Two subsets of circulating Ly6Clo monocytes distinguished by CD138 (syndecan-1) expression and Nr4a1 dependence in pristane-treated mice

Chronic peritoneal inflammation following pristane injection induces lupus with diffuse alveolar hemorrhage (DAH) and pulmonary capillaritis in C57BL/6 mice. The pathogenesis involves pristane-induced microvascular lung injury. BALB/c mice are resistant to endothelial injury and DAH. Lung disease in C57BL/6 mice is abolished by depleting monocytes/macrophages. The objective of this study was to define the role of myeloid subsets in DAH. Hemorrhage and vasculitis were abolished in Ccr2-/- mice, indicating involvement of bone marrow-derived monocytes/macrophages. Along with Ly6Chi monocytes, we found two subsets of circulating Ly6Clo monocytes: one CD138- and a novel CD138+ subset. Nr4a1-dependent patrolling Ly6Clo monocytes maintain vascular integrity after endothelial injury. Circulating Ly6CloCD138+ monocytes were associated with DAH and were absent in mice without DAH. They also were absent in Nr4a1-/- mice, whereas Ly6CloCD138- monocytes were unaffected. However, Nr4a1-/- mice were susceptible to pristane-induced DAH and lung vasculitis, suggesting that disease onset does not require Ly6CloCD138- monocytes. Peritoneal Ly6CloCD138+ M? were unchanged in Nr4a1-/- mice, indicating that they are not derived from Ly6CloCD138+ monocytes. We conclude that pristane-induced lung microvascular lung injury stimulates a wave of Nr4h1-dependent Ly6CloCD138+ patrolling monocytes in an ineffectual effort to maintain vascular integrity in the face of ongoing endothelial damage.

Catastrophic antiphospholipid syndrome presented with coronary thrombosis, renal impairment, and suspected diffuse alveolar hemorrhage treated with rituximab biosimilar (CT-P10)

Catastrophic antiphospholipid syndrome (CAPS) is a lethal disease that occurs suddenly and progresses to multi-organ failure. We present a case of CAPS successfully treated with the rituximab biosimilar CT-P10. A 38-year-old man was referred with a sustained fever and unexplained elevated creatinine levels. Cardiac arrest by ventricular fibrillation occurred upon arrival at the hospital. We diagnosed probable CAPS because of coronary thrombus, renal impairment, suspected diffuse alveolar hemorrhage, and positive anticardiolipin antibody immunoglobulin G. We performed percutaneous coronary intervention for the cardiac arrest, and treated him with extracorporeal membrane oxygenation, mechanical ventilation, and continuous renal replacement therapy. When CAPS was diagnosed, we administered CT-P10 after administering high-dose glucocorticoid. Our case suggests that the use of a rituximab biosimilar is economically efficient in the treatment of CAPS, as in other rheumatic diseases. The patient was cured without recurrence at the 2-year follow-up.

Metagenomic next-generation sequencing in the diagnosis of leptospirosis presenting as severe diffuse alveolar hemorrhage: a case report and literature review

Background Leptospirosis is a common infectious disease in tropical and semitropical regions, and it is typically neglected. Leptospirosis-associated acute diffuse alveolar hemorrhage is one of its fatal complications. The use of bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing in the diagnosis of Leptospira interrogans infection has rarely been reported. Case presentation We present the case of a 62-year-old female who was transferred to our hospital with dyspnea, and severe hemoptysis and was supported by a tracheal intubation ventilator. Bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) reported Leptospira interrogans. A diagnosis of diffuse alveolar hemorrhage caused by leptospirosis was made. After immediately receiving antibiotics and hormone therapy, the patient achieved a complete recovery upon discharge. Conclusion Leptospirosis presenting as severe diffuse alveolar hemorrhage is rare but should be considered in the differential diagnosis. mNGS can help identify pathogens and treat them early, which can improve prognosis.

Comparison of survivors and nonsurvivors of diffuse alveolar hemorrhage: risk factors for in-hospital death

Background: The objective of this study was to identify the predictors of in-hospital mortality among patients with diffuse alveolar hemorrhage (DAH).Methods: We conducted a retrospective review of 89 patients hospitalized for DAH at our institution. 49 patients who died during hospitalization and 40 patients who survived were compared. We reviewed their clinical course, radiologic and pathologic findings, along with medical management. We then performed univariate and multivariate analyses to identify the risk factors associated with in-hospital mortality.Results: We identified 12 factors to be associated with mortality when comparing survivor versus non-survivor cohorts: smoking (67 versus 42%, p=0.02), malignancy (17 versus 49%, p=0.002), interstitial lung disease (0 versus 14%, p=0.01), liver failure (2 versus 28%, p=0.001), autoimmune diseases (40 versus 8%, p=0.0006), thrombocytopenia (7 versus 71%, p<0.0001), ICU admission (57 versus 85%, p=0.004), mean ICU stay (p=0.4), steroid use (90 versus 63%, p=0.003), plasma exchange (15 versus 0 %, p=0.005), mechanical ventilation (37 versus 75%, p=0.0007) and acute respiratory distress syndrome (22 versus 77%, p<0.0001). On multivariate analysis, thrombocytopenia (p<0.0001) and ARDS (p=0.0013) were associated with higher odds of mortality in DAH while steroid use (p=0.0004) was associated with a lower risk of in-hospital mortality in patients with DAH.Conclusions: In DAH, thrombocytopenia and ARDS were predictors of in-hospital mortality whereas the use of steroid was associated with a more favorable prognosis.

TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation

Diffuse alveolar hemorrhage (DAH) is one of the serious complications associated with systemic lupus erythematosus, an autoimmune disease whose pathogenesis involves type I IFNs and cytokines. Here, we show that TANK, a negative regulator of the NF-κB signaling via suppression of TRAF6 ubiquitination, is critical for the amelioration of fatal DAH caused by lung vascular endothelial cell death in a mouse model of systemic lupus erythematosus. The development of fatal DAH in the absence of TANK is mediated by type I IFN signaling, but not IL-6. We further uncover that STING, an adaptor essential for the signaling of cytoplasmic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS), plays a critical role in DAH under Tank deficiency. TANK controls cGAS-mediated cGAMP production and suppresses DNA-mediated induction of IFN-stimulated genes in macrophages by inhibiting the formation of DNA-cGAS aggregates containing ubiquitin. Collectively, TANK inhibits the cGAS-dependent recognition of cytoplasmic DNA to prevent fatal DAH in the murine lupus model.

Abstract 16758: Unexplained Recurrent St-elevation Myocardial Infarction Complicated By Diffuse Alveolar Hemorrhage In Undiagnosed Granulomatosis With Polyangiitis

Case Presentation: A 53-year-old man with a history of well-controlled hypertension and dyslipidemia presented with chest pain due to anterior STEMI for which a proximal LAD stent was placed. A week later, he presented with recurrent chest pain and ST elevation in the anterior chest leads. Coronary angiography showed in-stent thrombosis with heavy thrombus burden extending through the LAD. Manual thrombectomy with a second stent placement was done. He was discharged on triple therapy (aspirin, clopidogrel, and rivaroxaban), later, he presented to our medical facility with a 1-week history of hemoptysis. His clinical condition deteriorated requiring intubation. Laboratory work-up revealed elevated renal functions, proteinuria, and significant hematuria. CXR showed diffuse patchy opacities while CT chest was consistent with diffuse alveolar hemorrhage (Figure 1). Further work-up revealed elevated anti-proteinase 3 (c-ANCA) and low C4. Based on microscopic hematuria, renal impairment, and a positive c-ANCA, a diagnosis of granulomatosis with polyangiitis (GPA) was made. Induction with methylprednisolone, cyclophosphamide, and rituximab was initiated. His condition gradually improved, he was extubated successfully with marked improvement of renal functions. He was discharged on clopidogrel and scheduled for follow-up. Discussion: Few case reports have described STEMI as the initial presentation of GPA, likely attributed to vasculitis and accelerated atherosclerosis from systemic inflammation. Our patient had well-controlled cardiovascular risk factors and renal involvement with hematuria and elevated creatinine at the time of STEMI diagnosis, together with intermittent joint pains, suggesting ongoing systemic vasculitis. Clinicians should have a high index of suspicion for the possibility of non-atherosclerotic coronary stenosis as in cases of coronary vasculitis for early detection and management of a potentially reversible condition.