Experimental Evidence That Granulocyte Transfusions Are Efficacious in Treatment of Neutropenic Hosts with Pulmonary Aspergillosis

Abstract

cAlthough polymorphonuclear leukocytes (PMNs) are powerfully anti-Aspergillus, transfusion therapy remains controversial, with conflicting results, and experimental support has been lacking. We devised a pulmonary infection model in neutropenic BALB/c mice, used an antibacterial regimen to prevent confounding sepsis, and optimized PMN induction, purifications, and dose. Mice were given 150 mg/kg cyclophosphamide every 4 days and a gentamicin-vancomycin-clindamycin-imipenem regimen daily beginning 4 days before intranasal challenge with 5 ؋ 10 5 Aspergillus conidia. This regimen produced leukopenia (ϳ10% of normal white blood cell [WBC] count; <10% PMNs) for 10 days, without bacterial superinfection. PMN donors given 100 g/kg recombinant murine granulocyte colony-stimulating factor (G-CSF) for 10 days yielded 11 ؋ 10 7 to 13.6 ؋ 10 7 WBC/ml (81 to 87% PMNs). Infected mice were given PMN transfusions intravenously. In 2 experiments with up to 70% mortality of neutropenic controls, transfusion of 10 7 PMNs 1 and 4 days after challenge had negligible effects on peripheral WBC counts but improved survival (P ‫؍‬ 0.007, 0.02), decreased lung CFU (P ‫؍‬ 0.03, 0.005), and cleared infection in 28 to 50% of survivors. Transfusion of 5 ؋ 10 6 PMNs showed partial protection. Transfusions given every other day did not improve protection. Our present results provide an experimental basis for enthusiasm for PMN transfusions in the therapy of aspergillosis in humans.

Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America

“…The overall benefit vs risk of granulocyte transfusions is currently unknown. Granulocyte transfusions were of benefit in experimental pulmonary aspergillosis in neutropenic mice [381]. Granulocyte transfusions can be considered for neutropenic patients with severe infections, including IA and other mold infections, which have failed or are unlikely to respond to standard therapy.…”

Rodent Models of Invasive Aspergillosis due to Aspergillus fumigatus: Still a Long Path toward Standardization

“…Oral and IM usage of aminosides was rarer (Supplementary Material 4 ). Injectable glycopeptides and carbapenems were sporadically used to prevent infections due to multi-resistant staphylococci and enterobacteriae (Melchers et al, 1994 ; Hashimoto et al, 1998 ; Yonezawa et al, 2000 ; Benjamim et al, 2005 ; Steinbach et al, 2006 ; Tansho et al, 2006 ; van Vianen et al, 2006 ; Cramer et al, 2008 ; Pinchai et al, 2009 ; Rivera et al, 2009 ; Petrik et al, 2010 , 2012 , 2014 ; Grahl et al, 2011 ; Martinez et al, 2013 ; Verwer et al, 2013 ). Likewise, multi-antibiotic associations were sometimes reported, like the following scheme: ciprofloxacin (660 mg/L) and polymyxin B (100 mg/L) in water, plus IM amoxicillin (40 mg/kg/day) and a single shot of IM gentamicin (6 mg/kg) at time of experimental infection (Leenders et al, 1996 ; Dams et al, 1999 ; Becker et al, 2000 , 2002a , b , 2003 , 2006 ; Van Etten et al, 2000 ; Ruijgrok et al, 2001 , 2005 , 2006 ).…”

Immune responses to invasive aspergillosis: new understanding and therapeutic opportunities

“…More recently, a dose-dependent beneficial effect of transfusing granulocyte colony-stimulating factor (G-CSF)-mobilized isogenic neutrophils was observed on murine survival in a neutropenic model of aspergillosis [67]. In humans, the concept of myeloid cell transfusions to improve infectious outcomes was recently examined in a randomized trial using G-CSF/dexamethasone-mobilized granulocytes [68].…”