Intrapulmonary Recombinant Factor VII as an Effective Treatment for Diffuse Alveolar Hemorrhage: A Case Series.

BACKGROUND: The diffuse alveolar hemorrhage (DAH) syndrome is a life-threatening pulmonary complication related to systemic vasculitides, posthematopoietic stem cell transplantation, drugs, or toxins. Once DAH develops, the mortality rate is as high as 50% to 80%. Initial treatment consists of high-dose steroids and supportive measures, including mechanical ventilation. We present a case series of 6 patients treated with intrapulmonary recombinant factor VIIa (rFVIIa) to treat refractory DAH. METHODS: Six patients with DAH were treated with intrapulmonary instillation of rFVIIa. Doses were divided equally between the right and the left lungs. Doses were 30, 50, or 60 mcg/kg and frequencies varied from a single administration to repeated doses on subsequent days on the basis of the clinical response. All patients received high-dose steroids, and 4 also received an aminocaproic acid infusion. RESULTS: Intrapulmonary rVFIIa treated DAH effectively in 5 of 6 patients. Doses used were smaller and less frequent than those described previously. CONCLUSIONS: Intrapulmonary factor VII is an effective adjunctive treatment for DAH. We achieved treatment success with both smaller and less frequent doses than those described previously. This may be a good therapeutic option for DAH, particularly when standard therapies have failed or bleeding is immediately life threatening. It is possible that intrapulmonary rFVIIa could save costs, while improving the intensive care unit length of stay. Further prospective studies are needed to assess the optimal dose and frequency for adequate therapeutic efficacy.

Comparison of pulmonary complications after nonmyeloablative and conventional allogeneic hematopoietic cell transplant.

Nonmyeloablative conditioning before allogeneic hematopoietic cell transplant (HCT) is an alternative to conventional conditioning in older patients and those with comorbidities. It is not known whether the decreased tissue injury associated with nonmyeloablative conditioning lowers the risk of pulmonary complications. The medical records of patients who underwent transplantation were reviewed and all pulmonary complications documented. Sixty-two consecutive patients with hematologic malignancies who underwent minimally intensive HCT (subjects) were compared to 48 consecutive patients who received conventional myeloablative allogeneic peripheral blood HCT (controls) over the same period at Indiana University Hospital. Pulmonary complications were categorized according to the type of complication and the time of onset after transplantation. Median follow-up times were similar between groups (P = .70). The study population (minimal intensity recipients) was older (P < .01), and the incidence of chronic graft-versus-host disease (cGVHD) was higher in subjects than controls (P = .02). Sixty-nine percent of subjects and 73% of controls developed pulmonary complications (P = .70). There was a trend in the minimally conditioned patients towards a lower incidence of pulmonary complications in older patients in the early posttransplantation period and a higher incidence of infectious pneumonias and bronchiolitis obliterans syndrome at later time points. The frequency of pulmonary complications seems to be similar after minimally intensive or myeloablative conditioning and allotransplantation. There was no difference in overall mortality or pulmonary-related mortality between the 2 groups.

Stimulation of sphingosine 1-phosphate signaling as an alveolar cell survival strategy in emphysema.

RATIONALE: Vascular endothelial growth factor receptor (VEGFR) inhibition increases ceramides in lung structural cells of the alveolus, initiating apoptosis and alveolar destruction morphologically resembling emphysema. The effects of increased endogenous ceramides could be offset by sphingosine 1-phosphate (S1P), a prosurvival by-product of ceramide metabolism. OBJECTIVES: The aims of our work were to investigate the sphingosine-S1P-S1P receptor axis in the VEGFR inhibition model of emphysema and to determine whether stimulation of S1P signaling is sufficient to functionally antagonize alveolar space enlargement. METHODS: Concurrent to VEGFR blockade in mice, S1P signaling augmentation was achieved via treatment with the S1P precursor sphingosine, S1P agonist FTY720, or S1P receptor-1 (S1PR1) agonist SEW2871. Outcomes included sphingosine kinase-1 RNA expression and activity, sphingolipid measurements by combined liquid chromatography-tandem mass spectrometry, immunoblotting for prosurvival signaling pathways, caspase-3 activity and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays, and airspace morphometry. MEASUREMENTS AND MAIN RESULTS: Consistent with previously reported de novo activation of ceramide synthesis, VEGFR inhibition triggered increases in lung ceramides, dihydroceramides, and dihydrosphingosine, but did not alter sphingosine kinase activity or S1P levels. Administration of sphingosine decreased the ceramide-to-S1P ratio in the lung and inhibited alveolar space enlargement, along with activation of prosurvival signaling pathways and decreased lung parenchyma cell apoptosis. Sphingosine significantly opposed ceramide-induced apoptosis in cultured lung endothelial cells, but not epithelial cells. FTY720 or SEW2871 recapitulated the protective effects of sphingosine on airspace enlargement concomitant with attenuation of VEGFR inhibitor-induced lung apoptosis. CONCLUSIONS: Strategies aimed at augmenting the S1P-S1PR1 signaling may be effective in ameliorating the apoptotic mechanisms of emphysema development.