ColdZyme Maintains Integrity in SARS-CoV-2-Infected Airway Epithelia.

SARS-CoV-2 infection causing the COVID-19 pandemic calls for immediate interventions to avoid viral transmission, disease progression, and subsequent excessive inflammation and tissue destruction. Primary normal human bronchial epithelial cells are among the first targets of SARS-CoV-2 infection. Here, we show that ColdZyme medical device mouth spray efficiently protected against virus entry, excessive inflammation, and tissue damage. Applying ColdZyme to fully differentiated, polarized human epithelium cultured at an air-liquid interphase (ALI) completely blocked binding of SARS-CoV-2 and increased local complement activation mediated by the virus as well as productive infection of the tissue model. While SARS-CoV-2 infection resulted in exaggerated intracellular complement activation immediately following infection and a drop in transepithelial resistance, these parameters were bypassed by single pretreatment of the tissues with ColdZyme mouth spray. Crucially, our study highlights the importance of testing already evaluated and safe drugs such as ColdZyme mouth spray for maintaining epithelial integrity and hindering SARS-CoV-2 entry within standardized three-dimensional (3D) in vitro models mimicking the in vivo human airway epithelium.IMPORTANCE Although our understanding of COVID-19 continuously progresses, essential questions regarding prophylaxis and treatment remain open. A hallmark of severe SARS-CoV-2 infection is a hitherto-undescribed mechanism leading to excessive inflammation and tissue destruction associated with enhanced pathogenicity and mortality. To tackle the problem at the source, transfer of SARS-CoV-2, subsequent binding, infection, and inflammatory responses have to be avoided. In this study, we used fully differentiated, mucus-producing, and ciliated human airway epithelial cultures to test the efficacy of ColdZyme medical device mouth spray in terms of protection from SARS-CoV-2 infection. Importantly, we found that pretreatment of the in vitro airway cultures using ColdZyme mouth spray resulted in significantly shielding the epithelial integrity, hindering virus binding and infection, and blocking excessive intrinsic complement activation within the airway cultures. Our in vitro data suggest that ColdZyme mouth spray may have an impact in prevention of COVID-19.

Multicenter clinical experience of real life Dalbavancin use in gram-positive infections.

Dalbavancin, a lipoglycopeptide with prolonged half-life approved for the treatment of acute bacterial skin and soft tissue infections, can be used for the treatment of infections caused by gram-positive bacteria requiring long term treatment such as endocarditis, prosthetic joint infections (PJI) or osteomyelitis. Clinical data are limited in these settings. OBJECTIVES: To evaluate indications, safety, tolerability and long-term outcomes of dalbavancin-treated patients. Patients and methods Our multicenter, retrospective study includes patients who received dalbavancin in Austria from September 2016 to March 2018. 90-day outcomes and tolerability were determined. RESULTS: A total of 101 patients were included in 3 centers (57% male, median age 65 years). The treated infections were PJI (31%), osteomyelitis (29%), endocarditis (25%) and acute bacterial skin and soft tissue infections (12%). Concomitant use of other antimicrobial substances was common (63%). The mean total cumulative dose of dalbavancin was 3,357mg (±2,283mg). Clinical success rate was 89%. Side effects occurred in 3/101 patients. CONCLUSION: In this real-life study dalbavancin was primarily used in off-label indications for treatment of PJI, osteomyelitis and endocarditis. Success rate was high (89%), tolerability and safety were excellent in this setting. Dalbavancin may therefore be used in these off-label indications as alternative treatment approach.

Acute Gouty Knee Arthritis: Ultrasound Findings Compared With Dual-Energy CT Findings.

OBJECTIVE: The purpose of this study was to compare findings of ultrasound (US) with dual-energy CT (DECT) findings in patients presenting with suspected gouty knee arthritis. SUBJECTS AND METHODS: This prospective study included 65 patients (52 men and 13 women; median age, 61.7 years [range, 38-87 years]) with an initial clinical diagnosis of acute gouty knee arthritis who underwent DECT performed using a 128-MDCT scanner and US performed using a 5-18-MHz transducer. Both intra- and extraarticular findings obtained using each modality were tabulated. RESULTS: DECT identified gout as the final diagnosis for 52 of 65 patients (80.0%). An alternative diagnosis was confirmed for the remaining 13 patients. US detected gout in 31 of 52 patients (sensitivity, 59.6%) and produced findings negative for gout in seven of 13 patients (specificity, 53.8%). The double contour sign on US was positive for gout in 23 of 52 patients (44.2%) and negative in 12 of 13 patients (92.3%). Extraarticular urate deposition was identified by DECT in 44 of 52 patients, compared with identification by US in 11 of 52 patients (p < 0.001). CONCLUSION: The sensitivity of US for the diagnosis of gouty knee arthritis is limited, particularly with respect to extraarticular urate deposition. The double contour sign is the single most valuable sign for the assessment of gouty knee arthritis by US.

Contrast-enhanced ultrasonography for the detection of joint vascularity in arthritis--subjective grading versus computer-aided objective quantification.

PURPOSE: To compare joint inflammation assessment using subjective grading of power Doppler ultrasonography (PDUS) and contrast-enhanced ultrasonography (CEUS) versus computer-aided objective CEUS quantification. MATERIALS AND METHODS: 37 joints of 28 patients with arthritis of different etiologies underwent B-mode ultrasonography, PDUS, and CEUS using a second-generation contrast agent. Synovial thickness, extent of vascularized pannus and intensity of vascularization were included in a 4-point PDUS and CEUS grading system. Subjective CEUS and PDUS scores were compared to computer-aided objective CEUS quantification using Qontrast® software for the calculation of the signal intensity (SI) and the ratio of SI for contrast enhancement. RESULTS: The interobserver agreement for subjective scoring was good to excellent (κ = 0.8 - 1.0; P < 0.0001). Computer-aided objective CEUS quantification correlated statistically significantly with subjective CEUS (P < 0.001) and PDUS grading (P < 0.05). The Qontrast® SI ratio correlated with subjective CEUS (P < 0.02) and PDUS grading (P < 0.03). Clinical activity did not correlate with vascularity or synovial thickening (P = N. S.) and no correlation between synovial thickening and vascularity extent could be found, neither using PDUS nor CEUS (P = N. S.). CONCLUSION: Both subjective CEUS grading and objective CEUS quantification are valuable for assessing joint vascularity in arthritis and computer-aided CEUS quantification may be a suitable objective tool for therapy follow-up in arthritis.

Accuracy of bedside antigen tests in the diagnosis of new influenza A/H1N1v infection.

To evaluate the clinical reliability of two rapid influenza detection tests (RIDTs), we analyzed 107 specimens from patients with clinically suspected pandemic influenza A/H1N1v by these tests as well as by real-time PCR as a standard. Both RIDTs had a moderate sensitivity (28-32%), a high specificity (93-99%) and a negative predictive value of 80%. These results will impact on the clinical management and isolation precautions in patients with suspected infection. Although a positive RITD is mostly confirmatory, a negative result in the presence of high clinical likelihood of infection should be interpreted with caution and be re-evaluated by PCR.

Indoleamine-2, 3-dioxygenase and other interferon-gamma-mediated pathways in patients with human immunodeficiency virus infection.

Human immunodeficiency virus type 1 (HIV) infection is characterized by progressive immunodeficiency despite of an overwhelming cellular immune activation. Patients show highly elevated serum/plasma concentrations of the proinflammatory cytokine interferon-gamma (IFN-gamma), which induces human monocytes to form neopterin, to produce reactive oxygen species (ROS) and in parallel, to degrade tryptophan. Enhanced tryptophan degradation by the enzyme indoleamine-2, 3-dioxygenase (IDO) contributes importantly to disease progression and "complications" of HIV infection: By a subsequent impairment of protein metabolism and serotonin formation, the development of neuropsychiatric disorders and weight loss in HIV infected patients can be enforced. Furthermore, increased IDO-activation efficiently suppresses the growth and proliferation of pathogens as well as host T-cells. IDO and other IFN-gamma-mediated pathways are strongly induced in patients with HIV infection and are also linked with disease progression: Neopterin formation by GTP-cyclohydrolase I sensitively reflects the stage of the disease, and determination of the pteridine in body fluids is useful to monitor the efficacy of antiretroviral therapy. Neopterin is an independent prognostic factor for the outcome of disease, and well suited to estimate the degree of immune activation in vivo and the responsiveness of immunocompetent cells to stimulation in vitro. ROS formation may contribute to the development of oxidative stress in HIV infection, resulting in depletion of antioxidants. The cause-effective role of an overwhelming Th1-type immune response together with the activation of IDO and other IFN-gamma-mediated biochemical pathways for the course of HIV infection, the development of immunodeficiency, anemia and weight loss in HIV patients is discussed.

Elimination of levofloxacin in critically ill patients with renal failure: influence of continuous veno-venous hemofiltration.

OBJECTIVES: Pharmacokinetic data on levofloxacin in critically ill patients are sparse and conflicting. Aim of the study was to assess the clearance of levofloxacin in critically ill patients treated with continuous veno-venous hemofiltration (CVVH). METHODS: Pharmacokinetics of levofloxacin were studied in 11 critically ill patients. Four patients were treated with CVVH because of renal failure, 4 patients had moderately impaired renal function but were not on hemofiltration, and 3 patients had approximately normal renal function. Patients received 0.5 g levofloxacin infused over 0.5 hours. Plasma levels of levofloxacin were determined by HPLC and pharmacokinetic parameters were calculated using a non-compartmental model. RESULTS: Levofloxacin clearance in critically ill patients with approximately normal renal function was similar to that in healthy subjects. In critically ill patients with impaired renal function not on CVVH, mean half-life was prolonged by a factor of about 3 (20-25 hours). The mean residence time and the volume of distribution were also increased. In renal failure treated with CVVH, a wide variability in pharmacokinetics was seen. The half-life was about 30 hours and the mean levofloxacin clearance was raised by a factor of 2. The area under the concentration-time curve was reduced by hemofiltration, while the volume of distribution was increased. There was a positive correlation between blood flow through the hemofilter and levofloxacin clearance. Variable amounts of the drug were recovered from the hemofilter. Most plasma levels, however, were in the therapeutic range and drug accumulation to toxic plasma concentrations was not observed in renal failure patients undergoing CVVH and receiving single daily administration of 0.5 g of levofloxacin i.v. CONCLUSIONS: During CVVH using polysulfone membrane hemofilters, plasma concentrations of levofloxacin are not easily predictable. Levofloxacin clearance may be affected by binding to secondary membranes formed in hemofilters during CVVH and blood flow rates have a significant impact on the pharmacokinetics of levofloxacin.

Imported malaria: six cases of severe Plasmodium falciparum infection in Innsbruck, Austria, within a period of five weeks (February/March 1999)

Six patients (age, 30-76; 3 male, 3 female) with severe malaria tropica were admitted to the Department of Internal Medicine of the Innsbruck University Hospital within a time period of five weeks. All patients had recently visited classical malaria regions some days before admission: five patients the sub-Saharan Africa and one patient Thailand and Vietnam. All six patients had to be treated in the Intensive Care Unit. Three patients developed an acute respiratory distress syndrome. Two patients died of multi-organ failure. All six patients were treated with quinine and doxycycline intravenously. In one case, exchange transfusion was performed. Only two of six patients had taken prophylactic medication: one patient chloroquine and proguanil and the other mefloquine (she suffered from a severe gastroenteritis during the journey).