Coronavirus Disease Mortality and Outcome in Macedonian Patients With Chronic Lymphocytic Leukemia: Single-Center Experience

Context: Patients with chronic lymphocytic leukemia (CLL) may be more predisposed to coronavirus disease 2019 (COVID-19) due to age, the nature of the disease, and treatment-related immunosuppression. Objective: The aim of the study was to assess risk factors of the outcome and course of COVID-19 for CLL patients in Macedonia. Design: Retrospective study of patients with CLL and COVID-19 infection in the period of time from the beginning of the pandemic to March 2022. Setting: Individual patient data from 55 CLL patients with COVID-19 infection were analyzed. The risk factors of COVID-19 disease severity and outcomes were investigated. Interventions: The outcome was the analysis of patients with COVID-19 infection in line with host risk factors and biological heterogeneity of the disease with previous therapy for CLL. Results: Our evaluation has shown that 80% of patients were male and 20% were female. The average age was 65 years. The average CIRS score was 2 and BMI was 23.6. Most of the patients (67.2%) have unmutated Ig genes. Ninety-one percent (91%) from that subgroup of patients have a severe form of COVID-19, 82% of patients were treated with chemotherapy, and 48% had a fatal outcome. Conclusions: CLL-directed treatment and unmutated Ig genes were significant risk factors for survival. Untreated patients and patients with mutated IGHV had a better chance of survival than those on treatment or who were recently treated.

Outcomes of COVID-19 Infections in Patients With Hematological Malignancies in Republic of North Macedonia

Context: Patients with hematological malignancies are at increased risk of complications and adverse outcomes associated with COVID-19, according to current available studies. These patients are particularly vulnerable due to impaired or compromised immune responses caused by treatment or the disease itself. Objective: Our aim was to examine the severity and outcomes of COVID-19 infections among patients with hematological malignancies in Republic of North Macedonia. Design: This is the first retrospective descriptive study on patients with COVID-19 and underlying hematological malignancies in Republic of North Macedonia. We focused on clinical characteristics and COVID-19 infection outcomes in different malignancy settings. Patients: We collected data on clinical characteristics, diagnosis, treatment, and outcomes in adult patients with hematologic malignancies and confirmed COVID-19 infections between June 2020 and April 2022. Parametric data were compared using Fisher's exact test. Results: Of 206 patients, 153 (74%) had lymphoid, and 53 (26%) had myeloid malignancies. Median age was 61 years (IQR 47–70 years), 118 (57%) patients were male, and 86 (74%) patients were older than 60 years and had ≥2 comorbidities, with only 16 (17%) patients younger than 60 years. Severe/critical clinical severity was identified in 77 (37%). Overall, 42 patients (20%) died, including 33 patients (78%) older than 60 years. Patients older than 60 years had significantly higher mortality (p=0.0015) than younger patients. The majority of patients (58%) became COVID-19–positive while on active treatment. Significantly worse outcomes were observed among patients who were on active treatment compared with patients who were in hematological remission (p=0.0028). Among lethal cases, the majority of patients were diagnosed with CLL and NHL. We found no significant differences in mortality between treated and untreated CLL and NHL patients. Among 37 patients treated with a cocktail of monoclonal antibodies (casirivimab/imdevimab), no significant difference in outcome was observed, although 86% of them survived. Conclusions: Patients with hematological malignancies and COVID-19 infection were associated with higher mortality associated with older age, more comorbidities, and active disease. Patients with B-cell malignancy were the most affected, but no significant difference in mortality rate was observed across different subgroups, which may suggest that B-cell impairment is a key factor leading to severe infection.

Prevalence of Allelic Variants and Clonality of IGHV1-69 Expressing B-Cells in Patients with Different Severity of COVID 19 Disease

Introduction: Since the first months of the COVID-19 pandemic, efforts have been made to understand the importance of broadly neutralising natural antibodies in determining the response to SARS-CoV-2. Previous studies have shown that allelic variants of the IGHV1-69 gene play a dominant role in protective natural antibody responses to several other viral pathogens, including influenza virus, hepatitis C virus, human immunodeficiency virus and, most notably, the SARS-CoV-2-related viruses SARS-CoV and MERS-CoV. These allelic variants are commonly known as 51p1-related and differ from the other IGHV1-69 alleles (known as hv1263-related) in the presence of a Phe54 residue in the CDR2 region. Importantly, crystallographic studies have shown that the Phe54 residue is critical for the binding of IGHV1-69 antibodies to the SARS-CoV and MERS-CoV spike proteins. In this study, we evaluated the prevalence of 51p1 and hv1263 alleles and the clonality of 51p1- and hv1263-expressing B cells in a large cohort of healthy individuals and COVID-19 patients and correlated the findings with the severity of the disease. Мaterials and methods: A total of 419 samples were included in the study, of which 78 asymptomatic/mildly symptomatic individuals, 200 hospitalized patients with severe disease, 94 critically ill patients and 47 healthy donors. Peripheral blood was collected 8-20 days after the onset of symptoms and total cellular RNA was extracted from whole blood using an automated procedure. Аllelle-specific Ig-gene fingerprinting of IgM heavy chain transcripts was used to simultaneously analyse the clonality of the IgM+ B-cell population and the clonality of the 51p1- and hv1263-expressing B cell populations. The significance of the differences in the prevalence of clonal B-cell populations between healthy donors and patients and between patients with different severity of the disease was calculated with the Chi-Square test. Results: Analysis of the clonality of the IgM+ B-cell population showed a polyclonal pattern in most of the investigated healthy individuals (33/47, 70%) but in only 20% of all SARS-CoV-2 infected individuals (75/372, p<0.001). A significant difference was also observed between mildly affected and severely/critically ill patients [31/78 (39.7%) vs. 44/294 (15%), respectively) (p<0.001)], but not between severely and critically ill patients [28/200 (14,%) vs. 16/94 (17,1%), (p=n.s.)]. No 51p1 transcripts were detected in 74/372 (19.9%) of SARS-CoV-2 infected individuals and in 14/47 (29,8%) of the control group (p>0,01), while hv1263 transcripts were not detected in 155/289 (53,6%) and in 27/47 (68,6%) tasted patients and controls, respectively (p>0,05). We did not find a statistically significant difference in the prevalence of 51p1 and hv1263 alleles between patients with different disease severity. However, a significantly higher number of patients displayed clonal expansions of 51p1- or hv1263-expressing B cells (219/372(58.9%) and 118/244 (48,4%), respectively in comparison to healthy donors [5/47(10.6%) and 7/47(14.9%), respectively]. There was no statistically significant difference between mildly affected and severely/critically ill patients in the clonallity status of 51p1- 38/61 (62,3%) and 182/237 (76,7%) respectively or between hv1263- expressing B cells in the same two groups of patients [20/25 (80%) and 98/109 (89,9%), p>0.05]. Conclusions: Our results show that SARS-CoV-2 infection stimulates clonal expansions of IGHV1-69 -expressing B-cells, but this is independent of the severity of the disease. In addition, no difference in the prevalence of IGHV1-69 alleles was observed between patients at different stages of the disease, indicating that natural neutralizing antibodies encoded by this gene are not an important determinant of COVID-19 severity and progression. Disclosures No relevant conflicts of interest to declare.

Insight in the Current Progress in the Largest Clinical Trials for Covid-19 Drug Management (As of January 2021).

The outbreak of the COVID-19 pandemic has generated the largest global health crisis of the 21st century, evolving into accelerating socioeconomic disruption. In spite of all rapidly and widely emerging scientific data on epidemiology, diagnosis, prevention and treatment of the COVID-19 disease, severe acute respiratory coronavirus 2 (SARS-CoV-2) is continuing to propagate in lack of definitive and specific therapeutic agents. Current therapeutic strategies are mainly focused on viral inhibition by antiviral drugs and hampering the exuberant immune response of the host by immunomodulatory drugs. In this review, we have studied the reports of the largest clinical trials intended to COVID-19 treatment published during the first year of the pandemics. In general, these results concentrate on seven therapeutic options: remdesivir, chloroguine/hydroxychloroquine, lopinavir-ritonavir combination, corticosteroids, tocilizumab, convalescent plasma and monoclonal antibodies. In line with the reviewed data, as of January 2021, most of the evidence support the use of remdesivir in hospitalized patients with moderate and severe forms of the disease and provide reliable data on the substantial beneficial effect of corticosteroids in patients requiring supplemental oxygen. Moreover, preliminary RECOVERY trial results have demonstrated the efficacy of tociluzumab in the treatment of critically ill patients. The reports presenting the outcomes of the other immune-based therapies under investigation are enthusiastically awaited.

The use of remdesivir outside of clinical trials during the COVID-19 pandemic.

With a scientific background from filoviruses, paramyxoviruses, SARS-CoV, and MERS-CoV, remdesivir entered into the COVID-19 battle to become one of the favorable therapeutic candidates with potential antiviral activity in the treatment of this disease. Globally, remdesivir was accessed and investigated through clinical research (clinical trials) and clinical practice (compassionate use, expanded access, early access scheme, and emergency use). Currently, remdesivir approval status differs between states. This paper aims to review and analyze regulatory approaches for accessing and investigating remdesivir, by communicating regulatory variability between countries in terms of terminology, modalities, and protocols.