Comparative immunogenicity and safety of Gam-COVID-Vac and Sinopharm BBIBP-CorV vaccines: results of a pilot clinical study.

Introduction: There are few comparative studies on efficiency of broad range COVID19 vaccination strategy. This pilot aims to describe the effect of mixed COVID19 vaccination on vaccination adoption and subsequent total immunity, Conducted in Republic of Belarus, this pilot clinical study shows varying immunogenic responses to Sputnik V (Gam-COVID-Vac), Russian Federation (RF) and Sinopharm (BBIBP-CorV), People's Republic of China (PRC) vaccines. Objective: To compare the immunogenicity and reactogenicity of Sputnik V (Gam-COVID-Vac) and Sinopharm (BBIBP-CorV) vaccines in vaccinated individuals.Materials and MethodsA total of 60 adults participated in the present study. The immune response after vaccination was assessed using enzyme immunoassay. IgG levels were measured in all participants at three time points: before vaccination, on the 42nd day after the first vaccine dose, and in 6 months after the first vaccine dose. Age, sex of participants, vaccine type, history of COVID-19/IgG seropositivity were included in the multivariate analysis. The results of the SARS-CoV-2 infection antibody test were quantified according to the WHO First International Standard (NIBSC code:20/136) and measured in international units (BAU/ml). Results: The study participants (n = 60) were divided into two groups where 50 % (n = 30) were vaccinated with Sputnik V (Gam-COVID-Vac), and 50 % (n = 30) were vaccinated with Sinopharm (BBIBP-CorV). Women represented 63 % and 77 % of Sputnik V and Sinopharm groups, respectively. The IgG levels on day 42 after the first vaccine dose were: Sputnik V (Gam-COVID-Vac): Me = 650.4 (642.2-669.4); Sinopharm (BBIBP-CorV: Me = 376.5 (290.9-526.4) (UMann-Whitney = 164, p = 0.000024). The IgG levels in 6 months after the first vaccine dose were: Sputnik V (Gam-COVID-Vac)Me = 608.7 (574.6-647.1); Sinopharm (BBIBP-CorV) Me = 106.3 (78.21-332.4); (UMann-Whitney = 172.5, p-value = 0.000042)). In a multivariate model Sputnik V vaccine type and IgG seropositivity at the baseline were significantly associated with higher levels of IgG both at 42 days and 6 months post-vaccination. Reactions after vaccination appeared in 27 vaccinated people (45 %). Conclusion: This pilot study demonstrated that Sputnik V (Gam-COVID-Vac) vaccine was more immunogenic than Sinopharm (BBIBP-CorV) vaccine. IgG levels in vaccinated individuals who previously recovered from SARS-CoV-2 infection (hybrid immunity) were higher than in SARS-CoV-2 infection immune-naive people. Reactions after vaccines administration were mild to moderate.

Age, successive waves, immunization, and mortality in elderly COVID-19 hematological patients: EPICOVIDEHA findings.

OBJECTIVES: Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail. METHODS: We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy. RESULTS: The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. CONCLUSION: These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts.

COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA).

Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible.

COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA).

BACKGROUND: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. METHODS: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. RESULTS: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. CONCLUSIONS: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.

Compositional Flux Within the Intestinal Microbiota and Risk for Bloodstream Infection With Gram-negative Bacteria.

BACKGROUND: Gram-negative bloodstream infections (BSIs) represent a significant complication facing allogeneic hematopoietic cell transplant (allo-HCT) recipients, as a result of intestinal translocation during neutropenia. In this study we sought to better understand how the composition of the intestinal microbiota is connected to risk of gram-negative BSIs, expanding on our prior work in these patients. METHODS: Fecal specimens were collected from recipients of allo-HCT and analyzed using 16S ribosomal RNA gene sequencing. Samples and clinical data extending from the pretransplant conditioning period through stem cell engraftment were used in the analysis. Intestinal domination (relative abundance ≥ 30%) by gram-negative bacteria was used as predictor of gram-negative BSI using Cox proportional hazards modeling. Further analysis of microbiota composition was performed at the genus level. RESULTS: Seven hundred eight allo-HCT subjects were studied (7.5% developed gram-negative infection), with 4768 fecal samples for analysis. Gram-negative intestinal domination was associated with subsequent BSI, which was observed overall and individually at the genus level: Escherichia, Klebsiella, Enterobacter, Pseudomonas, and Stenotrophomonas. Fluoroquinolone prophylaxis was associated with decreased BSI and intestinal colonization by gram-negative microbes. In fluoroquinolone-prophylaxed patients, Escherichia coli was more frequently observed as breakthrough, both in terms of intestinal colonization and BSIs, compared with nonprophylaxed patients. Initial colonization by members of Ruminococcaceae and Bacteroidetes were associated with protection against gram-negative BSI. CONCLUSIONS: Gram-negative intestinal colonization is highly predictive of BSI in the setting of allo-HCT. Fluoroquinolones appear to reduce these infections by influencing gut colonization.

Clinical efficacy of pneumococcal vaccination in multiple myeloma patients on novel agents: Results of a prospective clinical study.

INTRODUCTION: Among the high risk groups, patients with multiple myeloma (MM) have one of the highest incidence of invasive pneumococcal disease, mainly pneumonias. Recent changes in MM treatment have now led to an increase of survival, while the infection-related mortality remains high. The question of efficacy of pneumococcal vaccination in patients receiving novel target agents has not been clinically investigated before. PATIENTS AND METHODS: We have introduced the 3-dose vaccination regimen by 13-valent pneumococcal conjugate (PCV13) vaccine between the treatment courses with novel target agents (bortezomib, lenalidomide, ixazomib) with a minimum of 1 month interval. The incidence of pneumonias during the one-year observation period was taken as a primary outcome in this registered clinical trial. RESULTS: From 2017 to 2020, we have prospectively included 18 adult patients who were vaccinated by PCV13 along with 18 patients of a control matched group. No adverse effects of vaccination were registered in the study. We have observed an independent effect of PCV13 vaccination on the incidence of pneumonias. The absolute risk reduction of pneumonias in patients received PCV13 vaccination was 33.3%. Number needed to treat for PCV13 vaccination in multiple myeloma patients receiving novel agents was 3.0; (95% CI 1.61-22.1; p = 0.0571). CONCLUSION: Therefore, we have shown the clinical effectiveness of PCV13 vaccination schedule based on 3 doses given with a minimum 1 month interval between the courses of novel agents in multiple myeloma patients, despite the expected decrease in immunological response to vaccination during target and immunotherapy. ClinicalTrials.gov Identifier: NCT03619252.

Combination of sepsis biomarkers may indicate an invasive fungal infection in haematological patients.

Background: Invasive fungal infections are a major threat to a large cohort of immunocompromised patients, including patients with chemotherapy-associated neutropenia. Early differential diagnosis with bacterial infections is often complicated, which leads to a delay in empirical antifungal therapy and increases risk for adverse outcome. Accessibility and performance of specific fungal antigen and PCR-tests are still limited, while sepsis biomarkers are more broadly used in most settings currently. Methods: Haematological patients hospitalized to receive chemotherapy with proven or probable invasive fungal infection or microbiologically proven bacterial bloodstream infection were included in the study. C-reactive protein was assessed daily during the profound neutropenia period, while procalcitonin or presepsin were measured during the first 48 hours after the onset of febrile episode. Results: There were totally 64 patients included in the study, 53 with bacterial bloodstream infections and 11 with invasive fungal infections. Combination of CRP >120 with PCT <1.25 or presepsin <170 was shown to be a possible combined biomarker for invasive fungal infections in immunocompromised patients, with areas under the ROC-curves: 0.962 (95% CI 0.868 to 0.995) for PCT-based combination and 0.907 (95% CI 0.692 to 0.990) for presepsin-based combination.

Decolonization of Intestinal Carriage of MDR/XDR Gram-Negative Bacteria with Oral Colistin in Patients with Hematological Malignancies: Results of a Randomized Controlled Trial.

BACKGROUND: Intestinal colonization by MDR/XDR gram-negative bacteria leads to an increased risk of subsequent bloodstream infections (BSI) in patients receiving chemotherapy as a treatment for hematologic malignancies. OBJECTIVES: The objective of this study was to evaluate the efficacy of oral colistin in eradicating the intestinal carriage of MDR/XDR Gram-negative bacteria in patients with hematological malignancies. METHODS: In a tertiary hematology center, adult patients with intestinal colonization by MDR/XDR Gram-negative bacteria were included in a randomized controlled trial (RCT) during a period from November 2016 to October 2017. Patients were treated with oral colistin for 14 days or observed with the primary outcome set as decolonization on day 21 post-treatment. Secondary outcomes included treatment safety and changes in MICs of isolated microorganisms. ClinicalTrials.gov Identifier: NCT02966457. RESULTS: Short-time positive effect (61.3% vs 32.3%; OR 3.32; 95% CI 1.17-9.44; p=0.0241) was demonstrated on the day 14 of colistin treatment, without any statistical difference on day 21 post-treatment. The incidence of BSI in decolonization group was lower in the first 30 days after the intervention (3.2% vs. 12.9%), but overall in the 90-day observation period, it did not show any advantages comparing to control group (log-rank test; p=0.4721). No serious adverse effects or increase in resistance to colistin was observed. CONCLUSIONS: This study suggests that in hematological patients the strategy of selective intestinal decolonization by colistin may be beneficial to decrease the rate of MDR/XDR Gram-negative intestinal colonization and the risk of BSI in the short-term period, having no long-term sustainable effects.

Mesenchymal stem cells transplantation in hematological patients with acute graft-versus-host disease: characteristics and risk factors for infectious complications.

The role of MSCs in infection prevention and treatment is still discussed in transplant and hematological patients. The spectrum and risk factors for infections after MSCs transplantation in patients with acute GVHD have not been studied before. To determine the risk factors and spectrum of infectious complications in patients received mesenchymal stem cell transplantation as a treatment for acute GVHD. A prospective observational study was performed to evaluate the risk factors and characteristics of infectious complications after MSCs transplantation in adult patients having acute GVHD. Thirty-four episodes of MSCs transplantation in patients with acute GVHD after allogeneic HSCT were enrolled in the study. MSCs were given at a median dose of 1.32 (interquartile range 0.87-2.16) mln cells/kg per infusion at 91 days (interquartile range 31-131 days) after HSCT. Data relating to age, gender, date, and type of transplantation, characteristics of MSCs, infectious agents, and antimicrobial therapy and prevention regimens were prospectively collected in all of the enrolled patients. The episode of proven infectious complication was set as a primary outcome. There were totally 68 patients with acute GVHD in the study; among them there were 34 cases of MSCs transplantation performed. Among the registered infectious episodes were viral infections (CMV-associated disease, EBV-associated disease), invasive pulmonary aspergillosis, bacterial bloodstream infections, and pneumonia. MSCs transplantation has shown no statistically significant association with risk of infectious complications in patients with acute GVHD in a performed multivariate analysis. Among the most frequent infections in acute GVHD, we have described CMV, invasive aspergillosis, and bacterial infections (bloodstream infections or pneumonia). Among risk factors for infectious complications in patients with acute GVHD with/without MSCs transplantation are progression of main disease and neutropenia below 500 cells/mm3 (for aspergillosis) and unrelated HSCT in the past history and progression of main disease (for bacterial bloodstream infections and pneumonia).

Diagnostic value of sepsis biomarkers in hematopoietic stem cell transplant recipients in a condition of high prevalence of gram-negative pathogens.

OBJECTIVE/BACKGROUND: A decision about the need for antimicrobial therapy in a patient with febrile neutropenia after hematopoietic stem cell transplantation (HSCT) is often complicated because of the low frequency of culture isolation and reduced clinical manifestation of infection. Usefulness and choice of sepsis biomarkers to distinguish bloodstream infection (BSI) from other causes of febrile episode is still argued in HSCT recipients in modern epidemiological situations characterized by the emergence of highly resistant gram-negative microorganisms. In this study a comparative analysis of diagnostic values of presepsin, procalcitonin (PCT), and C-reactive protein (CRP) was performed as sepsis biomarkers in adult patients after HSCT in a condition of high prevalence of gram-negative pathogens. METHODS: A prospective observational clinical study was performed at the Center of Hematology and Bone Marrow Transplantation in Minsk, Republic of Belarus. The biomarkers (presepsin, PCT, and CRP) were assessed in a 4-hour period after the onset of febrile neutropenia episode in adult patients after HSCT. Microbiologically-confirmed BSI caused by a gram-negative pathogen was set as a primary outcome. RESULTS: Clinical and laboratory data were analyzed in 52 neutropenic patients after HSCT aged 18-79years. Out of the biomarkers assessed, the best diagnostic value was shown in presepsin (area under the curve [AUC]: 0.889, 95% confidence interval [CI]: 0.644-0.987, p<.0001) with 75% sensitivity and 100% specificity, then in PCT (AUC: 0.741, 95% CI: 0.573-0.869, p=.0037) with 62% sensitivity and 88% specificity. The optimal cut-off value for CRP was set as 165mg/L, while it had an average diagnostic value (AUC: 0.707, 95% CI: 0.564-0.825, p=.0049) with low sensitivity (40%) and should not be routinely recommended as a biomarker in adult patients with suspected BSI after HSCT. CONCLUSION: Presepsin may be recommended in adult patients with suspected gram-negative BSI after HSCT as a possible additional supplementary test with a cut-off value of 218pg/mL. PCT is inferior to presepsin in terms of sensitivity and specificity, but still shows a good quality of diagnostic value with an optimal cut-off value of 1.5ng/mL. CRP showed an average diagnostic value with low sensitivity (40%) and should not be routinely recommended as a biomarker in adult patients with suspected BSI after HSCT in a condition of high prevalence of gram-negative pathogens.

Risk factors for mortality in patients with bloodstream infections during the pre-engraftment period after hematopoietic stem cell transplantation.

BACKGROUND: Bloodstream infections (BSI) remain a frequent complication during the pre-engraftment period after hematopoietic stem cell transplantation (HSCT), resulting in high mortality rates. This study evaluated risk factors for mortality in hematopoietic stem cell transplant recipients with BSI in the pre-engraftment period. METHODS: This prospective case control study was performed at the Center of Hematology and Bone Marrow Transplantation in Minsk, Republic of Belarus. Data relating to patient age and gender, date and type of transplantation, conditioning chemotherapy regimen, microorganisms isolated from blood, and antibacterial therapy were prospectively collected from all hematopoietic stem cell recipients with microbiologically proven cases of BSI in the pre-engraftment period. The primary outcome was all-cause 30-day mortality after onset of febrile neutropenia. RESULTS: A total of 135 adult patients with microbiologically proven BSI after HSCT were studied, with 65.2% of cases caused by gram-negative microorganisms and 21.5% by non-fermenting bacteria. Inadequate empiric antibacterial therapy and isolation of carbapenem-resistant non-fermenting gram-negative bacteria (Acinetobacter baumannii and Pseudomonas aeruginosa) were independently associated with increased all-cause 30-day mortality in these patients. CONCLUSION: The risk factors for mortality in adult patients with BSI in the pre-engraftment period after HSCT were inadequacy of empirical antibacterial therapy and isolation of carbapenem-resistant A. baumannii or P. aeruginosa.