Vasculitis in critical illness

Contents

Overview

Vasculitis is inflammation of blood vessel walls, causing end-organ ischaemia, haemorrhage, or both. Patients with vasculitis may present to the ICU at first diagnosis — with pulmonary haemorrhage, acute kidney injury, or multiorgan failure — or may develop ICU-requiring complications during treatment. The ICU physician must recognise vasculitis in a broad differential, initiate timely immunosuppression, and manage the consequences of both disease and treatment.

Classification

The Chapel Hill Consensus Conference (2012) classifies vasculitis by vessel size:

Large vessel: Giant cell arteritis (GCA), Takayasu arteritis

Medium vessel: Polyarteritis nodosa (PAN), Kawasaki disease

Small vessel:

  • ANCA-associated: granulomatosis with polyangiitis (GPA, formerly Wegener's), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss)
  • Immune complex-mediated: IgA vasculitis (Henoch-Schönlein purpura), cryoglobulinaemic vasculitis, anti-GBM disease

Variable vessel: Behçet's disease

Single organ: Cutaneous leucocytoclastic vasculitis

Vasculitis may also be secondary to infection (hepatitis B/C, HIV), drugs (see drug-induced vasculitis), or malignancy.

ANCA-Associated Vasculitis

ANCA-associated vasculitis (AAV) is the most common systemic vasculitis to cause ICU admission. The three main conditions share pauci-immune small vessel inflammation (minimal or no immune complex deposition) and ANCA positivity.

Granulomatosis with polyangiitis (GPA): Granulomatous inflammation of the upper and lower respiratory tract plus pauci-immune glomerulonephritis. PR3-ANCA (c-ANCA) positive in most. Upper airway features: sinusitis, nasal crusting, saddle-nose deformity, subglottic stenosis. Lower respiratory: pulmonary nodules, cavitation, pulmonary haemorrhage.

Microscopic polyangiitis (MPA): Pauci-immune necrotising vasculitis without granulomas. MPO-ANCA (p-ANCA) positive in most. Predominantly causes necrotising glomerulonephritis and alveolar haemorrhage.

EGPA (Churg-Strauss): Eosinophil-rich granulomatous inflammation associated with asthma and blood eosinophilia. MPO-ANCA in ~40%. Cardiac involvement (eosinophilic myocarditis) is the leading cause of death.

Critical Presentations

Pulmonary-renal syndrome: Simultaneous alveolar haemorrhage and rapidly progressive glomerulonephritis. Causes include GPA, MPA, anti-GBM disease, and SLE. Alveolar haemorrhage presents with haemoptysis, progressive hypoxaemia, bilateral infiltrates on CXR, and a rising haemoglobin in BAL fluid (haemosiderin-laden macrophages on cytology). Despite haemoptysis, haemoglobin may paradoxically rise (iron sequestered in lung). AKI with haematuria and red cell casts on urinalysis is the renal signal. Diagnosis is urgent: renal biopsy confirms pauci-immune or immune-complex glomerulonephritis; ANCA serology; anti-GBM antibodies.

Rapidly Progressive Glomerulonephritis (RPGN): Crescent formation on renal biopsy, causing rapid AKI. Often requiring RRT at presentation.

Investigations

ANCA titre and type (MPO/PR3), anti-GBM antibodies, complement (low in immune complex disease), ANA/anti-dsDNA (SLE), hepatitis B and C serology, cryoglobulins. Urine microscopy for red cell casts. Renal biopsy (urgently in AKI). CT chest. Bronchoscopy and BAL if alveolar haemorrhage suspected.

Management

Induction: High-dose corticosteroids (methylprednisolone 500–1000 mg IV daily for 3 days, then prednisolone 1 mg/kg/day) plus cyclophosphamide (IV pulse preferred over oral in severe disease) or rituximab.

Rituximab: Non-inferior to cyclophosphamide for induction in AAV (RITUXVAS and RAVE trials), with similar remission rates. Rituximab is preferred in relapsed disease, in patients wishing to preserve fertility, and when cyclophosphamide toxicity is a concern.

Plasma exchange (PLEX): Used in severe alveolar haemorrhage or in patients with high anti-GBM titres. The PEXIVAS trial (Walsh et al., NEJM 2020) found that plasma exchange did not reduce the rate of end-stage renal disease or death in AAV at 12 months compared with immunosuppression alone. Plasma exchange is no longer recommended routinely for severe AAV renal disease, though it remains used in alveolar haemorrhage and in anti-GBM disease.

Maintenance: Following induction, maintenance therapy with azathioprine or rituximab for 18–24 months prevents relapse.

Large Vessel Vasculitis

Giant Cell Arteritis

GCA affects the aorta and its branches, predominantly in patients over 50. Cranial features (headache, scalp tenderness, jaw claudication, visual loss from anterior ischaemic optic neuropathy) are well recognised. Systemic features include polymyalgia rheumatica (proximal limb girdle pain and stiffness), constitutional symptoms, and elevated ESR/CRP.

ICU-relevant complications: aortic aneurysm and dissection (GCA causes aortopathy in 20–25%), mesenteric ischaemia, limb ischaemia.

Treatment: high-dose prednisolone (40–60 mg/day). When visual loss threatens, IV methylprednisolone 500–1000 mg daily for 3 days before oral therapy.

Takayasu Arteritis

Granulomatous inflammation of the aorta and its major branches, predominantly affecting women under 40. Clinical features depend on the vessels affected: arm claudication, absent pulses, renal hypertension, aortic regurgitation, and ischaemic stroke.

Other Vasculitides in the ICU

Anti-GBM disease (Goodpasture's): Autoantibodies against type IV collagen in glomerular and alveolar basement membranes. Classic presentation is pulmonary-renal syndrome, often with severe alveolar haemorrhage. Anti-GBM antibodies are confirmatory. Management: plasma exchange (to remove circulating antibody) plus immunosuppression.

Cryoglobulinaemic vasculitis: Immune complex deposition with cryoglobulins (proteins that precipitate at cold temperatures). Associated with hepatitis C (type II/III). Presents with purpura, arthralgia, peripheral neuropathy, and glomerulonephritis. Treatment targets the underlying infection (direct-acting antivirals for HCV) as well as immunosuppression.

Behçet's disease: Recurrent oral and genital ulceration, uveitis, skin lesions, and variable vessel involvement. May cause large vessel aneurysm (particularly pulmonary — risk of haemoptysis), venous thrombosis, or CNS involvement (neuro-Behçet's). Pulmonary artery aneurysm is a rare but life-threatening complication managed with immunosuppression and often endovascular intervention.

Management Principles

Do not delay immunosuppression in life-threatening vasculitis. The urgency of starting treatment often outweighs the delay needed to obtain biopsy confirmation, particularly in pulmonary-renal syndrome or alveolar haemorrhage. Empirical treatment can be started while investigations are completed.

Infection screening before immunosuppression: Latent TB (IGRA), hepatitis B (reactivation risk with rituximab/cyclophosphamide), HIV.

Complications of treatment: Cyclophosphamide causes haemorrhagic cystitis (prevent with mesna and adequate hydration), immunosuppression (PCP prophylaxis with co-trimoxazole), infertility. Rituximab causes severe B-cell depletion; hypogammaglobulinaemia and infection risk are long-term sequelae. High-dose corticosteroids cause hyperglycaemia, osteoporosis, infection susceptibility, and psychiatric effects.

RRT: AAV-associated AKI may require haemodialysis; recovery of renal function is possible even after dialysis-dependent disease if treated promptly.

Viva Questions

How do you recognise and initially manage pulmonary-renal syndrome in the ICU?

Pulmonary-renal syndrome is the combination of diffuse alveolar haemorrhage and rapidly progressive glomerulonephritis. It should be suspected in any patient with haemoptysis, bilateral pulmonary infiltrates, and concurrent AKI with active urinary sediment (haematuria, proteinuria, red cell casts on microscopy). The principal causes are ANCA-associated vasculitis (GPA or MPA), anti-GBM disease, and, less commonly, SLE. The diagnosis is urgent: blood should be sent immediately for ANCA (MPO and PR3), anti-GBM antibodies, ANA, and complement levels. Bronchoscopy with BAL confirms alveolar haemorrhage if the diagnosis is uncertain. Renal biopsy confirms the underlying pathology and guides treatment intensity. Management must not be delayed while results are awaited — start IV methylprednisolone 500–1000 mg daily. Respiratory support ranges from supplemental oxygen to HFNO or invasive ventilation depending on severity. Haemostatic measures are of limited value; the haemorrhage is immunologically driven and responds to immunosuppression. RRT may be required from the outset if AKI is severe.

What is the evidence for plasma exchange in ANCA-associated vasculitis?

The use of plasma exchange in AAV has been reassessed by the PEXIVAS trial (Walsh et al., NEJM 2020), which randomised 704 patients with severe AAV (defined by a creatinine >250 µmol/L or alveolar haemorrhage) to plasma exchange or no plasma exchange in addition to standard immunosuppression. At 12 months, there was no significant difference in the composite outcome of end-stage renal disease or death (28.4% in the plasma exchange group vs 31.0% in the control group). The trial also found no benefit in the alveolar haemorrhage subgroup. On the basis of this evidence, plasma exchange is no longer recommended routinely for severe renal disease in AAV. However, plasma exchange is still used in anti-GBM disease, where circulating anti-GBM antibodies are pathogenic and removal by apheresis reduces ongoing tissue injury. It may also still be considered for life-threatening alveolar haemorrhage on a case-by-case basis, pending further evidence.

What are the critical ICU presentations of EGPA and how are they managed?

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) typically presents in a patient with a history of asthma and blood eosinophilia. The critical presentations are cardiac, neurological, and respiratory. Eosinophilic myocarditis is the most feared complication and the leading cause of death: it presents with acute cardiomyopathy, arrhythmias, and heart failure, and may occur as the initial manifestation. Endomyocardial biopsy shows eosinophilic infiltration. Echocardiography typically shows diffuse myocardial dysfunction. Treatment requires high-dose corticosteroids urgently, with consideration of mepolizumab (anti-IL-5 monoclonal antibody) for corticosteroid-sparing in chronic disease. Mononeuritis multiplex from peripheral nerve vasculitis causes motor and sensory deficits. Pulmonary infiltrates are common but massive haemorrhage is less frequent than in GPA or MPA. ANCA is positive in only 40% of EGPA cases, so a negative ANCA does not exclude the diagnosis. The key investigation in a patient with asthma, eosinophilia, and cardiac or neurological features is immediate echocardiography, cardiac MRI, and specialist rheumatology input.