Idiopathic pneumonia syndrome (IPS) is a common, often fatal, complication following hematopoietic stem cell transplantation (HSCT) characterized by severe pneumonitis and interstitial fibrosis. Fully reconstituted syngeneic bone marrow transplant (BMT) mice infected with murine gammaherpesvirus (γHV-68) develop IL-17-driven pneumonitis and fibrosis which mimics clinical manifestations of IPS. We found CD103+ and CD11b+ dendritic cells (DCs) are selectively deficient for the Notch ligand, DLL4, following BMT and CD4+ T-cells isolated from lungs and spleens of infected BMT mice display Notch signaling defects. Mice transplanted with CD4-Cre-driven dominant-negative Notch transcriptional regulator Mastermind Like (CCD mice) bone marrow displayed elevated IL-17 and TGFβ in the lungs, a further expansion of Th17 cells, and developed more fibrosis than WT-BMT mice. Culture of BMT lung leukocytes with recombinant Notch ligand, DLL4, restored Notch signaling and decreased production of IL-17. Adoptive transfer of CD11c+ DCs could restore Th1 and limit Th17 in WT-BMT but not CCD-BMT mice indicating a specific DC / CD4+ T-cell Notch interaction modulates IL-17 production following reconstitution in syngeneic BMT mice. Given recent clinical observations showing that patients with pulmonary complications post-transplant harbor occult herpesvirus infections, these data provide mechanistic insight and suggest potential therapies for these devastating conditions.
BackgroundEarly diagnosis of IPA is challenging and has a direct impact on mortality. Several diagnostic modalities have been developed with variable performance. AspID is a new multiplex Aspergillus qRT-PCR assay and AspLFD is a rapid test that targets the Aspergillus specific antigen JF5; both tests were developed by OLM Diagnostics. We evaluated the performance characteristics of AspID used alone and in combination with AspLFD on BAL fluid of patients at high risk for IPA.MethodsSamples had been prospectively banked in our BAL repository. Forty-two samples, 14 from patients with proven/probable IPA by EORTC/MSG criteria and 28 from control patients without IPA, were tested with AspID and AspLFD. For AspID, DNA extraction and qRT-PCR were performed per manufacturer instructions. For AspLFD, 100 μL of sample was applied to the device. AspID and AspLFD results were each read by three different blinded observers. Only patient with a valid result for both tests were included in the analysis. Sensitivity, specificity, and accuracy of AspID alone and in combination with AspLFD were calculated.ResultsOf the 42 samples, 22 were excluded because the AspID internal extraction control showed the assay to be invalid and one sample was excluded because the AspLFD internal control line was not visible. Thus, 19 patients were analyzed, eight with IPA and 11 without IPA. Among eight IPA cases, seven were positive by AspID and one was negative; two tested positive by AspLFD and six were negative. Of the 11 control patients without IPA, four were positive by AspID and seven were negative; all 11 were negative by AspLFD. AspID sensitivity was significantly higher than that of AspLFD (87.5% vs. 25%, P = .0001), but specificity of AspLFD was superior to that of AspID (100% vs. 64%, P = 0.049). Accuracy was 74% for AspID and 68% for AspLFD. When deciding whether doing both tests was beneficial for diagnosis, union analysis showed the sensitivity to be 87.5% and the specificity to be 64%. Accuracy was not improved and remained at 74%.Conclusion
AspID had higher sensitivity than AspLFD and AspLFD had higher specificity than AspID. Using both tests in combination did not improve the ability to diagnose IPA in patients with classic risk factors.Disclosures
All authors: No reported disclosures.
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