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.

Large randomized clinical trials in severe Coronavirus Disease 2019 (COVID-19) patients have proven efficacy of intravenous tocilizumab. Our aim was to describe the laboratory parameters predicting in-hospital mortality of patients with tocilizumab administration in COVID-19 associated cytokine release syndrome (CRS).We evaluated high-dose (8 mg/kg) intravenous tocilizumab administration in severe and critically ill COVID-19 adult patients fulfilling predefined strict CRS criteria. A single-centre, prospective, observational cohort study was carried out among consecutive adult (≥18 years of age) in-patients with COVID-19 between April 1 and December 31, 2020. The primary endpoint was 28-day all-cause mortality. The changes in laboratory parameters from baseline on day 7 and 14 after administration of tocilizumab were analysed.In total, 1801 patients were admitted to our centre during the study period. One hundred and six patients received tocilizumab, and among them 62 (58.5%) required intensive care unit admittance while 25 (23.6%) deceased. At day 7 after tocilizumab administration, inflammatory markers (CRP, IL-6, ferritin) and lactate dehydrogenase (LDH) values were significantly lower among survivors. Subsequently, at day 14, differences of IL-6 and LDH levels has become more pronounced between subgroups. Restoration of absolute lymphocyte count (ALC) by day 7 and 14 was insufficient among patients who died.In our cohort, administration of high-dose tocilizumab for COVID-19 patients with CRS demonstrated clinical and sustained biochemical parameter improvement in 76.4%. In this patient population high and increasing LDH, IL-6, and low ALC levels had a predictive role for mortality.

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.

BackgroundPreliminary data suggests that favipiravir might have a role in COVID-19 treatment. Our aim was to assess the role of favipiravir in the treatment of COVID-19.MethodsA single-center, prospective, observational, sequential cohort study was performed among consecutive adults hospitalized with PCR-confirmed COVID-19 between March– July,2020. Patients were screened for inclusion by a priori criteria, and were included in the favipiravir cohort if SOC+FVP, or the non-favipiravir group if SOC±other antiviral medications without FVP were administered for >48 hours. Treatment allocation was done per national guidelines. For COVID-19 diagnosis and severity, ECDC and WHO definitions were utilized, and daily per protocol hospital follow-up was done. Primary composite end-point was disease progression (14-day all-cause death, need for mechanical ventilation, or immunomodulatory therapy). For statistical comparison, Fisher’s exact test and Mann– Whitney U-test were used.ResultsIn all, 75 patients were included per cohort. In the FVP cohort, chronic heart disease (36/75, 48.0% vs. 16/75, 21.3%, p<0.01) and diabetes mellitus (23/75, 30.7% vs. 10/75, 13.3%, p<0.01) were more prevalent, hospital LOS (18.5±15.5 days vs. 13.0±8.5 days, p<0.01) was higher. 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 ventillation (8/75, 10.7% vs. 4/75, 5.3%, p=0.22) were similar between groups. Immunomodulatory therapies were administered frequently among patients receiving FVP (10/75, 13.3% vs. 1/75, 1.3%, p<0.01).ConclusionsIn this study, favipiravir did not seem to affect disease progression. Further data are needed to position this drug among the anti-SARS-CoV-2 armamentarium.

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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.

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.

A COVID–19 kapcsán tapasztalható jelenség a szérummájenzim-aktivitásnak a laboratóriumi vizsgálat során észlelt emelkedése. Ezen változások hátterében feltehetően három patomechanizmus áll: 1) a SARS-CoV-2 direkt citotoxikus és indirekt sejtszintű és szisztémás következményei, 2) a COVID–19-ben alkalmazott gyógyszeres kezeléseknek (remdesivir, favipiravir, tocilizumab, baricitinib, szisztémás kortikoszteroid) a farmakológiai hatásai, illetve 3) a betegekben korábban fennálló krónikus májbetegség(ek) progressziója. A májenzim-emelkedés kiváltó okának differenciáldiagnosztikája és a terápiával kapcsolatos döntéshozatal kihívást jelenthet a klinikus számára, mivel a nem megfelelő kezelés a COVID–19 vagy a májkárosodás progresszióját okozhatja. A jelen összefoglaló a COVID–19-betegeket ellátó klinikusok számára kíván alapvető támpontot nyújtani a helyes döntéshez. Orv Hetil. 2022; 163(36): 1415–1421.