The diffuse alveolar hemorrhage syndromes

INTRODUCTION — Bleeding into the alveolar spaces of the lungs characterizes the syndrome of diffuse alveolar hemorrhage (DAH) and is due to disruption of the alveolar-capillary basement membrane. This disruption is caused by injury or inflammation of the arterioles, venules, or alveolar septal (alveolar wall or interstitial) capillaries. Hemoptysis is the usual presenting symptom; however, it is not always present, even when hemorrhage is severe [1-3].

An overview of the DAH syndromes will be presented here. The evaluation and treatment of hemoptysis are discussed separately. (See "Evaluation of nonlife-threatening hemoptysis in adults" and "Evaluation and management of life-threatening hemoptysis" and "Etiology of hemoptysis in adults".)

ETIOLOGY AND HISTOLOGY — A variety of diseases are associated with the development of the diffuse alveolar hemorrhage (DAH) syndrome (table 1) [1,3-21]. The underlying cause of DAH is generally reflected in the histopathologic pattern, which therefore has both therapeutic and prognostic implications. One of three different histopathologic patterns may be seen: pulmonary capillaritis, bland pulmonary hemorrhage, and diffuse alveolar damage (DAD).

Pulmonary capillaritis — The pathologic pattern of pulmonary capillaritis, also referred to as alveolar capillaritis, is characterized by neutrophilic infiltration of the alveolar septa (lung interstitium) (picture 1A-B), which sequentially leads to necrosis of these structures, loss of capillary structural integrity, and spilling of red blood cells into the alveolar space and interstitium [3-6,22-25].

Many of the neutrophils undergo fragmentation and eventually become pyknotic, findings which support a pathogenetic role for neutrophil by-products (toxic oxygen radicals and proteolytic enzymes) in this form of lung injury. The fragmented neutrophils, nuclear dust, and fibrin also enter the alveolar spaces, and true fibrinoid necrosis of the interstitium may be seen.

Causes of pulmonary capillaritis include the systemic vasculitides, antiglomerular basement membrane (anti-GBM; Goodpasture) disease, rheumatic diseases, certain drugs, and idiopathic pulmonary capillaritis (table 1). Idiopathic pulmonary capillaritis, also known as pauci-immune pulmonary capillaritis, is characterized by the histopathologic findings of pulmonary capillaritis, but without clinical or serologic evidence of an associated systemic illness [16]. It is classified within the family of idiopathic, small-vessel vasculitides, despite being antineutrophil cytoplasmic antibody negative [26].

Bland pulmonary hemorrhage — Bland pulmonary hemorrhage is characterized by hemorrhage into the alveolar spaces without inflammation or destruction of the alveolar structures (picture 2). Causes include elevated left ventricular end diastolic pressure, bleeding disorders, and anticoagulant therapy (table 1) [27-29]. Occasionally, anti-GBM disease or systemic lupus erythematosus can cause bland hemorrhage, although they are more commonly associated with pulmonary capillaritis.

Diffuse alveolar damage — DAD, the underlying lesion of the acute respiratory distress syndrome (ARDS), can lead to alveolar hemorrhage (picture 3) [30-33]. DAD is characterized by edema of the alveolar septa and by formation of hyaline membranes that line the alveolar spaces. DAD has numerous causes, including cytotoxic and noncytotoxic drugs, infection, including coronavirus disease 2019 (COVID-19), rheumatic diseases, and other causes of ARDS (table 1) [34,35]. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

CLINICAL PRESENTATION — Patients with diffuse alveolar hemorrhage (DAH) present with a constellation of symptoms, signs, and laboratory results that may suggest a specific underlying diagnosis (eg, granulomatosis with polyangiitis, complications of drug therapy) or only permit the general diagnosis of the syndrome without favoring a specific etiology.

Issues relating to the general presentation of patients with DAH will be reviewed first, followed by a discussion of the clinical findings that favor the diagnosis of a specific underlying cause.

Symptoms and signs — The onset of DAH is most often abrupt or of short duration (less than seven days). Common initial symptoms are often nonspecific and may include cough, hemoptysis, fever, and dyspnea, although hemoptysis may be absent at presentation in one-third of patients. Some patients, however, present with acute severe respiratory distress requiring immediate ventilatory support with mechanical ventilation.

The pulmonary examination is usually nonspecific; tachypnea, crackles, or bronchial breath sounds may be noted. The findings associated with individual causes of DAH are described below. (See 'Clinical features' below.)

Radiographic findings — A chest radiograph is obtained in virtually all adults with recent onset of hemoptysis or dyspnea. The chest radiograph findings in DAH are nonspecific and most commonly show new patchy or diffuse opacities (image 1A-B).

The finding of diffuse opacities on chest radiograph usually leads to thoracic computed tomography (CT) scanning to further characterize the abnormalities if the patient is sufficiently stable. In DAH, the characteristic findings on CT are ground glass or consolidative opacities that are usually diffuse and bilateral (image 2), but may occasionally be unilateral. These opacities tend to be more central than peripheral [36].

Recurrent episodes of DAH may lead to pulmonary fibrosis and reticular opacities, as seen in some patients with idiopathic pulmonary hemosiderosis [3]. (See "Idiopathic pulmonary hemosiderosis", section on 'Imaging'.)

Laboratory abnormalities — Laboratory findings in DAH are often nonspecific. A low or decreasing hemoglobin and an elevated white blood cell count are common, but not essential to the diagnosis. Platelet counts may be increased or decreased relative to normal. The erythrocyte sedimentation rate is usually increased, particularly in those cases of DAH caused by systemic diseases. Coagulation abnormalities should be excluded by checking a platelet count, prothrombin time, international normalized ratio, and partial thromboplastin time. Iron deficiency may be present in patients with recurrent DAH.

A number of diseases that result in the pulmonary-renal syndrome present with pulmonary hemorrhage in combination with focal segmental necrotizing glomerulonephritis. In this setting, an elevated plasma creatinine concentration, usually with an abnormal urinalysis (red blood cells, white blood cells, proteinuria, red and white blood cell casts), is typically seen. (See 'Laboratory testing' below and "Glomerular disease: Evaluation and differential diagnosis in adults".)

DIAGNOSTIC EVALUATION — Diffuse alveolar hemorrhage (DAH) is generally suspected in patients with hemoptysis, diffuse radiographic opacities, and severe gas transfer abnormalities. Sequential bronchoalveolar lavage (BAL) showing progressively more hemorrhagic effluent is the usual method for diagnosis of DAH. While an increased diffusing capacity for carbon monoxide (DLCO), when available, lends support for the diagnosis of DAH, most patients are not sufficiently stable to undergo pulmonary function testing. (See 'Bronchoalveolar lavage' below.)

As noted, hemoptysis may be absent at presentation in up to 33 percent of patients with DAH from any cause. In the absence of hemoptysis, DAH should be suspected in patients with new respiratory symptoms and ground glass or consolidative opacities (either localized or diffuse) on imaging studies, especially when the patient has a decreasing hemoglobin level.

The differential diagnosis of DAH includes acute respiratory distress syndrome (ARDS), multilobar pneumonia, aspiration pneumonitis, acute eosinophilic pneumonia, excessive anticoagulation, and pulmonary edema. Thus, the diagnostic approach is to seek affirmation of DAH via flexible bronchoscopy and to exclude infection, eosinophilia, or other alternative diagnoses.

Bronchoalveolar lavage — Flexible bronchoscopy with sequential BAL is the preferred method for diagnosis of DAH and should be performed promptly to expedite the evaluation. The fiberoptic bronchoscope is wedged into a subsegmental bronchus in an area where radiographic opacities are noted. Sequential BAL is performed by instilling and retrieving three aliquots of 50 to 60 mL sterile saline from that subsegmental bronchus. Alveolar hemorrhage is confirmed when lavage aliquots are progressively more hemorrhagic, a finding characteristic of DAH from all causes. (See "Basic principles and technique of bronchoalveolar lavage", section on 'Technique'.)

Hemosiderin-laden macrophages, which may be demonstrated by Prussian blue staining, are characteristically found in BAL fluid from patients with DAH, but are also reported in diffuse alveolar damage (DAD) and idiopathic pulmonary fibrosis [37]. Prussian blue staining of BAL cells may be helpful in the diagnosis of DAH, especially in the absence of hemoptysis or a grossly hemorrhagic BAL. (See "Basic principles and technique of bronchoalveolar lavage", section on 'Cytologic analysis'.)

Pulmonary function tests — Abnormal gas transfer is a characteristic finding in DAH. While the degree of hypoxemia varies, it is often of sufficient severity to require ventilatory support. Due to the severity of illness, most patients are unable to undergo pulmonary function testing. However, for patients who are stable enough to undergo pulmonary function testing, an increase in the DLCO above 100 percent of predicted or above a prior known value is a sensitive marker for DAH. The increase in DLCO results from the increased availability of hemoglobin within the alveolar compartment, which removes carbon monoxide from the exhaled air [38].

Monitoring the DLCO may be useful in detecting exacerbations of DAH in established cases, such as patients with idiopathic pulmonary hemosiderosis (IPH) or antiglomerular basement membrane (anti-GBM; Goodpasture) disease [38].

Occasionally, obstructive airways disease may be noted on spirometry in patients with recurrent DAH and pulmonary capillaritis secondary to microscopic polyangiitis (MPA) [39].

Clues to a specific etiology — Clues to the underlying cause of DAH may be identified through a detailed history and physical examination, selected serologic and radiographic studies, BAL stains and culture, and biopsy of affected tissues. Identifying the underlying cause is often essential to successful treatment.

Clinical features — Useful diagnostic clues include a history of:

●Exposure to possible offending drugs or other causative agents, such as abciximab, amiodarone, carbimazole, crack cocaine, leflunomide, nitrofurantoin, penicillamine, propylthiouracil, sirolimus, a tumor necrosis factor-alpha antagonist, or trimellitic anhydride [40-42]. With crack cocaine inhalation, the cutting agent levamisole can cause DAD or capillaritis. A minority of cases of DAH are due to drug toxicity [2].

●Conditions associated with the development of ARDS including coronavirus disease 2019 (COVID-19) [43]. (See 'Diffuse alveolar damage' above.)

●Hematopoietic cell transplantation, lung transplantation, and exposure to chemotherapeutic agents. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes" and "Pulmonary complications after autologous hematopoietic cell transplantation" and "Evaluation and treatment of antibody-mediated lung transplant rejection", section on 'Acute antibody-mediated rejection' and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents", section on 'Gemcitabine' and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Agents targeting VEGF'.)

●Vaping, which has been associated with a number of acute lung injuries, including DAH [44]; and cigarette smoking, which is a strong risk factor for DAH among patients with anti-GBM antibodies. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

●Systemic vasculitis or rheumatic disease; a history of thrombophlebitis or thrombocytopenia, which may suggest systemic lupus erythematosus (SLE) or antiphospholipid antibody syndrome.

●Intermittent chest pain, palpitations, and peripheral edema might suggest mitral valve disease.

●Exposure to rodents or farm animals or travel to leptospirosis endemic areas (eg, Southeast Asia). (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

The physical examination in the patient with DAH is generally nonspecific; however, the presence of uveitis, nasal or oral ulcers, petechiae or palpable purpura (picture 4 and picture 5), foot drop, arthritis, or malar rash may suggest an underlying systemic disorder responsible for DAH (such as a vasculitis or rheumatic disease).

Laboratory testing — When the diagnosis of DAH is strongly suspected or has been diagnosed, additional laboratory tests are needed to identify the specific etiology (table 2). A key step is obtaining microbiologic studies to exclude infection. A blood urea nitrogen, creatinine, and urinalysis should be obtained in all patients to assess for a pulmonary-renal syndrome. An elevated plasma creatinine concentration and/or an abnormal urinalysis (red blood cells, white blood cells, proteinuria, red and white blood cell casts) are suggestive of a pulmonary-renal syndrome. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

A brain natriuretic peptide (BNP) or N-terminal pro-BNP may be helpful if mitral stenosis or pulmonary edema is suspected. (See "Natriuretic peptide measurement in heart failure".)

The finding of specific antibodies, positive microbiologic culture or specific staining, or positive drug screen may suggest or permit the diagnosis of a particular underlying disorder of DAH. As examples:

●Antineutrophil cytoplasmic antibodies (ANCA) – A positive ANCA can be associated with DAH due to granulomatosis with polyangiitis (GPA) or MPA [7-10,45]. Cytoplasmic ANCA, as determined by immunofluorescence and antiproteinase 3 (anti-PR3) antibodies (by enzyme linked immunosorbent assay, anti-PR3 enzyme-linked immunoassay [ELISA]), is most consistent with GPA (90 percent of patients), while perinuclear ANCA (P-ANCA) with antimyeloperoxidase (anti-MPO) specificity (anti-MPO ELISA) favors the diagnosis of MPA or eosinophilic GPA (Churg-Strauss) syndrome; there is, however, some overlap (picture 6A-B). (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

●Antiglomerular basement membrane antibodies – The possibility of anti-GBM antibody (Goodpasture) disease is evaluated by serologic testing for anti-GBM antibodies using a direct ELISA. A positive test is strongly suggestive of anti-GBM antibody disease, but a renal biopsy is frequently performed to confirm the diagnosis, unless contraindicated [11,12]. The diagnosis of this condition is discussed separately. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation and diagnosis'.)

●Serologic findings suggestive of systemic lupus erythematosus – Initial testing for SLE as an underlying cause of DAH usually includes complement levels (C3, C4, or CH50), antinuclear antibodies, and anti-double stranded DNA antibodies (anti-dsDNA) [13]. The diagnosis of SLE is based on a set of clinical criteria that are discussed separately. If drug-induced SLE is suspected as a cause of DAH, additional testing should include antihistone antibodies (table 3). (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Pulmonary manifestations of systemic lupus erythematosus in adults" and "Drug-induced lupus", section on 'Diagnosis'.)

●Antiphospholipid antibodies – The presence of anticardiolipin antibodies, anti-beta-2-glycoprotein I, and/or a lupus anticoagulant is consistent with the antiphospholipid syndrome. (See "Clinical manifestations of antiphospholipid syndrome".)

●Antitransglutaminase or antiendomysial immunoglobulin A (IgA) antibodies – The presence of antitransglutaminase or antiendomysial IgA antibodies may suggest the combination of celiac disease and pulmonary hemosiderosis, known as Lane-Hamilton syndrome. IPH most commonly occurs in children and young adults under age 30. (See "Idiopathic pulmonary hemosiderosis".)

●Antistreptococcal antibodies or positive blood cultures – Antibodies directed against streptococcal antigens, including antistreptolysin O, anti-DNase B or hyaluronidase, or the documentation of positive blood cultures can suggest a diagnosis of poststreptococcal glomerulonephritis or bacterial endocarditis, respectively [46,47]. (See "Glomerular disease: Evaluation and differential diagnosis in adults" and "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt".)

●Drug screening – Drug screening should be obtained in patients with suspected cocaine abuse. (See "Pulmonary complications of cocaine use".)

●COVID-19 – Severe acute respiratory syndrome coronavirus (SARS-CoV-2) nucleic acid amplification testing or antigen testing in patients presenting with ARDS and suspected pulmonary hemorrhage. (See "COVID-19: Diagnosis", section on 'Choosing an initial diagnostic test'.)

Radiographic and echocardiographic findings — Certain radiographic or echocardiographic findings may suggest a particular underlying disorder:

●Although the heart size is usually normal in DAH, cardiomegaly (from myocarditis or a pericardial effusion) is occasionally seen in DAH associated with the systemic vasculitides and rheumatic diseases. An abnormal left heart contour can be seen in mitral stenosis due to enlargement of the left atrium.

●Pulmonary infarction can present as DAH, but the radiographic features differ. Pulmonary infarction is typically associated with segmental or subsegmental, wedge-shaped, pleural–based opacities, often with an ipsilateral pleural effusion.

●Kerley B lines on a chest radiograph point to the possible presence of mitral stenosis or pulmonary veno-occlusive disease [48].

●Echocardiography can be used to evaluate for mitral stenosis. Left ventricular dysfunction, and elevated pulmonary artery pressures. (See "Rheumatic mitral stenosis: Clinical manifestations and diagnosis" and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

Bronchoalveolar lavage — While BAL is a key step in the diagnosis of DAH, it is of limited utility in identifying a specific etiology for DAH. In the setting of ARDS, culture, immunoassays (eg, Pneumocystis, viruses including SARS-CoV-2), and cytologic analysis of BAL fluid can be helpful in identifying an infectious agent responsible for the syndrome. (See "Basic principles and technique of bronchoalveolar lavage".)

Biopsy — Biopsy of lung, kidney, or skin is occasionally needed when the diagnosis remains uncertain after the above evaluation. Generally, the biopsy site is chosen based on the least invasive method (skin, if a rash or purpura is present) or the greatest likelihood of securing a diagnosis (usually lung histopathology is more specific than kidney). Sometimes, a kidney biopsy is needed to assess the degree of kidney involvement or exclude concomitant diseases, even when there is a strong suspicion for a particular etiologic process such as anti-GBM disease or systemic vasculitis.

In the presence of a rash, a skin biopsy may identify the diagnosis by demonstrating a leukocytoclastic vasculitis, eosinophilic GPA, or other vasculitis. Alternatively, the presence of IgA deposits in postcapillary venules is suggestive of IgA vasculitis (IgAV; Henoch-Schönlein purpura [HSP]). (See "Overview of cutaneous small vessel vasculitis".)

When a lung biopsy is needed to identify the cause of DAH, histopathologic clues to the etiology of DAH include the following:

●Linear IgG deposition along the pulmonary capillary basement membranes is virtually diagnostic of anti-GBM antibody (Goodpasture) disease, which sometimes is isolated to the lungs (5 to 10 percent of cases) (picture 7) [49]. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation and diagnosis'.)

●Marked granular immune complex deposition along the pulmonary capillary basement membranes is found in the rheumatic diseases, particularly SLE. If, however, the immune deposits are primarily IgA, then IgAV (HSP) or IgA nephropathy are the probable diagnoses [32]. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Diagnosis' and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Diagnosis'.)

●Lung biopsy in patients with DAH due to GPA, MPA, or isolated pulmonary capillaritis typically shows neutrophilic infiltration of the capillary wall and hemorrhage (picture 1A and picture 1B); larger vessels are often uninvolved. Small punctate neutrophilic aggregates and a small vessel leukocytoclastic vasculitis (ie, degenerating neutrophils with formation of nuclear dust in the vessel wall) (picture 8) may be present. There are few, if any, deposits by immunofluorescence or electron microscopy (therefore called pauci-immune) in patients with GPA, MPA, or isolated pulmonary capillaritis [16].

Diffuse alveolar hemorrhage without systemic findings — Once the clinician has excluded drug and environmental exposures, mitral valve disease, bleeding disorders, and predisposing conditions that could lead to ARDS (and thereby DAH), four principal diagnostic possibilities remain:

●Anti-GBM antibody (Goodpasture) disease confined to the lung

●Isolated pulmonary capillaritis with perinuclear or P-ANCA (usually directed against myeloperoxidase)

●Isolated pulmonary capillaritis without autoantibodies

●IPH

Goodpasture disease can occasionally present or recur as DAH without glomerulonephritis [12]. In this setting, circulating anti-GBM antibodies are often absent, and the only way to establish the diagnosis is by demonstrating linear immunofluorescence in lung tissue. The underlying histology may be either bland hemorrhage or pulmonary capillaritis.

Isolated pulmonary capillaritis with or without P-ANCA positivity is a form of small vessel vasculitis limited to the lung [8,16,23]. These entities do not fit into the usual vasculitic syndromes. Follow-up evaluation of ANCA-negative patients four years after initial presentation has found no evidence of further systemic involvement [16].

IPH is a diagnosis of exclusion. The disease is primarily seen in younger patients, as only 20 percent of reported cases occur in adults [50]. In the pediatric age group, this disorder is associated with celiac disease and elevated IgA levels in 50 percent of patients. These associations are lacking, however, in the majority of affected adults. The diagnosis of IPH is established by lung biopsy, which demonstrates bland pulmonary hemorrhage without immune complexes. It is likely, however, that cases of isolated pulmonary capillaritis have been diagnosed as IPH, since pathologists are generally unfamiliar with the capillaritis lesion described above. (See "Idiopathic pulmonary hemosiderosis".)

TREATMENT — The treatment of diffuse alveolar hemorrhage (DAH) has not been rigorously studied in randomized trials except in the context of severe presentations of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and mixed cryoglobulinemia, so treatment decisions are based upon extrapolation from these studies (when capillaritis is suspected), observations from case series, and our clinical experience.

When an underlying cause is identified, specific treatment of that disease or process is appropriate when available. Thus, cessation of implicated drugs and exposures, treatment of infection, and reversal of excess anticoagulation are key. Inflammatory causes of DAH (eg, rheumatic diseases, differentiation [retinoic acid] syndrome, and some drug-induced) are typically treated with systemic glucocorticoids, with additional immunosuppressive therapy as described below.

Given that the differential diagnosis for DAH includes acute respiratory distress syndrome due to infection, careful evaluation to exclude infection must be performed prior to initiation of systemic glucocorticoids or immunosuppressive therapy. As prompt therapy for DAH is essential, empiric antimicrobial therapy is often initiated while waiting for results of microbial studies.

Supportive care — Patients with DAH typically have hypoxemia requiring supplemental oxygen; often the hypoxemia is severe enough to require noninvasive or invasive mechanical ventilation. The implementation of noninvasive or invasive mechanical ventilation for acute respiratory failure is discussed separately. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Acute respiratory distress syndrome: Ventilator management strategies for adults" and "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications".)

Extracorporeal membrane oxygenation (ECMO) has been used in a few patients to support patients with refractory hypoxemic respiratory failure due to DAH [51]. However, the use of ECMO in this setting is controversial due to the necessity for anticoagulation and the attendant risk of worsening alveolar hemorrhage. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

All known or suspected coagulation abnormalities should be reversed, as described below. In addition, patients with severe hemoptysis may require general supportive therapy that is based on the degree of bleeding. (See 'Excess anticoagulation or bleeding disorder' below and "Evaluation and management of life-threatening hemoptysis".)

Diffuse alveolar hemorrhage with capillaritis — DAH with capillaritis is a life-threatening condition and requires prompt treatment. The majority of diseases causing capillaritis are treated with a combination of systemic glucocorticoids and immunosuppressive therapy such as cyclophosphamide or rituximab with or without plasmapheresis. Often, high-dose glucocorticoids are initiated while waiting for the results of testing to confirm a specific cause of capillaritis, which will then guide selection of an additional immunosuppressive agent.

Glucocorticoids — For patients with DAH due to capillaritis (eg, systemic vasculitis, antiglomerular basement membrane [anti-GBM] syndrome, or rheumatic disease), we initiate systemic glucocorticoid therapy promptly, as glucocorticoids are part of accepted regimens for all of these diseases. By extrapolation, we also use systemic glucocorticoids for patients with isolated, pauci-immune pulmonary capillaritis [16,23]. Most experts, including us, administer intravenous pulse methylprednisolone (500 to 1000 mg in divided daily doses) for up to five days followed by transition to an oral preparation with gradual tapering to a maintenance dose.

Additional immunosuppressive therapy — The decision about which specific immunosuppressive agent (eg, cyclophosphamide, rituximab, plasma exchange) to initiate for DAH with capillaritis is dependent upon the severity of the illness, the anticipated responsiveness to glucocorticoids, and the specific underlying disease.

Some disease-specific suggestions are outlined here:

●Systemic vasculitis – For patients with DAH due to granulomatosis with polyangiitis or microscopic polyangiitis, we recommend prompt initiation of an induction regimen consisting of either cyclophosphamide or rituximab in combination with pulse glucocorticoid therapy, rather than other agents or glucocorticoids alone. This is based on data from the landmark multicenter, randomized RAVE trial, which demonstrated similar efficacy of rituximab and cyclophosphamide for inducing remission in severe ANCA-associated vasculitis [52].

An important caveat to the RAVE study is that the true efficacy of either rituximab or cyclophosphamide has not been rigorously assessed in patients with respiratory failure due to DAH. Approximately a quarter of the patients in the trial presented with alveolar hemorrhage, but did not require intubation at baseline. A separate single-center retrospective analysis that included 68 ANCA-positive patients with DAH, of which 31 required intubation, found that rituximab was associated with a higher rate of achieving complete remission by six months compared with cyclophosphamide (odds ratio 6.45, 95% CI 1.78-29), including the patients with respiratory failure [53]. The advantages and disadvantages of selecting cyclophosphamide versus rituximab in this setting are discussed separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Initial treatment approach'.)

For patients treated with cyclophosphamide, it is our practice to give one intravenous dose of cyclophosphamide (0.75 g/m² if renal function is relatively normal). We subsequently pay close attention to the nadir of the peripheral white blood cell count and initiate oral therapy in approximately two weeks if neutropenia does not occur. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Initial treatment approach'.)

For treatment with rituximab, we use the dose that was used in the RAVE trial, specifically 375 mg/m² per week for four weeks. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Rituximab-based regimen'.)

The use of plasma exchange for life-threatening or ventilator-dependent DAH secondary to vasculitis remains controversial, as retrospective studies have demonstrated mixed results and randomized trials have not been performed [53-55]. We individualize the use of plasma exchange in patients with vasculitis-associated, life-threatening DAH, as described separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Role of plasma exchange' and "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

●Antiglomerular basement membrane antibody (Goodpasture) disease – For patients with DAH due to anti-GBM antibody (Goodpasture) disease, concurrent plasma exchange, high-dose glucocorticoids, and an immunosuppressive agent (preferably cyclophosphamide) are recommended. Several retrospective studies and a small, randomized trial have demonstrated improved outcomes in patients with anti-GBM disease treated with plasma exchange, and its use has thus become standard of care. The treatment of anti-GBM disease is discussed in more detail separately. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Initial therapy'.)

●Severe mixed cryoglobulinemia – In the setting of mixed cryoglobulinemia complicated by DAH, it is critical to identify and treat the underlying inciting condition whenever possible. Patients with HIV or hepatitis B should receive antiviral therapy prior to or concurrent with immunosuppressive therapy; those with hepatitis C can receive immunosuppression prior to receiving antiviral treatment. Immunosuppressive therapy typically consists of pulse glucocorticoids followed by a taper plus rituximab or, if rituximab is unavailable, cyclophosphamide. Although convincing evidence for plasma exchange in mixed cryoglobulinemia is lacking, some providers recommend its use for severe cases that involve the hyperviscosity syndrome or pulmonary hemorrhage [56]. Importantly, care must be taken to warm the exchange fluid to prevent precipitation of circulating cryoglobulins. The details of immunosuppressive and antiviral therapy in mixed cryoglobulinemia are discussed separately. (See "Mixed cryoglobulinemia syndrome: Treatment and prognosis", section on 'Summary and recommendations'.)

●Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), or catastrophic APS – DAH in the setting of SLE or APS is typically treated with intravenous pulses of methylprednisolone (500 to 1000 mg for three to five days) in combination with an additional immunosuppressive agent. Although cyclophosphamide is often used, alternative regimens with azathioprine, rituximab, and mycophenolate have been reported, and no randomized trials comparing agents exist [57-66]. Catastrophic APS is a life-threatening form of APS with rapid onset multiorgan involvement that can include DAH.

The management of DAH due to SLE or CAPS is discussed separately. (See "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Treatment and prognosis' and "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Management'.)

Concurrent pulmonary infection is common in patients with DAH secondary to SLE, with an incidence ranging from 32 to 45 percent in two small series [58,67]. Therefore, empiric coverage with antibiotics prior to the initiation of immunosuppression is advisable, pending results of studies to exclude infection.

●Isolated pauci-immune pulmonary capillaritis – Initial treatment of isolated pauci-immune pulmonary capillaritis associated with DAH generally includes a combination of systemic glucocorticoids and cyclophosphamide, similar to the induction regimens for systemic vasculitis described above. Data for pauci-immune DAH are limited to isolated cases, and there are no studies to suggest the superiority of one immunosuppressant agent over another [3,16,23]. For patients not requiring mechanical ventilation, systemic glucocorticoid dosing with the equivalent of prednisone 1 mg/kg per day is reasonable; for patients with respiratory failure, high-dose methylprednisolone is usually substituted.

The possible role of intravenous immune globulin in patients with DAH due to vasculitis or other rheumatic disease is unknown.

Drug-induced diffuse alveolar hemorrhage — Drug-induced DAH can arise from a capillaritis resembling that seen in the systemic vasculitides and connective tissue diseases, which may represent an autoimmune or hypersensitivity reaction to the drug [68]. When drug-induced DAH is suspected, the culprit agent should be stopped immediately, and treatment decisions involving the use of immunosuppression for severe or refractory cases are extrapolated from the treatment of DAH secondary to underlying autoimmune conditions.

For most patients with actual or impending respiratory failure, we suggest initiation of systemic glucocorticoids. This choice is based upon the potentially life-threatening nature of DAH, the response to glucocorticoids described in case reports, and evidence of an inflammatory component in the few patients who underwent lung biopsy [2,69,70]. However, the use of systemic glucocorticoids in this setting has not been formally evaluated, and in milder cases or where systemic glucocorticoids are contraindicated, a more conservative approach of simply stopping the culprit drug with close observation may be acceptable.

Excess anticoagulation or bleeding disorder — When DAH is caused by drugs or processes that result in a bleeding disorder, the mainstays of therapy are reversal of excess anticoagulation and treatment of the bleeding diathesis.

As DAH is life-threatening, it is an indication for discontinuation of anticoagulant agents and, depending on the specific agent, administration of vitamin K, 4-factor prothrombin complex concentrate, antifibrinolytic agents, and/or platelet transfusions (table 4). (See "Management of bleeding in patients receiving direct oral anticoagulants" and "Management of warfarin-associated bleeding or supratherapeutic INR" and "Heparin and LMW heparin: Dosing and adverse effects".)

A number of processes can cause thrombocytopenia resulting in DAH, including immune thrombocytopenia, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. The management of these diseases is discussed separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Immune TTP: Initial treatment".)

The use of recombinant human coagulation factor VIIa in patients with DAH or other cause of pulmonary hemorrhage is discussed separately. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'CNS bleeding'.)

Idiopathic pulmonary hemosiderosis — Idiopathic pulmonary hemosiderosis (IPH) is considered a form of bland hemorrhage (see 'Bland pulmonary hemorrhage' above), but patients with this condition benefit from long-term glucocorticoid therapy. For patients with an acute episode of DAH due to IPH, we suggest systemic glucocorticoid therapy, as case reports and case series suggest that systemic glucocorticoids reduce morbidity and mortality during acute episodes of alveolar bleeding. In the setting of respiratory failure, we recommend intravenous methylprednisolone; we typically start with a pulse dose of 500 to 1000 mg per day for up to five days. The use of glucocorticoids in IPH is described separately. (See "Idiopathic pulmonary hemosiderosis", section on 'Treatment'.)

The role of additional immunosuppressive therapy is less clear. Case reports have described success with cyclophosphamide, azathioprine, and hydroxychloroquine, but most of these cases were in patients requiring chronic suppressive therapy, as described separately. (See "Idiopathic pulmonary hemosiderosis", section on 'Immunosuppressive drugs'.)

Diffuse alveolar damage due to infection — Patients with DAH caused by diffuse alveolar damage due to infection (ie, adult respiratory distress syndrome) require prompt initiation of broad spectrum antimicrobial therapy, possibly including antiviral therapy depending on the presentation, while awaiting results of microbial studies. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Intensive care unit'.)

Elevated pulmonary capillary pressures — The management of pulmonary vein stenosis, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, and mitral stenosis are discussed separately. (See "Rheumatic mitral stenosis: Overview of management" and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Clinical manifestations of pulmonary hypertension'.)

Experimental therapies — A retrospective review of DAH in allogeneic hematopoietic cell transplant recipients found an improved survival in eight patients treated with aminocaproic acid infusion in addition to methylprednisolone, compared with methylprednisolone alone [71]. However, a subsequent study did not find a benefit to aminocaproic acid in this setting [72].

PROGNOSIS — Repeated episodes of diffuse alveolar hemorrhage (DAH) can result in irreversible interstitial fibrosis, particularly in patients with underlying idiopathic pulmonary hemosiderosis (IPH), granulomatosis with polyangiitis, and mitral stenosis. In addition, a post-DAH syndrome that consists of severe progressive obstructive lung disease and emphysema has been described in patients with recurrent DAH due to microscopic polyangiitis [39].

The short- and long-term survival rates vary with the underlying cause of DAH. Patients with systemic lupus erythematosus, vasculitis, antiglomerular basement membrane antibody disease, and IPH have a very high early mortality with rates ranging from 25 to 50 percent [1]. Nevertheless, these immune causes of DAH can be successfully treated with subsequent long-term remission, whereas many patients with nonimmune etiologies have severe comorbidities that portend a poor prognosis. For example, in one retrospective study evaluating 88 patients, those with nonimmune DAH were more likely to die than patients with immune-mediated DAH [73].

SUMMARY AND RECOMMENDATIONS

●Overview – The syndrome of diffuse alveolar hemorrhage (DAH) is caused by injury or inflammation of the arterioles, venules, or alveolar septal (alveolar wall or interstitial) capillaries. DAH is associated with a wide variety of disease processes (table 1) that can be divided into three categories, pulmonary capillaritis (picture 1A-B), bland alveolar hemorrhage (picture 2), and diffuse alveolar damage (picture 3). (See 'Etiology and histology' above.)

●Clinical presentation – Cough, hemoptysis, fever, and dyspnea are common initial symptoms, although hemoptysis may be absent in up to 33 percent of patients with DAH from any cause. New radiographic opacities (either localized or diffuse), a falling hemoglobin level, and the finding of increasingly hemorrhagic fluid on sequential bronchoalveolar lavage (BAL) favor the diagnosis. (See 'Symptoms and signs' above.)

●Diagnostic evaluation – DAH is generally suspected in patients with hemoptysis, diffuse radiographic opacities, and severe gas transfer abnormalities, although hemoptysis can be absent in up to a third of patients. (See 'Diagnostic evaluation' above.)

•Laboratory testing – Laboratory testing focuses on bleeding disorders, concomitant kidney disease, and clues to an underlying cause (table 2). A key step is obtaining microbiologic studies to identify or exclude infection (eg, bacterial pneumonia, coronavirus disease 2019 [COVID-19]). (See 'Laboratory testing' above.)

•Imaging – Thoracic computed tomography scanning typically shows ground glass or consolidative opacities that are diffuse and bilateral (image 2) but spare the periphery; opacities may occasionally be unilateral. (See 'Radiographic findings' above.)

•Bronchoalveolar lavage – Sequential BAL in an area where radiographic opacities are noted is a key step in the diagnosis of DAH, although it rarely identifies a specific etiology. Progressively more hemorrhagic BAL is characteristic of DAH from all causes. (See 'Bronchoalveolar lavage' above.)

•Identifying an underlying cause – Once the diagnosis of DAH is made, the underlying cause is sought through careful review of the history (including medication use, toxic or infectious exposures, extrapulmonary symptoms), physical examination (especially skin), and laboratory tests (table 2). A skin biopsy may be helpful in patients with a rash suggestive of vasculitis or immunoglobulin A vasculitis (Henoch-Schönlein purpura). When the underlying cause remains unclear after a careful evaluation, a lung or kidney biopsy may be necessary to determine the underlying cause. (See 'Biopsy' above and 'Clues to a specific etiology' above.)

●Treatment – Prompt initiation of therapy is required due to the life-threatening nature of DAH. Depending on whether the underlying cause of DAH is clear or remains under investigation, initial therapy will be empiric (pending identification of the cause) or cause-specific.

•Supportive care – For all patients, supportive care typically includes supplemental oxygen; noninvasive or invasive mechanical ventilation may be needed depending on the severity of hypoxemia. Patients with severe hemoptysis/DAH may require additional interventions. (See 'Supportive care' above and "Evaluation and management of life-threatening hemoptysis".)

•Initial empiric therapy – For patients in whom the underlying cause of DAH is unclear, we recommend broad spectrum antibiotics and systemic glucocorticoids (Grade 1C). DAH is a life-threatening condition, and prompt initiation of therapy can be life-saving.

-Acute respiratory distress syndrome (ARDS) due to infection (eg, bacteria, viral including COVID-19) is a common cause of DAH, so empiric broad spectrum antimicrobial therapy, possibly including antiviral therapy, should initiated while waiting for results of microbial studies. (See 'Treatment' above and 'Diffuse alveolar damage due to infection' above and "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Intensive care unit'.)

-Systemic glucocorticoids are part of the initial regimen for many of the causes of DAH (eg, systemic vasculitis, rheumatic disease, antiglomerular basement membrane (anti-GPM; Goodpasture) disease, idiopathic pulmonary hemosiderosis [IPH]). A reasonable initial dose is pulse methylprednisolone 500 to 1000 mg/day intravenously in divided doses, for up to five days, followed by transition to oral prednisone and then gradual tapering. For stable patients with mild IPH, oral therapy is an alternative. (See 'Glucocorticoids' above.)

-Drugs that are potential causes of DAH should be withheld. Excess anticoagulation should be reversed. (See 'Drug-induced diffuse alveolar hemorrhage' above and 'Elevated pulmonary capillary pressures' above.)

•Cause-specific therapy – Once the cause of DAH is identified, therapy is focused accordingly:

-For patients with ARDS due to infection, initial empiric antimicrobial therapy (eg, antibacterial, antiviral) should be tailored to cover implicated organisms. (See 'Diffuse alveolar damage due to infection' above and "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Intensive care unit'.)

-For drug-induced DAH, in addition to cessation of the culprit drug, we suggest systemic glucocorticoid therapy (Grade 2C), due to the potential severity of the disease and the histopathologic observation of inflammation in some patients. Exceptions might include patients who are stable, do not require mechanical ventilation, or have a contraindication to glucocorticoids. (See 'Treatment' above.)

-Specific treatment of DAH due to systemic vasculitis, rheumatic disease, and anti-GPM disease virtually always includes pulse methylprednisolone (500 to 1000 mg/day intravenously in divided doses) for up to five days, followed by transition to oral prednisone 1 mg/kg per day and then gradual tapering. For IPH, systemic glucocorticoids are dosed according to the severity of DAH. Treatment of many of these diseases requires additional immunosuppressive therapy (eg, cyclophosphamide, rituximab, plasma exchange), as described separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Initial treatment approach' and "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Treatment and prognosis' and "Anti-GBM (Goodpasture) disease: Treatment and prognosis" and "Idiopathic pulmonary hemosiderosis", section on 'Treatment'.)

-For DAH caused by excess anticoagulation or a bleeding disorder, the mainstays of treatment are reversal of medication-induced anticoagulation and treatment of any bleeding diathesis. Additional therapy, depending on the specific cause of the bleeding disorder, may include administration of vitamin K, 4-factor prothrombin complex concentrate, antifibrinolytic agents, platelet transfusions, or plasma exchange (table 4). (See 'Excess anticoagulation or bleeding disorder' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marvin I Schwarz, MD, who contributed to earlier versions of this topic review.