Rate Of Severe Infections Research Articles

Metabolic Dysfunction-Associated Steatotic Liver Disease Increases the Risk of Severe Infection: A Population-Based Cohort Study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to various intrahepatic and extrahepatic diseases, but its association with severe infectious disease remains to be investigated. We analysed data from the Shanghai Suburban Adult Cohort and Biobank, encompassing participants enrolled in 2016 and 2017 with available abdominal ultrasonography data, and followed them up until December 2022 (median follow-up = 5.71 years). We categorised the participants into the MASLD group and those without steatotic liver disease (non-SLD). Multivariable-adjusted Cox regression was used to estimate hazard ratios (HR) for severe infections in patients with MASLD compared to the non-SLD group. Cumulative incidences were calculated while accounting for competing risks (non-infection-related deaths). Mediation analyses were performed to explore the roles of cardiometabolic risk factors in the association between MASLD and severe infections. Among the 33 072 eligible participants (mean age 56.37 years; 38.20% male), 11 908 (36.01%) were diagnosed with MASLD at baseline. Severe infections occurred in 912 (7.66%) MASLD patients and 1258 (5.94%) non-SLD. The rate of severe infections per 1000 person-years was higher in MASLD patients (13.58) than in comparators (10.48) (fully adjusted HR 1.18, 95% CI 1.07-1.30). The most frequent infections in MASLD were respiratory (7.25/1000 person-years) and urinary tract infections (2.61/1000 person-years). The 5-year cumulative incidence of severe infections was 6.79% (95% CI 6.36-7.26) in MASLD and 5.08% (95% CI 4.79-5.38) in comparators. Cardiometabolic risk factors, including waist circumference, triglycerides and HbA1C, partially mediate the association between MASLD and severe infections. Patients with MASLD were at significantly higher risk of incident severe infections compared to the non-SLD group. Future studies are needed to elucidate the mechanisms linking MASLD to severe infections.

When Chinese patients with plasma cell disorders encountered the nationwide Omicron outbreak (December 2022): a real-world multicenter and multiregional study.

This study aims to assess the impact of the nationwide Omicron outbreak in December 2022 on Chinese patients with plasma cell disorders (PCD), focusing on the clinical characteristics of PCD patients with COVID-19 and the risk factors contributing to adverse clinical courses (severity and hospitalization) and outcomes. A multicenter retrospective study was performed from December 1, 2022, to January 19, 2023. The study population includes 404 PCD patients, divided into a COVID-19 group (n = 342) and an uninfected group (n = 62). The frequency of COVID-19 infection was 84.7% (342/404), and 16.4% (56/342) were severe COVID-19. Among the 277 patients with complete follow-up, 2 deaths (0.7%) were reported, while 231 (83.4%) recovered from COVID-19. Age > 65 (P = 0.02) and prior anti-CD38 monoclonal antibody (mAb) treatment within six months (P = 0.03) were independent risk factors for severe infection. Additionally, previous chimeric antigen receptor T-cell (CAR-T) therapy within six months was correlated with a higher risk of hospitalization (P = 0.04) and prolonged recovery time (P = 0.03). No significant protective effect of vaccination on infection or severe infection was observed (P > 0.05). The latest Omicron outbreak results in higher rates of severe infection and mortality in PCD patients compared with the general population in China, highlighting the need to protect this vulnerable population during the pandemic. Recent use of anti-CD38 mAb and CAR-T therapy are associated with poorer clinical courses and outcomes of PCD patients with COVID-19.

Investigation of infections status in pediatric patients with acute myeloid leukemia during the induction period-a retrospective study in two medical centers.

This study aims to investigate the clinical characteristics of infections following induction chemotherapy for acute myeloid leukemia (AML) in children and identify risk factors associated with severe infections. Newly diagnosed children with AML treated at the Hematology Oncology Center of Beijing Children's Hospital affiliated to Capital Medical University (referred to as the "Beijing ward") and Baoding Hospital of Beijing Children's Hospital (referred to as the "Baoding ward") between November 2019 and August 2022 were enrolled. The diagnosis and treatment of the patients were carried out in accordance with the CCLG-AML 2019 protocol. Their essential information and infection-related indicators were collected. The various indicators between the two centers were compared. The incidence of infection in children with AML was 100%, with a severe infection rate of 15.3% and an infection-related mortality rate of 2.4%. Respiratory infections accounted for 39.7% of all infections events, and unspecified site infection for 32.2%. Bacterial infections were predominant at 51.2%. The bed unit area (BUA) varied significantly with 4.1 m2 in the Beijing ward and 10 m2 in the Baoding ward. Significant differences were observed in gastrointestinal infections (P < 0.001) and severe infections (P = 0.014) between the two wards. Several factors were identified as risk factors for severe infections, including BUA difference (OR = 4.353, 95% CI: 1.078-17.578), time of entering neutropenia phase after chemotherapy (OR = 6.369, 95% CI: 1.713-23.675) and bloodstream infection (OR = 7.466, 95% CI: 1.889-29.507). Respiratory tract infections and infections of unspecified site are most common during induction phase for pediatric AML. Bacteria, especially G- bacteria, are the leading pathogens. Risk factors for severe infections include a small BUA, entering neutropenia phase ≤ 5.5days after chemotherapy, and bloodstream infection. Recognizing these risk factors can aid in the early identification and intervention of severe infections.

Exploring the Relationship Between Cannabis Use And COVID-19 Outcomes.

Background: Cannabis use is becoming increasingly prevalent worldwide, yet the full spectrum of its effects largely remain unknown. Although cannabis have immunomodulatory properties, there remains a significant gap in our understanding of the potential impact of marijuana use on COVID-19 outcomes. The purpose of this study is to evaluate the effect of chronic cannabis use on severe COVID-19. Materials and Methods: National Inpatient Sample Database was used to sample individuals admitted with the diagnosis of COVID-19. Patients were divided into two groups based on cannabis use. Baseline demographics and comorbidities were collected using ICD-10 codes. Patients with missing data or age under 18 were excluded. Propensity matching using R was performed to match cannabis users to non-cannabis users 1:1 on age, race, gender, and 17 other comorbidities. The primary outcome was severe COVID-19 infection, defined as a composite of acute respiratory failure, intubation, acute respiratory distress syndrome (ARDS), or severe sepsis with multiorgan failure. Results: Out of 322,214 patients included in the study, 2,603 were cannabis users. Cannabis users were younger and had higher prevalence of tobacco use. On initial analysis, cannabis users had significantly lower rates of severe COVID-19 infection, intubation, ARDS, acute respiratory failure, severe sepsis with multiorgan failure, mortality, and shorter length of hospital stay. After 1:1 matching, cannabis use was associated with lower rates of severe COVID-19 infection, intubation, ARDS, acute respiratory failure, severe sepsis with multiorgan failure, mortality, and shorter length of hospital stay. Conclusion: Cannabis users had better outcomes and mortality compared with non-users. The beneficial effect of cannabis use may be attributed to its immunomodulatory effects.

Ofatumumab in the treatment of multiple sclerosis - A summary of preclinical and clinical data

B-cell targeted therapies are highly effective in multiple sclerosis (MS). Most of these therapies are administered intravenously at long intervals. Ofatumumab, an anti-CD20 antibody that is administered subcutaneously at low doses on a monthly basis due to its high affinity to the target structure, became available for the treatment of MS in 2021. An overview of practice-relevant immunological and clinical data on ofatumumab is provided. The high affinity of ofatumumab to the target structure allows low dose and low volume administration, with the release and absorption profile after subcutaneous application allowing for high concentrations in the lymph nodes and gradual depletion of B-cells. Rapid onset of action is achieved as well as B-cell repletion within a few months in case of discontinuation of therapy. Long-term data show stable IgG levels over up to four years and high efficacy with respect to relapse rate, progression, and cognition. According to current study data, the effect compared to teriflunomide is greater the earlier therapy is initiated. Ofatumumab has a specific B-cell depletion pattern. CD20 expressing B-cell progenitor cells in the bone marrow are preserved and therefore also the inducibility and differentiation of plasma cells. The formation of a humoral immunological memory is therefore possible. Four-year study data showed no abnormalities in the rate of severe infections or malignancies. Ofatumumab is an innovative B-cell targeted therapy. It is highly effective with a good safety and tolerability profile, well controllable and maintains immunocompetence against pathogens.

Impact of the COVID-19 Pandemic on Conduct and Results of CLEAR Outcomes Trial.

The COVID-19 pandemic disrupted clinical research. CLEAROutcomes investigated the effect of bempedoic acid (BA) versus placebo in 13 970 patients with statin intolerance and high cardiovascular (CV) risk. BA reduced the risk of the primary endpoint (composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13%. CLEAROutcomes began beforeand continued for 2.7 years afterthe start of the pandemic. The impact of the COVID-19 pandemic on patient disposition, adverse events, and major adverse CV events (MACE) in CLEAROutcomes was assessed. Rates of severe infection, hospitalization, or first MACE associated with a positive COVID-19 test were low and balanced between treatment groups. Rates of all-cause death, non-CV death, and undetermined death increased in the pandemic period compared with the pre-pandemic period, while rates of CV death with a known etiology remained stable. A sensitivity analysis excluding undetermined deaths occurring after the onset of the pandemic from the CV death designation yielded hazard ratios of 0.84 (95% CI, 0.76-0.93) for the primary endpoint and 0.94 (95% CI, 0.76-1.16) for the secondary endpoint of CV death, compared with 0.87 (95% CI, 0.79-0.96) and 1.04 (95% CI, 0.88-1.24), respectively, in the original analysis. The CLEAR Outcomes trial continued uninterrupted throughout the COVID-19 pandemic. Certain trial endpoints may have been impacted by the pandemic. Specifically, the classification of undetermined deaths as CV deaths may have attenuated the effect of BA on key efficacy endpoints.

Optimum tacrolimus trough levels for enhanced graft survival and safety in kidney transplantation: a retrospective multicenter real-world evidence study.

The current study aimed to determine the optimal tacrolimus trough levels for balancing graft survival and patient safety following kidney transplantation. We conducted a retrospective cohort study involving 11,868 kidney transplant recipients from five medical centers. The association between tacrolimus exposures (periodic mean trough level, coefficient of variability, time in therapeutic range) and composite allograft outcome (de novo donor specific antibody, biopsy-proven rejection, kidney dysfunction, and graft failure), as well as safety outcomes (severe infection, cardiovascular events, malignancy, and mortality) were assessed. Data were sourced from Clinical Data Warehouses and analyzed using advanced statistical methods, including Cox marginal structural models with inverse probability treatment weighting. Tacrolimus levels of 5.0-7.9ng/mL and 5.0-6.9ng/mL during the 2-12 month and 12-72 month post-transplantation periods, respectively, were associated with reduced risks of composite allograft outcomes. During the first post-transplant year, the adjusted hazard ratios (aHR) for composite allograft outcomes were: 0.69 (95% CI 0.55-0.85, P<0.001) for 5.0-5.9ng/mL; 0.81 (95% CI 0.67-0.98, P=0.033) for 6.0-6.9ng/mL; and 0.73 (95% CI 0.60-0.89, P=0.002) for 7.0-7.9ng/mL (compared to levels ≥8.0ng/mL). For the 6-year composite outcomes, aHRs were 0.68 (95% CI 0.53-0.87, P=0.002) for 5.0-5.9ng/mL and 0.65 (95% CI 0.50-0.85, P=0.001) for 6.0-6.9ng/mL. These optimal ranges showed reduced rates of severe infection (6y), malignancy (6y), and mortality (1y). This multicenter study provides robust evidence for optimal tacrolimus trough levels during the periods 2-12 and 12-72 months following kidney transplantation.

Comparison of infectious complications with BCMA-directed therapies in multiple myeloma

B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25−0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31−3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05–3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21−0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17–0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.

#1720 Insights from sodium-glucose transport 2 (SGLT2) inhibitors treatment in patients with systemic lupus erythematosus

Abstract Background and Aims Kidney involvement is common among patients with systemic lupus erythematosus (SLE) and it is an important cause of morbidity and mortality among this population. Recently, the EULAR 2023 update of the recommendations for the management of SLE advised considering the use of sodium-glucose transport 2 inhibitors (SGLT2i) as kidney protective agents in patients with chronic kidney disease with reduced glomerular filtration rate (GFR). Aims: To assess clinical characteristics and outcomes of Israeli patients with SLE treated with SLGT2i. Method This retrospective study, conducted between 2014–2023, included adult patients with SLE diagnosed for at least 12 months. Patients receiving SGLT2i for a duration of three months or longer were compared with a control group consisting of patients who were not treated with these agents. Associated variables were assessed including disease-related characteristics, kidney-related factors, and comorbidities such as diabetes and heart failure. Clinical outcomes including severe infections, hospitalizations, and all-cause mortality were recorded. Repeated measures analysis model was applied to compare the estimated GFR (eGFR) at different time points (before diagnosis, at diagnosis, and at the last follow-up), among the SGLT2i-treated patients and controls. Protein to creatinine ratio was compared before starting treatment with SGLT2i and on treatment at the last follow-up. Results A total of 165 consecutive patients were included in this analysis, with a mean follow-up from SLE diagnosis of 15.6 ± 11.8 years. Of them, 7 were treated chronically with SGLT2i and had available data. While age at SLE diagnosis was comparable between the two groups (29.8 ± 12.2 years in the SGLT2i group and 32.6 ± 14.3 years in controls, p = 0.6), SGLT2i treated patients were significantly older at last follow-up (62.1 ± 13.5 years vs. 47.3 ± 16.3 years, p = 0.019), and as a consequence, the duration of follow-up since SLE diagnosis was longer among them (26.2 ± 11 years vs. 15.3 ± 11.7 years in the controls, p = 0.04). Diabetes was diagnosed in 16 out of 165 patients (9.7%), and 5 out of 7 patients treated with SGLTi were diabetic (71.4% vs. 7.0% in controls, p &amp;lt; 0.01). Heart failure was diagnosed in 7.3% of the cohort, and was more prevalent among the SGLTi group (28.6% vs 6.3% in controls, p = 0.03). Only 26.6% of patients with diabetes and 16.7% of patients with heart failure were treated with SGLTi. On repeated measures analysis, eGFR decreased significantly during the study period (p = 0.043, Fig. 1). The decline in eGFR throughout the study period was comparable between the groups. Protein to creatinine ratio decreased significantly in the SGLTi-treated patients after starting treatment (1516 ± 1685 mg/g before treatment vs. 611 ± 875 mg/g after treatment, p = 0.05). The prevalence of severe infections requiring hospitalization was comparable between groups (28.6% in SGLTi vs 29.9% in controls, p = 0.9). Hospitalizations for SLE exacerbations, as well as hospitalization for cardiovascular events, were similarly comparable between groups (28.6% vs, 28.5%, p = 0.9 and 14.3% vs. 15.3%, p = 0.9; respectively). During the study period, 10 patients developed end-stage kidney disease and 11 patients died, with no significant difference between groups. Conclusion While the SGLT2i-treated patients were older and had higher rates of comorbidities such as diabetes, chronic kidney disease, and heart failure, a similar rate of kidney function decline was observed in both SGLT2i-treated patients and controls. Additionally, a comparable rate of severe infections was found in both groups of patients. This relatively small cohort could support the use of these kidney and heart protective agents in patients with SLE and kidney involvement. A special consideration should be given to patients with comorbid diabetes and heart failure.

Prognostic analysis of childhood T-lymphoblastic lymphoma treated with leukemia regimen

To investigate the prognosis of childhood T-lymphoblastic lymphoma (T-LBL) treated with acute lymphoblastic leukemia (ALL) regimen and related influencing factors. A retrospective analysis was performed for the prognostic characteristics of 29 children with T-LBL who were treated with ALL regimen (ALL-2009 or CCCG-ALL-2015 regimen) from May 2010 to May 2022. The 29 children with T-LBL had a 5-year overall survival (OS) rate of 84%±7% and an event-free survival (EFS) rate of 81%±8%. The children with B systemic symptoms (unexplained fever >38°C for more than 3 days; night sweats; weight loss >10% within 6 months) at initial diagnosis had a lower 5-year EFS rate compared to the children without B symptoms (P<0.05). The children with platelet count >400×109/L and involvement of both mediastinum and lymph nodes at initial diagnosis had lower 5-year OS rates (P<0.05). There were no significant differences in 5-year OS and EFS rates between the children treated with CCCG-ALL-2015 regimen and those treated with ALL-2009 regimen (P>0.05). Compared with the ALL-2009 regimen, the CCCG-ALL-2015 regimen reduced the frequency of high-dose methotrexate chemotherapy and the incidence rate of severe infections (P<0.05). The ALL regimen is safe and effective in children with T-LBL. Children with B systemic symptoms, platelet count >400×109/L, and involvement of both mediastinum and lymph nodes at initial diagnosis tend to have a poor prognosis. Reduction in the frequency of high-dose methotrexate chemotherapy can reduce the incidence rate of severe infections, but it does not affect prognosis.

Retrospective clinical study on cryopreservation-free integrated autologous hematopoietic stem cell transplantation model for newly diagnosed multiple myeloma

Objective: To explore the efficacy and safety of cryopreservation-free integrated autologous hematopoietic stem cell transplantation (HSCT) model for patients with multiple myeloma. Methods: A total of 96 patients with newly diagnosed multiple myeloma (NDMM) between July 31, 2020, and December 31, 2022, were retrospectively analyzed, of which 41 patients in the observation group received integrated non-cryopreserved transplantation mode. After hematopoietic stem cells were mobilized and collected, melphalan was started immediately for pre-transplant conditioning, and non-cryopreserved grafts from the medical blood transfusion refrigerator were directly injected intravenously into the patient within 24-48 h after the melphalan conditioning. The control group consisted of 55 patients who received traditional transplantation mode. After hematopoietic stem cells were collected, stem cell cryopreservation was performed in liquid nitrogen, and then the transplant plans were started at the right time. All patients received mobilization of autologous hematopoietic stem cells using the G-CSF combined with the plerixafor. Results: ① A total of 34 patients (82.9% ) with VGPR plus CR in the observation group were significantly higher than 33 patients (60.0% ) in the control group (P=0.016). ②Compared with the control group, the incidence of grade 1 oral mucosal inflammation was higher in the observation group (P<0.001) ; however, the incidence of grades 2 and 3 oral mucosal inflammation was lower (P=0.004, P=0.048), and neither group experienced grade 4 or above oral mucosal inflammation. The incidence of grade 1 diarrhea was higher in the observation group (P=0.002), whereas the incidence of grade 3 diarrhea was lower (P=0.007). No statistically significant difference was observed in the incidence of grade 4 diarrhea (P=0.506), and neither group experienced grade 5 diarrhea. ③ The incidence of bacterial infection in the observation group was lower than that in the control group (34.1% vs 65.5%, P=0.002), whereas no statistically significant difference was observed in the incidence of fungal infection (29.3% vs 31.4%, P=0.863) and viral infection (4.88% vs 3.64%, P=0.831). ④No statistically significant difference was observed in the implantation time of granulocytes and platelets between the observation and control groups [10 (8-20) days vs 11 (8-17) days, P=0.501; 13 (10-21) days vs 15 (10-20) days, P=0.245]. ⑤ All patients did not receive lenalidomide treatment 100 days post-transplantation. At 30 days post-transplantation, the CTL, NK, and Th cell counts in the observation group were lower than those in the control group (P<0.001, P=0.002, P=0.049), and the NKT cell counts were higher than those in the control group (P=0.024). At 100 days post-transplantation, the CTL, NKT, and Th cell counts in the observation group were higher than those in the control group (P=0.025, P=0.011, P=0.007), and no statistically significant difference in NK cell counts was observed between the two groups (P=0.396). ⑥ The median follow-up was 18 (4-33) months. The overall 2-year survival rates of the observation and control groups post-transplantation were 91.5% and 78.2%, respectively (P=0.337). The recurrence-free survival rates were 85.3% and 77.6%, respectively (P=0.386), and the cumulative recurrence rates were 9.8% and 16.9%, respectively (P=0.373) . Conclusion: In NDMM, the cryopreservation-free integrated autologous HSCT model can achieve similar therapeutic effects as traditional transplantation models, with lower rates of severe mucosal inflammation and infection compared with traditional transplantation models.

Current perspective on infections and mitigation strategies in primary systemic vasculitis.

The purpose of this review is to summarize and evaluate most recent evidence on the epidemiology of infections and associated risk factors in patients with primary systemic vasculitides (PSV), as well as discuss mitigation strategies including the risk of antibiotic prophylaxis. Infections remain one of the leading causes of mortality in patients with PSV, with rates of severe infection ranging from 16 to 40% in different cohorts. Older age, frailty, renal and pulmonary involvement, and higher burden of comorbidities have been recognized as important patient-associated risk factors. Treatments including higher cumulative doses of glucocorticoids are associated with an increased risk of infections, and recent studies show the potential benefit of interventions such as reduced-dose glucocorticoid regimens. Existing mitigation strategies include screening, vaccination, and infection prophylaxis. The latter remains particularly important for Pneumocystis jirovecii pneumonia; however, the benefit-risk ratio seems to be less clear outside of induction phase (i.e., high dose of glucocorticoids) and optimal treatment duration remains less clear. Patients with PSV are at increased risk of infections, due to disease itself, comorbidities, and treatment side effects. Awareness of the timing and types of infection, as well as mitigation strategies are imperative to ensure treatment success and survival for patients.

Patients with aggressive B-cell lymphoma receiving CAR T-cell therapy have a low rate of severe infections despite lack of universal antibacterial and antifungal prophylaxis.

Our aim was to describe the frequency and severity of infectious complications after chimeric antigen receptor (CAR) T-cell therapy in patients with large B-cell lymphoma (LBCL). We retrospectively reviewed clinical records of LBCL patients treated with CD19-targeted CAR T-cell therapy from July/2018 to December/2021 at our institution, and identified all infectious episodes from CAR T-cell infusion until disease progression, death or last follow-up. Overall, 137 patients were included. Thirty six percent had received ≥3 previous lines of therapy and 26% an autologous hematopoietic cell transplantation (auto-HCT). Cytokine release syndrome occurred in 87 (64%) patients. Antibacterial prophylaxis was not used in any patient; only 38% received antifungal prophylaxis. Sixty three infectious events were observed in 41 (30%) patients. Fifty two (83%) of the infectious events had at least one pathogen identified (bacteria [n = 38], virus [n = 11], and fungi [n = 3]). Most of the infectious events occurred during hospitalization for CAR-T treatment. Infection-related mortality was observed in two patients. Independent risk factors for infection included male gender, previous auto-HCT, ≥3 lines of treatment and pre-lymphodepletion neutropenia. Infections after CAR T-cell therapy in patients with lymphoma are frequent but generally not severe. A conservative and tailored antimicrobial prophylaxis seems to be a safe approach.

Burden and distribution of mortality due to sepsis and severe infection in children and adolescents in Aotearoa/New Zealand.

The aims of this research were to determine the mortality from sepsis and severe infection in the paediatric and adolescent populations of Aotearoa/New Zealand, and to determine the distribution of mortality by sub-populations. We used three different methods to identify deaths from sepsis and severe infection and compared the groups: All deaths primarily coded with any ICD-10-AM code relating to sepsis; The presence of A40, A41 and P36 in any cause of death field; Deaths due to pneumonia and meningitis. Cases were selected from a national mortality database, with cause of death as ascribed in the national mortality collection for the years 2002-2020 inclusive. Overall sepsis and severe infection rates were calculated from the sum of unique cases from all three methods for determining sepsis and severe infection cases. Substantially different results were obtained depending on the method of identifying cases. In total, 577 deaths due to sepsis and severe infection were detected, with an overall rate of 1.99/100 000 age-specific population and statistically significant disparity by ethnic grouping. Rates were highest in post-neonatal infants at 22.7 per 100 000, regardless of the method of identification. There is a considerable opportunity to improve the mortality from sepsis and severe infection in children and young people. The ethnic disparities described in this paper show the need to ensure a high level of care for those most marginalised in society through the development and provision of systems and structures that meet, rather than fail to meet need.

Secondary infections and long-term outcomes among hospitalized elderly and non-elderly patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and treated with baricitinib: a comparative study from the national centre of Hungary

Baricitinib is considered a first-line treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected adult patients with an associated cytokine storm syndrome (CSS). Our objective was to compare rates of secondary infections and long-term outcomes of elderly and non-elderly patients who received baricitinib for COVID-19. We conducted a single-centre observational study between November 2020 and September 2023, focusing on hospitalized adult SARS-CoV-2 patients with CSS, categorized as elderly (≥ 65 years) and non-elderly (< 65 years). Enrolment, severity stratification, and diagnosis of infectious complications followed predefined criteria. Outcomes of all-cause mortality and rates of non-severe and severe secondary infections were assessed at 1-year post-treatment initiation. Kaplan–Meier analysis was performed for survival analysis. In total, 490 patients were enrolled (median age 65 ± 23 (21–100) years (years, median ± IQR, min–max); 49.18% elderly; 59.59% male). Elderly patients were admitted to the hospital significantly earlier (7 ± 5 days vs. 8 ± 4 days; p = 0.02), experienced a higher occurrence of severe COVID-19 (121/241, 50.21% vs. 98/249, 39.36%; p = 0.02), and required the use of non-invasive ventilation at baseline (167/225, 74.22% vs. 153/236, 64.83%; p = 0.03). At 1 year, all-cause mortality was significantly higher in the elderly subgroup (111/241, 46.06% vs. 29/249, 11.65%; p < 0.01). At 90 days and 1 year, rates of any severe secondary infection were also more prevalent among the elderly (56/241, 23.24% vs. 37/249 14.86%; p = 0.02 and 58/241, 24.07% vs. 39/249, 15.66%; p = 0.02). In conclusion, elderly SARS-CoV-2-infected patients experience a more severe clinical course, higher secondary infection rates, and increased risk for long-term mortality, regardless of immunomodulatory therapy.

Fewer severe infections with tranexamic acid in patients with hematologic malignancies

BackgroundTranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty. ObjectivesTo address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies. MethodsWe performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901). ResultsTXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease. ConclusionPatients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population.

COVID-19 outcomes in patients with multiple sclerosis: Understanding changes from 2020 to 2022

Background: Epidemiologic studies on coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (pwMS) have focused on the first waves of the pandemic until early 2021. Objectives: We aimed to extend these data from the onset of the pandemic to the global coverage by vaccination in summer 2022. Methods: This retrospective, multicenter observational study analyzed COVISEP registry data on reported COVID-19 cases in pwMS between January 2020 and July 2022. Severe COVID-19 was defined as hospitalization or higher severity. Results: Among 2584 pwMS with confirmed/highly suspected COVID-19, severe infection rates declined from 14.6% preomicron wave to 5.7% during omicron wave (p < 0.001). Multivariate analysis identified age (odds ratio (OR) = 1.43, 95% confidence interval (CI) = [1.25–1.64] per 10 years), male sex (OR = 2.01, 95% CI = [1.51–2.67]), obesity (OR = 2.36, 95% CI = [1.52–3.68]), cardiac comorbidities (OR = 2.36, 95% CI = [1.46–3.83]), higher Expanded Disability Status Scale (EDSS) scores (OR = 2.09, 95% CI = [1.43–3.06] for EDSS 3–5.5 and OR = 4.53, 95% CI = [3.04–6.75] for EDSS ⩾6), and anti-CD20 therapies (OR = 2.67, 95% CI = [1.85–3.87]) as risk factors for COVID-19 severity. Vaccinated individuals experienced less severe COVID-19, whether on (risk ratio (RR) = 0.64, 95% CI = [0.60–0.69]) or off (RR = 0.32, 95% CI = [0.30–0.33]) anti-CD20. Discussion: In pwMS, consistent risk factors were anti-CD20 therapies and neurological disability, emerging as vital drivers of COVID-19 severity regardless of wave, period, or vaccination status.

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

AbstractCytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post–CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies.

Teclistamab in relapsed or refractory AL amyloidosis: a multinational retrospective case series

Teclistamab shows promising results in R/R AL amyloidosis, with VGPR or better in 88% of patients and involved FLC < 10 mg/L in 76%. We observed a 35% rate of severe infections and no cardiac or kidney related events.

The Role of Intravenous Immunoglobulin (IVIG) in Reducing Infection Risk in Multiple Myeloma (MM) Patients Receiving Immune-Based Therapies: A Single Center Experience

Introduction Immune-based therapies, including the anti-CD38 antibody daratumumab (Dara), and most recently bispecific antibodies (BsAb) targeting CD3 and BCMA, GPRC5D or FCRH5 are increasingly important strategies used to treat Multiple Myeloma. However, there are concerns that the prolonged use of these therapies predisposes patients (pts) to increased rates of infection, partly due to hypogammaglobulinaemia. To this date, most clinical trials on Dara and BsAb do not consistently capture rates of hypogammaglobulinaemia and leaves the use of intravenous immunoglobulin (IVIg) as prophylaxis to individual investigator discretion. There are currently a paucity of studies documenting IVIg as a means to reduce infection risk in these pts. Patient and Methods All patients with MM who started Dara or BsAb therapy at St Vincent's Hospital Melbourne from Jan 2021 to Dec 2022 were included in this retrospective chart review. Patients who received more than 2 months of treatment were included. The evaluation period for each patient began at the time of first Dara or BsAb dose and ended at the cut-off date of 28 th June 2023. The two time periods were “ON IVIg” defined as any time within 30 days of last IVIg administration and “OFF IVIg” defined as any time &amp;gt;30 days from last IVIg administration. The primary outcome was the incidence rate of all grade infections (expressed in events/person-year) during periods of ON IVIg vs OFF IVIg. Secondary outcomes included incidence rate of severe infection (CTCAE Grade 3-5). Incidence rate ratios (IRR) and the corresponding 95% confidence intervals were calculated using the Exact Poisson method. Results A total of 52 Dara or BsAb treated pts were identified of which 7 were excluded due to treatment cessation from progressive disease within 2 months. The remaining 45 pts were included in the study of which 16 were on Dara, 16 on a BCMA BsAb and 13 on a non-BCMA BsAb. All 16 of the patients on Dara received Dara as a triplet combination. Median age was 65 (IQR 59-70), 25 (56%) were male and median prior lines of therapy received was 1 (IQR 1-3). At the start of treatment, 34 pts (76%) had documented hypogammaglobinaemia of which 12 (27%) had severe hypogammaglobinaemia (defined uninvolved IgG &amp;lt;4.0 g/L). Median functional IgG was 5.0 g/L (IQR 3.9-6.5). Eleven pts (24%) were already on IVIG prior to Dara or BsAb therapy and a further 18 (40%) were commenced on IVIG during the course of treatment. At the cut-off date, 30 (67%) pts were still receiving Dara or BsAb therapy. Median time on treatment was of 8.94 months (IQR 5.06-14.30). The proportion of time ON IVIg for the cohort was 53%. Patient receiving BsAb spent a greater proportion of time ON IVG than patients receiving Dara-based therapy (56% vs 42%, p &amp;lt;0.002). There were 95 all grade infections during the evaluated period, most commonly in the respiratory tract; upper respiratory tract infections (36%), lower respiratory tract infections (31%) and COVID-19 (12%). There were 15 documented severe infections of which 10 occurred during the OFF IVIG period. There were no infection related deaths. The median time to first infection from commencement of Dara or BsAb was 3.12 (IQR 1.25-5.61) months. The rate of all grade infections ON IVIG was 1.54 (95% CI 1.07-2.15) per person years and lower compared to 2.56 (1.95-3.29) per person years OFF IVIG with IRR of 0.60 (95% CI 0.39-0.93; p=0.016) (figure 1). Rate of severe infections was 0.22 (0.07-0.51) and 0.43 (0.20-0.78) per person years respectively with IRR of 0.52 (0.14-1.66; p=0.234). BsAb therapy had a higher all grade infection rate vs Dara-based therapy; 2.86 (2.23-3.62) vs 1.39 (0.91-2.03) per person years respectively; IRR 2.06 (1.30-3.38; p=0.001) Conclusion There are high rates of pre-existing hypogammaglobinaemia in MM patients even during early lines of treatment. The use of IVIG during immune-based therapies appears to significantly reduce the yearly rate of all grade infections by 40% in our cohort. Differences between the rates of severe infection ON IVIg and OFF IVIg are not significant due to small number of events. Further prospective studies are needed to confirm these findings, towards an evidence-based approach in IVIg support for patients with myeloma on novel immunotherapies.