Influence of Polymorphisms in Innate Immunity Genes on Susceptibility to Invasive Aspergillosis after Stem Cell Transplantation

The innate immune system plays a pivotal role in the primary defence against invasive fungal infection. Genetic variation in genes that regulate this response, initiated by pulmonary macrophages, may influence susceptibility to invasive aspergillosis in patients at risk. We investigated in a clinical setting whether common polymorphisms in Toll-like receptor (TLR) and cytokine genes involved in macrophage regulation are associated with susceptibility to invasive aspergillosis. Forty-four allogeneic stem cell transplantation recipients diagnosed with probable or proven IA according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group, were enrolled. The control group consisted of 64 allogeneic stem cell transplantation recipients without invasive aspergillosis. The TLR4 1063A>G single nucleotide polymorphism was associated with invasive aspergillosis when present in donors of allogeneic stem cell transplantation recipients (unadjusted OR 3.77 95%CI 1.08–13.2, p = 0.03). In a multivariate analysis, adjusted for occurrence of graft-versus-host-disease, Cytomegalovirus serostatus and duration of neutropenia, paired presence of the TLR4 1063A>G and IFNG 874T>A single nucleotide polymorphisms showed a trend towards increased susceptibility to invasive aspergillosis (p = 0.04). These findings point to the relevant immunological pathway involved in resistance to invasive aspergillosis and warrant further study of the effects of TLR and cytokine polymorphisms and their interaction, which may occur on different levels of the complex biological interplay between the immunocompromised host and Aspergillus sp

Comparison of Mechanical Power During Adaptive Support Ventilation Versus Nonautomated Pressure-Controlled Ventilation-A Pilot Study

Objectives: The aim of this pilot study was to compare the amount of "mechanical power of ventilation" under adaptive support ventilation with nonautomated pressure-controlled ventilation. Design: Single-center, observational prospective pilot study adjoining unitwide implementation of adaptive support ventilation in our department. Setting: The ICU of a nonacademic teaching hospital in the Netherlands. Patients: Twenty-four passive invasively ventilated critically ill patients expected to need of invasive ventilation beyond the following calendar day. Measurements and Main Results: In patients under adaptive support ventilation, only positive end-expiratory pressure and Fio2 were set by the caregivers-all other ventilator settings were under control of the ventilator; in patients under pressure-controlled ventilation, maximum airway pressure (Pmax), positive end-expiratory pressure, Fio2, and respiratory rate were set by the caregivers. Mechanical power of ventilation was calculated three times per day. Compared with pressure-controlled ventilation, mechanical power of ventilation with adaptive support ventilation was lower (15.1 [10.5-25.7] vs 22.9 [18.7-28.8] J/min; p = 0.04). Tidal volume was not different, but Pmax (p = 0.012) and respiratory rate (p = 0.012) were lower with adaptive support ventilation. Conclusions: This study suggests adaptive support ventilation may have benefits compared with pressure-controlled ventilation with respect to the mechanical power of ventilation transferred from the ventilator to the respiratory system in passive invasively ventilated critically ill patients. The difference in mechanical power of ventilation is not a result of a difference in tidal volume, but the reduction in applied pressures and respiratory rate. The findings of this observational pilot study need to be confirmed in a larger, preferably randomized clinical trial

Effect of intellivent‐asv versus conventional ventilation on ventilation intensity in patients with covid‐19 ards— an observational study

Driving pressure (ΔP) and mechanical power (MP) are associated with outcomes in critically ill patients, irrespective of the presence of Acute Respiratory Distress Syndrome (ARDS). INTELLiVENT‐ASV, a fully automated ventilatory mode, controls the settings that affect ΔP and MP. This study compared the intensity of ventilation (ΔP and MP) with INTELLiVENT‐ASV versus conventional ventilation in a cohort of COVID‐19 ARDS patients in two intensive care units in the Netherlands. The coprimary endpoints were ΔP and MP before and after converting from conventional ventilation to INTELLiVENT‐ASV. Compared to conventional ventilation, INTELLiVENT‐ASV delivered ventilation with a lower ΔP and less MP. With conventional ventilation, ΔP was 13 cmH2O, and MP was 21.5 and 24.8 J/min, whereas with INTELLiVENT‐ASV, ΔP was 11 and 10 cmH2O (mean difference –2 cm H2O (95 %CI –2.5 to –1.2 cm H2O), p < 0.001) and MP was 18.8 and 17.5 J/min (mean difference –7.3 J/Min (95% CI –8.8 to –5.8 J/min), p < 0.001). Conversion from conventional ventilation to INTELLiVENT‐ASV resulted in a lower intensity of ventilation. These findings may favor the use of INTELLiVENT‐ASV in COVID‐19 ARDS patients, but future studies remain needed to see if the reduction in the intensity of ventilation translates into clinical benefits

Genetic polymorphisms in the innate immune system considered of potential influence on susceptibility to invasive aspergillosis.

<p><b>Legenda:</b> IL denotes interleukin; TLR: toll-like receptor; IFN: interferon; ASCT: allogeneic stem cell transplantation; IA: invasive aspergillosis; SNPdb id: Single Nucleotide Polymorphism database identification number.</p

Final results of contingency table analysis for the association between the paired presence of TLR and cytokine polymorphisms in donors of ASCT recipients and development of invasive aspergillosis using all 10 polymorphisms.

<p><b>Legenda:</b><i>∫</i>: p-value calculated with Fisher's exact test. IL: interleukin; TLR: toll-like receptor; IFN: interferon.</p><p>*: Adjusted for presence of GVHD, CMV serostatus of donor and acceptor (either one or both CMV IgG+), and prolonged neutropenia (>14 days) by binary logistic regression. OR: odds ratio; 95%CI: 95% confidence interval.</p

Genotype and allele frequencies of SNPs in <i>TLR</i>, <i>IL10, IL12</i> and <i>IFNG</i> genes in the donor DNA of patients who developed invasive aspergillosis after allogeneic stem cell transplantation.

<p><b>Legenda:</b> IL denotes interleukin; TLR: toll-like receptor; IFN: interferon; ASCT: allogeneic stem cell transplantation; IA: invasive aspergillosis; <i>X</i><b><i>²</i></b>: chi-square test value; OR: odds ratio; 95%CI: 95% confidence interval. ∑: distribution of this genotype was not in Hardy-Weinberg equilibrium (p = 0.045).</p><p>*:Due to incidental failing of genotyping the No. of cases and controls are not equal for each SNP; m: minor allele; M:major allele.</p

Clinical characteristics of patients with underlying hematological disease with (cases) or without (controls) invasive aspergillosis after allogeneic stem cell transplantation.

<p><b>Legenda:</b> IA: invasive aspergillosis; IQR: interquartile range, ASCT: allogeneic stem cell transplantation, CMV: Cytomegalovirus, AML: acute myeloid leukemia, CML: chronic myeloid leukemia, NHL: non-Hodgekin's lymphoma, ALL: acute lymphocytic leukemia, CLL: chronic lymphocytic leukemia, MDS: myelodysplastic syndrome.</p><p>†: Prolonged neutropenia was defined as absolute neutrophil count <500 cells/mm³ for a period of more than 14 days.</p><p>¶: IgG positive prior to transplantation. GVHD: graft versus host disease;</p><p>‡: p-values were calculated by student-t test for continous- and Fishers exact test for binary data.</p><p>*: The distribution of hematological diseases was comparable between groups (Pearson Chi-Square test p = 0.85).</p

Identification of Varicella-Zoster Virus-Specific CD8 T Cells in Patients after T-Cell-Depleted Allogeneic Stem Cell Transplantation▿

To study the role of CD8 T cells in the control of varicella-zoster virus (VZV) reactivation, we developed multimeric major histocompatibility complexes to identify VZV-specific CD8 T cells. Potential HLA-A2 binding peptides from the putative immediate-early 62 protein (IE62) of VZV were tested for binding, and peptides with sufficient binding capacity were used to generate pentamers. Patients with VZV reactivation following stem cell transplantation were screened with these pentamers, leading to the identification of the first validated class I-restricted epitope of VZV. In 42% of HLA-A2 patients following VZV reactivation, these IE62-ALW-A2 T cells could be detected ex vivo