Alveolar Hemorrhage Syndromes (Diffuse Alveolar Hemorrhage)

What every physician needs to know:

Diffuse alveolar hemorrhage (DAH) is a life-threatening disorder characterized clinically by the presence of hemoptysis, falling hematocrit, diffuse pulmonary infiltrates and hypoxemic respiratory failure. DAH should be considered a medical emergency due to the morbidity and mortality associated with failure to treat the disorder promptly. The treatment of DAH ranges from supportive care and withdrawal of offending drugs, to high-dose steroids, immunosuppressant drugs and plasmapheresis.

Classification:

DAH can be broadly categorized into 4 main groups

• Immune (vasculitis, connective tissue disease)

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• Congestive Heart Failure (systolic/diastolic, valvular)

• Miscellaneous (infection, trauma, clotting disorder, cancer, drugs)

• Idiopathic

DAH is associated with a number of clinical entities. Pulmonary renal syndromes, connective tissue disorders and drugs make up the majority of the cases of DAH. Hemorrhage originates in the pulmonary microvasculature, rather than from the bronchial circulation or parenchymal abnormalities. DAH is a clinico-pathologic syndrome characterized by intra-alveolar accumulation of red blood cells that originates from the interstitial capillaries (precapillary arterioles, alveolar capillaries, or post capillary venules). A retrospective review of 34 cases of DAH revealed nearly one-third of the cases were caused by granulomatosis with polyangiitis (previously termed Wegener granulomatosis).

Are you sure your patient has Diffuse Alveolar Hemorrhage? What should you expect to find?

Although hemoptysis is considered the cardinal sign of DAH, it may be absent in up to 33 percent of all patients; therefore, the absence of hemoptysis does not rule out DAH. Hemoptysis may be a dramatic event or it may evolve over days to weeks. The symptoms of DAH, other than hemoptysis, tend to be non-specific; they can include but are not limited to fever, chest pain, cough, and dyspnea. Exam findings may include rales on examination and respiratory failure.

A detailed history and physical exam should be obtained, including questions pertaining to connective tissue disorders, HIV status, drug exposures, occupational exposures and a cardiac history.

The cornerstone of diagnosis is a multi-faceted approached involving:

• History and physical

• Laboratories

• Imaging studies

• Non-invasive pulmonary diagnostic studies

• Diagnostic procedures

It is important to establish the cause of DAH, since virtually all cases, except those associated with overwhelming diffuse alveolar damage, are potentially reversible. Treatment is directed at the underlying etiology and typically includes corticosteroids, total plasma exchange, and immunosuppressant therapy.

Beware: there are other diseases that can mimic Diffuse Alveolar Hemorrhage:

Any disorder that can lead to ground glass changes on imaging and hypoxia can appear similar to alveolar haemorrhage. These include inflammatory disorders, ILD, congestive heart failure, pneumonia, vasculitis, eosinophilic syndromes, infectious diseases.

How and/or why did the patient develop Diffuse Alveolar Hemorrhage?

Common to all causes of DAH is injury to the basement membrane of the alveolar capillary bed, which injury allows for accumulation of red blood cells into the alveolar space. However, the injury to the basement membrane is unique to the specific systemic disease that underlies the DAH, and in some cases the mechanism of injury remains unknown (see Table I).

Table I.

Table II.

Table III.

Figure 1.

Which individuals are of greatest risk of developing Diffuse Alveolar Hemorrhage?

By far the greatest risk factor for the development of DAH is an established diagnosis of a systemic vasculitis (ANCA-associated granulomatous vasculitis, anti-GBM disease, SLE, etc.)

Alveolar hemorrhage may be the presenting manifestation of granulomatosis with polyangiitis (GPA) in approximately 8% of patients with the disease. It is diagnosed in less than 2–4% of SLE patients; however, the mortality rate approaches 50%. DAH is found in up to 66% of patients in autopsy series. Only 5–10% of cases of Goodpasture syndrome (anti-GBM disease) will have presented with DAH alone. Although the literature about HIV and DAH is limited, a case series of HIV patients with Kaposi sarcoma (KS) found that 75% of these patients had alveolar hemorrhage. There was no effect on 12-month mortality.

Other important clinical causes of DAH that are not vasculitic in nature are infection, ARDS, the use of anticoagulants with supra-therapeutic bleeding times, and the use of IIB/IIIA medications following percutaneous interventions. DAH after hematopoietic stem cell transplant (HSCT) is a devastating complication that carries an overall mortality of 70–100%. Median time to onset after transplant was between 21 and 23.5 days according to two reviews.

There are no prospective studies that estimate the relative frequency of DAH. Epidemiologic studies show that the prevalence and incidence of the autoimmune disorders is increasing, with the overall prevalence of the primary systemic vasculitis’ of 90 to 257 per million and the incidence is estimated at 10 to 20 per million.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

An unexplained drop in hemoglobin in the setting of respiratory failure with diffuse infiltrates should prompt a suspicion for DAH. Further work up should be directed at the etiology of DAH: autoimmune serologies (e.g., ANA, dsDNA, ANCA, anti-GBM), coagulation studies, and peripheral blood smear should routinely be sent. Urinalysis with microscopic evaluation should be performed to evaluate for possible pulmonary-renal syndrome. There are no genetic tests available to confirm the diagnosis of DAH.

What imaging studies will be helpful in making or excluding the diagnosis of Diffuse Alveolar Hemorrhage?

• Chest radiograph is nonspecific and reveals an alveolar filling process that can be patchy, focal, or diffuse in nature. Chest radiograph can also be used to follow the clinical course of disease.

• Chest CT will typically show diffuse and frequently bilateral ground glass opacities. CT can also be used to further define the extent of the disease and help to localize the segment where bronchoalveolar lavage (BAL) should be performed.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of Diffuse Alveolar Hemorrhage?

Pulmonary function tests (PFT) are rarely indicated in the acute setting. If obtained, an increased diffuse capacity of carbon dioxide (DLCO) should alert the physician to the possibility of alveolar hemorrhage. Pulmonary function testing should be performed following resolution of DAH, particularly in those patients who are at risk of recurrence of DAH (i.e. systemic vasculitis).

Transthoracic echocardiography (TTE) should be performed to rule out the presence of valvular disease or myocardial dysfunction as a cause of DAH.

What diagnostic procedures will be helpful in making or excluding the diagnosis of Diffuse Alveolar Hemorrhage?

The diagnosis is established after bronchoscopy with serial bronchoalveolar lavage (BAL) revealing progressively bloodier fluid or increasing RBC counts.

• The bronchoscope is wedged in a sub-segmental bronchus proximal to the region of involvement, and three serial aliquots of 30 to 60 mL of saline are instilled and withdrawn. If the BAL becomes progressively more hemorrhagic, suggesting alveolar or capillary origin, the diagnosis of DAH is confirmed. Alternatively, if the returned BAL aspirate clears with each aliquot, the bleeding is not consistent with DAH. The presence of hemosideren-laden macrophages on the BAL (>20%) is helpful in detecting DAH as well. Bronchoalveolar lavage fluid should be sent for bacterial cultures and viral PCR to rule out infectious causes of diffuse alveolar damage and to ensure no infection is present prior to high dose immunosuppression, if needed.

Surgical lung biopsy should be considered if the clinical history or serologic testing is unrevealing or the disease is refractory to treatment. Transbronchial biopsies are insufficient for histopathologic diagnosis.

If there is a suspicion for a pulmonary-renal syndrome, a renal biopsy with direct immunofluorescence should be pursued, as this procedure has a low morbidity rate.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of Diffuse Alveolar Hemorrhage?

DAH has three histopathologic patterns on open lung biopsy:

• Pulmonary capillaritis: Neutrophilic infiltration of the alveolar wall and destruction of the capillary leading to hemorrhage into the alveolar sacks.

• Bland hemorrhage: Hemorrhage without alveolar destruction or inflammation.

• Diffuse alveolar damage: Edematous septa but no inflammation.

The most common histopathologic pattern found to cause DAH is pulmonary capillaritis, typically in the setting of a rheumatologic disease or systemic vasculitis.

Renal biopsy to assess pulmonary renal syndromes, if indicated and to rule out other disorders that can present with pulmonary haemorrhage:

• Immunofluorescence can show:

  SLE: “clusters” immune complex

  Anti-GBM: linear deposition in the basement membranes

  ANCA-associated granulomatous vasculitis and Microscopic Polyangiitis: absence of immune complex deposition

If you decide the patient has Diffuse Alveolar Hemorrhage, how should the patient be managed?

The goal of management is to stabilize the patient, halt the progression of the disease process, and limit end organ damage. Treatment should be directed at the underlying cause of DAH (see Table 2), most common being systemic vasculitis. In rapidly progressive or fulminant cases, institution of empiric treatment is appropriate.