Microscopic polyangiitis (MPA) is another of the small vessel ANCA associated vasculitides and has a predilection for the microvasculature of the kidney and the lung. MPA is universally associated with a focal segmental necrotizing glomerulonephritis and is characterized by marked constitutional symptoms. MPA can be differentiated from classic polyarteritis nodosa by the lack of involvement of medium sized blood vessels and the absence of systemic hypertension. Distinguishing MPA from GPA can be difficult, but MPA lacks the granulomatous inflammation seen in GPA, only affects the upper airway in <15 % of patients, and is commonly associated with a peri-nuclear ANCA staining pattern (p-ANCA) rather than a c-ANCA pattern. DAH due to pulmonary capillaritis occurs in up to one-third of patients with MPA and represents by far the most common pulmonary manifestation of the disease. In patients with recurrent bouts of DAH related to MPA, both obstructive lung disease and pulmonary fibrosis have been reported [20, 26].

As mentioned above, a diagnosis of MPA essentially requires that the patient have a focal segmental necrotizing glomerulonephritis. Other common clinical manifestations include arthralgias/arthritis, myalgias/myositis, gastrointestinal disease, peripheral nervous system involvement and cardiac disease. As seen in other AAV, non-specific inflammatory markers are elevated (erythrocyte sedimentation rate and C-reactive protein), and non-specific increases in both serum antinuclear antibodies and rheumatoid factor may be present. Circulating immune complexes may be found in a significant minority of patients with MPA, but tissue localization of circulating immune complexes is rarely seen. ANCA are frequently present in patients with MPA, but less so than with GPA, on the order of 50–75 %. Additionally, 85 % of the ANCAs will have a p-ANCA staining pattern that in turn is more commonly associated with anti-myeloperoxidase (MPO) antibodies [17, 26, 27].

As with GPA, DAH in MPA represents life-threatening disease and is associated with an increased mortality. Indeed, an episode of DAH secondary to MPA is associated with a 30 % mortality. For those patients who do survive, the 1-year and 5-year survival is reduced to 82 and 68 %, respectively [26, 28].

Treatment of DAH secondary to MPA is very similar to GPA and consists of supportive care elements plus glucocorticoids and plasmaphresis followed by cyclophosphamide or rituximab. Additionally, recombinant factor VIIa has been tried at the case report level as a modality by which to control refractory alveolar hemorrhage and unremitting respiratory failure in severe cases of DAH due to MPA [29].

Granulomatosis with polyangiitis is the entity formerly known as Wegener granulomatosis and represents one of the more common etiologies associated with pulmonary capillaritis as well as pulmonary renal syndrome. GPA is one of the AAVand is characterized by granulomatous inflammation of the upper and lower respiratory tract and a necrotizing small vessel vasculitis. While the American College of Rheumatology and Chapel Hill Consensus Conference have developed criteria for the classification of the AAV, these criteria perform poorly when used to diagnose an individual patient. The diagnosis of GPA and the other AAV rests upon the clinician integrating clinical, laboratory, radiographic and pathologic data and making an informed clinical judgment that the data do or do not support a diagnosis of GPA.

DAH is estimated to occur in 5–15 % of patients with GPA. Indeed, the presence of DAH alone should raise the possibility of GPA and the other AAV within the differential diagnosis [17]. DAH can occur as an initial manifestation of the disease or it may occur during an exacerbation of a previously established case. DAH may occur as an isolated finding or in conjunction with other pulmonary manifestations of GPA. In a patient series published by Cordier and colleagues, pulmonary capillaritis was identified in 31 % of open lung biopsies obtained in patients with GPA [18]. The presence of DAH, by definition, represents severe, life-threatening disease and correlates with a considerably increased mortality [19].

As mentioned above, GPA commonly presents with upper airway involvement (>80 %) and may manifest with epistaxis, nasal discharge or crusting, septal perforation, otitis, hearing loss, or subglottic or tracheal stenosis. Similarly, the lower respiratory tract is also frequently involved (>80 %) and patients may manifest with cough, dyspnea, chest discomfort or hemoptysis. Radiographically, patients may have infiltrates, consolidation, nodules, cavities, and/or effusion(s). Extra-pulmonary manifestations will commonly include renal involvement/glomerulonephritis, constitutional symptoms, myalgias, arthralgias/arthritis, cutaneous involvement, ocular involvement, and cardiac manifestations [20].

Anti-neutrophil cytoplasmic antibodies (ANCA) are a hallmark of GPA and contribute to the pathogenesis of AAV. Three distinct ANCA staining patterns have been identified, namely cytoplasmic, peri-nuclear and atypical, and it is the cytoplasmic or c-ANCA that have been most closely associated with GPA. c-ANCA in turn, have been shown to recognize the proteinase-3 (PR3) antigen in the vast majority of cases. 85–90 % of patients with generalized active GPA will be c-ANCA and/or anti-PR3 positive [17]. While ANCA titers correlate with disease activity, a rise in ANCA titers needs to be considered within the context of the full clinical assessment, as a change in ANCA titers alone lacks sufficient sensitivity and specificity for predicting disease relapse to be used as such [21]. Also, it should be noted that while a positive c-ANCA or PR3 is very helpful in diagnosing AAV, a negative test does not exclude GPA or AAV in an individual patient.

Treatment of DAH begins with basic supportive care elements such as a secure airway, oxygen therapy and ventilatory support. Once the patient has been stabilized and the “A, B, Cs” of airway, breathing and circulation have been addressed, and any potential coagulopathic state or bleeding diasthesis similarly addressed, treatment directed towards the underlying precipitating disease may begin.

Treatment of GPA requires the use of immunosuppressive agents (cytotoxic medications and systemic corticosteroids) that carry the risk of serious adverse side effects. As such, the intensity of the immunosuppresion must carefully be titrated to disease activity, and disease activity must be careful assessed in each patient. DAH clearly represents organ and life threatening disease and as such qualifies as “severe” disease that necessitates the use of more aggressive immunosuppressive regimens to control the disease activity.

The initial regimen of choice for both generalized active and severe life-threatening disease had been oral cyclophosphamide plus oral corticosteroids based upon the original National Institutes of Health studies demonstrating the efficacy of this regimen for the induction of disease remission [22]. In 2007, Jayne and colleagues published the MEPEX trial (Randomized Trial of Plasma Exchange or High-Dosage Methylprednisolone as Adjunctive Therapy for Severe Renal Vasculitis) in which patients with severe renal disease were treated with corticosteroids and oral cyclophosphamide and additionally randomized to plasma exchange or high dose intravenous methylprednisolone [23]. Dialysis-independent survival was greater in the plasma exchange group than the intravenous corticosteroid group such that the addition of plasma exchange to corticosteroids and cyclophosphamide has since been recommended for the management of patients with severe renal disease. Whether this same strategy may be applied to patients with DAH was tested in a 20 patient case series, and indeed, this strategy appears to be effective in diffuse alveolar hemorrhage as well [24].

In 2010, the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial evaluated the anti-CD-20 monoclonal biologic rituximab for the management of generalized active and severe AAV and found that rituximab was non-inferior when compared with cyclophosphamide [25]. No significant differences in total or serious adverse events were noted between the treatment groups. Subgroup analysis further showed that rituximab was equally effective with cyclophosphamide for the management of alveolar hemorrhage. Thus, rituximab may be used as a potential alternative to cyclophosphamide in severely ill patients, including those with DAH.

Isolated pulmonary capillaritis or idiopathic pauci-immune pulmonary capillaritis refers to a small vessel vasculitis that is confined to the lungs. Some experts liken this entity to a lung-limited MPA. DAH in isolated pulmonary capillaritis may or may not be p-ANCA positive, and while no differences can be discerned between those patients who are ANCA positive and ANCA negative, this may be due to inadequate longitudinal follow-up. In one case series of 29 patients, isolated pulmonary capillaritis was the most common cause of DAH with biopsy proven pulmonary capillaritis, followed by GPA and MPA [30]. In this study, isolated pulmonary capillaritis accounted for 28 % of the cases, and there were no clinical, serologic, or histologic features of an alternative systemic disorder. Clinically, three quarters of patients presented with respiratory distress and half required mechanical ventilation. Despite this, there was an 88 % in hospital survival and an overall favorable prognosis for the group. Isolated pulmonary capillaritis is treated along the same lines as AAV and responds well to standard therapy with corticosteroids and cytotoxic medications [27, 31].

DAH affects only 4 % of patients with SLE, but along with acute lupus pneumonitis represents one of the most devastating pulmonary complications of SLE with a mortality rate approaching 50 %. Histopathologically, DAH due to SLE is associated with pulmonary capillaritis in the vast majority of cases, but bland pulmonary hemorrhage and DAH secondary to diffuse alveolar damage may also be seen. Co-morbid and/or precipitating infectious complications should excluded as a contributing factor to the DAH [3, 32, 33].

As with SLE itself, there is a strong female preponderance in DAH secondary to SLE, and patient are on average in their third to fourth decade. In the majority of cases of DAH associated with SLE, glomerulonephritis is also present at the time of presentation. As with other cases of DAH, patients present with dyspnea, hemoptysis, hypoxemia and respiratory distress/respiratory failure; however, this clinical presentation is common to both DAH and acute lupus pneumonitis (ALP) and distinguishing between these entities can be exceedingly difficult. In point of fact, 20 % of cases of ALP may present with hemoptysis. Still, the majority of DAH cases occur in patients with a known diagnosis of SLE and will frequently have concomitant glomerulonephritis, whereas 50 % of cases of ALP are an initial presentation of SLE. Ultimately, as with most cases of DAH, diagnosis is made at time of BAL. In those patients who undergo biopsy, ALP is characterized by diffuse alveolar damage complicated by hemorrhage and may also have features of organizing pneumonia, but should not demonstrate frank capillaritis [3, 6].

As mentioned previously, mortality rates associated with DAH in SLE are high and have traditionally ranged from 50–90 %, although more recent data suggests that the use of aggressive immunosuppressive treatment, increased recognition of concomitant infections, and advances in the management of critically-ill patients, survival is far better. Negative prognostic factors include the need for mechanical ventilation, the presence of infection, and the requirement for cyclophosphamide therapy [3, 6, 33].

Treatment of DAH secondary to SLE includes the use of intravenous, high-dose methylprednisolone and cyclophosphamide. While plasmapharesis is also used for DAH complicating SLE, it is unclear whether or not this intervention provides additional benefit [27, 33].

Antiphospholipid antibody syndrome, along with GPA, MPA, idiopathic pauci-immune capillaritis, and SLE, represents one of the more common etiologies of capillaritis. As with the other entities, DAH may be an initial presentation or later complication of the disease. Symptoms again include cough, dyspnea, fatigue, malaise, fever, hemoptysis, hypoxemia, and acute respiratory failure. Thrombocytopenia may be present at the time of the DAH episode helping to focus the differential diagnosis on APLAS along with SLE, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura. On histology, there is evidence of pulmonary capillaritis with or without concomitant microvascular thrombosis [7, 34].

The management of APLAS is commonly complicated thromboemoblic disease and the need for anti-coagulation. When an episode of DAH occurs in a patient with an established diagnosis of APLAS, the presence of capillaritis and diffuse hemorrhage is further complicated by the presence of therapeutic anti-coagulation (as well as the possibility of concomitant pulmonary thromboemboli.) Nevertheless, it must be recognized that more often than not, it is the capillaritis driving the DAH and controlling the vasculitis is key to achieving therapeutic success. At the same time, diagnosing, treating and/or preventing the thromboembolic manifestations of the disease, as well as controlling the DAH, cannot be ignored. Thus, even in centers experienced in the management of complex autoimmune diseases, the management of these patients is extremely challenging and referral to a center of expertise is recommended when feasible. Nevertheless, first line therapy for DAH associated with antiphospholipid antibody syndrome is intravenous corticosteroids combined with optimal supportive care. Rapid resolution of most cases of DAH is typically seen after treatment with corticosteroids. In cases of catastrophic antiphospholipid syndrome, IVIG or plasma exchange may be added to the intravenous corticosteroids and supportive care. Most recently, case reports describing the use of rituximab for refractory APLAS, including APLAS complicated by refractory DAH, have suggested that this agent may ultimately proven to have a role when more conventional therapies are unsuccessful [1, 34–36].

As with other cases of chronic and/or recurrent DAH, fibrosis and/or obstructive disease may evolve over time. Lastly, it should be noted that in catastrophic cases of APLAS (Asherson’s syndrome), ARDS and multi-system organ dysfunction may develop. In these cases, the pathology will demonstrate diffuse alveolar damage, capillaritis and diffuse small vessel occlusion and obliteration [14, 35].

Goodpasture’s Syndrome, or anti-basement membrane antibody disease, is an autoimmune disorder mediated by antibodies directed against the non-collagenous domain (NC1) of the alpha-3 chain of type IV collagen (and to a lesser degree the alpha-5 chain) found in basement membranes [37]. The majority of patients, approximately 60–80 %, present with a pulmonary-renal syndrome of diffuse alveolar hemorrhage and glomerulonephritis. Indeed, the presence of a true pulmonary renal syndrome helps focus the differential diagnosis upon ABMA disease, GPA, MPA, and SLE. Still, 15–30 % of cases may present with isolated glomerulonephritis, and conversely up to 10 % of patients may present with DAH alone without renal involvement. Interestingly, although type IV collagen is found elsewhere in the body, including skin, eye, and gastrointestinal tract, end organ damage in ABMA disease is limited to the kidneys and lung. DAH represents a major cause of mortality in patients with ABMA disease, and among the competing causes of DAH, ABMA disease has a relatively poorer prognosis. On the other hand, in those cases of ABMA disease in which the pulmonary manifestations are dominant, renal outcomes are better when compared to patients who present with renal disease alone [13, 37].

The clinical presentation of DAH due to ABMA disease is very similar to other cases of DAH of differing etiologies of DAH with the caveat that glomerulonephritis is present in most albeit not all cases. Again, patients will complain of dyspnea, cough, hemoptysis, hypoxemia, and/or constitutional symptoms (fatigue, fever, anorexia, weight loss, arthralgias and myalgias). ABMA disease preferentially affects men more than women (approximately 2:1) and has a predilection for young adults (the average patient age reported ranges between 20 and 30). In those patients with ABMA who develop DAH, a history of smoking is extremely common (50–90 %), although recent viral infection or other inhalation exposures (e.g. hydrocarbons, marijuana, fire smoke, cocaine) may also be seen immediately antecedent to the onset of DAH. In point of fact, it is hypothesized that cigarette smoking (or alternatively infection or other inhalational exposure) plays a pathophysiologic role in the development of DAH either through a secondary injury to the alveolar-capillary unit, facilitating antigen presentation, or allowing ABMAs entry into the lung [13]. On laboratory testing, anemia will commonly be present, and frequently will be accompanied by an elevated blood urea nitrogen or serum creatinine consistent with renal insufficiency. Urinalysis frequently reveals microscopic hematuria, proteinuria, and red blood cell casts diagnostic of glomerulonephritis. Interestingly, 3–7 % of patients will be p-ANCA positive, suggesting the possibility of an overlap syndrome with MPA. ABMA disease has also been shown to have an association with specific human leukocyte antigen (HLA)-DR alleles, specifically HLA-DRB1*1501 [37]. Chest imaging studies, as with other cases of DAH, will show patchy diffuse alveolar infiltrates that appears as ground glass infiltrates or consolidation on HRCT. While it is rare to obtain pulmonary function testing in acutely-ill patients, in more chronic cases or more slowly evolving cases, an increased diffusing capacity of carbon monoxide may be identified.

Diagnosis may be made by identifying the presence of serum anti-basement membrane antibodies (ABMAs) in a patient with a compatible clinical presentation and circulating antibodies may be identified in two thirds to three quarters of patients at time of diagnosis [37]. At the bedside, it may be necessary to make a tentative clinical diagnosis and initiate therapy while awaiting the results of the serologic testing which frequently must be sent to a referral laboratory. Of note, while antibody titers appear to correlate with the severity of the renal disease, no such correlation has been identified with the pulmonary manifestations of the disease. Alternatively, patients may be diagnosed via lung or kidney biopsy and immunofluorescence studies. On light microscopy, the histopathology of the lung in ABMA disease may demonstrate either bland hemorrhage or capillaritis (although the appearance of the capillaritis in ABMA disease tends to lack some of the more aggressive and destructive features seen in MPA or GPA). Similarly, the renal biopsy will demonstrate a focal, segmental, rapidly progressive glomerulonephritis with crescent formation that is indistinguishable from other etiologies of rapidly progressive glomerulonephritis. However, the frozen sections should demonstrate a positive immunofluorescence pattern with a linear, continuous, “ribbon-like” appearance, reflecting antibody that has bound to the basement membrane. This immunofluorescence pattern is distinct from the punctate, patchy staining pattern seen in SLE and the negative or “pauci-immune” pattern associated with the AAV, and hence, is diagnostic for ABMA disease [38].

DAH associated with Goodpasture’s is managed very similarly to DAH (or severe renal failure) secondary to GPA or MPA. Plasmapharesis combined with corticosteroids and a cytotoxic agent (i.e. cyclophosphamide) has been shown to be effective in both of these clinical contexts and is associated with improved mortality and renal recovery [39]. Early diagnosis and prompt institution of therapy is crucial to optimizing outcomes, and as such, it is sometimes necessary to initiate therapy pending a conclusive diagnosis. Ultimately, the similarities in therapeutic recommendations for pulmonary renal syndrome, whether it is due to ANCA associated vasculitis, SLE or Goodpasture’s syndrome combined with the adverse effects associated with delays in therapy makes this approach judicious. Steroids alone, or steroids combined with cytotoxic agents without the use of plasmaphresis do not achieve equivalent results. While there is no definitive data informing the optimal duration of plasmaphresis, the duration of therapy for Goodpasture’s tends to be longer than in AAV, on the order of 10–14 exchanges, or until ABMAs become undetectable. With regard to choice of cytotoxic agent, cyclophosphamide is the most common agent utilized for life threatening alveolar hemorrhage. In more mild cases or as the patient’s conditions improves, azathioprine (and more recently mycophenolate mofetil) have been used [20]. Lastly, rituximab has been proposed by some experts as a potential therapeutic agent for Goodpasture’s syndrome based upon its mechanism of action and the pathogenetic role of ABMAs in the disease; however, beyond a handful of anecdotal reports, there is currently no evidence to support its use and its role in managing ABMA disease awaits further study.