ELIMINATE: a PCR record-based macroelimination project for systematic recall of HCV-RNA-positive persons in Austria.

BACKGROUND AND AIMS: Micro-elimination projects targeted to specific hepatitis C virus (HCV) risk populations have been successful. Systematic identification of persons with HCV viremia, regardless of risk group, based on already available laboratory records may represent an effective macroelimination approach to achieve global HCV elimination. METHODS: Persons with a last positive HCV-RNA PCR result between 2008-2020 in the reference virology laboratories in eastern Austria were identified. First, (i) we described their demographic characteristics, (ii) we systematically recalled persons to the respective centers and (iii) started antiviral treatment if HCV-RNA viremia was confirmed, and (iv) recorded sustained virologic response (SVR). This interim report includes the preliminary results from 8 participating centers. RESULTS: During the study period 22,682 persons underwent HCV-RNA PCR testing, 11,216 (49.4%) were positive at any point in time, and 6006 (26.5%) showed detectable HCV-RNA at the last PCR test, suggesting ongoing HCV viremia. At the time of this interim report, 2546/6006 HCV-RNA PCR(+) persons were evaluated: 443/2546 (17.4%) had died, 852/2546 (33.5%) had invalid contact data, and 547/2546 (21.5%) had achieved SVR between data retrieval and recall. Contact could be established in 236/704 (33.5%) of the remaining target population with 97/236 (41.1%) presenting at the clinic for treatment evaluation. Ultimately, 71/236 (30.1%) started antiviral treatment and SVR was documented in 47/71 (66.2%). CONCLUSION: This ELIMINATE project based on systematic assessment of HCV-RNA PCR-records, identified 6006 persons with potential persisting HCV viremia. Invalid contact data and missed visits for treatment evaluation were the main barriers towards HCV elimination within this project. Importantly, many subjects with HCV viremia lost to follow-up were successfully linked to care and started antiviral treatment.

Tocilizumab vs. baricitinib in hospitalized severe COVID-19 patients: results from a real-world cohort.

BACKGROUND: Tocilizumab and baricitinib are recommended treatment options for hospitalized COVID-19 patients requiring oxygen support. Literature about its efficacy and safety in a head-to-head comparison is scarce. METHODS: Hospitalized COVID-19 patients requiring oxygen were treated with tocilizumab or baricitinib additionally to dexamethasone. Tocilizumab was available from February till the 19th of September 2021 and baricitinib from 21st of September. The primary outcome was in-hospital mortality. Secondary outcome parameters were progression to mechanical ventilation (MV), length-of-stay (LOS) and potential side effects. RESULTS: 159 patients (tocilizumab 68, baricitinib 91) with a mean age of 60.5 years, 64% male were included in the study. Tocilizumab patients were admitted 1 day earlier, were in a higher WHO category at the time of inclusion and had a higher CRP level on admission and treatment initiation. Patients receiving Tocilizumab were treated with remdesivir more often and only patients in the baricitinib group were treated with monoclonal antibodies. Other characteristics did not differ significantly. In-hospital mortality (18% vs. 11%, p = 0.229), progression to MV (19% vs. 11%, p = 0.173) and LOS (13 vs. 12 days, p = 0.114) did not differ between groups. Side effects were equally distributed between groups, except ALAT elevation which was significantly more often observed in the tocilizumab group (43% vs. 25%, p = 0.021). CONCLUSIONS: In-hospital mortality, progression to MV and LOS were not significantly different in patients treated with tocilizumab or baricitinib additionally to standard of care. Both drugs seem equally effective but further head-to-head trials are needed.

SARS-CoV-2 Pre-Exposure Prophylaxis with Sotrovimab and Tixagevimab/Cilgavimab in Immunocompromised Patients-A Single-Center Experience.

Immunocompromised patients experience reduced vaccine effectiveness and are at higher risk for coronavirus disease 19 (COVID-19) death. Pre-exposure prophylaxis (PrEP) aims to protect these patients. So far, only tixagevimab/cilgavimab is authorized for use as PrEP. This paper aims to provide real-world data on the use of tixagevimab/cilgavimab and sotrovimab as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PrEP in immunocompromised patients, comparing the evolution of antibody levels and reporting the incidence of breakthrough infections. A retrospective, single-center analysis was conducted including 132 immunocompromised patients with inadequate vaccine response, who received COVID-PrEP at our clinic between January and June 2022. Initially, 95 patients received sotrovimab while 37 patients received tixagevimab/cilgavimab. Antibody levels after first PrEP with sotrovimab remain high for several months after infusion (median 10,058 and 7235 BAU/mL after 1 and 3 months, respectively), with higher titers than after tixagevimab/cilgavimab injection even 3 months later (7235 vs. 1647 BAU/mL, p = 0.0007). Overall, breakthrough infections were rare (13/132, 10%) when compared to overall infection rates during this period (over 30% of the Austrian population), with mild disease course and rapid viral clearance (median 10 days). Sotrovimab may be an additional option for SARS-CoV-2 PrEP.

Early administration of remdesivir may reduce mortality in hospitalized COVID-19 patients : A propensity score matched analysis.

BACKGROUND: Remdesivir is the only antiviral agent approved for the treatment of hospitalized coronavirus disease 2019 (COVID-19) patients requiring supplemental oxygen. Studies show conflicting results regarding its effect on mortality. METHODS: In this single center observational study, we included adult hospitalized COVID-19 patients. Patients who were treated with remdesivir were compared to controls. Remdesivir was administered for 5 days. To adjust for any imbalances in our cohort, a propensity score matched analysis was performed. The aim of our study was to analyze the effect of remdesivir on in-hospital mortality and length of stay (LOS). RESULTS: After propensity score matching, 350 patients (175 remdesivir, 175 controls) were included in our analysis. Overall, in-hospital mortality was not significantly different between groups remdesivir 5.7% [10/175] vs. control 8.6% [15/175], hazard ratio 0.50, 95% confidence interval (CI) 0.22-1.12, p = 0.091. Subgroup analysis showed a significant reduction of in-hospital mortality in patients who were treated with remdesivir ≤ 7 days of symptom onset remdesivir 4.2% [5/121] vs. control 10.4% [13/125], hazard ratio 0.26, 95% CI 0.09 to 0.75, p = 0.012 and in female patients remdesivir 2.9% [2/69] vs. control 12.2% [9/74], hazard ratio 0.18 95%CI 0.04 to 0.85, p = 0.03. Patients in the remdesivir group had a significantly longer LOS (11 days vs. 9 days, p = 0.046). CONCLUSION: Remdesivir did not reduce in-hospital mortality in our whole propensity score matched cohort, but subgroup analysis showed a significant mortality reduction in female patients and in patients treated within ≤ 7 days of symptom onset. Remdesivir may reduce mortality in patients who are treated in the early stages of illness.

Comparison of clinical characteristics among patients infected with alpha vs. delta SARS-CoV-2 variants.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone different molecular changes, sprouting genetic variants of the original wildtype. Clinical comparisons between patients infected with alpha versus delta are scarce. METHODS: In this retrospective observational study, adult patients hospitalized with coronavirus disease 2019 (COVID-19) due to confirmed SARS-CoV­2 alpha or delta infection were included. Patient characteristics, virologic and laboratory parameters, as well as the clinical course were compared in patients infected with alpha vs. delta variants. RESULTS: A total of 106 patients infected with alpha and 215 patients infected with delta were included. Patients infected with the delta variant were admitted to hospital earlier after symptom onset (6 vs. 7 days, p < 0.001). Blood levels of C­reactive protein (43.3 vs. 62.9 mg/l, p = 0.02) and neutrophil count (3.81 vs. 4.53 G/l, p = 0.06) were lower in delta patients. Furthermore, at hospital admission cycle threshold (CT) values were significantly lower in patients infected with the delta variant (22.3 vs. 24.9, p < 0.001). Patients infected with the delta variant needed supplemental oxygen less often during disease course (50% vs. 64%, p = 0.02). Furthermore, there was a statistically non-significant trend towards a lower ICU admission rate among delta patients (16% vs. 24%, p = 0.08) CONCLUSION: Patients diagnosed with the delta variant were admitted to the hospital earlier, had a less severe course of disease and a higher viral replication on admission. This may provide a window of opportunity for antivirals in the hospital setting.

Evaluation of RT-qPCR of mouthwash and buccal swabs for detection of SARS-CoV-2 in children and adults.

BACKGROUND: The use of nasopharyngeal (NP) swabs as a specimen collection method to diagnose SARS-CoV-2 infection is frequently perceived as uncomfortable by patients and requires trained personnel. In this study, detection rate of SARS-CoV-2 in mouthwash samples and buccal swabs were compared in both children and adults. MATERIAL AND METHODS: In patients admitted to hospital with confirmed COVID-19 within the previous 72 hours, NP and buccal swabs as well as mouthwash samples were collected. RT-qPCR was performed on all samples. RESULTS: In total, 170 samples were collected from 155 patients (137 adults and 18 children). Approximately 91.7% of the collected NP swabs were positive in RT-PCR compared to 63.1% of mouthwash samples and 42.4% of buccal swabs. Compared to NP swabs, the sensitivity of using mouthwash was 96.3% and 65.4% for buccal swabs in NP swab samples with a CT value <25. With increasing CT values, sensitivity decreased in both mouthwash and buccal swabs. The virus load was highest during the first week of infection, with a continuous decline observed in all three collection methods over time. DISCUSSION: Mouthwash presents an alternative collection method for detecting SARS-CoV-2 in the case of unfeasible NP swab sampling. Buccal swabs should not be used due to their low sensitivity.

Hepatitis D virus (HDV) prevalence in Austria is low but causes considerable morbidity due to fast progression to cirrhosis.

BACKGROUND: Hepatitis D virus (HDV) coinfection aggravates the course of hepatitis B virus (HBV). The prevalence of HDV in Austria is unknown. OBJECTIVE: This national study aimed at (i) recording the prevalence of HDV-infection in Austria and (ii) characterizing the "active" HDV cohort in Austria. METHODS: A total of 10 hepatitis treatment centers in Austria participated in this multicenter study and retrospectively collected their HDV patients between Q1/2010 and Q4/2020. Positive anti-HDV and/or HDV-RNA-polymerase chain reaction (PCR) results were retrieved from local database queries. Disease severity was assessed by individual chart review. Viremic HDV patients with clinical visits in/after Q1/2019 were considered as the "active" HDV cohort. RESULTS: A total of 347 anti-HDV positive patients were identified. In 202 (58.2%) patients, HDV-RNA-PCR test was performed, and 126/202 (62.4%) had confirmed viremia. Hepatocellular carcinoma was diagnosed in 7 (5.6%) patients, 7 (5.6%) patients underwent liver transplantation, and 11 (8.7%) patients died during follow-up. The "active" Austrian HDV cohort included 74 (58.7%) patients: Evidence for advanced chronic liver disease (ACLD, i.e., histological F3/F4 fibrosis, liver stiffness ≥10 kPa, varices, or hepatic venous pressure gradient ≥6 mmHg) was detected in 38 (51.4%) patients, including 2 (5.3%) with decompensation (ascites/hepatic encephalopathy). About 37 (50.0%) patients of the "active" HDV cohort had previously received interferon treatment. Treatment with the sodium-taurocholate cotransporting polypeptide inhibitor bulevirtide was initiated in 20 (27.0%) patients. CONCLUSION: The number of confirmed HDV viremic cases in Austria is low (<1% of HBV patients) but potentially underestimated. Testing all HBV patients will increase the diagnostic yield. More than half of viremic HDV patients had ACLD. Improved HDV testing and workup strategies will facilitate access to novel antiviral therapies.

High Dose Lopinavir/Ritonavir Does Not Lead to Sufficient Plasma Levels to Inhibit SARS-CoV-2 in Hospitalized Patients With COVID-19.

Background: Despite lopinavir/ritonavir (LPV/RTV) demonstrating in-vitro activity against SARS-CoV-2, large trials failed to show any net clinical benefit. Since SARS-CoV-2 has an EC50 of 16.4 µg/ml for LPV this could be due to inadequate dosing. Methods: COVID-19 positive patients admitted to the hospital who received high dose LPV/RTV were included. High dose (HD) LPV/RTV 200/50 mg was defined as four tablets bid as loading dose, then three tablets bid for up to 10 days. Trough plasma concentrations were measured after the loading dose and on day 5-7 in steady state (SS). Post loading dose (PLD) and SS plasma trough levels were compared with SS trough levels from COVID-19 patients who received normal dose (ND) LPV/RTV (2 tablets bid) at the beginning of the pandemic. Results: Fifty patients (30% female) with a median age of 59 years (interquartile range 49-70.25) received HD LPV/RTV. Median HD-PLD concentration was 24.9 µg/ml (IQR 15.8-30.3) and significantly higher than HD-SS (12.9 µg/ml, IQR 7.2-19.5, p < 0.001) and ND-SS (13.6 µg/ml, IQR 10.1-22.2, p = 0.013). HD-SS and ND-SS plasma levels did not differ significantly (p = 0.507). C-reactive-protein showed a positive correlation with HD-SS (Spearman correlation-coefficient rS = 0.42, p = 0.014) and ND-SS (rS = 0.81, p = 0.015) but not with HD-PLD (rS = 0.123, p = 0.43). Conclusion: HD-PLD plasma trough concentration was significantly higher than HD-SS and ND-SS concentration, but no difference was detected between HD-SS and ND-SS trough levels. Due to the high EC50 of SARS-CoV-2 and the fact that LPV/RTV is highly protein bound, it seems unlikely that LPV/RTV exhibits a relevant antiviral effect against SARS-CoV-2 in vivo.

COVID-19-associated myoclonus in a series of five critically ill patients.

BACKGROUND: In addition to respiratory symptoms, many patients with coronavirus disease 2019 (COVID-19) present with neurological complications. Several case reports and small case series described myoclonus in five patients suffering from the disease. The purpose of this article is to report on five critically ill patients with COVID-19-associated myoclonus. MATERIAL AND METHODS: The clinical courses and test results of patients treated in the study center ICU and those of partner hospitals are described. Imaging, laboratory tests and electrophysiological test results are reviewed and discussed. RESULTS: In severe cases of COVID-19 myoclonus can manifest about 3 weeks after initial onset of symptoms. Sedation is sometimes effective for symptom control but impedes respiratory weaning. No viral particles or structural lesions explaining this phenomenon were found in this cohort. CONCLUSION: Myoclonus in patients with severe COVID-19 may be due to an inflammatory process, hypoxia or GABAergic impairment. Most patients received treatment with antiepileptic or anti-inflammatory agents and improved clinically.

Adjunctive treatment with high-titre convalescent plasma in severely and critically ill COVID-19 patients - a safe but futile intervention. A comparative cohort study.

BACKGROUND: Convalescent plasma (CP) containing antibodies derived from coronavirus disease 2019 (COVID-19) survivors has been proposed as a promising therapeutic option for severe COVID-19. METHODS: In our intensive care unit (ICU), 55 patients (46 male, median age 61 years) with PCR-confirmed COVID-19 (35 = 63.6% on mechanical ventilation, 7 = 14.5% on high-flow nasal oxygen, 12 = 20% on non-invasive ventilation, 1 = 1.8% without respiratory support) were treated with high-titre CP (200 mL per dose, range 1-6 doses, median 3 doses per patient, minimum titre > 1:100, Wantai test). 139 COVID-19 patients treated in the same ICU who did not receive CP served as control group. In 27 patients, the effect of CP on the individual levels of SARS-CoV-2 IgG antibodies was assessed by ELISA in serum sample pairs collected before and after CP transfusion. RESULTS: The first CP dose was administered at a median of 8 days after symptom onset. 13 patients in the plasma cohort died (28-day mortality 24.1%), compared to 42 (30.2%) in the cohort who did not receive CP (p = 0.5, Pearson Chi-squared test). Out of the 27 individuals investigated for the presence of IgG antibodies, 8 did not have detectable IgG levels before the first CP transfusion. In this subpopulation, 3 patients (37.5%) died. Not a single confirmed adverse reaction to CP was noted. CONCLUSIONS: While adjunctive treatment with CP for severe and life-threatening COVID-19 was a very safe intervention, we did not observe any effect on mortality.

COVID-19 is not "just another flu": a real-life comparison of severe COVID-19 and influenza in hospitalized patients in Vienna, Austria.

BACKGROUND: COVID-19 is regularly compared to influenza. Mortality and case-fatality rates vary widely depending on incidence of COVID-19 and the testing policy in affected countries. To date, data comparing hospitalized patients with COVID-19 and influenza is scarce. METHODS: Data from patients with COVID-19 were compared to patients infected with influenza A (InfA) and B (InfB) virus during the 2017/18 and 2018/19 seasons. All patients were ≥ 18 years old, had PCR-confirmed infection and needed hospital treatment. Demographic data, medical history, length-of-stay (LOS), complications including in-hospital mortality were analyzed. RESULTS: In total, 142 patients with COVID-19 were compared to 266 patients with InfA and 300 with InfB. Differences in median age (COVID-19 70.5 years vs InfA 70 years and InfB 77 years, p < 0.001) and laboratory results were observed. COVID-19 patients had fewer comorbidities, but complications (respiratory insufficiency, pneumonia, acute kidney injury, acute heart failure and death) occurred more frequently. Median length-of-stay (LOS) was longer in COVID-19 patients (12 days vs InfA 7 days vs. InfB 7 days, p < 0.001). There was a fourfold higher in-hospital mortality in COVID-19 patients (23.2%) when compared with InfA (5.6%) or InfB (4.7%; p < 0.001). CONCLUSION: In hospitalized patients, COVID-19 is associated with longer LOS, a higher number of complications and higher in-hospital mortality compared to influenza, even in a population with fewer co-morbidities. This data, a high reproduction number and limited treatment options, alongside excess mortality during the SARS-CoV-2 pandemic, support the containment strategies implemented by most authorities.

Clinical and Angiographic Features in Three COVID-19 Patients with Takotsubo Cardiomyopathy. Case Report.

While coronavirus disease 2019 (COVID-19), caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has often been perceived as a predominantly respiratory condition, it is characterized by complications in multiple organ systems. Especially the involvement of the cardiovascular system, along with the possibly severe pulmonary injury, is crucial for prognosis. We identified three COVID-19 patients with takotsubo (TT) cardiomyopathy at our infectious diseases treatment center and present their clinical, laboratory, echocardiographic, electrocardiographic, and angiographic features. All patients were female (median age, 67 years); disease severity regarding COVID-19 ranged from asymptomatic to ARDS (adult respiratory syndrome) necessitating mechanical ventilation for 22 days. Angiography revealed normal coronary arteries in patient 1, severe three-vessel coronary artery disease (CAD) in patient 2, and insignificant bystander CAD in patient 3. All patients showed classic apical hypokinesia with basal hyperkinesia. In patient 3, TT cardiomyopathy resulted in transient cardiogenic shock. Twenty-eight-day mortality was 0% in this case series. In conclusion, takotsubo cardiomyopathy may be yet another clinical entity associated with SARS-CoV-2 infection.

Diagnosis of COVID-19 using multiple antibody assays in two cases with negative PCR results from nasopharyngeal swabs.

We report of two cases of progressed COVID-19 with negative PCR tests from nasopharyngeal swabs, in whom diagnosis was made by different antibody assays, including a lateral flow rapid test and multiple commercial ELISAs, finally confirmed by comprehensive serological assays. These cases highlight that commercial ELISAs and even rapid tests might significantly aid the diagnosis of COVID-19, particularly, if a combination of serological assays is used with a specific clinical question, in severely ill patients after seroconversion and when comprehensive serological methods are used for confirmation.

Hydroxychloroquine versus lopinavir/ritonavir in severe COVID-19 patients : Results from a real-life patient cohort.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a high mortality. To date no trial comparing hydroxychloroquine (HCQ) and lopinavir/ritonavir (LPV/RTV) has been performed. METHODS: Hospitalized patients ≥18 years old with severe coronavirus disease 2019 (COVID-19) were treated with either HCQ or LPV/RTV if they had either respiratory insufficiency (SpO2 ≤ 93% on room air or the need for oxygen insufflation) or bilateral consolidations on chest X­ray and at least 2 comorbidities associated with poor COVID-19 prognosis. Outcomes investigated included in-hospital mortality, intensive care unit (ICU) admission, length of stay, PCR (polymerase chain reaction) negativity and side effects of treatment. RESULTS: Of 156 patients (41% female) with a median age of 72 years (IQR 55.25-81) admitted to our department, 67 patients fulfilled the inclusion criteria (20 received HCQ, 47 LPV/RTV). Groups were comparable regarding most baseline characteristics. Median time from symptom onset to treatment initiation was 8 days and was similar between the groups (p = 0.727). There was no significant difference (HCQ vs. LPV/RTV) in hospital mortality (15% vs. 8.5%, p = 0.418), ICU admission rate (20% vs. 12.8%, p = 0.470) and length of stay (9 days vs. 11 days, p = 0.340). A PCR negativity from nasopharyngeal swabs was observed in approximately two thirds of patients in both groups. Side effects led to treatment discontinuation in 15% of patients in the LPV/RTV group. CONCLUSION: No statistically significant differences were observed in outcome parameters in patients treated with HCQ or LPV/RTV but patients in the LPV/RTV group showed a numerically lower hospital mortality rate. Additionally, in comparison to other studies we demonstrated a lower mortality in patients treated with LPV/RTV despite having similar patient groups, perhaps due to early initiation of treatment.

CD4 T Cell Determinants in West Nile Virus Disease and Asymptomatic Infection.

West Nile (WN) virus infection of humans is frequently asymptomatic, but can also lead to WN fever or neuroinvasive disease. CD4 T cells and B cells are critical in the defense against WN virus, and neutralizing antibodies, which are directed against the viral glycoprotein E, are an accepted correlate of protection. For the efficient production of these antibodies, B cells interact directly with CD4 helper T cells that recognize peptides from E or the two other structural proteins (capsid-C and membrane-prM/M) of the virus. However, the specific protein sites yielding such helper epitopes remain unknown. Here, we explored the CD4 T cell response in humans after WN virus infection using a comprehensive library of overlapping peptides covering all three structural proteins. By measuring T cell responses in 29 individuals with either WN virus disease or asymptomatic infection, we showed that CD4 T cells focus on peptides in specific structural elements of C and at the exposed surface of the pre- and postfusion forms of the E protein. Our data indicate that these immunodominant epitopes are recognized in the context of multiple different HLA molecules. Furthermore, we observed that immunodominant antigen regions are structurally conserved and similarly targeted in other mosquito-borne flaviviruses, including dengue, yellow fever, and Zika viruses. Together, these findings indicate a strong impact of virion protein structure on epitope selection and antigenicity, which is an important issue to consider in future vaccine design.