Diffuse alveolar hemorrhage (DAH) is caused by a group of disorders that result in hemorrhage originating in the alveoli and involving the lungs diffusely. DAH needs to be distinguished from localized pulmonary hemorrhage and hemorrhage secondary to other diseases (Table 29.1). This distinction is determined in part based on the clinical and radiologic findings. It is an important distinction in assessing for a potential etiology.

Most cases of primary DAH are due to an immune capillary injury, often resulting in capillaritis.^1,2 Capillaritis is commonly associated with glomerular disease and is discussed in detail in Chapter 47. The term “pulmonary-renal syndrome” refers to the acute onset of renal failure (generally in patients with autoimmune connective tissue diseases) and DAH of any cause.³

DAH has been described in most autoimmune disorders that involve the lung (see Chapter 47). Capillaritis is the most frequent cause of alveolar hemorrhage in these patients, followed by acute alveolar injury and thrombotic microangiopathy (TMA). In some cases, there is no histologic finding other than hemorrhage. Drugs used in the treatment of autoimmune diseases may precipitate DAH by immune-mediated mechanisms or direct lung toxicity. DAH usually occurs when there is active symptomatic disease. The mean duration of underlying autoimmune disease before onset of DAH varies and has been reported 15.7 months in systemic lupus erythematosus (SLE)⁴ and 6.4 years in systemic sclerosis.⁵

DAH is an uncommon complication of anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis, namely, granulomatosis with polyangiitis (Wegener granulomatosis),^6,7 microscopic polyangiitis,⁸ and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).⁹ These conditions are discussed in Chapters 48 and 49.

DAH in patients with SLE is usually caused by capillaritis¹⁰ and less frequently TMA.¹¹ The true incidence of various types of underlying pathology in DAH associated with lupus and other autoimmune diseases is probably unknown, however, since lung biopsies are often not performed. An autopsy-proven case of DAH in a patient with mixed connective tissue disease demonstrated hemorrhage without vasculitis or acute lung injury.¹² D-penicillamine, an immunosuppressive drug frequently prescribed in patients with Sjögren syndrome, rheumatoid arthritis, and systemic sclerosis may rarely result in DAH (see below). Like other autoimmune disease, DAH in systemic sclerosis has three most frequent causes, capillaritis, TMA (typically with scleroderma renal crisis), and penicillamine-related hemorrhage,¹³ and occurs more frequently when there is pulmonary fibrosis⁵ or after steroid treatment.³ The histologic changes of TMA are generally seen in the kidney and rarely documented in lung biopsies. DAH has been described in patients with Sjögren syndrome,¹⁴ cryoglobulinemia,^15,16 and rheumatoid arthritis,¹ the latter isolated to the lung.

Anti-glomerular basement membrane (GBM) disease (Goodpasture syndrome) is characterized by alveolar hemorrhage. Most patients are young, and there is an association with cigarette smoking. Chronic lung disease is rare in anti-GBM disease, although chronic renal failure is common. Renal outcome is relatively favorable, however, in the subgroup of patients with predominant pulmonary involvement.¹⁷

DAH is a rare complication of antiphospholipid syndrome (APS). As of 2014, fewer than 30 cases had been reported.^18,19 Previously, it was thought that microthrombi were the cause of the bleeding into the alveolar spaces. More recent data show that capillaritis is the predominant pathology.^20,21,22 The exact mechanism of neutrophil activation and recruitment, which are increased in bronchoalveolar lavage (BAL) fluid, is unknown.^19,23 APS-associated DAH is defined, in a patient with established APS and no other cause of DAH, as bilateral pulmonary infiltrates and BAL fluid containing gross blood or >20% hemosiderinladen macrophages.¹⁸ The predominant inflammatory cell in the BAL fluid is the neutrophil. DAH carries a very poor prognosis in the setting of APS.¹⁸

In cases of DAH associated with APS, hematologic features of disseminated intravascular coagulation, such as thrombocytopenia, elevated fibrin split products, and schistocytes on peripheral blood smear, are not necessarily present.¹⁸ “Catastrophic antiphospholipid syndrome” (CAPS) is characterized by disseminated intravascular thrombosis resulting in multiorgan failure and ischemic injury and often DAH. Patients with CAPS develop hemoptysis, respiratory failure, microangiopathic hemolytic anemia, thrombocytopenia, elevated fibrin degradation products, and renal failure.²⁴ Histologic features of TMA are present in the renal biopsies in patients with CAPS.²³

A number of medications have been associated with DAH, with a variety of mechanisms. Up to one-third of patients with Graves disease treated with propylthiouracil develop positive serum ANCA, usually against myeloperoxidase. Fewer than 5% of ANCA-positive patients develop small-vessel vasculitis of the skin or lungs, the latter resulting in DAH.^25,26,27

Another drug associated with immune-related vasculitis is D-penicillamine, which can result in the formation of an anti-GBM autoantibody and a Goodpasture-like syndrome⁵ as well as ANCA-mediated vasculitis.^3,28 Because patients receiving penicillamine often have conditions predisposing to vasculitis, it is difficult to ascribe the DAH to the drug, although vasculitis has been reported in patients on penicillamine for Wilson disease,²⁹ and DAH is more common in scleroderma patients taking penicillamine than those not on the drug.⁵ Coumadin treatment may predispose to DAH, especially when given with other drugs that may inhibit its metabolism^30,31 or in cases of overdose.³² Transplant patients receiving sirolimus and everolimus may experience DAH that appears related to administration of the drug.^33,34 Other drugs associated with DAH include leflunomide, often with methotrexate,³⁵ which is also associated with pauci-immune glomerulonephritis (leflunomide-pulmonary-renal syndrome); etanercept³⁶; nitrofurantoin,³⁷ which also causes a microangiopathic reaction³⁸; etanercept³⁶; and the tyrosine kinase inhibitor nilotinib.³⁹

Various inhaled agents have been associated with DAH, including cocaine,⁴⁰ trimellitic anhydride,⁴¹ and aluminum hydroxide generally unnatural deaths.⁴²

In rare cases, seronegative biopsy-proven capillaritis has been reported in the absence of autoimmune diseases or renal involvement. In this rare group of patients, prognosis appears favorable.²

The primary thrombotic microangiopathic syndromes (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) rarely result in DAH, despite the presence of diffuse microvascular thrombi. Disseminated intravascular coagulation is also not associated with DAH, other than in context with CAPS.

Secondary TMA is relatively common in autoimmune collagen vascular syndromes and may also occur after solid organ, bone marrow, or stem cell transplant.⁴³ “Scleroderma renal crisis” is characterized by TMA and the abrupt onset of renal failure, usually with hypertension, and may be complicated by DAH.^13,44 Patients with SLE may develop TMA with overlapping clinical features, which may be precipitated by nitrofurantoin therapy.³⁸