["When it rains, it pours" - de novo diagnosed multiple myeloma with invasive Streptococcus pneumoniae infection in severe COVID-19 complicated with cytokine storm]. / "A baj nem jár egyedül" ­ de novo diagnosztizált myeloma multiplex invazív Streptococcus pneumoniae fertozéssel citokinviharral szövodött COVID­19-ben.

With the appearance of SARS-CoV-2, the range of infections, considered the most common cause of death for people with multiple myeloma, has expanded. Although the omicron variant (PANGO B.1.1.529) of SARS-CoV-2, that dominates the world at the time of manuscript writing, is less likely to cause fatal infection in immunocompetent patients compared to the delta variant (PANGO B.1.617.2), its transmissibility did not decrease. The likelihood of a severe or critical course of COVID-19 in patients with multiple myeloma is increased by the humoral and cellular immunosuppression caused by the malignancy itself, its targeted hematological treatment, and other comorbidities associated with the disease (e.g., chronic kidney failure). Antiviral therapies, monoclonal antibody preparations used as pre- or post-exposure prophylaxis, and possibly convalescent plasma therapy, started as early as possible might prevent the clinical progression of COVID-19. While the incidence of community-acquired co-infections accompanying COVID-19 in the average population is not exceptionally high, in people with multiple myeloma, Streptococcus pneumoniae infection that follows respiratory viral diseases is approximately 150 times more likely to cause invasive disease. As a result of modern oncohematological treatment, multiple myeloma has now become a chronic disease accompanied by relapses, and those affected should be immunized against the above two pathogens. In our manuscript, we describe the case of an adult patient with severe COVID-19 complicated by cytokine storm and invasive Streptococcus pneumoniae infection who was diagnosed with de novo multiple myeloma during hospital care, and, finally, we briefly review the related literature data. Orv Hetil. 2023; 164(20): 763-769.

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.

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.

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.

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.

ESCMID COVID-19 living guidelines: drug treatment and clinical management.

SCOPE: In January 2021, the ESCMID Executive Committee decided to launch a new initiative to develop ESCMID guidelines on several COVID-19-related issues, including treatment of COVID-19. METHODS: An ESCMID COVID-19 guidelines task force was established by the ESCMID Executive Committee. A small group was established, half appointed by the chair, and the remaining selected with an open call. Each panel met virtually once a week. For all decisions, a simple majority vote was used. A long list of clinical questions using the PICO (population, intervention, comparison, outcome) format was developed at the beginning of the process. For each PICO, two panel members performed a literature search with a third panellist involved in case of inconsistent results. Voting was based on the GRADE approach. QUESTIONS ADDRESSED BY THE GUIDELINE AND RECOMMENDATIONS: A synthesis of the available evidence and recommendations is provided for each of the 15 PICOs, which cover use of hydroxychloroquine, bamlanivimab alone or in combination with etesevimab, casirivimab combined with imdevimab, ivermectin, azithromycin and empirical antibiotics, colchicine, corticosteroids, convalescent plasma, favipiravir, remdesivir, tocilizumab and interferon ß-1a, as well as the utility of antifungal prophylaxis and enoxaparin. In general, the panel recommended against the use of hydroxychloroquine, ivermectin, azithromycin, colchicine and interferon ß-1a. Conditional recommendations were given for the use of monoclonal antibodies in high-risk outpatients with mild-moderate COVID-19, and remdesivir. There was insufficient evidence to make a recommendation for use of favipiravir and antifungal prophylaxis, and it was recommended that antibiotics should not be routinely prescribed in patients with COVID-19 unless bacterial coinfection or secondary infection is suspected or confirmed. Tocilizumab and corticosteroids were recommended for treatment of severe COVID-19 but not in outpatients with non-severe COVID-19. SCOPE: The aim of the present guidance is to provide evidence-based recommendations for management of adults with coronavirus disease 2019 (COVID-19). More specifically, the goal is to aid clinicians managing patients with COVID-19 at various levels of severity including outpatients, hospitalized patients, and those admitted to intensive care unit. Considering the composition of the panel, mostly clinical microbiologists or infectious disease specialists with no pulmonology or intensive care background, we focus only on pharmacological treatment and do not give recommendations on oxygen supplement/support. Similarly, as no paediatricians were included in the panel; the recommendations are only for adult patients with COVID-19. Considering the current literature, no guidance was given for special populations such as the immunocompromised.

Invasive fungal infections among critically ill adult COVID-19 patients: First experiences from the national centre in Hungary.

INTRODUCTION: Data suggests that invasive fungal infections (IFI) might complicate COVID-19. Our goal was to describe characteristics of IFI among critically ill COVID-19 adults. METHODS: A retrospective observational case-series analysis was done between March-July 2020. Consecutive patients with critical COVID-19 were eligible, and have been included when proven or putative/probable IFI could be confirmed during their course. For COVID-19 diagnosis, ECDC definitions and WHO severity criteria were followed. Candidaemia was diagnosed according to the ESCMID 2012 guideline. Invasive pulmonary aspergillosis (IPA) was defined following EORTC/MSG, ECMM/ISHAM and modified AspICU criteria. Outcome variables were rates of IFIs, in-hospital all-cause mortality, rate and time to negative respiratory SARS-CoV-2 PCR. RESULTS: From 90 eligible patients, 20 (22.2%) fulfilled criteria for IFI. Incidence rate for IFI was 2.02 per 100 patient-days at ICU. Patients were mostly elderly males with significant comorbidities, requiring mechanical ventilation because of ARDS. IFI could be classified as candidaemia in 7/20 (40%), putative/probable IPA in 16/20 (80.0%). Isolated species of candidaemia episodes were Candida albicans (4/9, 44.4%), Candida glabrata (3/9, 33.3%), Candida parapsilosis (1/9, 11.1%), Candida metapsilosis (1/9, 11.1%). Mold isolates from lower respiratory tract were Aspergillus fumigatus, BAL galactomannan positivity was prevalent (16/20, 80.0%). Mortality was 12/20 (60.0%) with a median time to death of 31.0±37.0 (5-89) days. Only 9/20 (45.0%) patients reached SARS-CoV-2 PCR negativity after a median time of 20.0±12.0 (3-38) days. CONCLUSION: In this small cohort of critically ill COVID-19 adults, morbidity and mortality related to invasive fungal infections proved to be significant.

Laboratory parameters predicting mortality of adult in-patients with COVID-19 associated cytokine release syndrome treated with high-dose tocilizumab.

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.