key: cord-0035136-so0v8h54 authors: Desai, Hem; Smith, Joshua; Williams, Mark Daren title: Diffuse Alveolar Hemorrhage date: 2019-07-24 journal: Evidence-Based Critical Care DOI: 10.1007/978-3-030-26710-0_33 sha: 62e2bd9185496aadfd405f99357fd85b2983bfac doc_id: 35136 cord_uid: so0v8h54 Diffuse alveolar hemorrhage[DAH] is a serious condition that can be life threatening. It can be caused by a constellation of disorders which presents with hemoptysis, anemia, and diffuse alveolar infiltrates. Respiratory failure from DAH can be so severe that it has been called an ARDS mimic/imitator. Early recognition is crucial because prompt diagnosis and treatment are required for survival. DAH should be distinguished from other causes of pulmonary hemorrhage caused by localized pulmonary abnormalities and the bronchial circulation. Early bronchoscopy with bronchoalveolar lavage (BAL) is generally required to confirm the diagnosis of DAH and rule out infection. Progressively bloody bronchoalveolar lavage samples can distinguish DAH. Systemic vasculitis is one of the most common causes of DAH and can be pathologically defined by the presence of cellular inflammation, vessel destruction, tissue necrosis, and eventually, organ dysfunction. Corticosteroids and immunosuppressive agents remain the gold standard for the treatment. The following case illustrates a patient who was dependent on dialysis, then presented with hemoptysis. Bronchoscopy demonstrated progressively bloody bronchoalveolar lavage samples consistent with diffuse alveolar hemorrhage. Serologic testing was consistent with microscopic polyangiitis. The patient experienced a clinical remission with cyclophosphamide and corticosteroids. This patient presented with hemoptysis confirmed to be diffuse alveolar hemorrhage and chronic renal failure. The initial suspected etiology was volume overload due to missed dialysis sessions due to the elevated BNP level. The patient was treated conservatively with dialysis and while his reported hemoptysis improved, his chest X-ray showed persistent alveolar infiltrates. The serologic analysis that confirmed the diagnosis included Antinuclear Antibody of 1:360, P-ANCA positivity, and antibody to Myeloperoxidase of greater than 8.0 units. The constellation of diffuse alveolar hemorrhage, renal involvement, and p-ANCA/MPO positivity confirmed a diagnosis of Microscopic Polyangiitis. Imaging of the sinuses showed no signs of inflammation of the upper respiratory tract. The patient was treated with prednisone and cyclophosphamide pulse dosing for six doses. He had one subsequent episode of hemoptysis requiring hospitalization 1 month after initial presentation. In general, he responded well to treatment and was weaned from corticosteroids over the next 3 months after completion of cyclophosphamide with improvement on chest imaging (Fig. 33.4 ). The differential diagnosis for diffuse alveolar hemorrhage can be quite extensive ranging from autoimmune to coagulopathy to medications. Three characteristic patterns have been identified: Capillaritis, 'Bland' pulmonary hemorrhage, and alveolar bleeding due to another process [1, 2] . Capillaritis is the most common cause of DAH and is typically a result of antibody-mediated cell damage. Autoimmune conditions associated with DAH include antineutrophil cytoplasmic antibody (ANCA) associated vasculitides, Goodpasture Syndrome, Systemic Lupus Erythematosus (Table 33 .1). Initial evaluation of a patient with hemoptysis and suspected diffuse alveolar hemorrhage typically includes fiberoptic bronchoscopy to identify a source of bleeding, identification of potential infectious etiologies, and serologic workup for autoimmune conditions. DAH should be distinguished from other causes of pulmonary hemorrhage caused by localized pulmonary abnormalities and the bronchial circulation. Microscopic Polyangiitis (MPA) is a member of the group of ANCA-associated vasculitides. This group also includes granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA or Churg-Strauss Syndrome). These diseases are characterized by pauciimmune necrotizing inflammation of small vessels [3] . MPA has previously been described as a subgroup of Polyarteritis Nodosa (small vessel form) and is distinguished from GPA by the absence of granuloma formation. MPA is most commonly associated with rapidly progressive glomerulonephritis, although alveolar hemorrhage has been reported in up to 12-29% of cases [4] . The diagnosis of ANCA-associated vasculitides is usually based upon findings of pulmonary and/or renal abnormalities with small-vessel necrotizing inflammation with the presence of auto-antibodies directed against neutrophilic anti-gens. Previously, ANCA directed antibodies were classified as cytoplasmic-pattern and perinuclear-patter, c-ANCA and p-ANCA, respectively. The two ANCA antigens commonly identified are proteinase 3 (PR3) and myeloperoxidase (MPO). MPO is more commonly associated with microscopic polyangiitis with a sensitivity of 50-70%, although PR3 has been identified in cases of MPA with a sensitivity of 26% [5] [6] [7] . Specificity of the combination of P-ANCA and MPO for ANCA-associated vasculitides is significantly greater at 99.8% [8] . In a review of patients with MPA and alveolar hemorrhage, 14 out of 27 patients revealed p-ANCA positivity while 11 out of 27 patients were c-ANCA positive [4] . Among those with p-ANCA antibodies, 12 out of 12 patients were positive for MPO specific antibodies. The requirement of biopsy for the diagnosis of ANCA associated vasculitides remains controversial. In the correct clinical setting with rapidly progressive glomerulonephritis, radiographic abnormalities, and serologic confirmation of antibody, the diagnosis of ANCA-associated vasculitis can be determined. Given the relapsing nature of disease and requirements for prolonged immunosuppression, it is suggested that confirmation of diagnosis by histopathology be determined whenever possible. Treatment of diffuse alveolar hemorrhage can be categorized as follows-management of the underlying cause such as vasculitis, management of the pulmonary hemorrhage, and treatment of the hypoxia. Historically, initial management of ANCA-associated vasculitides has centered on immunosuppression with corticosteroids and cyclophosphamide. The goal of treatment is induction of remission and maintenance of disease suppression. Therapy is typically tailored to severity of disease, notably mild vs. moderate to severe. These determinations are based upon organ-threatening or lifethreatening manifestations. Pulmonary involvement, and specifically alveolar hemorrhage, is considered moderate to severe disease. Plasmapheresis has been shown to be beneficial in patients with diffuse alveolar hemorrhage and ANCAassociated vasculitis [9] . In many cases the pulmonary hemorrhage may be exacerbated by coagulopathy. Aggressive treatment with platelets for thrombocytopenia or fresh frozen plasma may be needed for control of the alveolar hemorrhage. There may be a component of pulmonary congestion due to left heart pathology. Increasing positive end-expiratory pressure can improve pulmonary congestion by decreasing afterload and preload thus helping with alveolar hemorrhage. Also, as a patient with DAH becomes hypoxemic, increasing peep may recruit more alveoli and improve oxygenation. Ventilation in the prone position has been mostly studied in patients with acute respiratory distress syndrome (ARDS), but may be useful to treat hypoxia due to pulmonary hemorrhage. In addition to facilitate recruitment and improved v/q mismatch prone position can improve drainage of the bloody secretions [10] . ECMO can also be used as a rescue therapy for DAH patients with severe hypoxemia and PaO 2 /FiO 2 of <100 mmHg despite optimal ventilator settings [11] . There is concern that the ECMO circuit will need systemic anticoagulation to prevent thrombus formation. There have been cases of performing ECMO without systemic anticoagulation in patients with DAH without major complications. Another option is to use local citrate anticoagulation for the ECMO circuit. Reduced levels of anticoagulation represents another possibility although the optimal level of anticoagulation is unknown [12, 13] . Recently, there have been alternative treatment options identified in the treatment of ANCA-associated vasculitides. Cyclophosphamide carries several adverse reactions including cytopenias, infertility, bladder injury, and risk of malignancy. It has been identified that B lymphocytes play an integral in role in the pathogenicity of auto-immunity [14] . Rituximab, an anti-CD20 monoclonal antibody, has been successfully used to reduce B-lymphocyte populations. Since 2010, there has been growing evidence that Rituximab can be used as an alternative to cyclophosphamide in the treatment of ANCA-associated vasculitides. When compared with cyclophosphamide, Rituximab was found to be non-inferior at induction of remission and maintenance of remission [15, 16] . In fact, Rituximab was found to be more effective for inducing remission of relapsing disease (67% vs. 42) [15] . Rituximab has been found to be superior to azathioprine in disease remission over 2 years [17] . Thus, rituximab has been shown to be a viable option for treatment of ANCA-associated vasculitides. While the patient in the case report was treated with cyclophosphamide, the use of rituximab could have been entertained. Refractory diffuse alveolar hemorrhage can present a therapeutic dilemma. Systemic recombinant Factor VII has been successfully used in a case of massive hemoptysis due to community acquired pneumonia [18] . Case reports and observational studies have shown a beneficial effect of intrapulmonary administration of activated recombinant factor VII in cases of refractory diffuse alveolar hemorrhage [19] [20] [21] . Primarily, this practice has been shown to be beneficial in cases of DAH in allogeneic hematopoetic stem cell transplant recipients. Limited case reports, however, have reported successful cessation of bleeding in cases of ANCA-associated vasculitis [19, 21] . At this time, use of recombinant Factor VII is considered "off-label" but further study is warranted for general use in cases of diffuse alveolar hemorrhage refractory to standard therapy. TXA has antifibrinolytic activity by binding to plasminogen which is the precursor to plasmin. The rationale for its use in DAH is that it can enhance the activity of depleted antifibrinolytic factors in ongoing bleeding sites along the bronchial tree [22] . Case series have reported that 500 mg/5 mL through a nebulizer may be an effective dose to halt pulmonary hemorrhage. Although further research is needed, TXA can be a rescue therapy if a patient continues to bleed despite maximal therapy. Diffuse alveolar hemorrhage: diagnosing it and finding the cause Diffuse alveolar hemorrhage revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. 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