Abstract
Objective
Tocilizumab is effective in inducing and maintaining remission of GCA. Despite clinical and serological control of disease, magnetic resonance angiography may show persistence of ...inflammatory signals of unknown significance in arterial walls. Thus, there is an unmet need for tools to detect subclinical disease activity.
Methods
Immune-inflammatory markers were measured in prospectively collected sera of the first randomized, double-blind, placebo-controlled trial investigating the use of tocilizumab in GCA. As a comparison, immune-inflammatory markers were also measured in sera from age- and sex-matched healthy volunteers. The biomarkers were quantified using luminex technology.
Results
Of all the parameters determined, only MMP-3, pentraxin-3 and sTNFR2 were significantly elevated, while ICAM-1 and CD163 were significantly decreased during the early stages of the study, at time points of full clinical remission under treatment with tocilizumab plus glucocorticoids. In contrast, tocilizumab monotherapy towards the end of the study resulted in an almost complete normalization of immune-inflammatory molecules, as defined by the healthy controls. MMP-3 levels showed a weak association with magnetic resonance signal intensity; none of the biomarkers predicted relapse occurring within 6 months after study end.
Conclusion
The data documented a subclinical disease activity in GCA that was more pronounced during the early stages of treatment and almost disappeared towards the study end. They indicated that tocilizumab treatment of at least 52 weeks is necessary in order to reset a broad range of immune-inflammatory pathways.
Trial registration
ClinicalTrials.gov, http://clinicaltrials.gov, NCT01450137.
5D, free-running imaging resolves sets of 3D whole-heart images in both cardiac and respiratory dimensions. In an application such as coronary imaging when a single, static image is of interest, ...computationally expensive offline iterative reconstruction is still needed to compute the multiple 3D datasets.
Evaluate how the number of physiologic bins included in the reconstruction affects the computational cost and resulting image quality of a single, static volume reconstruction.
Retrospective.
15 pediatric patients following Ferumoxytol infusion (4 mg/kg).
1.5 T/Ungated 5D free-running GRE sequence.
The raw data of each subject were binned and reconstructed into a 5D (x-y-z-cardiac-respiratory) images. 1, 3, 5, 7, and 9 bins adjacent to both sides of the retrospectively determined cardiac resting phase and 1, 3 bins adjacent to the end-expiration phase are used for limited frame reconstructions. The static volume within each limited reconstruction was compared with the corresponding full 5D reconstruction using the structural similarity index measure (SSIM). A non-linear regression model was used to fit SSIM with the percentage of data used compared to full reconstruction (% data). A linear regression model was used to fit computation time with % raw data used. Coronary artery sharpness is measured on each limited reconstructed images to determine the minimal number of cardiac and respiratory bins needed to preserve image quality.
The coefficient of determination (R2) is computed for each regression model.
The % of data used in the reconstruction was linearly related to the computational time (R2 = 0.99). The SSIM of the static image from the limited reconstructions is non-linearly related with the % of data used (R2 = 0.80). Over the 15 patients, the model showed SSIM of 0.9 with 18% of data, and SSIM of 0.96 with 30% of data. The coronary artery sharpness of images reconstructed using no less than 5 cardiac and all respiratory phases is not significantly different from the full reconstructed images using all cardiac and respiratory bins.
Reconstruction using only a limited number of acquired physiological states can linearly reduce the computational cost while preserving similarity to the full reconstruction image. It is suggested to use no less than 5 cardiac and all respiratory phases in the limited reconstruction to best preserve the original quality seen on the full reconstructed images.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with cardiogenic shock (CS) display systemic inflammation and a high rate of infections, suggesting important immune disturbances. To explore the immune response to CS, we prospectively ...measured, in 24 consecutive CS patients, differential white blood cell (WBC) counts and the cytokines IL-1β, IL-5, IL-6, IL-10, TNFα, IFNγ, MCP-1 and eotaxin (CCL11), at Day 1 (T1), day 3 (T2) and day 6-8 (T3). Secondary infections and their influence on cytokines and WBCs were determined. CS induced early (T1) neutrophilia and elevated levels of IL-6, IL-10 and MCP-1, correlating with shock severity. The eosinophil chemoattractant eotaxin was elevated at T1 and decreased thereafter, and a progressive rise of blood eosinophils was noted over time. Patients with the most severe shock had reduced lymphocytes and monocytes at T2 and T3. Sixty-two percent of patients developed an infection, which did not alter the profile of immune response, except from higher IL-6 levels at T2. Therefore, CS elicits an acute pro-inflammatory response, followed by a delayed increase in blood eosinophils, consistent with the development of a tissue repair response, as well as depletion of immune cells in the most severely affected patients, which might predispose to secondary infections.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Drug-induced liver injury is a major safety issue. It can cause severe disease and is a common cause of the withdrawal of drugs from the pharmaceutical market. Recent studies have identified the ...HLA-B∗ 57:01 allele as a risk factor for floxacillin (FLUX)-induced liver injury and have suggested a role for cytotoxic CD8+ T cells in the pathomechanism of liver injury caused by FLUX. This study aimed to confirm the importance of FLUX-reacting cytotoxic lymphocytes in the pathomechanism of liver injury and to dissect the involved mechanisms of cytotoxicity. IHC staining of a liver biopsy from a patient with FLUX-induced liver injury revealed periportal inflammation and the infiltration of cytotoxic CD3+ CD8+ lymphocytes into the liver. The infiltration of cytotoxic lymphocytes into the liver of a patient with FLUX-induced liver injury demonstrates the importance of FLUX-reacting T cells in the underlying pathomechanism. Cytotoxicity of FLUX-reacting T cells from 10 HLA-B∗ 57:01+ healthy donors toward autologous target cells and HLA-B∗ 57:01-transduced hepatocytes was analyzed in vitro . Cytotoxicity of FLUX-reacting T cells was concentration dependent and required concentrations in the range of peak serum levels after FLUX administration. Killing of target cells was mediated by different cytotoxic mechanisms. Our findings emphasize the role of the adaptive immune system and especially of activated drug-reacting T cells in human leukocyte antigen-associated, drug-induced liver injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Allogeneic hematopoietic cell transplant recipients (allo-HCTRs) with positive cytomegalovirus (CMV) serology may have false-positive results due to blood product transfusion-associated passive ...immunity.
This single-center cohort study included allo-HCTRs with negative baseline (at malignancy diagnosis) CMV serology and indeterminate/low-positive (CMV IgG titer, ≥0.6-<50 U/mL) pretransplant CMV serology with negative pretransplant plasma CMV DNAemia. The CMV status of those patients was reclassified from R+ to R- (CMVR- reclassification group). We compared those patients to allo-HCTRs with negative (CMV IgG titer <0.6 U/mL) pretransplant CMV IgG (CMVR- group). We describe the number and type of patients whose pretransplant CMV status was reclassified from indeterminate/positive to negative. We reviewed all plasma CMV DNAemia tests performed during the first 6 months posttransplant in both groups to assess the safety of this approach.
Among 246 (84.5%) of 291 transplanted patients identified as CMVR+ pretransplant, 60 (24.4%) were reclassified from CMV serology indeterminate (N:10)/low-positive (N:50) to R-. Only 1 of 60 patients (1.67%) in the CMVR- reclassification group versus 3 of 44 (6.8%; P = .30) in the CMVR- group developed CMV DNAemia during the follow-up period. There were no significant differences in the number of CMV DNAemia tests performed, CMV DNAemia range, and time posttransplant between the 2 groups.
One of 4 allo-HCT CMVR+ may be falsely flagged as R+, with significant impact on donor selection and prophylaxis administration. A 2-step approach including CMV serology testing at hematologic malignancy diagnosis in allo-HCT candidates and careful review of pretransplant CMV IgG titers may help correctly classify CMV serology status.
Drug-induced liver injury (DILI) is a main cause of drug withdrawal. A particularly interesting example is flucloxacillin (FLUX)-DILI, which is associated with the HLA-B*57:01 allele. At present, the ...mechanism of FLUX-DILI is not understood, but the HLA association suggests a role for activated T cells in the pathomechanism of liver damage. To understand the interaction among FLUX, HLA molecules, and T cells, we generated FLUX-reacting T cells from FLUX-naive HLA-B*57:01(+) and HLA-B*57:01(-) healthy donors and investigated the mechanism of T cell stimulation. We found that FLUX stimulates CD8(+) T cells in two distinct manners. On one hand, FLUX was stably presented on various HLA molecules, resistant to extensive washing and dependent on proteasomal processing, suggesting a hapten mechanism. On the other hand, in HLA-B*57:01(+) individuals, we observed a pharmacological interaction with immune receptors (p-i)-based T cell reactivity. FLUX was presented in a labile manner that was further characterized by independence of proteasomal processing and immediate T cell clone activation upon stimulation with FLUX in solution. This p-i-based T cell stimulation was restricted to the HLA-B*57:01 allele. We conclude that the presence of HLA-B*57:01 drives CD8(+) T cell responses to the penicillin-derivative FLUX toward nonhapten mechanism.
Immunocompromised patients may be at increased risk for complications of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. However, comprehensive data of SARS‐CoV‐2 infection in ...solid organ transplant (SOT) recipients are still lacking. We performed a multicenter nationwide observational study within the Swiss Transplant Cohort Study (STCS) to describe the epidemiology, clinical presentation, treatment and outcomes of the first microbiologically documented SARS‐CoV‐2 infection among SOT recipients. Overall, 21 patients were included with a median age of 56 years (10 kidney, 5 liver, 1 pancreas, 1 lung, 1 heart and 3 combined transplantations). The most common presenting symptoms were fever (76%), dry cough (57%), nausea (33%), and diarrhea (33%). Ninety‐five percent and 24% of patients required hospital and ICU admission, respectively, and 19% were intubated. After a median of 33 days of follow‐up, 16 patients were discharged, 3 were still hospitalized and 2 patients died. These data suggest that clinical manifestations of SARS‐CoV‐2 infection in middle‐aged SOT recipients appear to be similar to the general population without an apparent higher rate of complications. These results need to be confirmed in larger cohorts.
This study describes the epidemiology, clinical presentation, treatment, and outcome of the first 21 solid organ transplant recipients infected with SARS‐CoV‐2 in the Swiss Transplant Cohort Study.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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