Answers

Short answers

1 Bilateral air space infiltration (figs 3 and 4) and haemoptysis suggest a relapse of Wegener’s granulomatosis, with pulmonary capillaritis causing diffuse alveolar haemorrhage. Pneumonia and pulmonary embolus are differential diagnoses. Haemoptysis could also be caused by bronchiectasis, malignancy, uraemia, coagulopathy, or congestive cardiac failure.

View larger version (288K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3 Chest radiograph showing bibasal and right upper lobe air space shadowing

View larger version (354K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4 Computed tomography of the chest confirming bilateral air space infiltrates (arrowheads) and surrounding ground glass shadowing

2 Bronchoscopy is useful because lavage specimens are increasingly blood stained in diffuse alveolar haemorrhage; gas transfer is raised on pulmonary function testing in this condition. Microbiological analysis of sputum, blood, and bronchoalveolar lavage specimens is needed to identify an infective component.

3 Diffuse alveolar haemorrhage—a severe complication of active vasculitis. Intravenous cyclophosphamide and methylprednisolone should be given promptly. Plasma exchange may be needed. Antimicrobials should be given if infection is suspected. Oral glucocorticoids, azathioprine, or mycophenolate can be used to maintain remission.

Long answers
1 Causes of haemoptysis
Common causes of haemoptysis include infection (especially atypical organisms such as Mycobacterium tuberculosis and fungi in immunosuppressed patients), bronchiectasis, pulmonary embolus, uraemia, congestive cardiac failure, coagulopathy, or malignancy.

The history of Wegener’s granulomatosis—a systemic vasculitis associated with cytoplasmic staining antineutrophil cytoplasmic antibodies (cANCA)—suggests that the symptoms might be caused by diffuse alveolar haemorrhage as a result of a relapse of active vasculitis. Diffuse alveolar haemorrhage is caused by pulmonary capillaritis, diffuse alveolar damage, or bland alveolar haemorrhage.^{1 2}

Although diffuse alveolar haemorrhage is a rare cause of haemoptysis, it should be suspected if glomerulonephritis (as in Goodpasture’s syndrome) or systemic vasculitis (such as Wegener’s granulomatosis or microscopic polyangiitis) is present. In Goodpasture’s syndrome, antibodies to type IV collagen are deposited along the alveolar and glomerular basement membranes, and this gives rise to haemoptysis and glomerular haemorrhage.³ Other rare causes of diffuse alveolar haemorrhage include systemic lupus erythematosus, Henoch-Schönlein purpura, IgA nephropathy, rheumatoid arthritis, Behçet’s syndrome, and cryoglobulinaemia.¹ Drugs such as propylthiouracil, carbimazole, and crack cocaine can also cause diffuse alveolar haemorrhage and positive ANCA serology.⁴

The occurrence of diffuse alveolar haemorrhage in such disorders is a sign of severe disease. Because the associated mortality is high, it is important to differentiate diffuse alveolar haemorrhage from other causes of haemoptysis.

2 Further investigations
Wegener’s granulomatosis is typified by upper airway granulomas. Symptoms of active disease include sinusitis, deafness, cough, visual disturbance, skin lesions (such as vasculitic rash or mucosal ulcers), arthralgia, arthritis, and eye signs (such as scleritis).

Our patient presented with haemoptysis, which is not always seen. He did not have dyspnoea, probably because of his good respiratory reserve and ability to compensate. More profound respiratory compromise can be a sign of severe vasculitis; mortality is high in such cases and ventilatory support may be needed. The new alveolar infiltrates on his chest imaging are typical of diffuse alveolar haemorrhage and are particularly suspicious when accompanied by a fall in haemoglobin, although microcytic anaemia is often absent in the acute setting.²

Bronchoscopy usually shows increasingly blood stained aspirates on sequential lavage, and haemosiderin laden macrophages may be present. Pulmonary function tests would be expected to show an increase in the transfer of carbon monoxide as a result of uptake by fresh blood. This test can be difficult to perform in acutely ill patients and may be less reliable 48 hours after the acute episode.

Wegener’s granulomatosis is characterised by cANCA and antibodies to proteinase 3 (PR3). Our patient had a high cANCA titre before admission, but it is unclear whether antibody titres are a good indicator of disease activity or a reliable guide to treatment.⁵

Antibodies to the glomerular basement membrane (anti-GBM) are consistently seen in Goodpasture’s syndrome, although positivity for both ANCA and anti-GBM is seen in some patients with Wegener’s granulomatosis. Antinuclear antibodies are seen in several connective tissue disorders and can be falsely positive in ANCA associated vasculitides and Goodpasture’s syndrome. If systemic lupus erythematosus is suspected, anti-double stranded DNA antibodies are highly specific and may also predict a flare in disease activity, particularly if concentrations of C4 and C3 are falling. The presence of anticardiolipin antibodies and lupus anticoagulant would support a diagnosis of systemic lupus erythematosus, but it could also be indicative of a pulmonary embolus secondary to an antiphospholipid syndrome.

Our patient had only trace amounts of protein and blood in his urine and a timed urine sample showed minimal protein. Creatinine was normal and no evidence of active sediment (casts) was seen on urine microscopy, which suggests that he had primarily a diffuse alveolar haemorrhage rather than a pulmonary-renal syndrome with acute glomerulonephritis.

In patients with symptoms of renal involvement (such as a rise in creatinine, active urinary sediment with casts, or heavy proteinuria), a renal biopsy should be considered to establish the presence of glomerulonephritis and the severity of renal injury, with a view to assessing potential response to treatment.⁶

In acute Wegener’s granulomatosis or microscopic polyangiitis, renal histology typically shows rapidly progressive (crescentic) glomerulonephritis, often on a background of focal segmental necrotising glomerulonephritis. Crescentic nephritis is also seen in Goodpasture’s syndrome, although in this case immunofluorescence shows linear deposition of anti-GBM antibodies on the glomerular basement membrane.³ This is in contrast to deposits of granular IgG and complement seen in immune complex mediated diseases such as systemic lupus erythematosus. Immunofluorescent staining in ANCA vasculitis is sparse, giving rise to the term "pauci-immune."^{7 8}

Open lung biopsy is hazardous and may not be discriminatory. Transbronchial biopsies are a safer alternative if the diagnosis is uncertain, but these are often unnecessary. Labelled red cell scans are occasionally used to localise the source of bleeding.

3 Diagnosis and treatment
Our patient had diffuse alveolar haemorrhage. Pulmonary haemorrhage reflects severe active vasculitis and the risk of death is high. Prompt aggressive treatment is crucial and referral to a specialist centre should be considered at an early stage.

Our patient, who was already taking methotrexate and low dose prednisolone, responded promptly to standard induction therapy of cyclophosphamide (pulsed intravenously to minimise side effects) and intravenous methylprednisolone.

He did not need plasma exchange, although it should be considered in such cases, especially if the patient relapses when given immunosuppressive treatment.⁹

Because our patient was febrile, had respiratory signs, and was immunosuppressed, he was given antibiotics to treat possible pneumonia. It is important in cases such as this that symptoms are not attributed to infection alone with the result that the true diagnosis is missed.

After he completed the course of cyclophosphamide he was given mycophenolate mofetil as maintenance therapy. Results of a randomised controlled trial of this approach are awaited, but several retrospective cohort studies support its role as induction therapy in refractory disease and as an alternative drug for maintaining remission.^{9 10} Unfortunately, two months later, he had a second flare-up, with diffuse alveolar haemorrhage, which required further cyclophosphamide. Maintenance therapy was then switched to azathioprine (as supported by the CYCAZAREM trial) and he has since remained stable.¹¹

Intravenous immunoglobulin may be useful in patients who are intolerant of or refractory to standard treatment, especially if they have concurrent infection. Patients with refractory disease should be referred to specialist centres experienced in the use of other new approaches, such as rituximab or anti-thymocyte globulin, although the evidence base for these treatments is limited.^{9 10} The results of a large randomised controlled trial of the tumour necrosis factor inhibitor, etanercept, in the treatment of Wegener’s granulomatosis have not been encouraging.¹²

The main differential diagnoses require a similar approach to treatment. Plasma exchange forms the mainstay of treatment in Goodpasture’s syndrome, in combination with cyclophosphamide and glucocorticoids. Pulsed methylprednisolone alone is inadequate.³ Diffuse alveolar haemorrhage associated with systemic lupus erythematosus may respond better to cyclophosphamide than corticosteroids, and plasma exchange may also be useful.^{2 13} The use of mycophenolate mofetil, rituximab, and azathioprine has also been described.

A considerable number of patients with diffuse alveolar haemorrhage need high dependency or critical care with mechanical ventilation, and the outcome is poorer in these patients. Correct diagnosis of diffuse alveolar haemorrhage and recognition of its severity is imperative so that appropriate treatment can be instituted.

Cite this as: BMJ 2009;338:b1461