Predicting the Outcome of Patients with Severe COVID-19 with Simple Inflammatory Biomarkers: The Utility of Novel Combined Scores-Results from a European Tertiary/Referral Centre.

Background: The clinical significance of combinations of inflammatory biomarkers in severe COVID-19 infection is yet to be proved. Although several studies have evaluated the prognostic value of biomarkers in patients with COVID-19, there are limited data regarding the value of the combination scores that could take full advantage of the prognostic value of several biomarkers and that could account for the heterogeneity of patients with severe COVID-19. We investigated the prognostic value of combination scores of admission values of inflammatory biomarkers in adults with severe COVID-19. Methods: Adults admitted to the Department of Respiratory Medicine of the UHL with severe COVID-19 (April-September 2021, NCT05145751) were included. Demographics, medical history, laboratory tests and outcome (high-flow nasal cannula (HFNC), admission to Intensive Care Unit (ICU) or death) were recorded. The optimal cut-off points of on admission values of C-reactive protein (CRP), CRP to lymphocyte ratio (CLR), lymphocyte to neutrophil ratio (LNR) and derived variation of neutrophil to lymphocyte ratio (dv-NLR (neutrophil/white blood count-lymphocyte)) for the predetermined outcome were defined. Based on the cut-off of CRP, LNR, dv-NLR and CLR, which were found to be predictors for HFNC, 3 scores were defined: CRP and LNR (C-CRP #1), CRP and dv-NLR (C-CRP #2), CRP and CLR (C-CRP #3). Likewise, based on the cut-off of CRP and CLR, which were found to be predictors for death, the score of CRP and CLR (C-CRP #3*) was defined. The combination scores were then classified as: 2 points (both biomarkers elevated); 1 point (one biomarker elevated) and 0 points (normal values). None of the biomarkers was predictive for the ICU admission, so no further analysis was performed. Binomial logistic regression analysis was used to establish the predictive role for each biomarker. Results: One hundred and fifteen patients (60% males, mean age 57.7 years) were included. Thirty-seven (32.2%) patients required HFNC, nine (7.8%) died and eight (7%) were admitted to ICU, respectively. As far as HFNC is concerned, the cut-off point was 3.2 for CRP, 0.231 for LNR, 0.90 for dv-NLR and 0.004 for CLR. Two points of C-CRP #1 and 2 points of C-CRP #3 predicted HFNC with a probability as high as 0.625 (p = 0.005) and 0.561 (p < 0.001), respectively. Moreover, 1 point of C-CRP #2 and 2 points of C-CRP #2 predicted HFNC with a probability of 0.333 and 0.562, respectively. For death, the optimal cut-off point for CRP was 1.11 and for CLR 3.2*1033. Two points of C-CRP #3* with an accuracy of 0.922 predicted mortality (p = 0.0038) in severe COVID-19. Conclusions: The combination scores of CRP and inflammatory biomarkers, based on admission values, are promising predictors for respiratory support using HFNC and for mortality in patients suffering from severe COVID-19 infection.

Case report of a patient with VEXAS syndrome.

RATIONALE: Hematological malignancies have always been a challenge for scientists because there is a constant need to better define these entities. Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis. Cytogenetics and molecular findings are a prerequisite for these syndromes as they confirm the clonal nature of the disease. However, MDS is often linked to autoimmunity and inflammation as part of its pathogenesis. Recently, VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) linked these two in a single mutation, suggesting that the heterogeneity among hematological malignancies often demands a more personalized medicine by tailoring medical treatment to the individual characteristics of each patient. PATIENT CONCERNS: We present a case of VEXAS syndrome regarding a 63-year-old male patient who initially presented with episodes of low fever, polyarthritis of the knees and ankles, polymyalgia, and fatigue. His laboratory examinations revealed increased levels of serum inflammatory markers. DIAGNOSES: Diagnosis was based on high clinical suspicion, laboratory findings, and vacuolization of the erythroid and myeloid precursors in the bone marrow evaluation. Mutational status of ubiquitin-like modifier activating enzyme 1 gene was positive with a 68.8% allelomorph frequency (rs782416867). INTERVENTIONS: Therapy was based on controlling inflammation with the use of glucocorticoids and treating MDS-related anemia with the use of erythropoietin. OUTCOMES: Currently, the patient visits our department regularly. He is still receiving the aforementioned treatment. He did not mention any new incidents for the time being. LESSONS: VEXAS syndrome as a newly identified entity might be often underestimated since its clinical presentation is notably diverse.

Pregnancy and thrombosis risk for women without a history of thrombotic events: a retrospective study of the real risks.

BACKGROUND: During pregnancy and puerperium women are at high VTE risk. Current guidelines recommend dynamic VTE-risk assessment during pregnancy. Based on related RCOG-guidelines we constructed a digital VTE-risk assessment tool: PATrisks ( www.PATrisks.com ). Using this tool, we retrospectively evaluated the thrombotic risk in 742 women from our previous work, women who received thromboprophylaxis based on clinical experience for A) pregnancy complications, B) IVF treatment and C) prothrombotic tendency, in order to investigate whether that practice was justified according to the PATrisks scoring system for VTE prevention. METHODS: Women with pregnancy complications [Group-A: 445], women who had undergone IVF [Group-B:132] and women with a prothrombotic tendency (thrombophilia, family history of VTE, other) [Group-C:165] were assessed using the PATrisks scoring system for thrombotic risk. The women were assigned into one of the following risk categories: low (score ≤ 2), intermediate (score = 3) and high (score ≥ 4). Further analysis per risk factor type (pre-existing or obstetric) and for various combinations of them, was also performed. We evaluated thrombotic risk early in pregnancy, and in the peripartum period. RESULTS: The mean risk score antepartum was higher for women in Group B (3.3 in comparison with 1.9 and 2.0 in Group A and Group C respectively). Moreover, the risk score increased significantly postpartum for all Groups. The chi-square test also proved that there was a higher percentage of women at high or intermediate risk in group B compared to C before birth (55.3% vs.26.1% respectively, p < 0.0001, OR: 3.5, 95% CI: 2.2 - 5.7) and similarly after birth (85.6% vs. 56.4%, OR: 4.6, 95%CI: 2.6-8.2, p < 0.0001). In total 12 (1.6%) out of 742 women experienced thrombotic events, whether pre- or post-partum. CONCLUSIONS: LMWHs are widely prescribed during pregnancy for a number of indications, even when a proven scientific basis for such a practice is lacking. However, a considerable percentage of women were already at VTE-risk according to PATrisks and might have derived an additional benefit from LMWH in the form of VTE prevention. The rational use of these drugs should be optimized by establishing and implementing routine risk assessment for all pregnant women and by providing the necessary education to healthcare professionals.

Case of an unusual diagnosis of primary antiphospholipid syndrome with multiple clinical complications.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease defined by the presence of antiphospholipid antibodies in association with thrombotic events and/or obstetric complications. Renal involvement is not infrequent in both primary and secondary APS. Kidney manifestations comprise a wide range of clinical features, including hypertension, major renal vessel thrombosis or microvascular endothelial injury, also described as APS nephropathy. In the absence of a thrombotic event, clinical manifestations of APS are often non-specific. We recently encountered a case of primary APS in a young male with newly diagnosed hypertension and renal impairment. The diagnosis of APS was initially suspected by his kidney biopsy findings, when electron microscopy examination showed the features of chronic microangiopathy, and was later confirmed by a triple positive antiphospholipid antibody profile and multiple organ involvement.

Acute macrovascular dysfunction in patients with type 2 diabetes induced by ingestion of advanced glycated ß-lactoglobulins.

OBJECTIVE: Recent evidence indicates that heat-enhanced food advanced glycation end products (AGEs) adversely affect vascular function. The aim of this study was to examine the acute effects of an oral load of heat-treated, AGE-modified ß-lactoglobulins (AGE-BLG) compared with heat-treated, nonglycated BLG (C-BLG) on vascular function in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: In a double-blind, controlled, randomized, crossover study, 19 patients with T2DM received, on two different occasions, beverages containing either AGE-BLG or C-BLG. We measured macrovascular [brachial ultrasound of flow-mediated dilatation (FMD)] and microvascular (laser-Doppler measurements of reactive hyperemia in the hand) functions at baseline (T0), 90 (T90), and 180 (T180) min. RESULTS: Following the AGE-BLG, FMD decreased at T90 by 80% from baseline and remained decreased by 42% at T180 (P < 0.05 vs. baseline, P < 0.05 vs. C-BLG at T90). By comparison, following C-BLG, FMD decreased by 27% at T90 and 51% at T180 (P < 0.05 vs. baseline at T180). A significant decrease in nitrite (T180) and nitrate (T90 and T180), as well as a significant increase in N(ε)-carboxymethyllisine, accompanied intake of AGE-BLG. There was no change in microvascular function caused by either beverage. CONCLUSIONS: In patients with T2DM, acute oral administration of a single AGE-modified protein class significantly though transiently impaired macrovascular function in concert with decreased nitric oxide bioavailability. These AGE-related changes were independent of heat treatment.

Do proton pump inhibitors attenuate the effect of aspirin on platelet aggregation? A randomized crossover study.

It is common practice to coadminister proton pump inhibitors with aspirin to diminish the risk of upper gastrointestinal bleeding. This is the first study that investigated the potential impact of a proton pump inhibitor on aspirin effects on platelet aggregation. Twenty-four hypertensive subjects eligible for treatment with low-dose enteric-coated aspirin (LDECA) for primary prevention of cardiovascular disease were randomized to receive 100 mg LDECA or 100 mg LDECA plus 30 mg lansoprazole for 4 weeks. Then, participants were crossed over to the alternative regimen for another 4 weeks. Salicylic, gastrin, and pepsinogen I blood level counting were used to ensure adherence to treatment. Platelet aggregation was evaluated by light transmittance aggregometry and PFA100. The LDECA administration reduced arachidonic acid (P < 0.001), collagen (P < 0.01), and epinephrine (P < 0.001) tests. These changes paralleled an increase in collagen/epinephrine duration (P < 0.001) but not in collagen/adenosine diphosphate duration and platelet count. No significant difference was found in any of these platelets' function tests with LDECA alone versus LDECA plus lansoprazole. A significant increase in salicylic levels was observed in patients on LDECA as well as in those on LDECA plus lansoprazole, whereas gastrin and pepsinogen I levels were increased only when lansoprazole was added. These data suggest that the concomitant use of the lansoprazole at 30-mg daily does not influence the long-term effect of LDECA on platelet aggregation. Furthermore, they might imply that an interaction of LDECA with other proton pump inhibitors on platelet aggregation is unlikely.

Population pharmacokinetics of recombinant factor VIII:C (ReFacto) in adult HIV-negative and HIV-positive haemophilia patients.

PURPOSE: The aim of this study was to explore possible differences in the pharmacokinetics (PK) of recombinant factor VIII:C (ReFacto - ReFacto ) in HIV+ vs. HIV- patients and also differences in the chromogenic substrate bioassay (CHS) and one-stage clotting (OSC) methods. METHODS: Twenty-eight haemophilia A adults (20 HIV- and eight HIV+) were assayed with both the CHS and OSC methods. An average of two and six samples were collected per patient for HIV-/+, respectively, after one, and occasionally two more, prophylactic doses (mean 2,003 IU; range 1,000-4,300 IU). The observations were analysed with the mixed-effects (population) compartmental PK modelling package NONMEM (nonlinear mixed-effects modelling) and the FOCE (first-order conditional estimation) method. Base modelling was performed independently for the CHS and OSC bioassays for comparison, and covariate models and simulation tests were done only for the commonly used OSC bioassay. The final covariate model was validated using the bootstrap method. Monte Carlo simulations were used to estimate the expected probability of exceeding 20%, 40% or 60% of normal factor VIII:C in plasma after a single dose, corresponding to required levels for preventing mild, moderate and life-threatening haemorrhages. RESULTS: One-compartment base-model population PK parameters were [mean parameter (interpatient variability %)] for CHS: clearance (CL) = 2.56 dl h(-1) (33.2%); volume of distribution (V) = 34.8 dl (12.8%); and for OSC: CL = 3.83 dl h(-1) (47.8%), V = 53.7 dl (22.4%). The volumes differed significantly between the CHS and OSC methods (p < 0.0001), and variabilities were higher for OSC. Nevertheless, the empirical half-lives (t(1/2) = l n (2) x V/CL) were similar for CHS and OSC, [(mean +/- standard deviation (SD)], 9.5 +/- 3 h and 10.2 +/- 4 h, respectively. In covariate modelling with the OSC-derived model, HIV status (VIR) was a significant categorical predictor (p < 0.005) for V. The final covariate models with OSC were for CL = 3.93 + 0.09 x (WT-75) and for V = 48.6 x (1 + 0.36 x VIR) + 0.55 x (WT-75); therefore, V for the typical HIV+ patient was 36% higher than for the HIV- patient. CONCLUSIONS: Both HIV- and HIV+ patients showed 100% success with the 20% threshold at doses >20 IU/kg. HIV- patients receiving >50 IU/kg had a 100% expected chance of success for all thresholds. HIV+ patients for moderate or life-threatening haemorrhage treatment need 10 IU/kg more than the HIV- patient equivalent to have the same probability of success.