Use of convalescent plasma therapy in hospitalised adult patients with non-critical COVID-19: a focus on the elderly from Hungary.

Convalescent plasma therapy might be a feasible option for treatment of novel infections. During the early phases of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, several promising results were published with convalescent plasma therapy, followed by more disappointing findings of randomised controlled trials. In our single-centre, open-label, prospective, cohort study, we assessed the findings of 180 patients treated with convalescent plasma during the first four waves of the pandemic in Hungary. The primary outcome was all-cause mortality; secondary outcomes were clinical improvement and need for intensive care unit admission by day 28. Subgroup analysis comparing elderly and non-elderly (less than 65 years of age) was performed. Twenty (11.4%) patients died by day 28, at significantly higher rates in the elderly subgroup (3 vs. 17, p < 0.01). One hundred twenty-eight (72.7%) patients showed clinical improvement, and 15 (8.5%) were transferred to the intensive care unit until day 28. Non-elderly patients showed clinical improvement by day 28 in significantly higher rates (improvement 74 vs. 54, no improvement 15 vs. 11, worsening or death 4 vs. 18 patients, p < 0.01). In conclusion, we found similar clinical outcome results as randomised controlled trials, and the impact of risk factors for unfavourable clinical outcomes among patients in the elderly population.

Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups.

Introduction: While complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood. Methods: We therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome. Results: We show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p<0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID. Conclusion: In conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted.

HIV treatment strategies across Central, Eastern and Southeastern Europe: New times, old problems.

INTRODUCTION: In the last decade, substantial differences in the epidemiology of, antiretroviral therapy (ART) for, cascade of care in and support to people with HIV in vulnerable populations have been observed between countries in Western Europe, Central Europe (CE) and Eastern Europe (EE). The aim of this study was to use a survey to explore whether ART availability and therapies have evolved in CE and EE according to European guidelines. METHODS: The Euroguidelines in Central and Eastern Europe (ECEE) Network Group conducted two identical multicentre cross-sectional online surveys in 2019 and 2021 concerning the availability and use of antiretroviral drugs (boosted protease inhibitors [bPIs], integrase inhibitors [INSTIs] and nucleoside reverse transcriptase inhibitors [NRTIs]), the introduction of a rapid ART start strategy and the use of two-drug regimens (2DRs) for starting or switching ART. We also investigated barriers to the implementation of these strategies in each region. RESULTS: In total, 18 centres participated in the study: four from CE, six from EE and eight from Southeastern Europe (SEE). Between those 2 years, older PIs were less frequently used and darunavir-based regimens were the main PIs (83%); bictegravir-based and tenofovir alafenamide-based regimens were introduced in CE and SEE but not in EE. The COVID-19 pandemic did not significantly interrupt delivery of ART in most centres. Two-thirds of centres adopted a rapid ART start strategy, mainly in pregnant women and to improve linkage of care in vulnerable populations. The main obstacle to rapid ART start was that national guidelines in several countries from all three regions did not support such as strategy or required laboratory tests first; an INSTI/NRTI combination was the most commonly prescribed regimen (75%) and was exclusively prescribed in SEE. 2DRs are increasingly used for starting or switching ART (58%), and an INSTI/NRTI was the preferred regimen (75%) in all regions and exclusively prescribed in SEE, whereas the use of bPIs declined. Metabolic disorders and adverse drug reactions were the main reasons for starting a 2DR; in the second survey, HIV RNA <500 000 c/ml and high cluster of differentiation (CD)-4 count emerged as additional important reasons. CONCLUSIONS: In just 2 years and in spite of the emergence of the COVID-19 pandemic, significant achievements concerning ART availability and strategies have occurred in CE, EE and SEE that facilitate the harmonization of those strategies with the European AIDS Clinical Society guidelines. Few exceptions exist, especially in EE. Continuous effort is needed to overcome various obstacles (administrative, financial, national guideline restrictions) in some countries.

Outcomes of high-risk adult outpatients treated with early remdesivir therapy during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron era: experiences from the national centre of Hungary.

Emerging evidence suggests that remdesivir might improve clinical outcome of high-risk outpatients with coronavirus disease 2019 (COVID-19). Our aim was to evaluate characteristics and outcomes of nonhospitalised adults diagnosed with COVID-19 and treated with early remdesivir therapy during the omicron wave. A single-centre prospective cohort study was performed among adult patients between February and June 2022, during the circulation of phylogenetic assignment of named global outbreak (PANGO) subvariants BA.2, BA.4, and BA.5 in Hungary. Patients were enrolled based on pre-defined criteria. Clinical characteristics (demography, comorbidities, vaccination status, imaging, treatment, and disease course) and outcomes (COVID-19 related hospitalisation, oxygen supplementation, intensive care support, and all-cause death) were assessed at 28 days post-treatment. A subgroup analysis of patients with and without active haematological malignancies was also carried out. Altogether, 127 patients were enrolled: 51.2% (65/127) were female with a median age of 59 (IQR: 22, range: 21‒92) years, and 48.8% (62/127) had active haematological malignancy. At 28 days post-treatment, 7.1% (9/127) of patients required COVID-19-related hospitalisation, 2.4% (3/127) required oxygen supplementation, 1.6% (2/127) required intensive care, and 0.8% (1/127) died due to a non-COVID-19-related secondary infection at the intensive care unit, all with haematological malignancies. Early remdesivir treatment might be a feasible strategy among high-risk outpatients with COVID-19 during the omicron wave.

Lifelong vaccination strategy as a tool against pandemics in Hungary / Élethosszan át tartó oltási stratégia mint eszköz a pandémiák elleni védekezésben Magyarországon.

Összefoglaló. Különbözo tényezok következtében az új és újra felbukkanó fertozo betegségek megjelenésére a 21. században egyre nagyobb az esély, ezzel párhuzamosan a pandémiák kialakulása is nagyobb valószínuségu. A 2019-ben felbukkant COVID-19-járvány azt is közvetíti számunkra, hogy egyes új és újra jelentkezo fertozo betegségek - az eredményes intézkedések elmaradása, késlekedése esetén - gyorsan terjedhetnek. A fertozo betegségek elleni harc egyik fo eszköze a védooltás segítségével történo immunizáció. A jelen tanulmány célja bemutatni a védooltások elonyeit, fókuszba helyezve az elöregedo társadalomban az élethosszan tartó immunizációs stratégiának a személyes egészségre ható, közegészségügyi, gazdasági, valamint társadalmi érdekeit. Az oltás elonyeinek minél nagyobb fokú kihasználásához egy élethosszan tartó immunizációs stratégia felállítása javasolható, amelynek aspektusait és gyakorlatba ültetésének lehetséges lépéseit foglaltuk össze közleményünkben. Orv Hetil. 2022; 163(14): 535-543. Summary. Due to various factors, the chances of infectious disease emergence or re-emergence have increased in the 21st century, thus, the likelihood of new emerging pandemics has also increased. The COVID-19 pandemic, which appeared in 2019, has highlighted that certain new and re-emerging infectious diseases - in the case of lack or delay in effective measures - can spread very rapidly. The main tool for the fight against infectious diseases is immunization through vaccination. While focusing on the personal health, public health, economic and societal benefits of a lifelong immunization strategy, especially in light of the aging society, the goal of this paper is to present the benefits of vaccines. In order to increase the added value of vaccinations it is recommended to create a lifelong immunization strategy. Our paper summarizes the relevant aspects of such a strategy, highlighting potential practical steps towards implementation. Orv Hetil. 2022; 163(14): 535-543.

A COVID-19-hez kapcsolódó májenzim-emelkedés valószínuleg multifaktoriális eredetu.

Elevation of serum hepatic enzymes are common during the course of COVID-19. There are three possible mechanisms behind this phenomenon: 1) direct and indirect cytotoxic effects of SARS-CoV-2, 2) pharmacological side effects of COVID-19 drugs (e.g., remdesivir, favipiravir, tocilizumab, baricitinib, systemic corticosteroids, etc.) and 3) the progression of chronic hepatic diseases. Both the differential diagnosis and the clinical decision-making may pose difficulty for the the astute clinician, as an inappropriate treatment may result in COVID-19 progression or liver function deterioration. This review aims to provide basic guidance on the clinical decision-making for physicians managing patients with COVID-19. Orv Hetil. 2022; 163(36): 1415-1421.

Baricitinib vs tocilizumab treatment for hospitalized adult patients with severe COVID-19 and associated cytokine storm: a prospective, investigational, real-world study.

OBJECTIVES: Our aim was to compare outcomes of hospitalized adults with severe COVID-19 and cytokine storm treated with tocilizumab or baricitinib. METHODS: A prospective, investigational, real-world study was performed from April 2020 to April 2021 at our center. COVID-19 severity was classified by World Health Organization criteria, and cytokine storm was documented along predefined criteria. Eligible patients were enrolled at diagnosis if they fulfilled a priori inclusion criteria and received standard-of-care plus tocilizumab or baricitinib for >48 hours. Patients were followed per protocol for 28 days post-diagnosis. The primary outcome was all-cause mortality; secondary outcomes were invasive mechanical ventilation and major infectious complications. RESULTS: Of 463 patients, 102/463 (22.1%) received tocilizumab, and 361/463 (77.9%) baricitinib. Baseline characteristics were balanced. At 28 days, there was no difference in all-cause mortality (22/102, 21.6% vs 64/361, 17.7%; P-value = 0.38). Requirement for invasive mechanical ventilation was more frequent after tocilizumab (52/102, 50.9% vs 96/361, 26.6%; P <0.01), rate of major infectious complications was similar (32/102, 31.4% vs 96/361, 26.6%; P-value = 0.34). In logistic regression, the immunomodulatory drug was not retained as a predictor of all-cause mortality. Kaplan-Meier analysis revealed statistically similar survival distributions. CONCLUSION: All-cause mortality was similar between adults treated with baricitinib or tocilizumab for severe COVID-19 with cytokine storm.

Baricitinib versus tocilizumab treatment for hospitalized adult patients with severe COVID-19 and associated cytokine storm: A prospective, investigational, real-world study

Objectives Our aim was to compare outcomes of hospitalized adults with severe COVID-19 and cytokine storm, treated with tocilizumab or baricitinib. Methods A prospective, investigational, real-world study was performed between April 2020–April 2021 at our centre. COVID-19 severity was classified by World Health Organization criteria, cytokine storm was documented along pre-defined criteria. Eligible patients were enrolled at diagnosis if they fulfilled a priori inclusion criteria and received standard-of-care plus tocilizumab or baricitinib for >48 hours. Patients were followed per protocol for 28 days post-diagnosis. Primary outcome was all-cause mortality, secondary outcomes were invasive mechanical ventilation and major infectious complications. Results From 463 patients, 102/463 (22.1%) received tocilizumab, 361/463 (77.9%) baricitinib. Baseline characteristics were balanced. At 28 days, there was no difference in all-cause mortality (22/102, 21.6% vs. 64/361, 17.7%;p=0.38). Requirement for invasive mechanical ventilation was more frequent after tocilizumab (52/102, 50.9% vs. 96/361, 26.6%;p<0.01), rate of major infectious complications was similar (32/102, 31.4% vs. 96/361, 26.6%;p=0.34). In logistic regression, immunomodulatory drug was not retained as a predictor of all-cause mortality. Kaplan–Meier analysis revealed statistically similar survival distributions. Conclusions All-cause mortality was similar between adults treated with baricitinib or tocilizumab for severe COVID-19 with cytokine storm.

The Management of HIV Care Services in Central and Eastern Europe: Data from the Euroguidelines in Central and Eastern Europe Network Group.

INTRODUCTION: The COVID-19 pandemic has been challenging time for medical care, especially in the field of infectious diseases (ID), but it has also provided an opportunity to introduce new solutions in HIV management. Here, we investigated the changes in HIV service provision across Central and Eastern European (CEE) countries before and after the COVID-19 outbreak. METHODS: The Euroguidelines in Central and Eastern Europe Network Group consists of experts in the field of ID from 24 countries within the CEE region. Between 11 September and 29 September 2021, the group produced an on-line survey, consisting of 32 questions on models of care among HIV clinics before and after the SARS-CoV-2 outbreak. RESULTS: Twenty-three HIV centers from 19 countries (79.2% of all countries invited) participated in the survey. In 69.5% of the countries, there were more than four HIV centers, in three countries there were four centers (21%), and in four countries there was only one HIV center in each country. HIV care was based in ID hospitals plus out-patient clinics (52%), was centralized in big cities (52%), and was publicly financed (96%). Integrated services were available in 21 clinics (91%) with access to specialists other than ID, including psychologists in 71.5% of the centers, psychiatrists in 43%, gynecologists in 47.5%, dermatologists in 52.5%, and social workers in 62% of all clinics. Patient-centered care was provided in 17 centers (74%), allowing consultations and tests to be planned for the same day. Telehealth tools were used in 11 centers (47%) before the COVID-19 pandemic outbreak, and in 18 (78%) after (p = 0.36), but were represented mostly by consultations over the telephone or via e-mail. After the COVID-19 outbreak, telehealth was introduced as a new medical tool in nine centers (39%). In five centers (28%), no new services or tools were introduced. CONCLUSIONS: As a consequence of the COVID-19 pandemic, tools such as telehealth have become popularized in CEE countries, challenging the traditional approach to HIV care. These implications need to be further evaluated in order to ascertain the best adaptations, especially for HIV medicine.

The Management of HIV Care Services in Central and Eastern Europe: Data from the Euroguidelines in Central and Eastern Europe Network Group

Introduction: The COVID-19 pandemic has been challenging time for medical care, especially in the field of infectious diseases (ID), but it has also provided an opportunity to introduce new solutions in HIV management. Here, we investigated the changes in HIV service provision across Central and Eastern European (CEE) countries before and after the COVID-19 outbreak. Methods: The Euroguidelines in Central and Eastern Europe Network Group consists of experts in the field of ID from 24 countries within the CEE region. Between September 11 and September 29, 2021, the group produced an on-line survey, consisting of 32 questions on models of care among HIV clinics before and after the SARS-CoV-2 outbreak. Results: Twenty-three HIV centers from 19 countries (79.2% of all countries invited) participated in the survey. In 69.5% of the countries, there were more than four HIV centers, in three countries there were four centers (21%), and in four countries there was only one HIV center in each country. HIV care was based in ID hospitals plus out-patient clinics (52%), was centralized in big cities (52%), and was publicly financed (96%). Integrated services were available in 21 clinics (91%) with access to specialists other than ID, including psychologists in 71.5% of the centers, psychiatrists in 43%, gynecologists in 47.5%, dermatologists in 52.5%, and social workers in 62% of all clinics. Patient-centered care was provided in 17 centers (74%), allowing consultations and tests to be planned for the same day. Telehealth tools were used in 11 centers (47%) before the COVID-19 pandemic outbreak, and in 18 (78%) after (p = 0.36), but were represented mostly by consultations over the telephone or via e-mail. After the COVID-19 outbreak, telehealth was introduced as a new medical tool in nine centers (39%). In five centers (28%), no new services or tools were introduced. Conclusions: As a consequence of the COVID-19 pandemic, tools such as telehealth have become popularized in CEE countries, challenging the traditional approach to HIV care. These implications need to be further evaluated in order to ascertain the best adaptations, especially for HIV medicine.

Complement Levels at Admission Reflecting Progression to Severe Acute Kidney Injury (AKI) in Coronavirus Disease 2019 (COVID-19): A Multicenter Prospective Cohort Study.

Background: Dysregulation of complement system is thought to be a major player in development of multi-organ damage and adverse outcomes in patients with coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement system activity and development of severe acute kidney injury (AKI) among hospitalized COVID-19 patients. Materials and Methods: In this multicenter, international study, complement as well as inflammatory and thrombotic parameters were analyzed in COVID-19 patients requiring hospitalization at one US and two Hungarian centers. The primary endpoint was development of severe AKI defined by KDIGO stage 2+3 criteria, while the secondary endpoint was need for renal replacement therapy (RRT). Complement markers with significant associations with endpoints were then correlated with a panel of inflammatory and thrombotic biomarkers and assessed for independent association with outcome measures using logistic regression. Results: A total of 131 hospitalized COVID-19 patients (median age 66 [IQR, 54-75] years; 54.2% males) were enrolled, 33 from the US, and 98 from Hungary. There was a greater prevalence of complement over-activation and consumption in those who developed severe AKI and need for RRT during hospitalization. C3a/C3 ratio was increased in groups developing severe AKI (3.29 vs. 1.71; p < 0.001) and requiring RRT (3.42 vs. 1.79; p < 0.001) in each cohort. Decrease in alternative and classical pathway activity, and consumption of C4 below reference range, as well as elevation of complement activation marker C3a above the normal was more common in patients progressing to severe AKI. In the Hungarian cohort, each standard deviation increase in C3a (SD = 210.1) was independently associated with 89.7% increased odds of developing severe AKI (95% CI, 7.6-234.5%). Complement was extensively correlated with an array of inflammatory biomarkers and a prothrombotic state. Conclusion: Consumption and dysregulation of complement system is associated with development of severe AKI in COVID-19 patients and could represent a promising therapeutic target for reducing thrombotic microangiopathy in SARS-CoV-2 infection.

The Presence of Either Typical or Atypical Radiological Changes Predicts Poor COVID-19 Outcomes in HIV-Positive Patients from a Multinational Observational Study: Data from Euroguidelines in Central and Eastern Europe Network Group.

HIV-positive patients may present lungs with multiple infections, which may hinder differential diagnoses and the choice of treatment in the course of COVID-19, especially in countries with limited access to high-standard healthcare. Here, we aim to investigate the association between radiological changes and poor COVID-19 outcomes among HIV-positive patients from Central and Eastern Europe. Between November 2020 and May 2021, the Euroguidelines in Central and Eastern Europe Network Group started collecting observational data on HIV and COVID-19 co-infections. In total, 16 countries from Central and Eastern European submitted data (eCRF) on 557 HIV-positive patients. The current analyses included patients who had a radiological examination performed. Logistic regression models were used to identify the factors associated with death, ICU admission, and partial recovery (poor COVID-19 outcomes). Factors that were significant in the univariate models (p < 0.1) were included in the multivariate model. Radiological data were available for 224 (40.2%) patients, 108 (48.2%) had computed tomography, and 116 (51.8%) had a chest X-ray. Of these, 211 (94.2%) were diagnosed using RT-PCR tests, 212 (94.6%) were symptomatic, 123 (55.6%) were hospitalized, 37 (16.6%) required oxygen therapy, and 28 (13.1%) either died, were admitted to ICU, or only partially recovered. From the radiologist's description, 138 (61.6%) patients had typical radiological changes, 18 (8.0%) atypical changes, and 68 (30.4%) no changes. In the univariate models, CD4 count (OR = 0.86 [95% CI: 0.76-0.98]), having a comorbidity (2.33 [1.43-3.80]), HCV and/or HBV co-infection (3.17 [1.32-7.60]), being currently employed (0.31 [0.13-0.70]), being on antiretroviral therapy (0.22 [0.08-0.63]), and having typical (3.90 [1.12-13.65]) or atypical (10.8 [2.23-52.5]) radiological changes were all significantly associated with poor COVID-19 outcomes. In the multivariate model, being on antiretroviral therapy (OR = 0.20 [95% CI:0.05-0.80]) decreased the odds of poor COVID-19 outcomes, while having a comorbidity (2.12 [1.20-3.72]) or either typical (4.23 [1.05-17.0]) or atypical (6.39 [1.03-39.7]) radiological changes (vs. no changes) increased the odds of poor COVID-19 outcomes. Among HIV patients diagnosed with symptomatic SARS-CoV-2 infection, the presence of either typical or atypical radiological COVID-19 changes independently predicted poorer outcomes.

Decreased circulating dipeptidyl peptidase-4 enzyme activity is prognostic for severe outcomes in COVID-19 inpatients.

Aim: To investigate the serum circulating DPP4 activity in patients with COVID-19 disease. Materials & methods: Serum samples from 102 hospitalized COVID-19 patients and 43 post-COVID-19 plasma donors and 39 SARS-CoV-2 naive controls and their medical data were used. Circulating DPP4 activities according to different COVID-19 disease peak severity (WHO) groups at sampling and at peak were assessed. Results: A significant decrease (p < 0.0001) in serum DPP4 activity was found in study groups of higher disease severity. When the circulating DPP4 activity was assessed as a prognostic marker, the logistic regression (p = 0.0023) indicated that the enzyme activity is a predictor of mortality (median 9.5 days before death) with receiver operating characteristic area under the curves of 73.33% (p[area = 0.5] < 0.0001) as single predictor and 83.45% (p[area = 0.5] < 0.0001) in combination with age among hospitalized patients with COVID-19. Conclusion: Decreased circulating DPP4 activity is associated with severe COVID-19 disease and is a strong prognostic biomarker of mortality.

Associations between the von Willebrand Factor-ADAMTS13 Axis, Complement Activation, and COVID-19 Severity and Mortality.

BACKGROUND: Endothelial and complement activation were both associated with immunothrombosis, a key determinant of COVID-19 severity, but their interrelation has not yet been investigated. OBJECTIVES: We aimed to determine von Willebrand factor (VWF) antigen (VWF:Ag) concentration, VWF collagen binding activity (VWF:CBA), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (ADAMTS13:Ac), and their ratios in hospitalized COVID-19 patients, and to investigate how these parameters and their constellation with complement activation relate to disease severity and in-hospital mortality in COVID-19. METHODS: Samples of 102 hospitalized patients with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 positivity were included in our observational cohort study. Patients were stratified according to the peak severity of COVID-19 disease in agreement with the World Health Organization ordinal scale. Twenty-six convalescent plasma donors with previous COVID-19 disease formed the control group. VWF:Ag concentration and VWF:CBA were determined by enzyme-linked immunosorbent assay (ELISA); ADAMTS13:Ac was determined by fluorescence resonance energy transfer. Complement C3 and C3a were measured by turbidimetry and ELISA, respectively. Clinical covariates and markers of inflammation were extracted from hospital records. RESULTS: VWF:Ag and VWF:CBA were elevated in all groups of hospitalized COVID-19 patients and increased in parallel with disease severity. ADAMTS13:Ac was decreased in patients with severe COVID-19, with the lowest values in nonsurvivors. High (> 300%) VWF:Ag concentrations or decreased (< 67%) ADAMTS13:Ac were associated with higher risk of severe COVID-19 disease or in-hospital mortality. The concomitant presence of decreased ADAMTS13:Ac and increased C3a/C3 ratio-indicating complement overactivation and consumption-was a strong independent predictor of in-hospital mortality. CONCLUSION: Our results suggest that an interaction between the VWF-ADAMTS13 axis and complement overactivation and consumption plays an important role in the pathogenesis of COVID-19.

Favipiravir treatment does not influence disease progression among adult patients hospitalized with moderate-to-severe COVID-19: a prospective, sequential cohort study from Hungary.

Data suggests that favipiravir (FVP) could be used against SARS-CoV-2. Our aim was to investigate the role of FVP in COVID-19 treatment. A prospective sequential cohort study was performed among adults hospitalized at our center between March and August 2020 with moderate-to-severe, PCR-confirmed COVID-19. For diagnosis and severity, ECDC and WHO definitions were utilized. Patients were screened for inclusion by a priori criteria and included in the FVP cohort if standard-of-care (SOC) + FVP or the non-FVP cohort if SOC ± other antivirals without FVP were administered for > 48 h from diagnosis. Treatment allocation was done per national guidelines, based on severity and drug availability. Primary endpoint was disease progression, a composite of 14-day all-cause death, need for mechanical ventilation, or immunomodulatory therapy. The impact of FVP exposure on disease progression was analyzed by binomial logistic regression. In all, 150 patients were included, 75 in each cohort. Disease progression (17/75, 22.7% vs. 10/75, 13.3%, p = 0.13), 14-day all-cause death (9/75, 12.0% vs. 10/75, 13.3%, p = 0.8), and need for mechanical ventilation (8/75, 10.7% vs. 4/75, 5.3%, p = 0.22) were similar, while immunomodulatory therapies were required more frequently among patients receiving FVP (10/75, 13.3% vs. 1/75, 1.3%, p < 0.01). The use of favipiravir was not retained as a protective factor against disease progression in multivatiate analysis. Time to antiviral therapy from PCR positivity, disease severity, need for oxygen supportation, and ICU admittance rates did not differ statistically between cohorts. In this study, favipiravir did not seem to positively affect disease progression.

Retrospective evaluation of an observational cohort by the Central and Eastern Europe Network Group shows a high frequency of potential drug-drug interactions among HIV-positive patients receiving treatment for coronavirus disease 2019 (COVID-19).

OBJECTIVES: The aim of this international multicentre study was to review potential drug-drug interactions (DDIs) for real-life coadministration of combination antiretroviral therapy (cART) and coronavirus disease 2019 (COVID-19)-specific medications. METHODS: The Euroguidelines in Central and Eastern Europe Network Group initiated a retrospective, observational cohort study of HIV-positive patients diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Data were collected through a standardized questionnaire and DDIs were identified using the University of Liverpool's interaction checker. RESULTS: In total, 524 (94.1% of 557) patients received cART at COVID-19 onset: 117 (22.3%) were female, and the median age was 42 (interquartile range 36-50) years. Only 115 (21.9%) patients were hospitalized, of whom 34 required oxygen therapy. The most frequent nucleoside reverse transcriptase inhibitor (NRTI) backbone was tenofovir disoproxil fumarate (TDF)/tenofovir alafenamide (TAF) with lamivudine or emtricitabine (XTC) (79.3%) along with an integrase strand transfer inhibitor (INSTI) (68.5%), nonnucleoside reverse transcriptase inhibitor (NNRTI) (17.7%), protease inhibitor (PI) (13.7%) or other (2.5%). In total, 148 (28.2%) patients received COVID-19-specific treatments: corticosteroids (15.7%), favipiravir (7.1%), remdesivir (3.1%), hydroxychloroquine (2.7%), tocilizumab (0.6%) and anakinra (0.2%). In total, 62 DDI episodes were identified in 58 patients (11.8% of the total cohort and 41.9% of the COVID-19-specific treatment group). The use of boosted PIs and elvitegravir accounted for 43 DDIs (29%), whereas NNRTIs were responsible for 14 DDIs (9.5%). CONCLUSIONS: In this analysis from the Central and Eastern European region on HIV-positive persons receiving COVID-19-specific treatment, it was found that potential DDIs were common. Although low-dose steroids are mainly used for COVID-19 treatment, comedication with boosted antiretrovirals seems to have the most frequent potential for DDIs. In addition, attention should be paid to NNRTI coadministration.

Common points of therapeutic intervention in COVID-19 and in allogeneic hematopoietic stem cell transplantation associated severe cytokine release syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) and coronavirus disease 2019 (COVID-19) infection can both lead to severe cytokine release syndrome (sCRS) resulting in critical illness and death. In this single institution, preliminary comparative case-series study we compared clinical and laboratory co-variates as well as response to tocilizumab (TCZ)-based therapy of 15 allogeneic-HSCT- and 17 COVID-19-associated sCRS patients. Reaction to a TCZ plus posttransplant cyclophosphamide (PTCY) consolidation therapy in the allogeneic-HSCT-associated sCRS group yielded significantly inferior long-term outcome as compared to TCZ-based therapy in the COVID-19-associated group (P = 0.003). We report that a TCZ followed by consolidation therapy with a Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitor given to 4 out of 8 critically ill COVID-19 patients resulted in their complete recovery. Non-selective JAK/STAT inhibitors influencing the action of several cytokines exhibit a broader effect than TCZ alone in calming down sCRS. Serum levels of cytokines and chemokines show similar changes in allogeneic-HSCT- and COVID-19-associated sCRS with marked elevation of interleukin-6 (IL-6), regulated upon activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1) and interferon γ-induced protein 10 kDa (IP-10) levels. In addition, levels of IL-5, IL-10, IL-15 were also elevated in allogeneic-HSCT-associated sCRS. Our multi-cytokine expression data indicate that the pathophysiology of allogeneic-HSCT and COVID-19-associated sCRS are similar therefore the same clinical grading system and TCZ-based treatment approaches can be applied. TCZ with JAK/STAT inhibitor consolidation therapy might be highly effective in COVID-19 sCRS patients.

National strategies for vaccination against COVID-19 in people living with HIV in Central and Eastern European region.

INTRODUCTION: People living with HIV (PLWH) are at higher risk of poorer COVID-19 outcomes. Vaccination is a safe and effective method of prevention against many infectious diseases, including COVID-19. Here we investigate the strategies for national COVID-19 vaccination programmes across central and eastern Europe and the inclusion of PLWH in vaccination programmes. METHODS: The Euroguidelines in Central and Eastern Europe Network Group consists of experts in the field of infectious diseases from 24 countries in the region. Between 1 November 2020 and 19 March 2021 the group proceeded an on-line survey consisting of 20 questions. RESULTS: Twenty-two countries (out of 24 invited) participated in the survey and 20/22 countries in the period between December 2020 and March 2021 had already started their COVID-19 vaccination programme. In total, seven different vaccines were used by participating countries. In 17/21 countries (81%), vaccinated persons were centralized within the national registry. In 8/21 countries (38%) PLWH were prioritized for vaccination (the Czech Republic, Greece, Hungary, Lithuania, Montenegro, Romania, Slovakia, Slovenia) and the Czech Republic, Greece and Serbia had put in place national guidelines for vaccination of PLWH. In 14/20 countries (70%) vaccination was only provided by designated centres. Eighteen respondents (18/21; 85.7%) reported that they planned to follow up HIV patients vaccinated against COVID-19, mainly by measuring antibody levels and checking COVID-19 incidence (11/21; 52.3%). CONCLUSIONS: This survey-based study suggests that there are significant differences in terms of prioritizing PLWH, the types of vaccines used, vaccination coverage, and the development and implementation of a vaccination programmes within the region. Regardless of heterogenicity and existing barriers within the region, systematic vaccination in PLWH should have the highest priority, especially in those with severe immunodeficiency, risk factors, and in the elderly, aiming for prompt and high vaccination coverage.

A COVID-19-association-dependent categorization of death causes in 100 autopsy cases.

From March through December 2020, 100 autopsies were performed (Semmelweis University, Budapest, Hungary), with chart review, of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection demonstrated by real-time reverse-transcription polymerase chain reaction testing (mean age, 74.73 years, range 40-102 years; 50 males, mean age 71.96 years, and 50 females, mean age 77.5 years). Classified by the date of death, 21 cases were from the pandemic's "first wave" (March through July) and 79 from the "second wave" (August through December). Three mortality categories were defined by relevance of SARS-CoV-2 infection: (1) "strong" association (n=57), in which COVID-19 was primary responsible for death; (2) "contributive" association (n=27), in which a pre-existing condition independent of COVID-19 was primary responsible for death, albeit with substantial COVID-19 co-morbidity; (3) "weak" association (n=16), in which COVID-19 was minimally or not at all responsible for death. Distributions among categories differed between the first wave, in which the "contributive" association cases dominated (strong: 24%, contributive: 48%, weak: 28%), and the second wave, in which the "strong" association cases dominated (strong: 66%, contributive: 21%, weak: 13%). Charted co-morbidities included hypertension (85 %), cardiovascular diseases (71 %), diabetes (40 %), cerebrovascular diseases (31 %), chronic respiratory diseases (30 %), malignant tumors (20 %), renal diseases (19 %), diseases of the central nervous system (15 %), and liver diseases (6 %). Autopsy evaluation analyzed alterations on macroscopy as well as findings on microscopy of scanned and scored sections of formalin-fixed, paraffin-embedded tissue samples (50-80 blocks/case). Severity of histological abnormalities in the lung differed significantly between "strong" and "contributive" (p<0.0001) and between "strong" and "weak" categories (p<0.0001). Abnormalities included diffuse alveolar damage, macrophage infiltration, and vascular and alveolar fibrin aggregates (lung), with macro- and microvascular thrombi and thromboemboli (lung, kidney, liver). In conclusion, autopsies clarified in what extent COVID-19 was responsible for death, demonstrated the pathological background of clinical signs and symptoms, and identified organ alterations that led to the death. Clinicopathologic correlation, with conference discussions of severity of co-morbidities and of direct pathological signs of disease, permitted accurate categorization of cause of death and COVID-19 association as "strong," "contributive," or "weak." Lung involvement, with reduced ventilatory capacity, was the primary cause of death in the "strong" and "contributive" categories. Shifts in distribution among categories, with "strong" association between COVID-19 and death dominating in the second wave, may reflect improved clinical management of COVID-19 as expertise grew.