Pulmonary Haemosiderosis

Pulmonary haemosiderosis is recurrent diffuse alveolar haemorrhage that leaves haemosiderin-laden macrophages and iron in the alveoli and interstitium. It causes anaemia, haemoptysis, and over time fibrosis.

• Idiopathic pulmonary haemosiderosis (a diagnosis of exclusion, mostly children aged 1 to 7 years, incidence about 1 per million children per year, with a smaller adult peak) and secondary forms.
• Secondary causes: antineutrophil cytoplasmic antibody associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis), anti-glomerular basement membrane disease (Goodpasture syndrome), systemic lupus erythematosus, antiphospholipid syndrome, mitral stenosis and chronic left heart disease.
• Other secondary causes: coeliac disease (Lane-Hamilton syndrome), cow's milk hypersensitivity (Heiner syndrome), drugs (penicillamine, nitrofurantoin, amiodarone, anticoagulants), bone marrow transplant, and inhaled toxins (trimellitic anhydride).
• Mechanism: capillaritis or capillary wall injury with bleeding into the alveoli; macrophages convert haemoglobin to haemosiderin over 48 to 72 hours.

Triad of haemoptysis (may be absent in young children who swallow blood), iron deficiency anaemia (often severe), and diffuse pulmonary infiltrates; cough, breathlessness, fever, pallor, fatigue, failure to thrive, wheeze.

• Acute episodes: rapid onset of respiratory distress with a fall in haemoglobin of 20 g/L or more, hypoxaemia and diffuse crackles; chronic course with recurrent episodes at intervals of weeks to months.
• Systemic features pointing to secondary disease: haematuria, hypertension and renal impairment (vasculitis, anti-glomerular basement membrane disease), sinus disease, rash, arthritis, diarrhoea and growth failure (coeliac disease), cardiac murmur (mitral stenosis), exposure history.
• Differential diagnosis: infection (tuberculosis, pneumonia), cystic fibrosis, bronchiectasis, pulmonary embolism, bleeding disorder, cardiac causes of haemoptysis, asthma, foreign body, vascular malformation, child abuse (suffocation) with intrapulmonary haemorrhage, pulmonary hypertension.
• Complications: respiratory failure, iron deficiency and iron overload from transfusion, pulmonary fibrosis, pulmonary hypertension, corticosteroid adverse effects, relapse, and death during massive haemorrhage (mortality about 10 to 25% in severe cases).

Chest X-ray: bilateral patchy or diffuse alveolar shadows, often sparing the apices and costophrenic angles, clearing in 2 to 3 days with reticular change later.

• High-resolution CT: ground glass opacities, consolidation, centrilobular nodules in acute bleeding; septal thickening and fibrosis in chronic disease.
• Blood tests: full blood count (microcytic hypochromic anaemia, reticulocytosis), ferritin, iron profile, clotting profile, creatinine, urinalysis for blood and protein, C-reactive protein.
• Immune tests: antineutrophil cytoplasmic antibody (anti-proteinase 3 and anti-myeloperoxidase), anti-glomerular basement membrane antibody, antinuclear antibody, anti-double stranded DNA, antiphospholipid antibodies, complement, tissue transglutaminase IgA with total IgA, and cow's milk precipitins or specific IgE.
• Bronchoalveolar lavage: serially bloody return in sequential aliquots, with haemosiderin-laden macrophages in more than 20% (haemosiderin score of more than 100); gastric aspirate for macrophages in young children; infection tests (Xpert MTB/RIF).
• Diffusing capacity for carbon monoxide is raised in acute haemorrhage (older children and adults); spirometry; echocardiogram for mitral stenosis and pulmonary hypertension.
• Biopsy (lung or kidney) when the diagnosis remains unclear: capillaritis or immune complex deposition for secondary forms, and bland haemorrhage with haemosiderin in idiopathic disease; endoscopic duodenal biopsy for coeliac disease.

Acute haemorrhage:

• Oxygen to SpO2 94 to 98%, and positive pressure ventilation with positive end-expiratory pressure for respiratory failure.
• Correct coagulopathy.
• Transfuse red cells to keep haemoglobin at 70 g/L or more (80 to 100 g/L if cardiac disease or severe hypoxaemia).
• Tranexamic acid 1 g IV every 8 hours for 24 to 48 hours (evidence limited).

• Immunosuppression for idiopathic and immune forms:
  • Methylprednisolone 500 to 1000 mg IV daily for 3 days (children 10 to 30 mg/kg daily, maximum 1 g) for severe bleeding.
  • Then prednisolone 1 mg/kg daily (usual 40 to 60 mg) for 4 weeks, with slow taper over 6 to 12 months to the lowest dose that prevents relapse (often 5 to 10 mg daily).
  • Inhaled budesonide 800 to 1600 micrograms daily has been used in children (evidence limited).
  • Steroid sparing: azathioprine 2 mg/kg daily (check thiopurine methyltransferase), hydroxychloroquine 5 to 6.5 mg/kg daily (maximum 400 mg), or methotrexate 10 to 15 mg weekly with folic acid 5 mg weekly.
  • Cyclophosphamide 500 to 750 mg/m2 IV monthly or rituximab 375 mg/m2 weekly for 4 weeks (or 1 g twice 2 weeks apart) in refractory or relapsing disease.
• Vasculitis and systemic lupus: methylprednisolone 500 to 1000 mg IV daily for 3 days then prednisolone 1 mg/kg daily tapered, with rituximab 375 mg/m2 weekly for 4 weeks or cyclophosphamide 15 mg/kg IV every 2 to 3 weeks for 6 doses.
• Plasma exchange for severe pulmonary haemorrhage with renal involvement (7 sessions in 14 days, 60 mL/kg with 5% albumin).
• Anti-glomerular basement membrane disease: plasma exchange daily for 14 days or until antibody is undetectable, with cyclophosphamide 2 mg/kg daily (reduce for age and renal function) and prednisolone 1 mg/kg daily.
• Antiphospholipid syndrome: heparin and warfarin to INR 2.0 to 3.0 only once the bleeding source is controlled, with specialist advice.
• Coeliac disease: a strict lifelong gluten free diet, with dietitian input; cow's milk hypersensitivity: a strict milk free diet with calcium and vitamin D supplementation.
• Mitral stenosis: balloon valvotomy or valve replacement, diuretics (furosemide 20 to 80 mg daily), and anticoagulation as indicated.
• Iron replacement (keep stores replete): ferrous sulfate 200 mg three times daily for 3 months (children 3 to 6 mg/kg/day of elemental iron), or intravenous ferric carboxymaltose 1000 mg once (maximum 20 mg/kg) when oral iron fails; monitor ferritin for iron overload after repeated transfusions.
• Steroid safety: co-trimoxazole 480 mg daily or 960 mg three times weekly for Pneumocystis prophylaxis when prednisolone is 20 mg or more for 4 weeks; calcium and vitamin D; bone protection; growth monitoring in children; vaccination (influenza and pneumococcal conjugate).
• Special groups: children (growth, weight-based dosing, school support, vaccination).
• Pregnancy (risk of relapse; prednisolone and azathioprine are acceptable, avoid cyclophosphamide, methotrexate and rituximab in the first trimester, antiphospholipid treatment with low molecular weight heparin 40 mg SC daily).
• Elderly (consider vasculitis and cardiac causes).
• Renal impairment (adjust cyclophosphamide, azathioprine and methotrexate; plasma exchange for renal disease).
• Immunosuppression (prophylaxis and vaccination).
• Red flags: massive haemoptysis, haemoglobin fall of 20 g/L or more, respiratory failure, haematuria or rising creatinine, new neurological or skin signs, pulmonary hypertension.
• Follow-up: full blood count and ferritin every 1 to 3 months, chest X-ray with each episode, spirometry and diffusing capacity every 3 to 6 months, creatinine and urinalysis every 3 months in vasculitis, CT yearly or with new symptoms.
• The 5 year survival is about 70 to 85% with treatment (approximate).