COVID-19 in cancer patients: clinical characteristics and outcome-an analysis of the LEOSS registry.

INTRODUCTION: Since the early SARS-CoV-2 pandemic, cancer patients have been assumed to be at higher risk for severe COVID-19. Here, we present an analysis of cancer patients from the LEOSS (Lean European Open Survey on SARS-CoV-2 Infected Patients) registry to determine whether cancer patients are at higher risk. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 435 cancer patients and 2636 non-cancer patients with confirmed SARS-CoV-2 infection, enrolled between March 16 and August 31, 2020. Data on socio-demographics, comorbidities, cancer-related features and infection course were collected. Age-, sex- and comorbidity-adjusted analysis was performed. Primary endpoint was COVID-19-related mortality. RESULTS: In total, 435 cancer patients were included in our analysis. Commonest age category was 76-85 years (36.5%), and 40.5% were female. Solid tumors were seen in 59% and lymphoma and leukemia in 17.5% and 11% of patients. Of these, 54% had an active malignancy, and 22% had recently received anti-cancer treatments. At detection of SARS-CoV-2, the majority (62.5%) presented with mild symptoms. Progression to severe COVID-19 was seen in 55% and ICU admission in 27.5%. COVID-19-related mortality rate was 22.5%. Male sex, advanced age, and active malignancy were associated with higher death rates. Comparing cancer and non-cancer patients, age distribution and comorbidity differed significantly, as did mortality (14% vs 22.5%, p value < 0.001). After adjustments for other risk factors, mortality was comparable. CONCLUSION: Comparing cancer and non-cancer patients, outcome of COVID-19 was comparable after adjusting for age, sex, and comorbidity. However, our results emphasize that cancer patients as a group are at higher risk due to advanced age and pre-existing conditions.

[Opportunistic infections by human herpes viruses]. / Opportunistische Infektionen durch humane Herpesviren.

Infections in immunosuppressed patients represent a particular challenge in the diagnostics and treatment. They often present with atypical and particularly severe courses, for which rapid diagnostics and treatment are decisive for treatment success. Opportunistic infections with human herpes viruses occur not only more frequently in immunocompromised patients compared to healthy people but also represent a special challenge. In the treatment of immunosuppressed patients, e.g. with human immunodeficiency virus infections and patients with solid organ transplantations, infections with herpes simplex virus, varicella zoster virus, Epstein-Barr virus and cytomegalovirus are particularly important. The symtoms are very variable, ranging from asymptomatic detection of viremia to vital life-threatening organ manifestations. This review article describes the most important clinical presentations of these opportunistic infections. Furthermore, the diagnostic, therapeutic and prophylactic strategies for human herpes viruses are summarized.

Decreased IL-10(+) regulatory B cells (Bregs) in lupus nephritis patients.

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell-dependent autoantibody production. Recently, a new B-cell subset was discovered that has a regulatory capacity. The aim of this study was to analyse regulatory B cells (Bregs) in SLE patients. METHOD: Peripheral mononuclear blood cells (PBMCs) of 34 SLE patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and 21 healthy controls (HC) were included. PBMCs were stained for CD19, CD24, and CD38 and analysed by flow cytometry. In vitro stimulated PBMCs with CpG and restimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin were investigated for IL-10(+) Bregs . RESULTS: The percentages of circulating CD19(+)CD24(hi)CD38(hi) cells in HC were not different those in from SLE patients. The percentages of IL-10(+) Bregs were significantly decreased in SLE patients, in particular those with lupus nephritis (LN), compared to HC. The proportion was independent of disease activity. CONCLUSIONS: This is the first study to demonstrate a decrease in IL-10-producing B cells in LN patients compared to HC, reflecting an impaired regulatory function.

Increased percentages of PD-1 on CD4+ T cells is associated with higher INF-γ production and altered IL-17 production in patients with systemic lupus erythematosus.

OBJECTIVES: Programmed death (PD)-1 is a cell death receptor that, upon stimulation, leads to apoptosis. Previous studies have shown alteration of PD-1 expression on T cells and PD-1 genes in patients with systemic lupus erythematosus (SLE). The aim of this study was to assess the expression of this receptor on effector T cells in patients with SLE. METHOD: In this study we enrolled 32 SLE patients and 31 healthy controls. T cells from peripheral blood were analysed by flow cytometry for the expression of PD-1. Interferon (IFN)-γ and interleukin (IL)-17-producing cells were investigated for the expression of this co-stimulatory marker. RESULTS: Percentages of CD4(+) T cells expressing PD-1 were significantly increased in patients with SLE compared to healthy controls. The percentage of PD-1 expression was correlated with the production of INF-γ (r = 0.83, p < 0.0001). We also investigated the production of IL-17 by PD-1(+) CD3(+) T cells. Inactive patients (3.2 ± 1.2% vs. 5.9 ± 3.5%, p = 0.002) and patients without lupus nephritis (LN) (3.2 ± 1.5% vs. 5.9 ± 3.5%, p = 0.005) showed lower levels of IL-17 compared to healthy controls. CONCLUSION: We have demonstrated increased expression of PD-1 on CD4(+) T cells in SLE patients and an association between PD-1 expression on CD4(+) T cells and IFN-γ expression on CD3(+) T cells. We have also shown that there is an altered subset of PD-1(+) T cells in inactive patients and patients without LN producing lower amounts of IL-17.

Characterization of urinary CD4⁺ and CD8⁺ T cells in kidney transplantation patients with polyomavirus BK infection and allograft rejection.

BACKGROUND AND OBJECTIVES: The objective of this study was to characterize CD4(+) and CD8(+) T-cell populations in blood and urine of renal transplant patients with BK virus (BKV) infection or allograft rejection. MATERIALS AND METHODS: Percentages and absolute numbers of CD4(+) and CD8(+) effector memory T-cell subtype (TEM ) and terminal differentiated T cells (TTD ) in renal transplant patients with BKV infection (n = 14), with an episode of allograft rejection (n = 9), and in uncomplicated renal transplant patients with a stable kidney function (n = 12) were measured and compared using 4-color fluorescence-activated cell sorting. Results were correlated with the number of CD4(+) and CD8(+) T cells in renal biopsies. RESULTS: In patients with allograft rejection, the number of urinary CD4(+) TEM and CD8(+) TEM cells was significantly increased compared to patients with BKV infection or patients without complications. Positive correlation was found between the number of CD4(+) and CD8(+) cells in the renal biopsies and the number of CD4(+) and CD8(+) cells in urine. In patients with rejection, after 2 months of immunosuppressive therapy, a reduction in urinary CD8(+) TEM cells was found. CONCLUSIONS: CD4(+) TEM and CD8(+) TEM cells in urine could be a marker to distinguish allograft rejection from BKV-associated nephropathy and to monitor therapy effectiveness in renal transplant patients with allograft rejection.

Cyclosporin but not everolimus inhibits chemokine receptor expression on CD4+ T cell subsets circulating in the peripheral blood of renal transplant recipients.

The peripheral chemokine receptors chemokine receptor 3 (CXCR3) and CC chemokine receptor 5 (CCR5) have been reported to be associated with allograft rejection. The impact of the expression of immunosuppressive drugs on peripherally circulating CD4(+) T cell subsets after renal transplantation is unknown. Expression of CXCR3 and CCR5 was investigated by flow cytometry in 20 renal allograft recipients participating in a prospective, randomized trial (NCT00514514). Initial immunosuppression consisted of basiliximab, cyclosporin A (CsA), mycophenolate sodium and corticosteroids. After 3 months, patients were treated either with CsA, mycophenolate sodium (MPA) plus corticosteroids (n = 6), CsA and everolimus plus corticosteroids (n =8) or CsA-free (CsA(free)) receiving everolimus, MPA and corticosteroids (n = 6). After initial reduction of CD4(+) forkhead box protein 3 (FoxP3)(+) and CD4(+) CD25(hi) FoxP3(+) regulatory T cells (T(regs)) (P < 0.05; P < 0.01), 3-month post-transplant percentages of T(regs) were reconstituted in CsA(free) and CsA(lo) arms compared to CsA(reg) 12 months post transplant. Expression of CCR5 and CXCR3 on CD4(+) FoxP3(+) and CD4(+) FoxP3(-) T cells 12 months post transplant was increased in CsA(free) versus CsA(reg). Increase in CCR5(+) CXCR3(+) co-expressing CD4(+) FoxP3(-) cells between 3 and 12 months correlated negatively with the glomerular filtration rate (GFR) slope/year [modification of diet in renal disease (MDRD); r = -0.59, P < 0.01]. CsA, but not everolimus, inhibits both T(reg) development and expression of CXCR3 and CCR5 on CD4(+) T cell subsets. Increase in CCR5(+) CXCR3(+) co-expressing CD4(+) FoxP3(-) T cells is associated with early loss in allograft function.

Peripherally circulating CD4⁺ FOXP3⁺ CXCR3⁺ T regulatory cells correlate with renal allograft function.

Peripheral immunoregulation depends on T regulatory cell trafficking into the allograft to modulate the local alloresponse. Little is known about the relevance of trafficking receptors for Tregs after solid organ transplantation in humans. In this study, expression of the peripheral chemokine receptors CXCR3 and CCR5 on CD4⁺ FOXP3⁺ Treg cells was analysed and correlated with allograft function in renal transplant recipients. Flow cytometry analysis of peripheral blood mononuclear cells of 54 renal transplant recipients receiving a calcineurin inhibitor-based immunosuppression was performed for CD4, CD25, FOXP3, CXCR3 and CCR5 within the first 18 months post-transplantation. Correlation analysis of chemokine receptor expression and glomerular filtration rate as calculated by MDRD (eGFR) was performed. Expression of the peripheral homing receptors CXCR3 (r = 0.44, P < 0.05) and CCR5 (r = 0.45, P < 0.05) on FOXP3⁺ Tregs correlated with renal allograft function (eGFR) in patients receiving tacrolimus (n = 28), but not cyclosporine A (CsA) (n = 26). CsA but not tacrolimus reduced surface expression of CXCR3 on FOXP3⁺ Tregs in renal transplant recipients as correlated to trough levels (r = -0.42, P < 0.05). In contrast to CD4⁺ CXCR3⁺ CD25(lo) T cells, flow-sorted CD4⁺ CXCR3⁺ CD25(hi) Tregs isolated from healthy individuals did not produce IFNγ or IL-17 ex vivo and expressed high levels of GARP mRNA both at baseline as well as after TCR activation indicating functional regulatory activity. Expression of the peripheral trafficking receptors CXCR3 and CCR5 on FOXP3⁺ Tregs is associated with renal allograft function. These results suggest that Treg trafficking may also depend on the interaction of CXCR3 or CCR5 and their respective ligands.

Impact of renal failure on metabolic bone parameters in a vitamin D-deficient patient cohort.

INTRODUCTION: Chronic renal failure is associated with major changes in bone metabolism, but studies evaluating bone metabolism with mild or moderate renal failure are rare. Moreover, the study populations were often heterogenous and/or patients were pretreated with calcium and vitamin-D preparations. Therefore, we prospectively evaluated metabolic bone parameters in patients with renal insufficiency (Stage 1 - 4) on their first visit to outpatient nephrologists. PATIENTS AND METHODS: 285 patients were prospectively evaluated regarding renal function, serum phosphorous, plasma parathyroid hormone (PTH), serum 25-OH-vitamin-D and serum bone specific alkaline phosphatase (BAP) concentrations. Patients were subdivided according to the stages of chronic kidney disease. RESULTS: Hypocalcemia occurred in only 10% of patients in Stage 4, whereas serum phosphorous was elevated at the same stage in 40% of the patients. PTH increased from Stage 1 to 4 continually with a high prevalence of elevated PTH levels (> 65 pg/ml) in Stage 1: 44%; Stage 4: 84%. Serum 25-OH-vitamin-D levels were very low irrespective of renal function: < 15 ng/dl, i.e., 37.5 nmol/l in 70% of all patients. 25-OH-D was negatively correlated with PTH (r = 0.3, p < 0.0002). BAP was within the normal range in all stages but with a high prevalence of BAP values < 7.5 ng/ml in up to 25% in Stage 4. Only 6.5% of patients had features of classical renal hyperparathyroidism. Nearly 20% had low BAP levels in the presence of normal (9.5%) or increased (9.6%) PTH levels. CONCLUSION: This study demonstrates a high prevalence of hyperphosphatemia in patients with moderate renal failure. Hyperparathyroidism was present even in earlier stages and was aggravated by a high prevalence of vitamin D deficiency. However, also in the presence of elevated PTH levels, there is indication of low bone turnover as evidenced by low BAP levels, suggesting adynamic bone disease.

Rapid recovery of hypogonadism in male patients with end stage renal disease after renal transplantation.

PURPOSE: End stage renal disease (ESRD) in male patients is associated with a high prevalence of hypogonadism. After renal transplantation (RTx) an improvement in gonadal function is often observed. However, the time course of changes in pituitary-gonadal axis after RTx and the influence of renal function, age and anthropometric parameters are not well characterized. We prospectively evaluated pituitary-gonadal axis in male patients with ESRD before and after RTx for up to 1 year. METHODS: Ninety-seven male patients with ESRD were consecutively investigated on day of surgery and 1, 3, 6, and 12 months after RTx. Time course of changes in sex hormones (total testosterone ((TT)), calculated free testosterone ((cfT)), estradiol (E2), LH, FSH and prolactin), and interdependence with renal function, age, anthropometric factors, cause of ERDS, time on dialysis, and transplant associated factors were analyzed. RESULTS: Hypogonadism (TT < 8 nmol/l) was present in 40% of pts prior to RTX and in only 18% at 1 year after RTX. Recovery from hypogonadism was significantly higher in pts < 50 years and occurred within 3 months. RTx resulted in a decrease in E2/T ratio starting at 1 month and suggesting a shift from estrogen to testosterone production. BMI and waist circumference had the similar impact on T levels after successful RTx compared to patients without renal disease. No specific impact on recovery of hypogonadism was found for time on dialysis prior to RTx and living or cadaver transplantation. CONCLUSIONS: Successful RTx is associated with a rapid recovery from hypogonadism within 3 months preceeded by improvement in renal function particularly in patients younger than 50 years.

Regulators of B-cell activity in SLE: a better target for treatment than B-cell depletion?

B cells, being a source of characteristic antinuclear autoantibodies, play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Evidences indicate that alterations in B-cell regulation are responsible for B-cell hyperactivity as seen in SLE. T cells, soluble factors, and even B cells themselves regulate effector B-cell functions. The latter, so-called regulatory B cells possess regulatory function through production of the cytokine interleukin-10 (IL-10) that can damp down the humoral immune responses. This review will focus on B-cell regulation in the pathogenesis of SLE as a target for intervention. In particular, the regulatory impact of T cells through costimulation, soluble factors such as B lymphocyte stimulator, and the characteristics of IL 10-producing regulatory B cells will be discussed. Therapies targeting B cells as well as B-cell regulation seem promising, but the precise mechanisms involved in these interventions are not completely understood. More insight into B-cell regulation in SLE, and particularly in regulatory B cells, could lead to novel therapeutic strategies.

Peripheral circulating activated b-cell populations are associated with nephritis and disease activity in patients with systemic lupus erythematosus.

B-cell-dependent autoantibody production is a hallmark of systemic lupus erythematosus (SLE) which requires costimulatory molecules. The aim of the study was to analyse the expression of costimulatory molecules on B cells in patients with SLE. Twenty-six patients with SLE (four male, 22 female, mean age 46 +/- 15 years) as defined by the American College of Rheumatology criteria and 13 healthy controls (three male, 10 female, mean age 43 +/- 15 years) were included in the study. In a subgroup analysis, SLE patients were divided according to renal involvement due to SLE (10 with and 16 patients without renal involvement). Clinical disease activity was assessed according to the systemic lupus erythematosus disease activity index (SLEDAI). Blood B-cell populations were analysed by FACS for the cell surface marker expression of CD27, CD38, CD71, CD80, CD86 and CD137 ligand. The expression levels of CD71, CD80 and CD86 on B cells were significantly enhanced in SLE patients when compared with healthy controls (27 +/- 3% versus 11 +/- 2%, P = 0.0003, 55 +/- 2% versus 28 +/- 4%, P < 0.0001, 34 +/- 3% versus 12 +/- 2%, P < 0.0001). CD86 expression was significantly elevated in patients with renal involvement when compared with patients without renal disease (43 +/- 6% versus 28 +/- 3%, P < 0.05). There was a significant correlation between the expression levels of CD80 and CD86 on CD19(+) B cells and disease activity. Moreover, prednisone dose significantly correlated with SLEDAI (r = 0.5, P = 0.02) and with the expression levels of CD86 (r = 0.47, P = 0.02). A pathological B-cell population is associated with disease activity and renal involvement in SLE which are obviously resistant to therapy with medium doses of prednisone.

Normal distribution and medullary-to-cortical shift of Nestin-expressing cells in acute renal ischemia.

Nestin, a marker of multi-lineage stem and progenitor cells, is a member of intermediate filament family, which is expressed in neuroepithelial stem cells, several embryonic cell types, including mesonephric mesenchyme, endothelial cells of developing blood vessels, and in the adult kidney. We used Nestin-green fluorescent protein (GFP) transgenic mice to characterize its expression in normal and post-ischemic kidneys. Nestin-GFP-expressing cells were detected in large clusters within the papilla, along the vasa rectae, and, less prominently, in the glomeruli and juxta-glomerular arterioles. In mice subjected to 30 min bilateral renal ischemia, glomerular, endothelial, and perivascular cells showed increased Nestin expression. In the post-ischemic period, there was an increase in fluorescence intensity with no significant changes in the total number of Nestin-GFP-expressing cells. Time-lapse fluorescence microscopy performed before and after ischemia ruled out the possibility of engraftment by the circulating Nestin-expressing cells, at least within the first 3 h post-ischemia. Incubation of non-perfused kidney sections resulted in a medullary-to-cortical migration of Nestin-GFP-positive cells with the rate of expansion of their front averaging 40 microm/30 min during the first 3 h and was detectable already after 30 min of incubation. Explant matrigel cultures of the kidney and aorta exhibited sprouting angiogenesis with cells co-expressing Nestin and endothelial marker, Tie-2. In conclusion, several lines of circumstantial evidence identify a sub-population of Nestin-expressing cells with the mural cells, which are recruited in the post-ischemic period to migrate from the medulla toward the renal cortex. These migrating Nestin-positive cells may be involved in the process of post-ischemic tissue regeneration.

CD134 expression on CD4+ T cells is associated with nephritis and disease activity in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by a deviation of the immune system that involves T cell-dependent autoantibody production. The aim of this study was to investigate the role of co-stimulatory markers on T cells in this disease. Twenty-eight patients with SLE as defined by the American College of Rheumatology (ACR) criteria and 11 healthy controls were included into the study. Eleven patients had biopsy-proven lupus nephritis while 17 patients had no clinical evidence of lupus nephritis. Clinical disease activity was assessed according to the systemic lupus erythematosus disease index (SLEDAI). CD4+ T cell populations in the peripheral blood were analysed for the expression of co-stimulatory markers CD45RO, CD70, CD80, CD86, CD137, CD137L, CD134, CD152, CD154 and ICOS. SLE patients showed an increased frequency of peripheral CD4+ T cells expressing high levels of CD80, CD86 and CD134 compared to healthy controls (7.1 +/- 1.5% versus 1.7 +/- 0.9%; P < 0.005; 2.3 +/- 0.4% versus 1.0 +/- 0.2%; P = 0.008, 20.2 +/- 2.0% versus 10.6 +/- 1.9%; P < 0.005, respectively). Significantly higher levels of CD80 on CD4+ T cells were detected in SLE patients with lupus nephritis compared to patients without nephritis (11.9 +/- 3.3% versus 4.0 +/- 0.7%; P < 0.005). There was an increased presence of CD134+ CD4+ cells in SLE patients with lupus nephritis (27.5 +/- 4.0% versus 15.5 +/- 1.3%; P < 0.005). CD80 and CD134 expression was significantly correlated with SLEDAI (r = 0.42, P = 0.03; r = 0.56, P < 0.005). Co-stimulatory molecules on CD4+ T cells are associated with renal disease and disease activity in patients with systemic lupus erythematosus.

Repaglinide in the management of new-onset diabetes mellitus after renal transplantation.

The purpose of this study was to investigate the use of the short-acting insulin secretion drug repaglinide in new-onset diabetes mellitus (NODM) after renal transplantation. Twenty-three Caucasian patients with NODM after renal transplantation were selected to receive repaglinide therapy and were followed for at least 6 months. A control group treated with rosiglitazone was chosen for comparison. Successful repaglinide treatment was defined as a significant improvement of blood glucose concentrations and HbA1c <7% in the absence of glucosuria and without the need for the addition of further anti-diabetic agents. After 6 months of treatment with repaglinide, 14 of the 23 patients were successfully treated. Mean HbA1c decreased from 7.6 +/- 0.6% to 5.8 +/- 0.6% in 14 patients treated successfully. In nine patients, hyperglycemia persisted, and they were switched to insulin treatment (HbA1c 8.5 +/- 2.9% at the beginning to 7.4 +/- 2.2%). Mean serum creatinine levels, cyclosporine A and tacrolimus blood levels did not change significantly following institution of repaglinide therapy. The rate of successful treatment and the degree of HbA1c decrease were similar compared to rosiglitazone-treated control patients. The data from our observational study indicate that repaglinide can be an effective treatment option in Caucasian patients with NODM after renal transplantation.