Severe Diffuse Alveolar Hemorrhage Research Articles

MEK1/2 and ERK1/2 mediated lung endothelial injury and altered hemostasis promote diffuse alveolar hemorrhage in murine lupus.

About 3% of lupus patients develop severe diffuse alveolar hemorrhage (DAH) with pulmonary vasculitis. B6 mice with pristane-induced lupus also develop DAH, but BALB/c mice are resistant. DAH is independent of TLR signaling and other inflammatory pathways. This study examined the role of the mitogen-activated protein kinase pathway (MEK1/2-ERK1/2, JNK, p38). B6 and BALB/c mice were treated with pristane ± inhibitors of MEK1/2 (trametinib/GSK1120212, "GSK"), ERK1/2 (SCH772984, "SCH"), JNK, or p38. Effects on lung hemorrhage and hemostasis were determined. GSK and SCH abolished DAH, whereas JNK and p38 inhibitors were ineffective. Apoptotic cells were present in lung from pristane-treated mice, but not mice receiving pristane+GSK and endothelial dysfunction was normalized. Expression of the ERK1/2-regulated transcription factor Egr1 increased in pristane-treated B6, but not BALB/c, mice and was normalized by GSK. Pristane also increased expression of the anticoagulant genes Tfpi (tissue factor pathway inhibitor) and Thbd (thrombomodulin) in B6 mice. The ratio of tissue factor (F3) to Tfpi increased in B6 (but not BALB/c) mice and was normalized by GSK. Circulating Thbd protein increased in B6 mice and returned to normal after GSK treatment. Consistent with augmented endothelial anticoagulant activity, pristane treatment increased tail bleeding in B6 mice. Pristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1/2-ERK1/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane-induced lupus are relevant to the pathophysiology of life-threatening DAH in SLE and may help to optimize therapy.

USE OF PLASMA EXCHANGE TO TREAT REFRACTORY DIFFUSE ALVEOLAR HEMORRHAGE FROM ANTINEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS

USE OF PLASMA EXCHANGE TO TREAT REFRACTORY DIFFUSE ALVEOLAR HEMORRHAGE FROM ANTINEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS

SEVERE IMMUNE-MEDIATED DIFFUSE ALVEOLAR HEMORRHAGE IN THE AGE OF COVID-19 AND EXTRACORPOREAL MEMBRANE OXYGENATION

SEVERE IMMUNE-MEDIATED DIFFUSE ALVEOLAR HEMORRHAGE IN THE AGE OF COVID-19 AND EXTRACORPOREAL MEMBRANE OXYGENATION

SIROLIMUS-INDUCED ARDS WITH DIFFUSE ALVEOLAR HEMORRHAGE

SIROLIMUS-INDUCED ARDS WITH DIFFUSE ALVEOLAR HEMORRHAGE

Severe pulmonary-renal syndrome in honeybee sting envenomation – A case report

Honeybee stings with features of envenomation (either local or allergic and rarely systemic toxicity) are often seen in agriculture workers. An initial presentation with severe diffuse alveolar hemorrhage or pulmonary-renal syndrome is rare and only confined to a few case reports. Herein, we describe a case of a 45-year-old male who presented with multiple bee stings and subsequently developed acute kidney injury and pulmonary hemorrhage. He was managed with hemodialysis, invasive mechanical ventilation, red-cell transfusion, and pulse methylprednisolone. However, he developed cardiac arrhythmias with ventricular tachycardia and died.

Ticagrelor Induced Diffuse Alveolar Hemorrhage - A Case Report

Drug-induced Alveolar Hemorrhage is a rare cause of Diffuse Alveolar Hemorrhage (DAH). It requires to be considered in the differential diagnosis among patients presenting with DAH and prompt management, including the need for mechanical ventilation in severe cases. Here we present a case of severe DAH following percutaneous coronary intervention and Ticagrelor therapy that responded well to discontinuation of Ticagrelor.

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

BackgroundLeptospirosis 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 presentationWe 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.ConclusionLeptospirosis 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.

Successful use of rituximab for hydralazine-induced anti-neutrophil cytoplasmic antibodies-associated vasculitis

Hydralazine is a commonly used anti-hypertensive medication. It can, however, contribute to the development of autoimmunity, in the form of drug-induced lupus and anti-neutrophil cytoplasmic antibodies-associated vasculitis. We report a 45-year-old patient with hypertension managed with hydralazine for four years who presented with rapidly progressive glomerulonephritis (RPGN), requiring hemodialysis, and diffuse alveolar hemorrhage (DAH), requiring mechanical ventilation, and extracorporeal membrane oxygenation. The patient's autoantibody profile was consistent with a drug-induced autoimmune process and renal histology revealed focal necrotizing crescentic GN. She was treated with high-dose steroids, plasma exchange and rituximab. DAH resolved and her renal function improved, allowing discontinuation of hemodialysis. This case reveals that rituximab can be successfully used in the setting of hydralazine-induced vasculitis, including critically ill patients with severe DAH and acute kidney injury from RPGN.

LIGHTNING STRIKES TWICE? ALVEOLAR HEMORRHAGE AND SINUS NODE DYSFUNCTION REQUIRING PACEMAKER AFTER INITIATING BORTEZOMIB FOR MULTIPLE MYELOMA

SESSION TITLE: Medical Student/Resident Pulmonary Manifestations of Systemic Disease 3 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma. Neuropathy, constipation, and edema are common side effects. Cardiotoxicity causing dysrhythmia and pacemaker placement have occurred, yet controversy exists regarding the risk of adverse cardiac events based on recent data. To date only 18 cases of alveolar hemorrhage (AH) associated with bortezomib have been described; symptoms occur after a median of four doses and respond to glucocorticoids. CASE PRESENTATION: DB is an 82 year old previously healthy male who presented with fatigue and arm pain admitted for a pathologic humerus fracture, acute renal failure and anemia. Bone marrow biopsy (48% k-restricted plasma cells via morphology, IgA K/L ratio of 345) confirmed the diagnosis of multiple myeloma. The patient received dexamethasone and 2.6mg of bortezomib on D1 and D4. Lenalidomide was held due to NSAID-induced nephropathy. The patient initially experienced distal neuropathy and extremity edema but was discharged and scheduled for outpatient therapy. At home, DB had a syncopal episode secondary to orthostasis and was admitted to the hospital where he received his third dose of bortezomib on D8 per protocol. A chest film ordered for worsening cough revealed right lower lobe infiltrates and bilateral pleural effusions. DB then developed sinus node dysfunction with multiple syncopal episodes requiring a pacemaker. On D26, he developed worsening hypoxia with increased effusions and ground glass opacities on CT imaging. He had preserved ejection fraction and normal IVC collapsibility on echocardiogram. Cefepime, vancomycin, sulfamethoxazole-trimethoprim, and prednisone yielded no improvements. Fat pad biopsy was negative for amyloid. Bronchial lavage was not done due to concern for inability to extubate post-procedure. Worsening renal function precluded CTA for pulmonary embolism. On D33 he was intubated due to respiratory failure. A BAL revealed three progressively bloody aliquots suggestive of AH and the patient was treated with 1g IV solumedrol for three days. Repeat BAL on D39 revealed markedly less bloody aliquots, suggestive of improvement and he was extubated on D48. DISCUSSION: Similar to previously cases, we demonstrate AH after three doses of bortezomib, bilateral infiltrates and effusions, lavage-proven hemorrhage and response to steroids. Unlike others, our case appears to be the first Caucasian male and the oldest known patient to experience this toxicity. Our case has an additional complexity of sinus node dysfunction after induction of bortezomib suggesting an even more rare potential toxicity of bortezomib. CONCLUSIONS: This may represent the first case of concomitant AH and sinus node dysfunction associated with bortezomib and highlights the importance of early recognition and rapid initiation of high dose glucocorticoid therapy. Reference #1: Sugita, Y., et al (2018). Early-Onset Severe Diffuse Alveolar Hemorrhage after Bortezomib Administration Suggestive of Pulmonary Involvement of Myeloma Cells. Reference #2: Diwadkar, Sachin, et al. “Bortezomib-Induced Complete Heart Block and Myocardial Scar: The Potential Role of Cardiac Biomarkers in Monitoring Cardiotoxicity.” Case Reports in Cardiology, vol. 2016, 2016, pp. 1–5., https://doi.org/10.1155/2016/3456287. Reference #3: Laubach, Jacob P., et al. “A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.” British Journal of Haematology, vol. 178, no. 4, Mar. 2017, pp. 547–560., https://doi.org/10.1111/bjh.14708. DISCLOSURES: No relevant relationships by Patrick Bagley, source=Web Response No relevant relationships by Alexander Dew, source=Web Response

Alveolar Hemorrhage in Vasculitis (Primary and Secondary).

Defined by the accumulation of red blood cells into the alveolar space, diffuse alveolar hemorrhage (DAH) is a severe and potentially fatal medical condition requiring careful attention. In contrast to simple extravasation of erythrocytes facilitated by impaired hemostasis or hemodynamic causes, DAH in vasculitis is due to capillaritis, that is, inflammation of capillaries. Dyspnea, hemoptysis, chest infiltrates, and abrupt fall of blood hemoglobin level represent the cardinal features of DAH; yet, hemoptysis is lacking in one-third of cases. Bronchoalveolar lavage, retrieving bright red fluid, is the best diagnostic clue, also excluding infection and other causes of hemoptysis. Although not recommended, lung biopsy is the gold standard for the diagnosis of DAH and pulmonary capillaritis. Pulmonary capillaritis may be primary as in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis or secondary to drugs (especially antithyroid drugs such as propylthiouracil), infections, connective tissue diseases especially systemic lupus erythematosus, or other small vessel vasculitides. Newer toxic causes of drugs of abuse may be difficult to diagnose. Granulomatosis with polyangiitis and microscopic polyangiitis are the most common causes of capillaritis and DAH, whereas DAH is extremely rare in eosinophilic granulomatosis with polyangiitis. When pulmonary capillaritis is not secondary to underlying systemic vasculitis, idiopathic pauci-immune pulmonary capillaritis may be considered, with or without ANCA. Supportive treatment strategy is mandatory in all cases of DAH. Mechanical ventilation and extracorporeal membrane oxygenation may be used in severe cases. Early identification and removal of the putative drug is crucial in drug-induced vasculitis/DAH and may obviate the need for immunosuppressive therapy. High-dose corticosteroids, intravenous cyclophosphamide, and recently rituximab are the mainstay of treatment in vasculitis. Plasma exchange is recommended in anti-glomerular basement membrane disease and in severe DAH associated with systemic lupus erythematosus and is used in selected cases in ANCA-associated vasculitis.

Rare cause of respiratory failure in a young woman: isolated diffuse alveolar haemorrhage requiring extracorporeal membrane oxygenation

A previously healthy 21-year-old young woman presented with worsening dyspnoea and haemoptysis. Imaging was suggestive of widespread pulmonary haemorrhage. There was no other organ system involvement in particular no evidence...

In Vivo Therapeutic Success of MicroRNA-155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage.

Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Pristane-treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA-155 (miR-155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. Recent studies have revealed a pathogenic role of miR-155 in various autoimmune disorders. The purpose of this study was to examine the role of miR-155 in the development of DAH in pristane-induced lupus using miR-155-knockout (miR-155(-/-)) mice and miR-155 antagomir to silence miR-155. DAH was induced by an intraperitoneal injection of 0.5 ml of pristane. MicroRNA-155 antagomir was administered intravenously to silence miR-155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analyzed using Ingenuity Pathway Analysis. Real-time quantitative polymerase chain reaction analysis was used for single-gene validation. Luciferase reporter assay and argonaute 2 immunoprecipitation were performed for target validation. MicroRNA-155 expression was significantly increased during the development of DAH. Disease progression was reduced in miR-155(-/-) mice as well as by in vivo silencing of miR-155 using a miR-155 antagomir. MicroRNA-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways and reduced the expression of proinflammatory cytokines. Several negative regulators of NF-κB signaling were inhibited by pristane and were reactivated in miR-155(-/-) mice. In particular, the antiinflammatory factor peroxisome proliferator-activated receptor α was identified as a direct target of miR-155. MicroRNA-155 promotes pristane-induced lung inflammation. It contributes to ectopic activation of NF-κB signaling pathways by targeting multiple negative regulators. MicroRNA-155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.

Severe Diffuse Alveolar Hemorrhage Associated with Bortezomib Administration in Patients with Multiple Myeloma

Background: Bortezomib, a proteasome inhibitor, is frequently used in treatment of patients with multiple myeloma (MM). Bortezomib is generally well tolerated with gastrointestinal symptoms and peripheral neuropathy being the most common adverse effects. Here we report cases of severe diffuse alveolar hemorrhage (DAH) associated with bortezomib administration.Methods and Results: We identified 3 cases of severe DAH that were associated with bortezomib administration in MM patients treated at our institution between 2010 and 2014 (Table 1). All 3 patients presented with fever and worsening hypoxia shortly after initiation of bortezomib therapy and later developed progressive respiratory failure due to DAH. None of 3 patients had any respiratory symptoms or preexisting pulmonary conditions prior to bortezomib initiation. In one patient respiratory symptoms developed after 4 doses of bortezomib, improved off therapy, however rapidly progressed to a respiratory failure with a subsequent bortezomib treatment. Imaging studies showed diffuse areas of ground-glass opacities, apparent prominence of segmental and subsegmental bronchi and interlobular septal thickening. Infectious workup, which included bronchoscopy with bronchoalveolar lavage and respiratory viral studies, was completely negative in all 3 patients. All patients received supportive care, empiric broad-spectrum antimicrobial therapy and high-dose glucocorticoids, which were started within 4 days of hospital admission. Two patients died from complications of DAH and 1 patient recovered without pulmonary sequelae.Conclusion: Bortezomib-associated DAH is a rare, but serious and potentially fatal adverse event. Pathogenesis remains unclear and is likely related to impaired regulation of the inflammatory response. Early recognition of bortezomib associated DAH is essential for immediate discontinuation of the drug and prompt initiation of high dose steroids. More reports are needed to provide further insights about the pathogenesis and most optimal management of bortezomib induced DAH.Abstract 5761. Table 1:Patients who developed DAH after bortezomib administrationPtAge/ Gender/RaceSmokerSxBor doseBor schedule# of Bor dosesTime of onset after last bor dose (days)Platelet count at the onset (103/mm3)Imaging/BAL findingsTime to initiation of high dose steroidsOutcome167/M/CNeverSOB, fever1.3 mg/m2IV/2Xwk85157Bilateral infiltrates and GGO/DAH2Death272/M/CYesFever, cough1.3 mg/m2IV/2Xwk23108Bilateral infiltrates/DAH4Recovery355/M/CYesFever, chills1.5 mg/m2IV/2Xwk12144Bilateral diffuse airspace disease/DAH4DeathAbbreviations: Pt, patient; M, male; C, Caucasian; Sx, symptoms; Bor, bortezomib; BAL, broncho-alveolar lavage; GGO, ground-glass opacities. DisclosuresNo relevant conflicts of interest to declare.

Severe diffuse alveolar haemorrhage after TAVI with CoreValve in patient with AAV and Horton disease in remission. An immuno-allergic reaction?

Severe diffuse alveolar haemorrhage after TAVI with CoreValve in patient with AAV and Horton disease in remission. An immuno-allergic reaction?

Alveolar Hemorrhage in Vasculitis: Primary and Secondary

Diffuse alveolar hemorrhage (DAH) in primary and secondary vasculitis occurs when capillaritis is present. The diagnosis of DAH is considered in patients who develop progressive dyspnea with alveolar opacities on chest imaging (with density ranging from ground glass to consolidation) that cannot be explained otherwise. Hemoptysis, a valuable sign, is often absent. A decline of blood hemoglobin level over a few days without hemolysis or any hemorrhage elsewhere should be an alert for DAH. Bronchoalveolar lavage, retrieving bright red fluid, is the best diagnostic clue. Lung biopsy is not recommended. A search for anti-neutrophil cytoplasmic autoantibodies (ANCAs) is mandatory. Once DAH is diagnosed and hemodynamic as well as infectious causes have been excluded, ANCA-associated vasculitis is taken into account (mainly microscopic polyangiitis or Wegener granulomatosis, and, exceptionally, Churg-Strauss syndrome). Drug-induced DAH, especially antithyroid drugs such as propylthiouracil may be coupled with ANCA. Isolated DAH with capillaritis with or without ANCA is rare. DAH in systemic lupus erythematosus is either associated or not with capillaritis. Treatment of DAH should target the underlying disorder. In the primary vasculitides, corticosteroids and immunosuppressants, especially cyclophosphamide, are the mainstay of therapy, but plasma exchange, particularly in severe DAH, is the rule, although evidence of its effectiveness is awaited.

Recombinant factor VIIa and intravenous immunoglobulin therapy for diffuse alveolar haemorrhage: A cautionary tale?

Summary Recent reports have described the successful use of recombinant factor VIIa in severe diffuse alveolar haemorrhage (DAH). We describe the clinical course of a young man with catastrophic recurrent idiopathic alveolar haemorrhage that was resistant to immunosuppression and recombinant factor VIIa. The bleeding only ceased following administration of high-dose intravenous immunoglobulins (IVIg). The case was subsequently complicated by bilateral pulmonary thromboemboli (PTE) requiring anticoagulation. This case is the first to clearly associate a benefit from IVIg therapy with an improvement in DAH. Furthermore it illustrates the difficulties in managing a patient with life-threatening alveolar haemorrhage and the subsequent thrombotic complications that may have been related to the therapy.