Current Immunosuppressive Therapy Research Articles

Increased oxidative stress response in circulating blood of systemic sclerosis patients – relation to disease characteristics and inflammatory blood biomarkers

BackgroundSystemic sclerosis (SSc) is a rare connective tissue disorder of unknown etiology characterized by organ fibrosis and microcirculation dysfunction. Emerging evidence suggests that SSc is related to increased oxidative stress, which contributes to further tissue and vascular damage. MethodsOxidative stress response in the peripheral blood was assessed in patients with SSc (n = 55) and well-matched controls (n = 44) using real-time monitoring of protein hydroperoxide (HP) formation by the coumarin boronic acid (CBA) assay. We also analyzed the relationship between HP generation and SSc clinics, systemic inflammation, and cellular fibronectin, an emerging biomarker of endothelial damage. ResultsSSc was characterized by a significantly faster (2-fold) fluorescent product generation in the CBA assay and higher cumulative HP formation (3-fold) compared to controls (p<0.001, both). The dynamics of HP generation were not associated with the form of the disease (diffuse vs. limited SSc), current immunosuppressive therapy use, presence of abnormal nailfold capillaries, and autoantibody profile. Still, it was enhanced in patients with more severe illness and certain clinical manifestations (i.e., pulmonary hypertension, digital ulcers, and cyclophosphamide treatment) and in smokers (current or past). Higher serum CRP, blood eosinophil count, and cellular fibronectin with lower hemoglobin levels were independent determinants of increased HP formation. ConclusionsOur data indicate a pro-oxidant imbalance in SSc, likely related to systemic inflammation and endothelial injury. However, extensive prospective studies are needed to verify whether it is also associated with clinical disease progression.

Negative predictive value of the FebriDx host response point-of-care test in patients presenting to a single Australian emergency department with suspected COVID-19: an observational diagnostic accuracy study

ObjectivesTo determine the negative predictive value (NPV) of the FebriDx point-of-care host response device in patients presenting with symptoms suggestive of COVID-19 infection in a mostly immunised Australian emergency department...

Lessons Learned from COVID-19 Pandemic: Outcomes after Sars-Cov-2 Infection in Hematopoietic Cell Transplant and Cell Therapy Recipients

Background: Coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic in March 2020. Over 500 million cases of SARS-CoV-2 have been reported worldwide, with over 90 million being in the US. More than 6 million lives, with over 1 million only from the US, have been claimed by the pandemic. Hematopoietic cell transplant (HCT) or chimeric antigen receptor-T (CART) cell therapy recipients have a higher risk of mortality with COVID-19. In this updated analysis, we investigated the outcomes after SARS-CoV-2 infection in HCT/CART recipients. Methods: We conducted a single-center prospective study, including all (n=196) adult HCT/CART recipients who were diagnosed with COVID-19 at the University of Kansas Medical Center from March 2020 to March 2022. Baseline and disease-related characteristics were ascertained from medical records. Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using the chi-square and t-test, were performed. Kaplan-Meier and cox regression analyses were conducted. Results: The study included 196 HCT/CART recipients who acquired SARS-CoV-2 infection, including allogeneic HCT (n=91, 46%), autologous HCT (n=89, 46%), and CART (n=16, 8%) recipients. The median age was 59.8 (21.9-79.5) years; 76.5% were Caucasians and 58% were males. The median time since HCT/CART to SARS-CoV-2 infection was 25.4 (0.2-201.9) months, and 12% of patients acquired SARS-CoV-2 within the first 100 days post-HCT/CAR-T. Plasma cell (37%), myeloid (34%), lymphoid (28%) or solid (1%) malignancies were primary diagnoses. Myeloablative conditioning was performed in 64% of patients. Donors were autologous (53%), matched sibling (12%), matched unrelated (21%), and haploidentical (14%). Prior acute graft-versus-host disease (GVHD), prior chronic GVHD, active GVHD, and current immunosuppressive therapy (IST) were noted in 20%, 26.5%, 23.5%, and 25.5% of patients respectively. Concurrent infections were observed in 12% of patients. COVID-19 severity was mild (n=136, 70%), moderate (n=24, 12%), severe (n=20, 10%) or critical/fatal (n=16, 8%). Clinical findings included pneumonia or abnormal chest imaging (31%), hypoxia (19%), intensive care unit admission (9%), and mechanical ventilation (6%). Therapies included remdesivir (31%), convalescent plasma (11%), dexamethasone (15%), monoclonal antibodies (32%), and tocilizumab/baricitinib (5%). At least one dose of SARS-CoV-2 vaccine was reported in 70% of patients (45% pre-COVID, 25% post-COVID) while 3% of patients had received pre-exposure prophylaxis. The median duration of viral shedding (positive SARS-CoV-2 PCR) was 6.5 (0.3-23.4) weeks. After a median follow-up of 5.4 (0.3-24.8) months, the mortality rate was 12% with COVID-specific mortality of 8%. Of allogeneic HCT patients, 18% (n=16) developed subsequent GVHD after COVID-19 requiring systemic steroids and additional immunosuppression. Eighty-four (43%) patients were diagnosed with COVID after Sep 2021 and had the lowest COVID-specific mortality (2% compared to 12.5% in preceding months of the pandemic). Significant predictors of COVID-19 mortality included allogeneic HCT (HR 3.7, 95% CI 1.2-11.6, p=0.023), COVID-19 within 100 days of HCT/CART (HR 4.8, 95% CI 1.7-13.2, p=0.002), COVID-19 diagnosis earlier in the pandemic (HR 5.2, 95% CI 1.1-24.4, p=0.037), prior acute GVHD (HR 3.2, 95% CI 1.2-8.5, p=0.022), active GVHD (HR 3.5, 95% CI 1.3-9.2, p=0.013), and concurrent IST (OR 7.0, 95% CI 2.4-20.1, p<0.001) while prior SARS-CoV-2 vaccination significantly reduced the COVID-19 mortality (HR 0.19, 95% CO 0.05-0.68, p=0.010). In 15 patients with available data, vaccination induced protective anti-spike protein antibody response (>100 U/mL) in 67% of patients with a median titer of 656 (9-688,000) U/mL after completion of the primary vaccination series. Conclusion: Hematopoietic stem cell transplant and CART cell therapy recipients have a higher risk of morbidity and mortality with SARS-CoV-2 infection. Our findings highlight factors associated with COVID-19 mortality in HCT/CAR-T recipients. In HCT/CART recipients, strict vigilance, infection prevention measures, vaccination prioritization, close monitoring, and early aggressive treatment interventions are suggested for COVID-19 and future emerging infectious diseases. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk and course of COVID-19 in immunosuppressed patients with myasthenia gravis

BackgroundPatients with myasthenia gravis (MG) are potentially prone for a severe COVID-19 course, but there are limited real-world data available on the risk associated with COVID-19 for patients with MG. Here, we investigate whether current immunosuppressive therapy (IST) influences the risk of SARS-CoV-2 infection and COVID-19 severity.MethodsData from the German myasthenia gravis registry were analyzed from May 2020 until June 2021 and included patient demographics, MG disease duration, comorbidities, current IST use, COVID-19 characteristics, and outcomes. Propensity score matching was employed to match MG patients with IST to those without, and multivariable binary logistic regression models were used to determine associations between IST with (1) symptomatic SARS-CoV-2 infection and (2) severe COVID-19 course, as measured by hospitalization or death.ResultsOf 1379 patients with MG, 95 (7%) patients (mean age 58 (standard deviation [SD] 18) presented with COVID-19, of which 76 (80%) received IST at time of infection. 32 patients (34%) were hospitalized due to COVID-19; a total of 11 patients (12%) died. IST was a risk factor for hospitalization or death in the group of COVID-19-affected MG patients (odds ratio [OR] 3.04, 95% confidence interval [CI] = 1.02–9.06, p = 0.046), but current IST was not associated with a higher risk for SARS-CoV-2 infection itself.DiscussionIn this national MG cohort study, current IST use was a risk factor for a severe disease course of COVID-19 but not for SARS-CoV-2 infection itself. These data support the consequent implementation of effective strategies to prevent COVID-19 in this high-risk group.Trial registration informationGerman clinical trial registry (https://www.drks.de), DRKS00024099, first patient enrolled: February 4th, 2019.

Impact of SARS-CoV-2 in Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Recipients

Coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic in March 2020, and has caused more than 600,000 deaths in the United States at the time of this report. Hematopoietic stem cell transplantation (HCT) or chimeric antigen receptor T cell (CAR-T) therapy recipients have a higher risk of mortality with COVID-19 owing to profound immune dysregulation. In this study, we investigated the impact of SARS-CoV-2 in HCT/CAR-T therapy recipients. This single-center prospective study included all (n = 58) adult HCT/CAR-T recipients who were diagnosed with COVID-19 at the University of Kansas Medical Center between March 2020 and May 2021. Baseline and disease-related characteristics were ascertained from medical records. Data were analyzed using SPSS version 21 (IBM, Armonk, NY). Bivariate analyses, using the chi-square and t-test, and logistic regression analyses were conducted. The study included 58 HCT/CAR-T patients who acquired SARS-CoV-2 infection, including recipients of allogeneic HCT (n = 32), autologous HCT (n = 23), and CAR-T therapy (n = 3). The median patient age was 58 years (range, 24 to 77 years), and 64% were males. The median time from HCT/CAR-T therapy to SARS-CoV-2 infection was 17.7 months (range, 0.2 to 201.9 months), and 22% of the patients acquired SARS-CoV-2 within the first 100 days post-HCT/CAR-T therapy. The primary hematologic disorders were plasma cell (36%), myeloid (38%), and lymphoid (26%) malignancies. Myeloablative conditioning was performed in 62% of patients. Donors were autologous (45%), matched sibling (15%), matched unrelated (21%), and haploidentical (19%). Prior history of grade II-IV acute graft-versus-host disease (GVHD), active GVHD, and current immunosuppressive therapy (IST) was noted in 22%, 31%, and 36% of patients, respectively. Concurrent infections were observed in 19%. Lymphopenia (P = .049) and high serum ferritin concentration (P = .020) were associated with mortality. COVID-19 severity was mild in 50% of the patients, moderate in 22%, and severe in 28%. Clinical findings included pneumonia or abnormal chest imaging (in 50%), hypoxia (28%), intensive care unit admission (19%), and mechanical ventilation (10%). Therapies included remdesivir (in 41%), convalescent plasma (35%), dexamethasone (22%), monoclonal antibodies (19%), and tocilizumab (3%). The median duration of viral shedding (positive SARS-CoV-2 PCR) was 7.7 weeks (range, 2 to 18.7 weeks), and 2 patients had a persistent infection for >5 months post-CAR-T therapy. After a median follow-up of 6.1 months (range, 0.5-13.6 months), the mortality rate was 16% in all patients and 28% in allogeneic HCT recipients. Among 9 patients who died, the median survival after SARS-CoV-2 infection was 23 days (range, 14 to 140 days). In survivors with moderate-severe COVID-19, the median time to recovery was 4.2 weeks (range, 1.1 to 24.7 weeks). Among allogeneic HCT recipients, 5 (16%) developed subsequent pulmonary chronic GVHD necessitating systemic steroids and additional IST. Significant predictors of COVID-19 severity included allogeneic HCT (odds ratio [OR], 3.6, 95% confidence interval [CI], 1.2 to 10.8; P = .020), history of grade II-IV acute GVHD (OR, 4.6; 95% CI, 1.10 to 18.86; P = .036) and concurrent IST (OR, 5.9; 95% CI, 1.8 to 19.8; P = .004). HCT and CAR-T cell therapy recipients are at an increased risk of moderate-severe COVID-19 pneumonia and higher mortality with SARS-CoV-2 infection. Our findings confirm the need for continuing vigilance with social distancing and masks, vaccination prioritization, close monitoring, and aggressive treatment of HCT/CAR-T therapy recipients.

MO560IS SERUM ERYTHROPOIETIN CORRELATED WITH IRON METABOLISM AND INFLAMMATION IN NON-DIALYSIS CHRONIC KIDNEY DISEASE PATIENTS WITH ANEMIA?

Abstract Background and Aims Both the relative erythropoietin (Epo) deficiency and its relationship with serum hemoglobin (Hb) are widely postulated in chronic kidney disease (CKD), but the influence of chronic inflammation and iron status on serum Epo levels is still a matter of debate, with yet divergent reported results. Therefore, we aimed to assess the determinants of serum Epo in non-dialysis CKD patients. Method Fifty-two adults with CKD and anemia (defined as Hb &amp;lt;12g/dL), in stable clinical condition, never treated with erythropoiesis-stimulating agents (ESA) entered this cross-sectional, single-center study. Diabetes mellitus, active infectious and inflammatory diseases, malignancy, anemia of other causes than CKD, current immunosuppressive therapy, iron supplementation and blood transfusions in the previous six months were exclusion criteria. The subjects were mostly men (56%), elderly (two thirds over 60 years), with advanced CKD [71% in CKD stages G4-G5, median estimated glomerular filtration rate – eGFR 14.5 (95%CI 16 to 25) mL/min], moderate anemia [Hb 9.8 (95%CI 9.2 to 9.9) g/dL], and mild to moderate inflammation [C-reactive protein 6 (95%CI 9.2 to 18.4) mg/L]. Serum Epo was assessed by ELISA (Abcam® 119522). Complete blood count, reticulocyte index, peripheral blood smear, bone marrow aspiration (Perls’ stain), serum ferritin, and transferrin saturation, were used to investigate anemia and iron metabolism. Parameters of kidney disease (CKD etiology, eGFR and proteinuria), demographic data (age, gender), C-reactive protein, serum albumin, and serum hepcidin-25 (Hep-25, Bachem® commercial ELISA kit) were also analyzed. Results The median serum Epo of the whole cohort was 4.8 (95%CI 5.1 to 9.9) mU/mL. According to median Epo, subjects were clustered in Group 1 (below median, G1) and Group 2 (above median, G2). Estimated GFR and serum Hep-25 were lower in G1 than in G2 [10.6 (95%CI 9.7 to 20.8) vs. 26 (95%CI 19.1 to 32.8) mL/min, p=0.004, and 62.6 (95%CI 51.0 to 85.1) vs. 95.4 (95%CI 77.0 to 108.5) ng/mL, p=0.03, respectively]. All the other investigated parameters were similar in the two groups. In bivariate analysis (Spearman rank correlation), serum Epo was positively associated only with eGFR (rs=0.40, p=0.003). Marginal associations with the percentage of bone marrow sideroblasts, as marker of the iron available for erythropoiesis (rs=0.25, p=0.08), erythrocyte mean corpuscular hemoglobin concentration (rs=−0.26, p=0.07), and reticulocyte index (rs=0.24, p=0.09) were observed. Conversely, serum Epo was not related to hemoglobin, indices of iron stores (e.g. serum ferritin and iron content in bone marrow macrophages), inflammation and nutritional status (e.g. C-reactive protein and serum albumin). In a model of multiple linear regression which explained 14% of serum Epo variation, eGFR was the only determinant: Beta 0.14 (95%CI 0.05 to 0.23), p=0.004. Also, a binary logistic multiple regression model predicting serum Epo lower or higher than the median retained the eGFR as an independent predictor, while serum hepcidin showed only borderline significance: Conclusion Kidney function is the main determinant of endogenous erythropoietin level in moderately anemic patients with advanced CKD, ESA or iron naive, while serum hepcidin-25 seems to exert a limited influence.

Macrophages in Organ Transplantation

Current immunosuppressive therapy has led to excellent short-term survival rates in organ transplantation. However, long-term graft survival rates are suboptimal, and a vast number of allografts are gradually lost in the clinic. An increasing number of animal and clinical studies have demonstrated that monocytes and macrophages play a pivotal role in graft rejection, as these mononuclear phagocytic cells recognize alloantigens and trigger an inflammatory cascade that activate the adaptive immune response. Moreover, recent studies suggest that monocytes acquire a feature of memory recall response that is associated with a potent immune response. This form of memory is called “trained immunity,” and it is retained by mechanisms of epigenetic and metabolic changes in innate immune cells after exposure to particular ligands, which have a direct impact in allograft rejection. In this review article, we highlight the role of monocytes and macrophages in organ transplantation and summarize therapeutic approaches to promote tolerance through manipulation of monocytes and macrophages. These strategies may open new therapeutic opportunities to increase long-term transplant survival rates in the clinic.

The Effects of Immunosuppressive Treatment during Pregnancy on the Levels of Potassium, Iron, Chromium, Zinc, Aluminum, Sodium and Molybdenum in Hard Tissues of Female Rats and Their Offspring.

The ideal immunosuppressive regimen should provide for excellent immunosuppression with no side effects. Yet, current immunosuppressive therapy regimens commonly used in clinical applications fail to meet this criterion. One of the complications caused by immunosuppressive drugs is mineralization disorders in hard tissues. In this study, we evaluated the effects of three immunosuppressive therapies used after transplantation on the levels of potassium, iron, chromium, zinc, aluminum, sodium and molybdenum in the bones and teeth of female rats and their offspring. The study was conducted on 32 female Wistar rats, subjected to immunosuppressive regimens (cyclosporine A, mycophenolate mofetil and prednisone; tacrolimus, mycophenolate mofetil and prednisone; and cyclosporine A, everolimus and prednisone). The hard tissues of rats were analyzed using inductively coupled plasma optical emission spectrometry (ICP-OES, ICAP 7400 Duo, Thermo Scientific) equipped with a concentric nebulizer and a cyclonic spray chamber. All the immunosuppressive regimens included in the study affected the concentrations of the studied minerals in hard tissues of female rats and their offspring. The therapy based on cyclosporine A, everolimus and prednisone led to a decline in the levels of iron in bone, zinc in teeth, and molybdenum in the bone and teeth of mothers, while in the offspring, it caused a decline of bone potassium, with a decrease in iron and increase of molybdenum in teeth. Moreover, the regimen caused an increase in aluminum and chromium in the teeth and aluminum in the bones of the offspring, and consequently, it seems to be the therapy with the most negative impact on the mineral metabolism in hard tissues.

Pembrolizumab and Copanlisib for the Treatment of Relapsed or Refractory Mature T-Cell Lymphomas

Pembrolizumab and Copanlisib for the Treatment of Relapsed or Refractory Mature T-Cell Lymphomas

Pharmacoeconomic analysis of everolimus immunosuppressive therapy for &lt;i&gt;de novo&lt;/i&gt; kidney transplant recipients in Russia

Currently, patients after kidney transplantation can receive mycophenolate mofetil (MPM), mycophenolic acid (MPA), cyclosporine (CSA) and tacrolimus (TAC) through the Federal High-cost Nosologies Program (VZN) in Russia. Use of everolimus (EVL) in combination with a reduced dose of calcineurin inhibitors has some advantages over the current practice of immunosuppressive therapy that is financed through VZN.Aim: to conduct a comprehensive pharmacoeconomic research of using EVL for immunosuppressive therapy of adult de novokidney transplantation recipients in comparison with the current immunosuppressive therapy practice that is covered by the VZN Program in the Russian Federation.Materials and methods. According to the latest clinical data, effectiveness of immunosuppressive therapy schemes based on EVL and MPA is comparable, which allows to use ‘cost minimization’ method for pharmacoeconomic research. We also performed budget impact analysis of the VZN Program expenditures for a period of 2020–2022.Results. The three-year medication costs of using EVL-based immunosuppressive scheme were 502,785 RUB, which was 508,493 RUB (50.3%) less than medication costs of using MPA-based schemes that are covered by the VZN Program in current practice. The inclusion of EVL to the VZN Program will reduce its costs by 90 million RUB during the first year (2020), by 181 million RUB – during the second year (2021), and by 262 million RUB during the third year (2022). In three years VZN Program costs could be reduced by 533 million RUB (48.6%).Conclusion. Use of EVL is a cost-saving approach for immunosuppressive therapy of adult de novo kidney transplant recipients, compared to MPA-based schemes, that are covered by the VZN Program in current practice in Russia.

The Efficacy of Rabbit Anti-Thymocyte Globulin for Acute Kidney Transplant Rejection in Patients Using Calcineurin Inhibitor and Mycophenolate Mofetil-Based Immunosuppressive Therapy.

BackgroundT cell depleting antibody therapy with rabbit anti-thymocyte globulin (rATG) is the treatment of choice for glucocorticoid-resistant acute kidney allograft rejection (AR) and is used as first-line therapy in severe AR. Almost all studies investigating the effectiveness of rATG for this indication were conducted at the time when cyclosporine A and azathioprine were the standard of care. Here, the long-term outcome of rATG for AR in patients using the current standard immunosuppressive therapy (i.e., tacrolimus and mycophenolate mofetil) is described.Material/MethodsBetween 2002 to 2012, 108 patients were treated with rATG for AR. Data on kidney function in the year following rATG and long-term outcomes were collected.ResultsOverall survival after rATG was comparable to overall survival of all kidney transplantation patients (P=0.10). Serum creatinine 1 year after rATG was 179 μmol/L (interquartile range (IQR) 136–234 μmol/L) and was comparable to baseline serum creatinine (P=0.22). Early AR showed better allograft survival than late AR (P=0.0007). In addition, 1 year after AR, serum creatinine was lower in early AR (157 mol/L; IQR 131–203) compared to late AR (216 mol/L; IQR 165–269; P<0.05). The Banff grade of rejection, kidney function at the moment of rejection, and reason for rATG (severe or glucocorticoid resistant AR) did not influence the allograft survival.ConclusionsTreatment of AR with rATG is effective in patients using current standard immunosuppressive therapy, even in patients with poor allograft function. Early identification of AR followed by T cell depleting treatment leads to better allograft outcomes.

Efficacy of Rabbit Anti-Thymocyte Globulin Therapy for Severe Acute Rejection in Kidney Transplant Patients using Calcineurin Inhibitor and Mycophenolate Mofetil based Immunosuppressive Therapy

Background T-cell depleting antibody therapy is the treatment of choice for glucocorticoid-resistant kidney allograft rejection and is used as first-line therapy in severe T-cell mediated rejection (TCMR). Most studies investigating the effectiveness of this treatment were conducted when cyclosporine and azathioprine combinatiwere therapy. However, there is little evidence for its effectiveness in combination with current standard maintenance immunosuppressive therapy consisting of tacrolimus (TAC), mycophenolate mofetil (MMF), and corticosteroids (CS) with or without induction therapy. Here, the long-term outcome of rATG therapy for AR in patients using the current standard immunosuppressive therapy (i.e. tacrolimus and mycophenolate mofetil), is described. Methods Between 2002 to 2012, we identified 108 patients, treated with rabbit anti-thymocyte globulin (rATG) for biopsy-proven severe (Banff TCMR grade IIA or more) or glucocorticoid-resistant acute rejection; 78 patients had TAC/MMF and/or CS therapy at time of rejection. Patients were treated with high dose methylprednisolone, followed by rATG when kidney function showed further deterioration or a biopsy showed TCMR grade II. Results Overall survival after rATG was comparable to overall survival of all kidney transplant patients (p = 0.10). Allograft survival 5 years after rATG was 55.6%. Serum creatinine 1 year after rATG was 179 μmol/L (interquartile range (IQR) 136-234 μmol/L) and was comparable to baseline serum creatinine (p = 0.22). Early AR showed better allograft survival than late AR (p = 0.0007). Remarkably, allograft survival was worse in patients with acute T cell mediated rejection (aTCMR) grade I versus aTCMR grade II+III (p = 0.03). This was associated with a longer interval between pulse glucocorticoids and rATG (31 days (IQR 23-92) versus 8 days (IQR 3-15; p < 0.05). After rATG (mean follow-up 1948 days) 212 infections requiring hospitalization, 12 solid tumors and 2 lymphomas occurred. Conclusion rATG is an effective anti-rejection therapy in patients using current standard immunosuppressive therapy, even in patients with poor allograft function. Treatment with rATG for AR in this study seems not to be associated with increased mortality compared to patients without rATG treatment. The timing of rATG therapy is important. Early recognition of severe and /or glucocorticoid-resistant AR followed by aggressive treatment leads to better allograft function and allograft survival. When this window of opportunity is used, the benefits may outweigh the risks of adverse events.

Utility of Surveillance Biopsies in Kidney Transplant Recipients with Delayed Graft Function Under Current Immunosuppressive Therapy

Utility of Surveillance Biopsies in Kidney Transplant Recipients with Delayed Graft Function Under Current Immunosuppressive Therapy

Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia.

Large granular lymphocyte (LGL) leukemia has been recognized in the World Health Organization classifications among mature T cell and natural killer cell neoplasms and is divided into three categories. Chronic T cell leukemia and natural killer cell lymphocytosis can be considered as a similar spectrum of an indolent disease characterized by cytopenias and autoimmune conditions. The last category, aggressive natural killer cell LGL leukemia is very rare, related to Epstein-Barr virus, and seen mainly in young Asian people. Clonal LGL expansion arises from chronic antigenic stimulation sustained by interleukin-15 and platelet-derived growth factor cytokine signal. Those leukemic cells are resistant to apoptosis, mainly because of constitutive activation of survival pathways including Jak/Stat, MapK, Pi3k-Akt, RasRaf-1, MEK1/ERK, sphingolipid, and NFκB. Stat3 constitutive activation is the hallmark of this lymphoproliferative disorder. Socs3 is downregulated, but no mutation could be found to explain this status. However, several somatic mutations, including Stat3, Stat5b, and tumor necrosis factor alpha-induced protein 3, have been demonstrated recently in LGL leukemia; they are identified in half of patients and cannot explain by themselves LGL leukemogenesis. Recurrent infections as a result of chronic neutropenia, anemia, and autoimmune disorders are the main complications related to LGL leukemia. Despite an indolent presentation, 10% of patients die, mainly because of infectious complications. Current treatments are based on immunosuppressive therapies. A better mechanistic understanding of LGL leukemia will allow future consideration of a personalized therapeutic approach perhaps based on Jak/Stat inhibitors, which may offer better results than current immunosuppressive therapy.

Phylogroup and virulence gene association with clinical characteristics of Escherichia coli urinary tract infections from dogs and cats.

Escherichia coli isolates from infections outside the gastrointestinal tract are termed extra-intestinal pathogenic E. coli (ExPEC) and can be divided into different subpathotypes; one of these is uropathogenic E. coli (UPEC). The frequency with which UPEC strains cause urinary tract infections in dogs and cats is not well documented. We used an oligonucleotide microarray to characterize 60 E. coli isolates associated with the urinary tract of dogs ( n = 45) and cats ( n = 15), collected from 2004 to 2007, into ExPEC and UPEC and to correlate results with patient clinical characteristics. Microarray analysis was performed, and phylogroup was determined by a quadruplex PCR assay. Isolates that were missing 1 or 2 of the gene determinants representative of a function (capsule, iron uptake related genes, or specific adhesins) were designated as "non-classifiable" by microarray. Phylogroup B2 was positively associated with the UPEC subpathotype ( p < 0.0005) and negatively associated with "non-classifiable" isolates ( p < 0.0005). Phylogroup D was positively associated with ExPEC pathotype ( p = 0.025) and negatively associated with UPEC subpathotype ( p = 0.014). The ExPEC pathotype was positively associated with hospitalization for one or more days ( p = 0.031). The UPEC subpathotype was negatively associated with previous antimicrobial therapy ( p = 0.045) and previous hospitalization within the 3 mo prior to the positive culture ( p = 0.041). The UPEC subpathotype was positively associated with prostatitis ( p = 0.073) and negatively associated with current immunosuppressive therapy ( p = 0.090). Our results indicate that the case history observations may be critically important during the interpretation of laboratory results to encourage judicious use of antimicrobials.

Intestinal transplantation: a review.

The purpose of this article is to review the existing literature on the current indications, surgical techniques, immunosuppressive therapy and outcomes following intestinal transplantation (ITx). Over recent years, ITx has become a more common operation with approximately 2500 procedures carried out worldwide by 2014. It is reserved for patients with intestinal failure and who have developed complications of home parenteral nutrition or who have a high risk of dying from their underlying disease. Recent advances such as the improvement in survival rates, not only for isolated small bowel transplants but also following inclusion of a liver graft in combined liver-small bowel transplant, and the utility of citrulline as a noninvasive biomarker to appreciate acute rejection herald an exciting shift in the field of ITx. With advancements in immunosuppressive drugs, induction regimens, standardization of surgical techniques and improved postoperative care, survival is increasing. In due course, it will most likely become as good as remaining on home parenteral nutrition and as such could become a viable first-line option.

Moving Biomarkers toward Clinical Implementation in Kidney Transplantation.

Long-term kidney transplant outcomes remain suboptimal, delineating an unmet medical need. Although current immunosuppressive therapy in kidney transplant recipients is effective, dosing is conventionally adjusted empirically on the basis of time after transplant or altered in response to detection of kidney dysfunction, histologic evidence of allograft damage, or infection. Such strategies tend to detect allograft rejection after significant injury has already occurred, fail to detect chronic subclinical inflammation that can negatively affect graft survival, and ignore specific risks and immune mechanisms that differentially contribute to allograft damage among transplant recipients. Assays and biomarkers that reliably quantify and/or predict the risk of allograft injury have the potential to overcome these deficits and thereby, aid clinicians in optimizing immunosuppressive regimens. Herein, we review the data on candidate biomarkers that we contend have the highest potential to become clinically useful surrogates in kidney transplant recipients, including functional T cell assays, urinary gene and protein assays, peripheral blood cell gene expression profiles, and allograft gene expression profiles. We identify barriers to clinical biomarker adoption in the transplant field and suggest strategies for moving biomarker-based individualization of transplant care from a research hypothesis to clinical implementation.

High-dose-rate brachytherapy in the treatment of skin Kaposi sarcoma.

PurposeThe aim of the study is to review our experience in treatment of Kaposi sarcoma (KS) lesions with high-dose-rate (HDR) brachytherapy.Material and methodsWe present five new KS lesions (three patients) that were treated in our hospital from May 2016 to February 2017 with HDR brachytherapy using Valencia applicators. The treatment was delivered in 5 Gy fractions over five sessions, on alternate days. Total dose of 25 Gy (EQD2 31.25 Gy) was delivered. All patients were male, Caucasian, without a history of HIV, organ transplantation, or current immunosuppressive therapy. The median age was 76 years.ResultsAll lesions (100%) were located in lower limbs (60% in the ankle, 20% in the leg, and 20% in the foot), and their development was progressive. No lesion was greater than 2 cm (range, 0.5-1.5 cm). With a median follow-up of 15 months, all patients had a complete response to the treatment, with no evidence of local recurrence or tumor progression. Most of the patients (80%) had no acute toxicity; only one patient developed erythema grade 2.ConclusionsHDR brachytherapy could be a good option of treatment for these types of lesions, especially in elderly patients, or when cosmetic results are not good after surgery. Brachytherapy with the Valencia applicator, using hypofractionated regimen provides excellent results in terms of cosmetic and local control, and furthermore, facilitates treatment compliance, which is very relevant in elderly patients. HDR brachytherapy offers a simple, safe, quick, and attractive non-surgical treatment option.

Treatment of transfusion-dependent nonsevere aplastic anemia with cyclosporine A plus ATG/ALG versus cyclosporine A plus androgens: a retrospective single center study

目的比较抗人胸腺／淋巴细胞球蛋白（ATG/ALG）联合环孢素A (CsA）与CsA联合雄激素一线治疗输血依赖非重型再生障碍性贫血（TD-NSAA）疗效。方法回顾性分析2007年8月至2014年9月125例TD-NSAA患者临床资料，比较一线采用ATG/ALG联合CsA与CsA联合雄激素治疗的血液学反应及生存情况。结果125例TD-NSAA患者中，男70例，女55例，男女比为1.27∶1；中位年龄27 (6~66）岁。其中48例一线接受ATG/ALG联合CsA治疗，77例一线接受CsA联合雄激素治疗，两组早期死亡率分别为2.1%（1/48）及0 (0/77）（P=0.384）。ATG/ALG联合CsA组患者治疗后3个月总体血液学反应率（70.8％对45.5%，P=0.006）和良好血液学反应率（27.1％对10.4%，P=0.015）均高于CsA联合雄激素组；两组治疗后6个月总体血液学反应率（75.0％对55.8%，P＝0.031）与良好血液学反应率（41.7％对22.1%，P=0.020）差异亦有统计学意义，治疗后6个月ATG/ALG联合CsA组脱离血制品输注依赖的中位时间为36.5 (0~149) d，明显短于CsA联合雄激素组的98 (14~180）d（P<0.001）。ATG/ALG联合CsA组与CsA联合雄激素组患者3年总生存率（97.9％对100.0%，P=0.227）和无事件生存率（71.2％对59.5%，P=0.227）差异无统计学意义。结论一线采用CsA联合雄激素治疗TD-NSAA血液学反应率和血液学反应质量均不及ATG/ALG联合CsA，两组患者短期生存率相同，应优选ATG/ALG联合CsA方案治疗TD-NSAA。

Immunosuppressive therapy alleviates murine cytomegalovirus recurrence by reducing TNF-α post cell transplantation with lethal GVHD

Cytomegalovirus (CMV) reactivation leads to obvious morbidity and mortality in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Current immunosuppressive therapy reduces the frequency of graft-versus-host disease (GVHD), and is generally accepted as a high risk factor for viral recurrence. In the present study, we investigated the influence of cyclosporin A (CsA) and rapamycin (RAPA), two commonly used immunosuppressive agents, on murine cytomegalovirus (MCMV) recurrence by two allo-HCT models: one with mild and one with severe GVHD. In models with mild GVHD and partial immune recovery, transplanted mice with CsA and RAPA showed a higher viral load and impaired CMV-specific immune recovery compared to those with placebo. In contrast, in HCT models with severe GVHD, groups treated with immunosuppressive therapy showed alleviation of viral recurrence as well as GVHD-related symptoms. In addition, no CMV-specific immune reconstitution was found in any group, implying immunosuppressive therapy was not relevant to antiviral response. Furthermore, a significant correlation between MCMV DNA copies and tumor necrosis factor alpha (TNF-α) was found, and recipients with immunosuppressive therapy showed a lower level of TNF-α. Finally, using lenalidomide (an inhibitor of TNF-α), a lower viral load was found in animals with lenalidomide. Having received lenalidomide, recipients showed no statistical difference in viral load between groups with and without immunosuppressive therapy. Taken together, we provide evidence of the dual effect of immunosuppressive therapy on viral reactivation. Importantly, we found that immunosuppressive therapy had the ability to alleviate viral load by reducing TNF-α in a mouse model with severe GVHD.