anca vasculitis in pediaric pts .pptx

anca vasculitis in pediaric pts .pptx

1. ANCA positive vasculitis in children Pramodhiya Sanduni Perera Grp 10 Sem 12

2. Introduction Childhood-onset anti- neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAVs) are a group of systemic autoimmune disorders characterized by inflammatory cells infiltration , necrosis of small-medium blood vessels and autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA ) or myeloperoxidase ( MPOANCA ). F> M

3. CAUSES AAVs may be primary or secondary. Several factors may have a role: Genetic : PR3-ANCA correlating with HLA-DP and genes encoding alpha-antitrypsin and proteinase 3, whereas anti-MPO-ANCA is mainly associated with HLA-DQ. Dysregulation of adaptive and innate immunity: involving B- and T-CD8+ memory cells, leading to a pathogenic production of ANCA and neutrophils activation. A role of complement alternative pathways has been proposed, especially of anaphylatoxin C5a and C5a receptor. Environmental triggers : silica, farming or organic solvents, associated with an increased risk of EGPA. Infections : Staphylococcus aureus , HIV or COVID-19 can be triggers. Drugs : penicillamine , propylthiouracil , dapsone and cocaine adulterated with levamisole . The presence of both anti-MPO and anti-PR3 antibodies in the same patient suggests drug-induced vasculitis .

4. GPA MPA EGPA

5. Granulomatosis with polyangiitis (GPA) Wegener granulomatosis Small-to-medium-sized vessel ANCA-associated systemic necrotizing vasculitis Granulomatous inflammation within arterial wall, perivascular, or extravascular area Affects nose+paranasal sinuses, respiratory tract and the kidneys Abs are against serine proteinase-3 Ag The classic triad – lungs: involved in 95% of cases// upper respiratory tract / sinuses: 75-90%// kidneys: 80% with pauci -immune crescentic glomerulonephritis . classical: full triad// limited: usually respiratory tract only/// widespread: skin (50%)eyes (45%)peripheral nervous system (35%)heart-GI

6. nose+paranasal sinuses, respiratory tract and the kidneys Chronic or recurrent sinusitis -- early manifestations Mucosal thickening of the paranasal sinuses and nasal septum perforation Erosion of the nasal turbinates and bony of the paranasal sinuses Pulmonary nodules

7. EULAR/ PReS classification criteria includes 3/6 Hematuria or proteinuria Granulomatous inflammation on biopsy Nasal sinus inflammation Subglottic/tracheal/ endobronchial stenosis Abnormal chest imaging Positive PR 3 ANCA or c-ANCA staining Granulomatosis with polyangiitis (GPA)

8. Granulomatosis with polyangiitis (GPA) Hematuria/proteinuria Granulomatous inflammation Nasal sinus inflammation Subglottic/tracheal/ endobronchial stenosis Abnormal chest imaging PR 3 ANCA or c-ANCA staining

9. Variable-sized lung nodules commonly > 5 mm (mms-10 cm) Cavitation (common in nodules > 2 cm) with either thin or thick wall Ground glass opacities and air space – hemorrhage/debris Perivascular fluffy or hazy multifocal opacities Mosaic perfusion Granulomatosis with polyangiitis (GPA)

10. Subglottic tracheal and bronchial stenosis Focal/diffuse DDx prolonged intubation, TB, amyloidosis or adenoid cystic tumors Long-standing bronchial stenosis >> recurrent chest infection and lung collapse Granulomatosis with polyangiitis (GPA)

11. Granulomatosis with polyangiitis (GPA) bilateral largesized pulmonary nodules with a small cavity

12. GPA >> necrotizing GN >> RPGN If absence of significant imaging findings >> rely on clinical+lab tests (e.g. Bx ) Typically PR3-ANCA positive. CT , MRI, PET scan may reveal large-/medium-sized vessel involvement Thrombosis , aneurysms, aortic dissection and aortic rupture Granulomatosis with polyangiitis (GPA) Diagnosis requires 3 of the following criteria: Typical histopathological findings Upper airway involvement Laryngo - tracheo -bronchial stenosis Pulmonary/renal involvement ANCA positivity

13. Treatment Induction Therapy (for Severe Disease) Used when lower respiratory tract or kidneys are significantly involved. Corticosteroids : 2 mg/kg/day (oral) OR 30 mg/kg/day for 3 days (IV pulse therapy) Cyclophosphamide : 2 mg/kg/day (oral daily) Rituximab : Alternative induction therapy for ANCA-positive vasculitis , primarily studied in adults. Maintenance Therapy (After Remission Achieved, 3–6 Months) Less toxic immunosuppressants : Methotrexate Azathioprine Mycophenolate mofetil Adjunct Therapy Trimethoprim-Sulfamethoxazole (TMP-SMX) : One 180 mg/800 mg tablet 3 times per week Used for Pneumocystis jiroveci pneumonia (PJP) prophylaxis . Helps reduce upper respiratory bacterial colonization with Staphylococcus aureus , which can trigger disease flares. Limited Disease (Upper Respiratory Tract Only) Corticosteroids (1–2 mg/kg/day, oral) Methotrexate (0.5–1.0 mg/kg/week, oral or subcutaneous) Complications Upper Respiratory Tract Complications Lesions invading the orbit → Risk of optic nerve damage and vision loss . Ear involvement → Can lead to permanent hearing loss . Subglottic stenosis → Can cause life-threatening upper airway obstruction . Pulmonary Complications Pulmonary hemorrhage → Potentially fatal . Chronic lung disease from granulomatous inflammation and scarring → Increased risk of infections. Renal Complications Chronic glomerulonephritis Can progress to end-stage renal disease (ESRD) if not treated effectively. Prognosis Variable disease course Relapse occurs in up to 60% of patients Mortality significantly reduced with: Cyclophosphamide Other immunosuppressive agents Children vs. Adults : Children are more likely to develop: Multiple organ involvement Renal disease Subglottic stenosis

14. Microscopic polyangiitis (MPA) Involves lungs and kidneys Renal disease is most frequent manifestation ( pauci -immune necrotizing crescentic glomerulonephritis ). No upper airway and non-granulomatous inflammation p-ANCA; directed against the myeloperoxidase Ag MPO-ANCA Pulmonary capillaritis >> pulmonary hemorrhage + renal dz >> pulmonary-renal syndrome

15. Presentation: Hypertension, edema, proteinuria , and hematuria . Pulmonary involvement: Less frequent and milder than GPA, may lead to hemoptysis , anemia, pulmonary hemorrhage. Eye involvement: Episcleritis , conjunctivitis. Nervous system: Peripheral neuropathy. Cardiovascular system: Similar to GPA.

16. Microscopic polyangiitis (MPA)

17. Eosinophilic granulomatosis with polyangiitis (EGPA) Churg -Strauss syndrome Necrotizing granulomatous inflammation Patients present asthma, sinusitis, lungs infiltrates, eosinophilia and nasal polyps . Literature reports associated cardiomyopathy , skin lesions such as purpura and urticarial skin rash, gastrointestinal involvement and neuropathy. Kidney biopsy is characterized by prominent eosinophil rich inflammation in granulomas surrounding necrotizing AAV in vasculitis of interlobular-sized and larger vessels. MPO-ANCA are detected. ANCA positivity is more frequently seen with GN

18. Transient, bilateral consolidation with symmetrically peripheral location (90 % of patients) +/- Peribronchial or patchy random distribution +/- Septal lines (50 % of patients) Eosinophilic granulomatosis with polyangiitis (EGPA)

19. EULAR/ PreS classification: 4/6 Eosinophilic granulomatosis with polyangiitis (EGPA) Asthma > 10% Eo in WBC count Mono-/polyneuropathy from systemic vasculitis Migratory/transient pulmonary opacities Paranasal sinus abnormalities Extravascular Eos in a biopsy

20. Diagnosis of ANCA-Associated Vasculitis (AAV) Biopsy : Gold standard for diagnosis. Laboratory tests : Inflammatory markers, complete blood count, kidney, liver, thyroid, and pancreatic function. Immunological screening : ANCA positivity (PR3-ANCA in GPA, MPO-ANCA in MPA, EGPA, and renal-limited vasculitis ). C-ANCA typically in GPA (PR3-ANCA), P-ANCA in MPA, EGPA (MPO-ANCA). Infectious disease screening : Rule out bacterial endocarditis . Imaging : Chest X-ray, CT, or MRI to assess organ involvement.

21. Management of AAV Goal : Induction of remission and prevention of relapses. Induction therapy (for patients with normal kidney function): Steroids and mycophenolate mofetil (MMF). Severe cases: Intravenous methylprednisolone , rituximab or cyclophosphamide , plasma exchanges. Maintenance therapy (2–4 years): Steroids in tapering doses. Rituximab or MMF (more effective than azathioprine for renal involvement). Alternatives: Oral cyclophosphamide or methotrexate . Kidney transplantation : Recommended for children with kidney failure in clinical remission.

22. Prognosis Children: Higher relapse rates, more severe damage, and longer maintenance therapy than adults. Low mortality (multicenter study): 61% achieved inactive disease at 12 months with induction therapy ( cyclophosphamide /RTX/MTX) followed by maintenance therapy (RTX, MMF, AZA, MTX). Kidney involvement: 1/3 had kidney damage (persistent proteinuria , eGFR <50%, kidney failure). Renal survival at 1 year: 70%, at 10 years: 60%. Severe kidney involvement at diagnosis: Strong predictor of poor long-term renal outcome. eGFR <50 mL /min/1.73m²: 50% risk of death or kidney failure at 5 years. Histological patterns (sclerotic/mixed) correlate with worse prognosis. Morbidity: Relapses, therapy side effects, and disease-related damage.

23. Case report

24. Case Presentation Initial Symptoms and Diagnosis A previously healthy 16-year-old female with a history of asthma was diagnosed with mild COVID-19. Approximately one week after recovery, she developed: Persistent cough and wheezing (non-responsive to bronchodilators). Hearing loss , arthralgia , and rash . Sinus pain , ear drainage , and chest tightness . Initial tests included: Chest X-ray: Normal at first but later showed progression to lung nodules. CT scan: Revealed bilateral pulmonary nodules , cavitary lesions, and bronchiectasis . Blood tests: Elevated inflammatory markers (CRP, ESR), positive C-ANCA and anti-PR3 antibodies . Aspergillus and tuberculosis tests: Negative. Kidney function: Normal. Progression of Symptoms Over a period of three months , her symptoms worsened despite multiple treatments, including: Antibiotics ( azithromycin , cefdinir , doxycycline ). Systemic corticosteroids (prednisone). Bronchodilators and inhaled corticosteroids. Additional findings: Bilateral serous otitis media requiring tympanostomy tube placement. Moderate obstructive lung disease on pulmonary function tests. Definitive Diagnosis and Treatment Based on ANCA positivity , respiratory symptoms , hearing loss , and radiographic findings , a diagnosis of granulomatosis with polyangiitis (GPA) , a subtype of AAV, was made. Treatment included: Induction therapy with rituximab and corticosteroids. Mycophenolate mofetil for maintenance therapy. Follow-up at six months showed: Significant improvement in lung lesions and pulmonary function. Persistent bilateral hearing loss , requiring hearing aids.

25. Discussion Comparison with Other Cases Four pediatric cases of AAV following COVID-19 (including this case) were identified. Common features among pediatric cases: Lung involvement : Multifocal nodules, cavitary lesions, alveolar hemorrhage . ANCA positivity : 2 with anti-PR3/C-ANCA and 2 with anti-MPO/P-ANCA. Treatment response : Marked improvement with corticosteroids and rituximab , except for persistent hearing loss in one case. Treatment was similar in both groups, including rituximab , corticosteroids, and cyclophosphamide for severe cases. A literature review found six adult cases of AAV following COVID-19, showing similarities such as: Pulmonary involvement ( cavitary lesions, alveolar hemorrhage ). Positive ANCA serology (either C-ANCA/PR3 or P-ANCA/MPO). Variable kidney involvement , with adults more likely to develop severe glomerulonephritis . Favorable treatment response , except for persistent hearing loss in one adult and one pediatric case. Possible Mechanisms Linking COVID-19 and AAV Viral infections, including Epstein-Barr virus and cytomegalovirus , have been implicated in triggering autoimmunity. Proposed mechanisms include: Molecular mimicry (SARS-CoV-2 proteins triggering autoantibody production). Neutrophil activation and immunothrombosis , leading to tolerance failure and ANCA production.

26. 5. Conclusion This case adds to growing evidence that COVID-19 may trigger autoimmune diseases , including AAV . Pediatric patients with post-COVID-19 AAV tend to have: Severe pulmonary involvement but mild or no kidney disease . Good treatment response , with rituximab and corticosteroids improving symptoms. Persistent hearing loss in some cases. Physicians should consider AAV in children presenting with pulmonary and renal symptoms following COVID-19, as early treatment can significantly improve outcomes.

27. References Silvia Bernardi , Laure Seugé , Olivia Boyer, ANCA-associated vasculitis in children,  Nephrology Dialysis Transplantation , Volume 38, Issue 1, January 2023, Pages 66–69,  https://doi.org/10.1093/ndt/gfac265 http://pubs.rsna.org/doi/full/10.1148/rg.344135028 Nelson book of pediatrics - 20 th edition