Development Of Idiopathic Pneumonia Syndrome Research Articles

Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Pediatric Patients With Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

<h3>Purpose/Objective(s)</h3> To evaluate the relationship between total body irradiation (TBI) and other factors in the development of idiopathic pneumonia syndrome (IPS) in pediatric patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute leukemia. <h3>Materials/Methods</h3> Between 2006-2019, 121 pediatric patients with acute leukemia (84 lymphoblastic, 37 myeloid), ranging in age from 1 to 21 years (median 12), underwent allogeneic HCT at a single institution with matched sibling (n = 33), single unrelated cord blood (sUCB; n = 57), or double unrelated cord blood (dUCB; n = 31) donor. Pretransplantation conditioning included cyclophosphamide (100-120 mg/kg) with (n = 89) or without fludarabine (75 mg/m²) (n = 32). TBI was delivered in 8 b.i.d. fractions of 1.65 Gy over 4 days via opposed lateral beams of 6, 18, or 25 MV prescribed to midplane at umbilicus, with the patient in a semi-recumbent position, and without lung shielding. Aluminum lung compensator was utilized if predicted mid-lung point dose was ≥3% higher than prescription dose (n = 28). Dose rate was specified at 9-20 cGy/min and depended on linear accelerator availability. Patients were stratified by receipt of high-dose-rate (HDR; > 15 cGy/min; 36%) or low-dose-rate (LDR; ≤15 cGy/min; 64%) delivery. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, or pulmonary function testing within 100 days of HCT in the absence of concurrent infection. The association between treatment factors and IPS was examined. <h3>Results</h3> Overall, IPS developed in 22 (18%) patients from day 6 to 83 (median 20) after HCT. On univariate analysis, factors associated with IPS included donor type (matched sibling 12%, sUCB 12%, dUCB 35%, <i>P</i> < 0.01), HDR TBI (35% vs 9% for LDR, <i>P</i> < 0.01), and lower beam energy (35% for 6 MV and 15% for 18/25 MV, <i>P</i> = 0.04). The finding of beam energy significance is likely the result of the 6 MV cohort having a greater dose rate (median 16 cGy/min) than the 18/25 MV cohort (11 cGy/min). On competing risk regression analysis, the pre-specified factors of dose rate, beam energy, lung compensator, age, HCT comorbidity index, and donor type were included in the model. All factors except age (hazard ratio [HR] 1.09, <i>P</i> = 0.20) and lung compensator (HR 1.8, <i>P</i> = 0.17) showed an independent statistically significant association with IPS. Kaplan-Meier estimated 1-year survival was 73% for the entire cohort. Time-dependent effect of IPS did not show an association with overall survival (HR 1.2, <i>P</i> = 0.76). <h3>Conclusion</h3> TBI dose rate is an important variable in the risk of pulmonary toxicity in children treated with allogeneic HCT. TBI dose rates ≤15 cGy/min reduced the risk of posttransplantation IPS and should be strongly considered as an easily implemented parameter in pre-transplantation TBI-based conditioning.

Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Acute Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

To determine the relationship between dose rate and other factors in the development of idiopathic pneumonia syndrome (IPS) in patients with acute lymphoblastic leukemia or acute myeloid leukemia who are undergoing total body irradiation (TBI)-based myeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT). From 2006 to 2016, 202 patients with acute leukemia (111 acute lymphoblastic leukemia, 91 acute myeloid leukemia) ranging in age from 1 to 57years (median, 25years) underwent allogeneic HCT at University of Minnesota. Pretransplantation conditioning included cyclophosphamide (120mg/kg) with (68%) or without fludarabine (75mg/m2) followed by 13.2Gy TBI given in 8 twice-daily fractions of 1.65Gy over 4days. Dose rate varied based on linear accelerator availability and ranged from 8.7 to 19.2cGy/min. Patients were stratified by receipt of high-dose-rate (HDR; >15cGy/min; 56%) or low-dose-rate (LDR; ≤15cGy/min; 44%) TBI for all 8 fractions. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, or pulmonary function testing within 100days of HCT in the absence of concurrent infection. IPS developed in 42 patients (21%) between 4 and 73days (median, 16days) after transplantation. HDR TBI was associated with a higher rate of IPS compared with LDR TBI (29% vs 10%; P<.01). On multiple regression analysis, HDR remained a significant predictor of IPS (hazard ratio, 2.6; 95% confidence interval, 1.2-5.3; P=.01), and this led to inferior 1-year overall survival (60% vs 76%; P=.01) and increased 1-year nonrelapse mortality (28% vs 15%; P=.02). TBI dose rates ≤15cGy/min reduce the risk of posttransplantation IPS and improve overall survival. LDR TBI should be strongly considered as an easily implemented parameter to improve the safety of pretransplantation TBI-based conditioning.

Translational Research Efforts in Biomarkers and Biology of Early Transplant-Related Complications

In the time since the first allogeneic hematopoietic stem cell transplantation (HSCT) was performed over 40 years ago, this life-saving procedure has been used increasingly for patients with hematologic, metabolic, and malignant diseases. Despite major advances in our understanding of the immunologic processes (both beneficial and injurious) that are associated with HSCT and improvements in supportive and critical care medicine, successful outcomes are still limited by several serious complications. As such, the establishment of effective therapeutic strategies for these complications will be crucial as increasing numbers of high-risk transplants are performed each year. The development of such approaches is fundamentally dependent upon a basic understanding of pathophysiologic mechanisms of disease and also on our ability to successfully translate these insights back to the bedside. This brief review will highlight breakthroughs in translational research endeavors that have paved the way for the development of novel strategies intended to change the standard of care and optimize outcomes for patients in whom allogeneic HSCT offers the only hope for a cure.

T helper17 Cells Are Sufficient But Not Necessary to Induce Acute Graft-Versus-Host Disease

T helper (Th)1 cells were considered responsible for the induction of graft-versus-host disease (GVHD), but recently the concept has been challenged. Th17 cells play a critical role in mediating autoimmune diseases, but their role in the pathogenesis of GVHD remains unclear. Herein we compare the ability of in vitro generated Th1 and Th17 cells from C57BL/6 mice to induce GVHD in lethally irradiated BALB/c recipients. Allogeneic Th17 cells had superior expansion and infiltration capabilities in GVHD target organs, which correlated with their increased pathogenicity when compared with naïve or Th1 controls. Th17 cells caused no pathology in the syngeneic recipients, indicating that antigen-activation was required for their pathogenicity. Polarized Th17 cells could not maintain their phenotype in vivo as they produced a significant amount of interferon (IFN)-gamma after being transplanted into allogeneic recipients; however, IFN-gamma was not required for Th17 cell-induced GVHD. Further, we evaluated the pathogenesis of Th17 cells in GVHD by using polyclonal nonprimed CD4T cells in a clinically relevant allogeneic bone marrow transplantation (BMT) setting. We found that disruption of Th17-differentiation alone by targeting RORgammat (Th17-specific transcription factor) had no significant effect on GVHD development. We conclude that Th17 cells are sufficient but not necessary to induce GVHD.

IFNγ differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract

AbstractAlthough proinflammatory cytokines are key mediators of tissue damage during graft-versus-host disease (GVHD), IFNγ has previously been attributed with both protective and pathogenic effects. We have resolved this paradox by using wild-type (wt), IFNγ−/−, and IFNγR−/− mice as donors or recipients in well-described models of allogeneic stem cell transplantation (SCT). We show that donor-derived IFNγ augments acute GVHD via direct effects on (1) the donor T cell to promote T helper 1 (Th1) differentiation and (2) the gastrointestinal (GI) tract to augment inflammatory cytokine generation. However, these detrimental effects are overwhelmed by a protective role of IFNγ in preventing the development of idiopathic pneumonia syndrome (IPS). This is the result of direct effects on pulmonary parenchyma to prevent donor cell migration and expansion within the lung. Thus, IFNγ is the key cytokine differentially controlling the development of IPS and gastrointestinal GVHD after allogeneic SCT.

Donor-derived TNF-α regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation

AbstractIdiopathic pneumonia syndrome (IPS) is a significant cause of mortality after allogeneic bone marrow transplantation (allo-BMT), and tumor necrosis factor-α (TNF-α) is a significant effector molecule in this process. However, the relative contribution of donor-versus host-derived TNF-α to the development of IPS has not been elucidated. Using a lethally irradiated parent → F1 mouse IPS model, we showed that 5 weeks after transplantation allo-BMT recipients developed significant lung injury compared with syngeneic controls, which was associated with increased bronchoalveolar lavage (BAL) fluid levels of TNF-α, elevated numbers of donor-derived TNF-α-secreting T cells, and increased pulmonary macrophage production of TNF-α to lipopolysaccharide (LPS) stimulation. Allo-BMT with TNF-α-/- donor cells resulted in significantly reduced IPS severity, whereas utilization of TNF-α-deficient mice as BMT recipients had no effect on IPS. We next determined that TNF-α secretion from both donor accessory cells (monocytes/macrophages) and T cells significantly contributed to the development of IPS. Importantly, the absence of donor T-cell-derived TNF-α resulted in a significant decrease in inflammatory chemokine production in the lung and near complete abrogation of IPS. Collectively, these data demonstrate that donor TNF-α is critical to the development of IPS and reveal a heretofore unknown mechanism for T-cell-derived TNF-α in the evolution of this process. (Blood. 2004;104:586-593)

A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation

AbstractIdiopathic pneumonia syndrome (IPS) is a major complication after allogeneic bone marrow transplantation (allo-BMT) and involves the infiltration of donor leukocytes and the secretion of inflammatory cytokines. We hypothesized that leukocyte recruitment during IPS is dependent in part upon interactions between chemokine receptor 2 (CCR2) and its primary ligand monocyte chemoattractant protein–1 (MCP-1). To test this hypothesis, IPS was induced in a lethally irradiated parent → F1 mouse BMT model. Compared with syngeneic controls, pulmonary expression of MCP-1 and CCR2 mRNA was significantly increased after allo-BMT. Transplantation of CCR2-deficient (CCR2-/-) donor cells resulted in a significant reduction in IPS severity compared with transplantation of wild-type (CCR2+/+) cells and in reduced bronchoalveolar lavage (BAL) fluid cellularity and BAL fluid levels of tumor necrosis factor–α (TNF-α) and soluble p55 TNF receptor (sTNFRI). In addition, neutralization of MCP-1 resulted in significantly decreased lung injury compared with control-treated allogeneic recipients. Experimental data correlated with preliminary clinical findings; patients with IPS have elevated levels of MCP-1 in the BAL fluid at the time of diagnosis. Collectively, these data demonstrate that CCR2/MCP-1 interactions significantly contribute to the development of experimental IPS and suggest that interventions blocking these receptor-ligand interactions may represent novel strategies to prevent or treat this lethal complication after allo-BMT.

Donor T cell-derived TNF alpha regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic stem cell transplantation

Donor T cell-derived TNF alpha regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic stem cell transplantation

Donor leukocyte-production of rantes significantly contributes to the development of idiopathic pneumonia syndrome after allogeneic stem cell transplantation

Donor leukocyte-production of rantes significantly contributes to the development of idiopathic pneumonia syndrome after allogeneic stem cell transplantation

3A critical role for CCR2 in the development of idiopathic pneumonia syndrome after allogeneic BMT

3A critical role for CCR2 in the development of idiopathic pneumonia syndrome after allogeneic BMT

108A role for the P75 but not the P55 TNFα receptor in the development of idiopathic pneumonia syndrome after allogeneic stem cell transplantation

108A role for the P75 but not the P55 TNFα receptor in the development of idiopathic pneumonia syndrome after allogeneic stem cell transplantation

Idiopathic pneumonia syndrome after syngeneic bone marrow transplant in mice.

Idiopathic pneumonia syndrome is characterized by noninfectious diffuse lung injury after myeloablative chemotherapy and bone marrow transplant. Because little is known about its pathogenesis after autologous-based regimens, we have developed a murine model that closely mimics the human lung disease process. Using an autologous regimen similar to that used for patients with metastatic breast cancer, mice developed pulmonary injury as early as 1 day posttransplant. This lung injury was most dramatically characterized by decreased lung compliance that was associated with an intense monocytic cellular infiltrate of activated macrophages. This influx was preceded by an acute elevation in monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha. The conditioning regimen caused substantial oxidative stress as manifest by elevations in lung lipid peroxidation and oxidized glutathione. To test the hypothesis that oxidation is directly responsible for the lung toxicity, we administered the antioxidant, n-acetylcysteine. These mice showed substantially less lung injury, thus providing direct evidence that oxidative stress plays a distinct role in the development of lung injury in the early periautologous bone marrow transplant period. Attenuation of lung oxidative stress and/or inflammation in patients undergoing autologous bone marrow transplant may reduce the subsequent development of idiopathic pneumonia syndrome.