Polyangiitis (MPA) and sometimes Eosinophilic Granulomatosis with Polyangiitis (EGPA).

ELISA (Enzyme-Linked Immunosorbent Assay):

Confirms and quantifies specific antibodies:

Anti-PR3 (proteinase 3)

Anti-MPO (myeloperoxidase)

b) Routine Laboratory Tests

Test Findings Purpose

ESR, CRP Elevated Inflammation markers

CBC Anemia, leukocytosis General inflammation

Serum creatinine, BUN Elevated Renal involvement

Urinalysis Hematuria, proteinuria, red cell casts Glomerulonephritis

Liver function tests May be altered Drug monitoring

Eosinophil count Elevated in EGPA Diagnostic clue

3. Imaging Studies

Findings / Use

Chest X-ray / CT scan Nodules, cavities, pulmonary infiltrates, alveolar hemorrhage

Sinus CT scan Sinusitis, bone destruction (especially in GPA)

MRI / CT (CNS) CNS involvement, granulomas

Ultrasound or CT of kidneys Assess renal size, exclude obstruction

4. Tissue Biopsy (Gold Standard)

Confirmatory test — provides histopathological evidence of vasculitis.

Kidney biopsy:

Pauci-immune necrotizing crescentic glomerulonephritis (typical finding).

Lung biopsy:

Granulomatous inflammation with necrosis and vasculitis.

Skin or nerve biopsy:

Leukocytoclastic vasculitis or necrotizing vasculitis.

5. Additional Diagnostic Criteria / Tools

American College of Rheumatology (ACR) and EULAR (European League Against Rheumatism) classification criteria can aid diagnosis.

Differential diagnosis should exclude:

Systemic lupus erythematosus (SLE)

Goodpasture’s syndrome

Cryoglobulinemic vasculitis

Infections and drug-induced vasculitis

Diagnostic Step Key Findings

Clinical evaluation Multi-organ involvement (kidneys, lungs, ENT, skin, nerves)

ANCA test (IIF/ELISA) PR3-ANCA or MPO-ANCA positivity

Routine labs Raised ESR/CRP, renal dysfunction, hematuria

Imaging Pulmonary or sinus lesions

Biopsy Pauci-immune necrotizing vasculitis (definitive)

Treatment

Treatment of AAV in children is divided into two phases: induction and maintenance of remission.

Induction therapy typically includes high-dose corticosteroids combined with cyclophosphamide or rituximab.

Maintenance therapy involves lower doses of corticosteroids with azathioprine or methotrexate to prevent relapse.

Recent evidence supports the use of biologics such as rituximab as an alternative to cyclophosphamide, especially in relapsing or refractory cases. Supportive care, including blood pressure control and infection prevention, remains essential.

Prognosis and Complications

With appropriate therapy, the prognosis of pediatric AAV has improved markedly over the past two decades. However, relapse occurs in approximately 30–40% of cases. Long-term complications may include chronic kidney disease, hypertension, and treatment-related side effects such as growth retardation or infertility due to cytotoxic drugs. Regular follow-up and early recognition of relapse are crucial for long-term survival.Complications of ANCA-Associated Vasculitis (AAV)

ANCA-associated vasculitis (which includes Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA)) can lead to a wide range of complications due to inflammation and destruction of small to medium blood vessels.

1. Renal (Kidney) Complications

Rapidly progressive glomerulonephritis (RPGN): A life-threatening condition leading to acute kidney injury and renal failure if untreated.

Chronic kidney disease (CKD): Results from persistent inflammation or scarring.

Hypertension and electrolyte imbalance due to renal dysfunction.

2. Pulmonary Complications

Diffuse alveolar hemorrhage: Caused by capillaritis, leading to hemoptysis, anemia, and respiratory failure.

Pulmonary fibrosis: Long-term inflammation can cause scarring and reduced lung function.

Nodules or cavitary lesions: Particularly in GPA.

3. ENT (Ear, Nose, Throat) and Airway Complications

Chronic sinusitis and nasal septum perforation (leading to saddle-nose deformity).

Subglottic stenosis: Narrowing of the airway due to inflammation and scarring.

Otitis media and hearing loss.

4. Neurological Complications

Peripheral neuropathy: Especially in EGPA (mononeuritis multiplex).

Central nervous system vasculitis: May cause stroke, seizures, or cognitive changes.

5. Cardiovascular Complications

Pericarditis and myocarditis.

Coronary arteritis: Can lead to myocardial infarction.

Heart failure: Secondary to long-term inflammation or hypertension.

6. Gastrointestinal Complications

Ischemia and infarction of bowel segments due to vasculitis.

GI bleeding or perforation.

7. Ocular Complications

Scleritis, uveitis, and orbital pseudotumor — may lead to vision loss if untreated.

8. Treatment-Related Complications

Due to prolonged immunosuppressive therapy:

Infections (bacterial, viral, fungal) due to immunosuppression.

Bone marrow suppression (from cyclophosphamide).

Malignancy risk: Especially bladder cancer and hematologic cancers.

Osteoporosis and diabetes mellitus: From long-term corticosteroid use.

9. Relapse and Chronic Organ Damage

AAV is prone to relapse, leading to progressive organ damage over time (especially kidneys and lungs).

Prevention and Follow-Up

There are no specific preventive measures for AAV, but early diagnosis and prompt initiation of immunosuppressive therapy can minimize organ damage. Vaccination and infection prophylaxis should be considered in immunocompromised children. Long-term monitoring with periodic ANCA testing, renal function assessment, and imaging is recommended to detect relapses early.

Conclusion

ANCA-associated vasculitis in children is a rare but severe autoimmune condition requiring prompt recognition and multidisciplinary management. Advances in immunopathogenesis understanding and biologic therapies have significantly improved patient outcomes. Continued research and international collaboration are essential to optimize pediatric treatment protocols and improve quality of life for affected children.

References

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