Correlation of serum interleukin-2 receptor-α levels with clinical manifestations in pulmonary tuberculosis

Setting: The analysis of serum levels of soluble interleukin-2 receptor alpha (sIL-2R-α) is an indirect method of studying the in vivo state of immune activation, particularly in patients with pulmonary tuberculosis (PTB) where the disease is associated with cellular immune reactions.Objective: To quantitate the serum sIL-2R-α in patients and correlate with disease activity.Design: The levels of sIL-2R-α were determined using ELISA in serum samples from untreated patients with PTB (n = 107), 30 of whom were later tested during treatment, household family contacts (n = 38), and healthy controls (n = 22).Results: Concentrations of sIL-2R-α were significantly higher in PTB patients than in controls (2845 ± 187 vs 1217 ± 80 pg/mL, P < 0.0001), and were even more pronounced in the sputum positive (3200 ± 148 pg/mL) and treatment failure (3335 ± 196 pg/mL) groups of patients. However, in household family contacts, the sIL-2R-α levels were found to be similar to those of healthy controls. The sIL-2R-α levels correlated positively with disease activity as assessed by roentgenographic findings. In six of the 16 responder patients, the sIL-2R-α levels fell from 3228 ± 144 pg/mL to 1497 ± 131 pg/mL (P < 0.0001) after 3 months of successful treatment with anti-tuberculosis drugs. However, no significant change was observed in the treatment failure patients even after one year of chemotherapy with second-line drugs.Conclusion: These studies indicate that determination of serum concentrations of sIL-2R-α is a sensitive and specific method for monitoring disease activity in terms of T cell activation in pulmonary tuberculosis.     

Systemic Inflammation and Complement Activation Parameters Predict Clinical Outcome of Severe SARS-CoV-2 Infections

Overactivation of the complement system has been characterized in severe COVID-19 cases. Complement components are known to trigger NETosis via the coagulation cascade and have also been reported in human tracheobronchial epithelial cells. In this longitudinal study, we investigated systemic and local complement activation and NETosis in COVID-19 patients that underwent mechanical ventilation. Results confirmed significantly higher baseline levels of serum C5a (24.5 ± 39.0 ng/mL) and TCC (11.03 ± 8.52 µg/mL) in patients compared to healthy controls (p < 0.01 and p < 0.0001, respectively). Furthermore, systemic NETosis was significantly augmented in patients (5.87 (±3.71) × 10⁶ neutrophils/mL) compared to healthy controls (0.82 (±0.74) × 10⁶ neutrophils/mL) (p < 0.0001). In tracheal fluid, baseline TCC levels but not C5a and NETosis, were significantly higher in patients. Kinetic studies of systemic complement activation revealed markedly higher levels of TCC and CRP in nonsurvivors compared to survivors. In contrast, kinetic studies showed decreased local NETosis in tracheal fluid but comparable local complement activation in nonsurvivors compared to survivors. Systemic TCC and NETosis were significantly correlated with inflammation and coagulation markers. We propose that a ratio comprising systemic inflammation, complement activation, and chest X-ray score could be rendered as a predictive parameter of patient outcome in severe SARS-CoV-2 infections.     

Serum 25-hydroxyvitamin D concentration and inflammatory bowel disease characteristics in Romania

AIM: To describe the relationship between vitamin D levels and inflammatory bowel disease (IBD) characteristics in northeastern Romanian patients.METHODS: This was a prospective study of 47 consecutive IBD patients admitted to The Institute of Gastroenterology and Hepatology in Iasi, Romania between March 2011 and June 2012. The diagnosis of IBD was established based on endoscopic, histologic and radiologic findings. Demographic data, disease characteristics, ongoing treatments and biological parameters of patients (including markers of inflammation: C-reactive protein level, fibrinogen level, and erythrocyte sedimentation rate) were recorded. Serum vitamin D levels were measured and compared with age- and sex-matched healthy volunteers from the same geographic area. Vitamin D levels were defined as sufficient (> 30 ng/mL), insufficient (20-30 ng/mL), or severely deficient (< 20 ng/mL).RESULTS: Thirty-three of the IBD patients included in this study had ulcerative colitis (UC) and 14 had Crohn’s disease (CD). Only 24% of the UC patients and 21% of the CD patients had sufficient vitamin D levels. The vitamin D levels were significantly lower in the CD patients with moderate to severe disease activity compared to the CD patients in remission or with mild disease activity (16 ± 6 ng/mL vs 26 ± 7 ng/mL; 16 ± 6 ng/mL vs 31 ± 9 ng/mL, respectively, P < 0.05). Vitamin D levels in the UC patients were not influenced by disease activity and no correlation was observed with the inflammation markers tested (C-reactive protein, fibrinogen, and erythrocyte sedimentation rate). No association was observed between vitamin D levels and smoking status or ongoing medication (5ASA, steroids, and anti-TNFα). Newly diagnosed IBD patients had lower vitamin D levels than patients with established cases, though these differences were not significant (UC: 22 ± 9 ng/mL vs 26 ± 12 ng/mL; CD: 18 ± 6 ng/mL vs 27 ± 11 ng/mL, respectively). Although no association was found between the season during which the visit was scheduled and vitamin D levels, the UC patients assessed during the winter tended to have lower levels than those assessed during the summer (22 ± 9 ng/mL vs 28 ± 13 ng/mL, respectively).CONCLUSION: Vitamin D levels are significantly reduced in IBD patients in northeastern Romania, with the lowest levels occurring in CD patients with moderate to severe disease activity.     

Clinical significance of serum procalcitonin in patients with ulcerative colitis

AIM:To investigate the association of procalcitonin(PCT)with ulcerative colitis(UC)activity.METHODS:Serum PCT levels,C-reactive protein(CRP)levels,the erythrocyte sedimentation rate,and the white blood cell count were analyzed in 18 patients with UC and 11 healthy volunteers.Serum PCT levels were analyzed by an electrochemiluminescence immunoassay.Severity assessments were based on Truelove and Witts’severity index.Correlation of serum PCT and CRP levels with UC activity was examined.Moreover,we assessed serum PCT and CRP levels in patients with a Mayo endoscopic subscore.RESULTS:Serum PCT levels in severe UC patients(n=7)(0.096±0.034 ng/mL)were significantly higher than in mild-to-moderate UC patients(n=11)(0.033±0.012 ng/mL)and healthy volunteers(n=11)(0.035±0.005 ng/mL)(P=0.0005 and P<0.0001,respectively).In addition,there was no difference in serum PCT levels between mild-to-moderate UC patients and healthy volunteers.Interestingly,patients with a Mayo endoscopic subscore of 3 points displayed significantly increased levels of serum PCT(0.075±0.043 ng/mL)compared with patients with a subscore of 2 points(0.03±0.011 ng/mL)(P=0.0302).Moreover,CRP levels in patients with severe UC or a Mayo endoscopic subscore of 3 points were not significantly higher than in patients with mild-to-moderate UC or a Mayo endoscopic subscore of 3 points.CONCLUSION:Serum PCT levels were significantly correlated with UC activity.     

High level of soluble interleukin-2 receptor in serum predicts treatment resistance and poor progression-free survival in multiple myeloma

The IL-2/IL-2 receptor (IL-2R) system plays a central role in maintaining normal T cell immunity, and its disturbance is associated with several hematologic disorders. Studies have found in several types of lymphoma that abnormal amounts of soluble IL-2R (sIL-2R) may result in imbalance of the IL-2/IL-2R system and hence of the T cell immunoregulation. Whether the level of sIL-2R in blood could predict treatment outcomes or not needs to be investigated in multiple myeloma (MM) patients. The level of sIL-2R in serum was measured using enzyme-linked immunosorbent assay (ELISA) in 81 patients with newly diagnosed MM. Twenty-six patients (32.1%) were treated with bortezomib-based regimens and 55patients (67.9%) received old drugs-based regimens. The mean concentration of sIL-2R for myeloma patients was 8.51 ng/ml, significantly higher than that of healthy controls (0.56 ng/ml, p < 0.0001). The best cutoff value for sIL-2R in predicting high risk for disease progression is 6.049 ng/ml with an area under curve (AUC) of 0.665 (p = 0.013). Thirty-six patients (44.4%) were classified as higher sIL-2R level group (> 6.049 ng/ml), and 45 patients (55.6%) as lower group (≤ 6.049 ng/ml). The overall response rate (ORR) was 60.0% in lower sIL-2R level group, and 41.7% in higher level group (p = 0.156). The median progression-free survival (PFS) and overall survival (OS) was 12 months (range, 2.0–65 months) and 20 months (range, 2.0–118 months), respectively. In a multivariate survival analysis, including Eastern Cooperative Oncology Group performance status score, treatment response, and sIL-2R level, it was found that all these three parameters were significantly independent prognostic factors for PFS (p = 0.032, 0.016, and 0.043, respectively), but none factors maintained their value in predicting OS. Subgroup analysis revealed that high level of sIL-2R is correlated with significantly inferior PFS in patients treated with bortezomib-based regimens (p = 0.004). Serum sIL-2R level is an independent prognostic factor for PFS, indicating novel drugs targeting the imbalance of IL-2/IL-2R system may be a promising strategy in MM.     

The combination of IL-6 and its soluble receptor is associated with the response of rheumatoid arthritis patients to tocilizumab

BackgroundIL-6 contributes significantly to the chronic inflammatory process of rheumatoid arthritis (RA). Tocilizumab, a humanized anti-human IL-6 receptor antibody that blocks the signaling originated by the IL-6/IL-6R complex, is an effective treatment. However, predictors of the response to tocilizumab are still required. We aimed to combine IL-6 and soluble IL-6R (sIL-6R) levels to identify groups of responses.MethodsHeparinized blood and clinical data from 63 RA patients were collected before treatment and after 3 and 6 months. Two-step clustering (SPSS v.18) was used to establish the relationship between IL-6 and sIL-6R. Then, we compared European League Against Rheumatism (EULAR) response criteria with remission achievement in the groups of patients.ResultsThree statistical significant clusters of RA patients (i.e., g1, g2, and g3) were defined by serum concentrations of IL-6 and sIL-6R at baseline. All groups of RA patients had higher IL-6 and sIL-6R levels than healthy donors. The levels of IL-6 expressed as median (IQR) in g1 patients were 124(90–183) pg/ml, in g2 12.3(4.4–24) pg/ml, and in g3 60.1(30–146) pg/ml (p < 0.001). The levels of sIL-6R expressed as mean ± sd in g1 patients were 250.5 ± 72 ng/ml, in g2 269.1 ± 125 ng/ml, and in g3 732.7 ± 243 ng/ml (p < 0.001). Disease activity score (DAS)28, C-reactive protein, and erythrocyte sedimentation rate were comparable in the three groups at baseline. Disease duration in g3 was the longest (median(IQR) years: g1 = 11(5–15), g2 = 12(8–20), and g3 23(16–26); p = 0.006), with years of disease evolution being correlated with sIL-6R levels (R = 0.417, p < 0.001). Simple and Clinical Disease Activity Index (SDAI and CDAI) decreased significantly in the three groups. However, EULAR response criteria and remission achievement at 6 m was different in the three groups (p = 0.03 and 0.04, respectively). In all. 17 out of the 18 patients in g1 had a good or moderate response to tocilizumab. Conversely, the percentage of patients with no response to tocilizumab was higher in g3 than in g1 and g2. We also observed different changing patterns of IL-6 and sIL-6R levels among the three groups.ConclusionsRA patients could be easily stratified prior to therapeutic intervention with two molecules related to the pathway blocked by tocilizumab. G1 patients, who had the best response to tocilizumab, had the highest level of IL-6 and the lowest level of sIL-6R.     

Secretory Phospholipase A2 Is Associated with the Odds of Acute Coronary Syndromes through Elevation of Serum Amyloid-A Protein

In coronary heart disease (CHD), levels of secretory phospholipase A2 (sPLA2) are commonly increased. Serum amyloid-A (SAA) is increased in acute coronary syndromes (ACS) as well. It is needed to verify the hypotheses that sPLA2 is associated with the odds of ACS through elevation of SAA. We conducted a case–control study with 57 male patients with ACS and 30 controls matched by gender category. Levels of sPLA2, SAA, and myeloperoxidase (MPO) were measured by immunoreactive assay on the basis of a double-antibody sandwich technique. Levels of sPLA2, MPO, and SAA were significantly higher in patients than those in controls (11,359.0 ± 10,372.4 pg/mL vs. 1,320.5 ± 654.5 pg/mL, p = 0.00; 438.6 ± 310.7 ng/mL vs. 271.1 ± 176.8 ng/mL, p = 0.01; 10,995.2 ± 2,842.6 ng/mL vs. 3,861.7 ± 3,173.5 ng/mL, p = 0.00). There were significant correlations between age, visceral obesity, MPO, sPLA2, and SAA (r = 0.43; p = 0.00; r = 0.30; p = 0.00; r = 0.28; p = 0.00 and r = 0.53; p = 0.00). On multivariate logistic regression analyses, there were significant and independent associations between sPLA2 and SAA with odds of ACS [OR (95% CI) = 14.2 (2.1 to 98.6), p = 0.00; OR (95% CI) = 44.9 (6.9 to 328.4), p = 0.00]. Our findings suggest that sPLA2 may be associated with the odds of ACS compared with controls through increased inflammation, represented by elevated SAA.     

Local corticosterone production and angiotensin-I?converting enzyme shedding in a mouse model of intestinal inflammation

AIM: To investigate local corticosterone production and angiotensin-I converting enzyme (ACE) protein expression and their interaction in healthy and inflamed intestine.METHODS: Acute intestinal inflammation was induced to six weeks old male Balb/c mice by administration of either 3% or 5% dextran sodium sulfate (DSS) in drinking water for 7 d (n = 12 in each group). Healthy controls (n = 12) were given tap water. Corticosterone production and ACE protein shedding were measured from ex vivo incubates of the small and large intestine using EIA and ELISA, respectively. Morphological changes of the intestinal wall were assessed in hematoxylin-eosin stained tissue preparations of jejunum and distal colon. Effects of angiotensin II, captopril and metyrapone on corticosterone production was assessed by incubating pieces of small intestine of healthy mice in the presence of 0.1, 1 or 10 μmol/L angiotensin II, 1, 10 or 100 μmol/L captopril or 1, 10 or 100 μmol/L metyrapone solutions and measuring corticosterone released to the incubation buffer after 90 min (n = 5 in each group).RESULTS: Both concentrations of DSS induced inflammation and morphological changes in large intestines but not in small intestines. Changes were observed as distortions of the crypt structure, mucosal erosion, immune cell infiltration to the mucosa and submucosal edema. Ex vivo corticosterone production (2.9 ± 1.0 ng/mL vs 2.0 ± 0.8 ng/mL, P = 0.034) and ACE shedding (269.2 ± 97.1 ng/mL vs 175.7 ± 52.2 ng/mL, P = 0.016) were increased in small intestines in 3% DSS group compared to the controls. In large intestine, corticosterone production was increased compared to the controls in both 3% DSS (229 ± 81 pg/mL vs 158 ± 30 pg/mL, P = 0.017) and 5% DSS groups (366 ± 163 pg/mL vs 158 ± 30 pg/mL, P = 0.002). Large intestine ACE shedding was increased in 5% DSS group (41.5 ± 9.0 ng/mL vs 20.9 ± 5.2 ng/mL, P = 0.034). Angiotensin II treatment augmented corticosterone production in small intestine at concentration of 10 μmol/L (0.97 ± 0.21 ng/mg protein vs 0.40 ± 0.09 ng/mg protein, P = 0.036).CONCLUSION: Intestinal ACE shedding is increased by DSS-induced intestinal inflammation and parallels local corticosterone production. ACE product angiotensin II stimulates corticosterone formation in healthy intestine.     

Decreased serum platelet derived growth factor BB levels in acute and increased in chronic pancreatitis

AIM: To examine circulating growth factor concentrations in patients with acute pancreatitis (AP) and chronic pancreatitis (CP), and walled-off pancreatic necrosis (WOPN).METHODS: Forty patients with mild AP, 40 patients with alcoholic CP, 33 patients with WOPN and 40 healthy subjects were examined. Serum concentrations of platelet derived growth factor BB (PDGF-BB), transforming growth factor β-1 (TGFβ-1), chemerin and high-mobility group box chromosomal protein 1 (HMBG1) were assayed by enzyme linked immunosorbent assay.RESULTS: Patients with mild AP and those with WOPN had significantly lower serum levels of PDGF-BB compared to healthy subjects (4.0 ± 0.61 ng/mL vs 6.2 ± 0.76 ng/mL, P = 0.027, and 1.60 ± 0.31 ng/mL vs 6.2 ± 0.76 ng/mL, P < 0.001, respectively), while CP was associated with higher serum levels of PDGF-BB (12 ± 1.3 ng/mL vs 6.2 ± 0.76 ng/mL, P < 0.001). Circulating TGFβ-1 and chemerin levels were elevated in CP patients (57 ± 3.6 ng/mL vs 39 ± 3.6 ng/mL, P < 0.001 and 73 ± 7.2 ng/mL vs 48 ± 2.3 ng/mL, P < 0.001, respectively), but not in patients with AP and WOPN. No significant changes in serum HMBG1 levels were found either in patients with AP, WOPN or CP.CONCLUSION: The serum levels of some growth factors and cytokines differ significantly in AP, WOPN and CP. These data suggest that selected growth factors and cytokines may be considered as potential diagnostic biomarkers in patients with pancreatic diseases.     

Hepcidin Levels in Children with Chronic Liver Disease

Background/Aim:

We aimed to analyze serum hepcidin level in children with chronic liver disease (CLD) and its relationship with serum cytokines level, liver function tests, hepatic iron content, and liver fibrosis.

Patients and Methods:

The study included 34 children with CLD, and 15 age- and gender-matched healthy children. Serum hepcidin, ferritin, iron level, interleukin-6 (IL-6), transforming growth factor-β (TGF-β ), total oxidant status (TOS), and antioxidant status (TAS) were studied in all patients and in the control group. Liver iron content (LIC) was measured from the liver biopsy specimen.

Results:

Serum ferritin levels were higher in patients with CLD than control group (100.1 ± 98.2 ng/mL vs 50.5 ± 32.2 ng/mL, P = 0.016). No significant difference was found in hepcidin levels. Hepcidin levels in children with CLD was positively correlated with ferritin (r = 0.75, P = 0.001), pediatric end-stage liver disease (PELD) score (r = 0.56, P = 0.001), TAS (r = 0.42, P = 0.02), but negatively correlated with albumin level (r = −0.45, P = 0.008). Transferrin saturation and hepcidin:ferritin ratio were significantly low in patients with severe fibrosis compared with patients with mild/without fibrosis (15.5 ± 5.5 vs 34.3 ± 30.1, P = 0.017 and 1 ± 0.5 vs 1.9 ± 1.4, P = 0.04, respectively).

Conclusion:

Serum hepcidin levels in children with CLD reflect both liver functions and TAS, and severe fibrosis is associated with low hepcidin:ferritin ratio in children with CLD.     

Higher vitamin D serum concentration increases health related quality of life in patients with inflammatory bowel diseases

AIM: To investigate the effect of vitamin D (VD) concentrations and VD supplementation on health related quality of life in inflammatory bowel disease (IBD) patients.METHODS: A cohort of 220 IBD patients including 141 Crohn’s disease (CD) and 79 ulcerative colitis (UC) patients was followed-up at a tertiary IBD center. A subgroup of the cohort (n = 26) took VD supplements for > 3 mo. Health related quality of life was assessed using the short IBD questionnaire (sIBDQ). VD serum concentration and sIBDQ score were assessed between August and October 2012 (summer/autumn period) and between February and April 2013 (winter/spring period). The mean VD serum concentration and its correlation with disease activity of CD were determined for each season separately. In a subgroup of patients, the effects of VD supplementation on winter VD serum concentration, change in VD serum concentration from summer to winter, and winter sIBDQ score were analyzed.RESULTS: During the summer/autumn and the winter/spring period, 28% and 42% of IBD patients were VD-deficient (< 20 ng/mL), respectively. In the winter/spring period, there was a significant correlation between sIBDQ score and VD serum concentration in UC patients (r = 0.35, P = 0.02), with a trend towards significance in CD patients (r = 0.17, P = 0.06). In the winter/spring period, VD-insufficient patients (< 30 ng/mL) had a significantly lower mean sIBDQ score than VD-sufficient patients; this was true of both UC (48.3 ± 2.3 vs 56.7 ± 3.4, P = 0.04) and CD (55.7 ± 1.25 vs 60.8 ± 2.14, P = 0.04) patients. In all analyzed scenarios (UC/CD, the summer/autumn period and the winter/spring period), health related quality of life was the highest in patients with VD serum concentrations of 50-59 ng/mL. Supplementation with a median of 800 IU/d VD day did not influence VD serum concentration or the sIBDQ score.CONCLUSION: VD serum concentration correlated with health related quality of life in UC and CD patients during the winter/spring period.     

Patient and Clinical Factors at Admission Affect the Levels of Neutralizing Antibodies Six Months after Recovering from COVID-19

The rate of decline in the levels of neutralizing antibodies (NAbs) greatly varies among patients who recover from Coronavirus disease 2019 (COVID-19). However, little is known about factors associated with this phenomenon. The objective of this study is to investigate early factors at admission that can influence long-term NAb levels in patients who recovered from COVID-19. A total of 306 individuals who recovered from COVID-19 at the Tongji Hospital, Wuhan, China, were included in this study. The patients were classified into two groups with high (NAb^high, n = 153) and low (NAb^low, n = 153) levels of NAb, respectively based on the median NAb levels six months after discharge. The majority (300/306, 98.0%) of the COVID-19 convalescents had detected NAbs. The median NAb concentration was 63.1 (34.7, 108.9) AU/mL. Compared with the NAb^low group, a larger proportion of the NAb^high group received corticosteroids (38.8% vs. 22.4%, p = 0.002) and IVIG therapy (26.5% vs. 16.3%, p = 0.033), and presented with diabetes comorbidity (25.2% vs. 12.2%, p = 0.004); high blood urea (median (IQR): 4.8 (3.7, 6.1) vs. 3.9 (3.5, 5.4) mmol/L; p = 0.017); CRP (31.6 (4.0, 93.7) vs. 16.3 (2.7, 51.4) mg/L; p = 0.027); PCT (0.08 (0.05, 0.17) vs. 0.05 (0.03, 0.09) ng/mL; p = 0.001); SF (838.5 (378.2, 1533.4) vs. 478.5 (222.0, 1133.4) μg/L; p = 0.035); and fibrinogen (5.1 (3.8, 6.4) vs. 4.5 (3.5, 5.7) g/L; p = 0.014) levels, but low SpO₂ levels (96.0 (92.0, 98.0) vs. 97.0 (94.0, 98.0)%; p = 0.009). The predictive model based on Gaussian mixture models, displayed an average accuracy of 0.7117 in one of the 8191 formulas, and ROC analysis showed an AUC value of 0.715 (0.657–0.772), and specificity and sensitivity were 72.5% and 67.3%, respectively. In conclusion, we found that several factors at admission can contribute to the high level of NAbs in patients after discharge, and constructed a predictive model for long-term NAb levels, which can provide guidance for clinical treatment and monitoring.     

The Clinical Presentation of Puumala Hantavirus Induced Hemorrhagic Fever with Renal Syndrome Is Related to Plasma Glucose Concentration

Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome characterized by thrombocytopenia, increased capillary leakage, and acute kidney injury (AKI). As glucosuria at hospital admission predicts the severity of PUUV infection, we explored how plasma glucose concentration associates with disease severity. Plasma glucose values were measured during hospital care in 185 patients with PUUV infection. They were divided into two groups according to maximum plasma glucose concentration: P-Gluc < 7.8 mmol/L (n = 134) and P-Gluc ≥ 7.8 mmol/L (n = 51). The determinants of disease severity were analyzed across groups. Patients with P-Gluc ≥7.8 mmol/L had higher hematocrit (0.46 vs. 0.43; p < 0.001) and lower plasma albumin concentration (24 vs. 29 g/L; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. They presented with higher prevalence of pulmonary infiltrations and pleural effusion in chest radiograph, higher prevalence of shock and greater weight change during hospitalization. Patients with P-Gluc ≥ 7.8 mmol/L were characterized by lower platelet count (50 vs. 66 × 10⁹/L; p = 0.001), more severe AKI (plasma creatinine 272 vs. 151 µmol/L; p = 0.001), and longer hospital treatment (8 vs. 6 days; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. Plasma glucose level is associated with the severity of capillary leakage, thrombocytopenia, inflammation, and AKI in patients with acute PUUV infection.     

Soluble interleukin-2 receptor level on day 7 as a predictor of graft-versus-host disease after HLA-haploidentical stem cell transplantation using reduced-intensity conditioning

In the present study, we analyzed the kinetics of serum soluble interleukin-2 receptor (sIL-2R) using data from 77 patients undergoing HLA-haploidentical transplantation using reduced-intensity conditioning (RIC), who were at an advanced stage or at high risk for relapse, to clarify the usefulness of sIL-2R as a biomarker of acute graft-versus-host disease (GVHD). Anti-T-lymphocyte globulin and methylprednisolone were used as GVHD prophylaxis. While the median sIL-2R in 38 patients not developing GVHD was suppressed at levels <740 U/ml, sIL-2R in 25 patients developing severe GVHD peaked on day 11 (1,663 U/ml), and thereafter decreased to <1,000 U/ml after day 30. The occurrence of GVHD was not limited to times of high sIL-2R level, but occurred at any time point on the sIL-2R curve. Most patients developing GVHD, however, experienced a higher sIL-2R level early in their transplant course. The combination of RIC and glucocorticoids sufficiently suppressed sIL-2R levels after HLA-haploidentical transplantation. In a multivariate analysis to identify factors associated with GVHD, day 7 sIL-2R >810 U/ml was the only factor significantly associated with the occurrence of severe GVHD (p = 0.0101).     

Clinical characteristics and determinants of mortality in coronavirus disease 2019 (COVID-19) patients on an intensive care unit—a retrospective explorative 1-year all-comers study

BackgroundClinical outcome in patients with coronavirus disease 2019 (COVID-19) requiring treatment on intensive care units (ICU) remains unfavourable. The aim of this retrospective study was to exploratively identify potential predictors of unfavourable outcome in ICU patients diagnosed with COVID-19.MethodsIn all patients with COVID-19 (n=50) or severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) as comorbidity (n=11) at our ICU we assessed clinical, respiratory and laboratory parameters with a potential role for outcome. Main outcome variables were intubation and mortality rates.ResultsBetween March 2020 and March 2021, 573 patients were hospitalized with SARS-CoV-2 infection. Of these, 61 patients (10.6%, 44.3% women) aged 66.4±13.3 were admitted to ICU. A proportion of 73.8% of patients had moderate or severe acute respiratory distress syndrome (ARDS). COVID-19 patients differed clinically from those with SARS-CoV-2 as comorbidity, such as severe heart or renal failure or sepsis as the leading cause of ICU admission, despite similar mortality rates (44.0% vs. 45.5%, P>0.5). Among COVID-19 patients, those who died had more often severe ARDS (91% vs. 46%, P=0.001), longer non-invasive ventilation (NIV) therapy prior to ICU (6.3±5.9 vs. 2.5±2.0 days, P=0.046), and higher interleukin-6 (IL-6) and lactate dehydrogenase (LDH) values as compared to survivors. In multivariable analysis, NIV duration ≥5 days on admission [odds ratio (OR): 42.20, 95% confidence interval (CI): 1.22 to >99, P=0.038] and IL-6 [OR: 4.08, 95% CI: 1.16–14.33, P=0.028] remained independently predictive of mortality. In worsening tertiles of partial pressure of oxygen (pO₂)/inspiratory oxygen fraction (FiO₂) on admission (≥161.5, 96.5 to <161.5, <96.5) we observed a stepwise increase in intubation rates (P=0.0034) and mortality rates (P=0.031).ConclusionsAs inflammation, ARDS severity and longer NIV duration prior to ICU are associated with intubation and mortality rates, prognosis appears to be largely determined by disease severity. Whether NIV aggravates ARDS or if it indicates lack of recovery independent from type of ventilation, or both should be clarified in a prospective trial.     

Tumor necrosis factor-α and interleukin-6 in cirrhotic patients with spontaneous bacterial peritonitis

AIM: To evaluate the role of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cirrhotic patients who have hepatic and renal impairment with spontaneous bacterial peritonitis (SBP).METHODS: We prospectively studied 120 cirrhotic patients with SBP and 80 cirrhotic patients with sterile ascitic fluid. They included 144 males and 56 females with ages ranging between 34 and 62 years. The diagnosis of cirrhosis was established by clinical and laboratory criteria that did not require histological confirmation. The severity of underlying liver disease was evaluated using Pugh’s modification of Child’s criteria (Child-Pugh scores). Ascitic fluid was sent to the laboratory for cell count, culture, sensitivity testing, and measurement of chemical elements (i.e., albumin, glucose). Specimens were inoculated into aerobic and anaerobic blood culture bottles. Serum and ascitic fluid were also collected in sterile tubes at study entry (before the initiation of antibiotic treatment) and 48 h later. Assays for TNF-α and IL-6 in the serum and ascitic fluid were performed with an immunoenzymometric assay using manufacture’s instructions.RESULTS: Cytokine levels in serum and ascitic fluid were significantly higher in the patients with SBP. (plasma TNF-α: 135.35 ng/mL ± 11.21 ng/mL vs 92.86 ng/mL ± 17.56 ng/mL, P < 0.001; plasma IL-6: 32.30 pg/mL ± 7.07 pg/mL vs 12.11 pg/mL ± 6.53 pg/mL, P < 0.001; ascitic fluid TNF-α: 647.54 ± 107.11 ng/mL vs 238.43 ng/mL ± 65.42 ng/mL, P < 0.001); ascitic fluid IL-6: 132.84 ng/mL ± 34.13 vs 40.41 ± 12.85 pg/mL, P < 0.001). About 48 (40%) cirrhotic patients with SBP developed renal and hepatic impairment and showed significantly higher plasma and ascitic fluid cytokine levels at diagnosis of infection. [(plasma TNF-α: 176.58 ± 17.84 vs 135.35 ± 11.21 ng/mL) (P < 0.001) and (IL-6: 57.83 ± 7.85 vs 32.30 ± 7.07 pg/mL) (P < 0.001); ascitic fluid TNF-α: 958.39 ± 135.72 vs 647.54 ± 107.11 ng/mL, (P < 0.001), ascitic fluid IL-6: 654.74 ± 97.43 vs 132.84 ± 34.13 pg/mL, (P < 0.001)]. Twenty nine patients (60.4%) with SBP and renal impairment died whereas, only four patients (5.55%) with SBP but without renal impairment died from gastrointestinal hemorrhage (P < 0.0005).CONCLUSION: It appears that TNF-α production may enhance liver cell injury and lead to renal impairment. This correlated well with the poor prognosis and significantly increased mortality associated with SBP in cirrhotic patients.     

Soluble interleukin-2 receptor in Sjögren's syndrome: relation to main serum immunological and immunohistochemical parameters

Our aim was to study sIL-2R relationship with main serum immunological and LSG immunohistochemical parameters, including surface antigen expression of immune activation, in 27 patients with primary SS. Serum sIL-2R levels were significantly higher in SS (p<0.00005), as well as in SLE (p<0.05) and RA (p< 0.000001) patients than in controls. In SS patients with abnormal sIL-2R values (n= 7) we found higher levels of anti-SSB/La antibodies (p<0.05), IgM-RF (p<0.014) and CRP (p<0.003) with respect to those with normal sIL-2R values (n= 20). Moreover, sIL-2R levels correlated positively with those of anti-SSB/La antibodies (p<0.0037) and with CRP (p<0.008). The comparison of groups with (A) and without (B) abnormal sIL-2R levels reveals a statistically different percentage of patients with foci number >1 (86% vs 40%; p<0.047), and CD25 expression on lymphocytes (100% vs 40%; p<0.008). The frequency (p<0.025) of CD25 expression on lymphocytes was higher in group A than in group B. The frequency of CD25 expression on the infiltrates correlated not only with sIL-2R levels (p<0.047), but also with anti-SSB/La antibody values (p<0.044), with Tarpley histological classes (p<0.009) and with frequency of HLA-DR expression on lymphocytes (p<0.004) and on epithelial cells (p<0.002). The frequency of epithelial CD25 expression also correlated with that of epithelial HLA-DR (p<0.004). Our report suggests that sIL-2R is linked to glandular involvement in primary SS. Received: 17 August 2000 / Accepted: 4 April 2001     

VCAM-1 as a Biomarker of Endothelial Function among HIV-Infected Patients Receiving and Not Receiving Antiretroviral Therapy

The Human Immunodeficiency Virus and retroviral therapy are both known risk factors for cardiovascular disease. It remains an open question whether HIV or ARV leads to increased arterial inflammation. The objective of this study was to investigate the changes in endothelial activation by measuring VCAM-1 levels among HIV-infected patients who were and were not treated with antiretroviral therapy. It is a retrospective study that included 68 HIV-infected patients, 23 of whom were never antiretroviral-treated, 15 who were ART-treated for no longer than a year, and 30 who were ART-treated for longer than a year. Blood samples were collected for biochemical analysis of the concentration of VCAM-1. The results show a statistically lower VCAM-1 level (p = 0.007) in patients treated with ART longer than a year (1442 ng/mL) in comparison to treatment-naïve patients (2392 ng/mL). The average VCAM-1 level in patients treated no longer than a year (1552 ng/mL) was also lower than in treatment-naïve patients, but with no statistical significance (p = 0.096). Long-term antiretroviral therapy was associated with the decline of VCAM-1 concentration. That may suggest the lowering of endothelial activation and the decreased risk of the development of cardiovascular disease among ARV-treated patients. However, VCAM-1 may not be a sufficient factor itself to assess this, since simultaneously there are a lot of well-known cardiovascular-adverse effects of ART.     

Coronary Artery Disease Severity and Cardiovascular Biomarkers in Patients with Peripheral Artery Disease

Cardiovascular mortality in peripheral artery disease (PAD) patients is higher in critical limb ischemia (CLI) than in intermittent claudication (IC). We sought to evaluate differential characteristics of coronary artery disease (CAD) severity and prognostic biomarkers for cardiovascular events between CLI and IC patients. Coronary angiography was performed on 242 PAD patients (age 73 ± 8 years) with either CLI or IC. High-sensitivity troponin T (hs-TnT), eicosapentaenoic acid–arachidonic acid ratio (EPA/AA), and lipoprotein(a), as biomarkers for prognostic factors, were measured from blood samples. The study patients were divided into a CLI-group (n = 42) and IC-group (n = 200). The Gensini score as an indicator of coronary angiographic severity was higher in the CLI-group than in the IC-group (39.1 ± 31.2 vs. 8.5 ± 8.3, p < 0.0001). Hs-TnT and lipoprotein(a) values were higher in the CLI-group than in the IC-group (0.152 ± 0.186 ng/mL vs. 0.046 ± 0.091, p < 0.0001, 45.9 ± 23.3 mg/dL vs. 26.2 ± 27.7, p = 0.0002, respectively) and EPA/AA was lower in the CLI-group than in the IC-group (0.22 ± 0.11 vs. 0.38 ± 0.29, p = 0.0049, respectively). Greater CAD severity, higher hs-TnT, and lipoprotein(a), and lower EPA/AA were observed in the CLI-group, which may explain higher cardiovascular events in patients with CLI.     

Direct-acting antiviral-based triple therapy on alpha-fetoprotein level in chronic hepatitis C patients

AIM: To investigate the impact of telaprevir-based triple therapy on the serum alpha-fetoprotein (AFP) level of chronic hepatitis C patients.METHODS: A total of 210 patients with chronic hepatitis C genotype 1 of high viral load (baseline serum hepatitis C virus RNA > 5.0 log₁₀ IU/mL) were divided into two groups by type of treatment: triple therapy with telaprevir, pegylated-interferon-α (PEG-IFNα), and ribavirin (RBV) for 24 wk (n = 88), or dual therapy with PEG-IFNα and RBV for 48 wk (n = 122). The relationship between virological response and the change in the serum AFP level from baseline to 24 wk after the end of treatment was examined.RESULTS: No significant difference in mean baseline AFP level was found between the triple and dual therapy groups (8.8 ng/mL vs 7.8 ng/mL). Triple therapy produced significant declines in the AFP level in sustained virological response (SVR) and non-SVR patients (7.8 ng/mL at baseline to 3.5 ng/mL at 24 wk after the end of treatment, P < 0.001 and 14.3 ng/mL to 9.5 ng/mL, P = 0.004, respectively). In contrast, dual therapy resulted in a significant decline in AFP level only in SVR patients (4.7 ng/mL to 2.8 ng/mL, P < 0.001), but not in non-SVR patients (10.2 ng/mL to 10.1 ng/mL). Among patients with a high-baseline AFP level (≥ 10 ng/mL), the decline in the AFP level was significantly higher in the triple therapy than in the dual therapy group (15.9 ng/mL vs 1.6 ng/mL, P = 0.037).CONCLUSION: Regardless of virological response, telaprevir-based triple therapy reduced the serum AFP level.