Pulmonary Capillaritis

Pulmonary capillaritis is a small vessel inflammation of the alveolar septal capillaries, with neutrophilic infiltration, fibrinoid necrosis and disruption of the capillary wall. It is the commonest histological cause of diffuse alveolar haemorrhage.

It occurs with ANCA-associated vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis), anti-glomerular basement membrane disease, systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, systemic sclerosis, mixed cryoglobulinaemia, Behçet disease, drugs (propylthiouracil, hydralazine, penicillamine, levamisole adulterated cocaine), stem cell transplantation, and as an isolated pauci-immune capillaritis with no systemic disease.

Pathophysiology. Neutrophils activated by ANCA or immune complexes release enzymes and reactive oxygen species, which damage the capillary basement membrane and endothelium. Red cells leak into the alveoli, and the haemorrhage fills the airspaces. Repeated bleeding leads to haemosiderin laden macrophages and, in time, fibrosis.

Cough, dyspnoea, haemoptysis (absent in a third, even with severe bleeding), fever, pleuritic pain, anaemia with a falling haemoglobin, and hypoxaemia that may progress to respiratory failure over hours to days. Features of the systemic disease: haematuria or renal failure (glomerulonephritis), sinus disease, rash, arthritis, neuropathy and eye disease.

Rapidly worsening hypoxaemia, a falling haemoglobin or renal impairment needs urgent admission, since mortality is high without early immunosuppression.

• Bilateral alveolar infiltrates on chest radiograph and CT: ground glass opacity and consolidation, central and perihilar, sparing the apices and costophrenic angles, with later septal thickening.
• Bronchoalveolar lavage: progressively more bloody return in sequential aliquots, over 20% haemosiderin laden macrophages (at 48 to 72 hours after bleeding), and neutrophils.
• DLCO is often raised (over 130% predicted, by red cell uptake of carbon monoxide) in acute haemorrhage, a useful bedside clue.
• Laboratory tests: haemoglobin and iron studies, creatinine, urinalysis with microscopy (dysmorphic red cells and casts), C-reactive protein, ANCA (myeloperoxidase and proteinase 3), anti-glomerular basement membrane antibody, antinuclear antibody, anti-double-stranded DNA, complement, antiphospholipid antibodies, cryoglobulins, and rheumatoid factor.
• Biopsy: renal biopsy for glomerulonephritis is easier and safer than lung biopsy. Surgical lung biopsy shows neutrophilic infiltration of the septa, fibrinoid necrosis and haemorrhage, and is needed only if the cause is unclear.
• Exclude infection, heart failure, coagulopathy, mitral stenosis and drug causes.

Differential diagnosis.

• Bland pulmonary haemorrhage (without inflammation)
• Heart failure and pulmonary oedema
• Pneumonia including opportunistic infection
• Coagulopathy and anticoagulant bleeding
• Goodpasture disease (anti-glomerular basement membrane)
• Idiopathic pulmonary haemosiderosis

• Oxygen and respiratory support: high flow oxygen, non-invasive ventilation or invasive ventilation with lung protective settings, and extracorporeal membrane oxygenation for refractory hypoxaemia. Transfuse red cells to keep haemoglobin over 70 g/L, and correct coagulopathy.
• Remission induction in severe disease: methylprednisolone 500 to 1000 mg intravenously daily for 3 days, then prednisolone 1 mg/kg daily (maximum 60 to 80 mg) with a taper over 4 to 6 months (or a reduced dose regimen).
• Add rituximab 375 mg/m2 weekly for 4 weeks (or 1 g on days 1 and 15), or cyclophosphamide 15 mg/kg intravenously every 2 weeks for 3 doses, then every 3 weeks, for 3 to 6 months. Rituximab is preferred in relapsing disease and in younger patients, and cyclophosphamide is reduced for age and renal function.
• Plasma exchange (7 sessions over 14 days, each 60 mL/kg with albumin replacement) for severe alveolar haemorrhage with respiratory failure, severe renal disease (creatinine over 300 micromol/L), or anti-glomerular basement membrane disease.
• Avacopan 30 mg twice daily as a steroid sparing agent in ANCA vasculitis.
• Maintenance in ANCA vasculitis: rituximab 500 mg every 6 months for 24 months or longer, or azathioprine 2 mg/kg daily (after thiopurine methyltransferase testing).
• Other causes: stop the offending drug (propylthiouracil, hydralazine), and antiphospholipid syndrome needs steroid, anticoagulation and plasma exchange with specialist care. Lupus: steroid with cyclophosphamide or rituximab, and hydroxychloroquine 200 to 400 mg daily.
• Prophylaxis during immunosuppression: co-trimoxazole 960 mg three times weekly (Pneumocystis), proton pump inhibitor, calcium and vitamin D, and bone protection.
• Isolated pauci-immune pulmonary capillaritis: steroid with azathioprine or mycophenolate mofetil (1 g twice daily), with relapse monitoring.

Complications and prognosis. Respiratory failure, relapse (30 to 50% in ANCA disease), pulmonary fibrosis, infection from immunosuppression, and renal failure. In hospital mortality of severe haemorrhage is 20 to 50%.

Monitoring. Daily haemoglobin, oxygen and creatinine in acute illness, then weekly for the first month, ANCA titres and B cell counts in follow up, spirometry with DLCO at 3 and 6 months, and review of drug toxicity.

Referral and escalation. Refer immediately to a nephrology, rheumatology or vasculitis service, and to intensive care for respiratory failure.