Early Initiation of Extracorporeal Blood Purification Using the AN69ST (oXiris®) Hemofilter as a Treatment Modality for COVID-19 Patients: a Single-Centre Case Series

Abstract Introduction: Severe coronavirus disease 2019 (COVID-19) is characterised by hyperinflammatory state, systemic coagulopathies, and multiorgan involvement, especially acute respiratory distress syndrome (ARDS). We here describe our preliminary clinical experience with COVID-19 patients treated via an early initiation of extracorporeal blood purification combined with systemic heparinisation and respiratory support. Methods: Fifteen patients were included; several biomarkers associated with COVID-19 severity were monitored. Personalised treatment was tailored according to the levels of interleukin (IL)-6, IL-8, tumour necrosis factor alpha, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio, thrombocyte counts, D-dimers, and fibrinogen. Treatment consisted of respiratory support, extracorporeal blood purification using the AN69ST (oXiris®) hemofilter, and 300 U/kg heparin to maintain activation clotting time ≥ 180 seconds. Results: Ten patients presented with severe to critical disease (dyspnoea, hypoxia, respiratory rate > 30/min, peripheral oxygen saturation < 90%, or > 50% lung involvement on X-ray imaging). The median intensive care unit length of stay was 9.3 days (interquartile range 5.3-10.1); two patients developed ARDS and died after 5 and 26 days. Clinical improvement was associated with normalisation (increase) of thrombocytes and white blood cells, stable levels of IL-6 (< 50 ng/mL), and a decrease of CRP and fibrinogen. Conclusion: Continuous monitoring of COVID-19 severity biomarkers and radiological imaging is crucial to assess disease progression, uncontrolled inflammation, and to avert irreversible multiorgan failure. The combination of systemic heparin anticoagulation regimens and extracorporeal blood purification using cytokine-adsorbing hemofilters may reduce hyperinflammation, prevent coagulopathy, and support clinical recovery.

Early Initiation of Extracorporeal Blood Purification Using the AN69ST (oXiris®) Hemofilter as a Treatment Modality for COVID-19 Patients: a Single-Centre Case Series.

INTRODUCTION: Severe coronavirus disease 2019 (COVID-19) is characterised by hyperinflammatory state, systemic coagulopathies, and multiorgan involvement, especially acute respiratory distress syndrome (ARDS). We here describe our preliminary clinical experience with COVID-19 patients treated via an early initiation of extracorporeal blood purification combined with systemic heparinisation and respiratory support. METHODS: Fifteen patients were included; several biomarkers associated with COVID-19 severity were monitored. Personalised treatment was tailored according to the levels of interleukin (IL)-6, IL-8, tumour necrosis factor alpha, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio, thrombocyte counts, D-dimers, and fibrinogen. Treatment consisted of respiratory support, extracorporeal blood purification using the AN69ST (oXiris®) hemofilter, and 300 U/kg heparin to maintain activation clotting time ≥ 180 seconds. RESULTS: Ten patients presented with severe to critical disease (dyspnoea, hypoxia, respiratory rate > 30/min, peripheral oxygen saturation < 90%, or > 50% lung involvement on X-ray imaging). The median intensive care unit length of stay was 9.3 days (interquartile range 5.3-10.1); two patients developed ARDS and died after 5 and 26 days. Clinical improvement was associated with normalisation (increase) of thrombocytes and white blood cells, stable levels of IL-6 (< 50 ng/mL), and a decrease of CRP and fibrinogen. CONCLUSION: Continuous monitoring of COVID-19 severity biomarkers and radiological imaging is crucial to assess disease progression, uncontrolled inflammation, and to avert irreversible multiorgan failure. The combination of systemic heparin anticoagulation regimens and extracorporeal blood purification using cytokine-adsorbing hemofilters may reduce hyperinflammation, prevent coagulopathy, and support clinical recovery.

Extracorporeal Blood Purification in Moderate and Severe COVID-19 Patients: A Prospective Cohort Study.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is characterized by hyperinflammation and coagulopathy. Severe cases often develop respiratory distress, requiring mechanical ventilation and with critical cases progressing to acute respiratory distress syndrome. Control of hyperinflammation has been proposed as a possible therapeutic avenue for COVID-19; extracorporeal blood purification (EBP) modalities offer an attractive mean to ameliorate maladaptive inflammation. With this work, we evaluated the longitudinal changes of systemic inflammatory markers in critically ill COVID-19 patients treated with blood purification using AN69ST (oXiris®) haemofilter. METHODS: We performed a time-series analysis of 44 consecutive COVID-19 cases treated with the AN69ST (oXiris®) cytokine adsorbing haemofilter (CAH) according to local practice; we visualize longitudinal results of biochemical, inflammatory, blood gas, and vital sign parameters focussing on systemic levels of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin. RESULTS: All patients were treated with ≥1 cycle extracorporeal continuous venovenous haemofiltration (CVVH) with CAH; of these, 30 severe patients received CVVH-CAH within 4-12 h of admission after recognizing a hyper-inflammatory state. Another 14 patients admitted with mild-to-moderate symptoms progressed to severe disease and were placed on EBP during hospitalization. The treatment was associated with a reduction of ferritin, CRP, fibrinogen, several inflammatory markers, and a resolution of numerous cytopenias. The observed mortality across the cohort was 36.3%. CONCLUSION: EBP with CAH was associated with a decrease in CRP, and control of IL-6 and procalcitonin.

Surgical plate fixation of multiple rib fractures: a case report.

BACKGROUND: The healthcare system in developing countries is limited; particularly, medical specialties such as emergency and trauma medicine are underdeveloped. Consequently, trauma injuries sustained in traffic accidents result in chronic morbidity more often than similar cases in developed countries. Multiple rib fractures induce significant patient morbidity. Current international guidelines recommend a multidisciplinary, surgery-based treatment approach to achieve optimal clinical benefit. CASE PRESENTATION: We admitted a 41-year-old Albanian man to our emergency department following a pedestrian-vehicle accident 5 days earlier. He presented with severe upper thoracic pain, chest deformity, dyspnea, tachycardia, subcutaneous emphysema, and hematoma. Chest radiography pointed to hypoventilated lung fields and a minor pleural effusion. Computed tomographic scans indicated displaced fractures of right lateral ribs 5 -11, hyperdensity regions from bone fragments, and pulmonary contusion. The treatment consisted of surgical fixation of ribs 7-10 using titanium reconstruction plates and cortical locking screws. The patient's clinical condition rapidly improved postoperatively. Follow-up at 6 weeks confirmed a full return to preoperative daily activities and a high quality of life. CONCLUSIONS: In this case report, we present a novel and promising development in the field of trauma medicine in the Republic of Macedonia. Trauma injuries can be treated via advanced multidisciplinary medical care according to international standards, allowing optimal health recovery.

DDRGK1 in urine indicative of tubular cell injury in intensive care patients with serious infections.

BACKGROUND: Acute kidney injury (AKI) is a life threatening condition. Despite intensive care treatment the occurrence cannot be predicted as very little indicators exist for direct measurement when tubular epithelial cell injury takes place. We therefore searched for novel peptide indicators expressed at intracellular level at the proximal kidney tubule for its appearance in urine samples. OBJECTIVES: Establishing a test for urinary C20orf116 protein measurement. PATIENTS AND METHODS: Generation of immunoreagents against C20orf116 also named DDRGK1. These were used to measure its presence in urine collected at 8-24 hours interval in a prospective study from 99 ICU patients at 4-6 time points. These patients received therapy because of serious infection and were categorized into 4 groups. RESULTS: 1) Ten tested highly for C20orf116 undergoing AKI graded Failure or Loss (3210 ± 4268 ng/mL) according to RIFLE criteria, all requiring renal replacement therapy (RRT) out of them 9 died. 2) Six patients with pre-existing kidney disease developed AKI and required RRT but had much lower C20orf116 levels of (33 ± 19), two of them died. 3) In contrast, out of 11 patients undergoing AKI grade Risk or Injury, four tested positive for C20orf116 but to much lower extent (66 ± 43) who recovered fully. 4) Out of 72 patients 25 tested positive (18 ± 12 ng/mL) not fulfilling criteria of AKI but with serum creatinine (sCr) rises of 1.2-1.4 (n = 52). Healthy donors (n = 48) showed no detectable C20orf116 at any time point. CONCLUSIONS: C20orf116 excretion was detectable more than 24 hours before sCr rise could be measured; high level seemed to indicate severity of organ failure.

Age related changes in pancreatic beta cells: A putative extra-cerebral site of Alzheimer's pathology.

Frequent concomitant manifestation of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has been recently demonstrated by epidemiological studies. This might be due to functional similarities between ß-cells and neurons, such as secretion on demand of highly specific molecules in a tightly controlled fashion. An additional similarity represents the age-related alteration of hyperphosphorylated tau in AD patients. Similarly, alterations have been identified in ß-cells of T2DM patients. The islet amyloid polypeptide has been associated with ß-cell apoptosis. As a consequence of increasing age, the accumulation of highly modified proteins together with decreased regenerative potential might lead to increasing rates of apoptosis. Moreover, reduction of ß-cell replication capabilities results in reduction of ß-cell mass in mammals, simultaneously with impaired glucose tolerance. The new challenge is to learn much more about age-related protein modifications. This can lead to new treatment strategies for reducing the incidence of T2DM and AD.

Expression of secretagogin in clear-cell renal cell carcinomas is associated with a high metastasis rate.

Renal cell carcinomas are divided into several subgroups according to their histopathologic characteristics. The outcome, therapy responses, and the applicability of molecular-targeted therapies depend on the tumor classification and on the tumor stage. Recent advances within the biomarker research facilitated the exact classification of the molecular character of the renal tumor. For example, the calcium-binding proteins parvalbumin and S-100A1 are characteristically expressed in renal cell carcinoma subgroups. This led us to investigate the expression of the novel calcium-binding protein secretagogin in renal cell carcinomas. Tissue microarray cylinders including 94 clear-cell renal cell carcinomas, 61 non-clear-cell renal cell carcinomas (37 papillary renal cell and 24 chromophobe carcinomas), and 30 oncocytomas were analyzed by immunohistochemistry. This showed remarkable secretagogin expression in 37% of the clear-cell renal cell carcinomas. Non-clear-cell renal cell carcinomas and oncocytomas were completely negative. Consequently performed immunoblotting analyses confirmed this expression profile. Because publicly available data direct toward a formation of a hierarchical cluster of secretagogin overexpressing clear-cell renal cell carcinomas, we conducted a clinical follow-up of the patients with clear-cell renal cell carcinoma. This revealed significantly more metastasis within the secretagogin-positive clear-cell renal cell carcinoma subgroup (49% versus 28%; P < .05). In conclusion, we report on detection of the novel calcium-binding protein secretagogin within a subgroup of clear-cell renal cell carcinomas. The increased metastasis rates within the secretagogin-positive subgroup of clear-cell renal cell carcinomas direct toward a clinical impact of our findings.

Elevated blood markers 1 year before manifestation of malignant glioma.

We detected distinct plasma concentration profiles of S100B, neuropeptide Y, and secretagogin in 3 of 191 patients enrolled in a previous study investigating brain-tissue-related markers in the blood of patients with atrial fibrillation. Intriguingly, 2 of these 3 patients, both of whom were without neurological symptoms at the time of blood sampling, were diagnosed with malignant glioma (MG) approximately 1 year later. To our knowledge, this is the first report indicating that distinct blood biomarker profiles may be detected long before clinical manifestation of MG.

Expression of TAU in insulin-secreting cells and its interaction with the calcium-binding protein secretagogin.

Tauopathies have been associated with Alzheimer's disease (AD), which frequently manifests together with diabetes mellitus type 2. Calcium-binding proteins such as the recently identified secretagogin (SCGN) might exert protective effects. As pancreatic beta-cells and neurons share common electrophysiological properties, we investigated the appearance of TAU (listed as MAPT in the HUGO and MGI Databases) protein at the islets of Langerhans and beta-cell-derived cell lines which highly express the neuroendocrine-specific protein SCGN. Six predominant TAU isoforms could be identified by immunoblotting, which formed TAU deposits detectable by immunofluorescence and sarkosyl-insoluble pellets. Using GST-SCGN pull-down assays, a calcium-dependent SCGN-TAU interaction was found. In this line, sucrose density gradient fractionation and differential ultracentrifugation studies of TAU and SCGN revealed co-appearance of both proteins. Co-localization of TAU and SCGN within insulinoma cells and islets of Langerhans mainly restricted to insulin-positive beta-cells was demonstrated by confocal microscopy. Motivated by these findings, we looked if SCGN overexpression could exert protective function on Rin-5F cells, which showed differences in TAU levels. Testing the vulnerability of Rin-5F clones by MTT assay, we revealed that high TAU levels going along with highest TAU aggregates could not be antagonized by high levels of SCGN protein. Our findings demonstrated for the first time the association of TAU and the calcium-binding protein SCGN and support earlier results implicating that beta-cells might represent an extra cerebral site of tauopathy.

Angiogenic factors in plasma of brain tumour patients.

BACKGROUND: Angiopoiesis and angiopoietic growth factors are of considerable importance in the development and progression of intracranial tumours. However, knowledge of the plasma detectability of distinct angiogenic factors in patients with brain tumour is very limited. This study evaluates the plasma concentrations of the angiogenic factors angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF) and platelet-derived growth factor BB (PDGF-BB) in patients with brain tumour. PATIENTS AND METHODS: Plasma samples of 78 patients suffering from various types of intracranial tumours (glioblastoma multiforme, GBM, n = 22; astrocytoma, n = 12; meningioma, n = 16; and intracranial metastasis, n = 28) were analysed. For determination of plasma concentrations of angiogenic factor, highly specific enzyme-linked immuno sorbent assays (ELISAs) were used. RESULTS: Ang-2 plasma concentration in GBM patients was significantly lower when compared with that in patients with meningioma and intracranial metastasis. Highest levels of VEGF concentrations were detected in plasma derived from patients suffering from meningioma. Interestingly, VEGF plasma levels depended on the number of intracranial lesions, with significantly higher concentrations in patients with 3 or more lesions when compared with those with 2 or fewer lesions. However, no correlation between the survival time of the patients and the plasma levels of the tested growth factors was obtained. Plasma levels of PDGF-BB did not differ between the individual tumour groups. CONCLUSION: The detectability of the angiogenic factors Ang-2 and VEGF, as well as of PDGF-BB, in the plasma of patients suffering from various types of brain tumours is described. The plasma detectability of the individual angiopoetic factors seems to depend at least partly on the tumour type as well as on tumour progression. This might be of prognostic and therapeutic relevance.