Cumulative Incidence Of Infection Research Articles

Impacts of testing and immunity acquired through vaccination and infection on covid-19 cases in Massachusetts elementary and secondary students

BackgroundDuring the 2021–22 academic year, Massachusetts supported several in-school testing programs to facilitate in-person learning. Additionally, COVID-19 vaccines became available to all school-aged children and many were infected with SARS-CoV-2. There are limited studies evaluating the impacts of these testing programs on SARS-CoV-2 cases in elementary and secondary school settings. The aim of this state-wide, retrospective cohort study was to assess the impact of testing programs and immunity on SARS-CoV-2 case rates in elementary and secondary students.MethodsCommunity-level vaccination and cumulative incidence rates were combined with data about participation in and results of in-school testing programs (test-to-stay, pooled surveillance testing). School-level impacts of surveillance testing programs on SARS-CoV-2 cases in students were estimated using generalized estimating equations within a target trial emulation approach stratified by school type (elementary/middle/high). Impacts of immunity and vaccination were estimated using random effects linear regression.ResultsHere we show that among N = 652,353 students at 2141 schools participating in in-school testing programs, surveillance testing is associated with a small but measurable decrease in in-school positivity rates. During delta, pooled testing positivity rates are higher in communities with higher cumulative incidence of infection. During omicron, when immunity from prior infection became more prevalent, the effect reversed, such that communities with lower burden of infection during the earlier phases of the pandemic had higher infection rates.ConclusionsTesting programs are an effective strategy for supporting in-person learning. Fluctuating levels of immunity acquired via natural infection or vaccination are a major determinant of SARS-CoV-2 cases in schools.

Comparing optimum prosthesis combinations of total stemmed, stemless and reverse shoulder arthroplasty revision rates for men and women with glenohumeral osteoarthritis

BackgroundThis study investigated prostheses from a large national arthroplasty registry with the lowest rates of revision, defined as optimum. We compared optimum shoulder arthroplasty revision rates for osteoarthritis (OA) to determine the most suitable/effective procedure for men and women. MethodsThere were three cohort groups of optimum primary shoulder arthroplasties for OA undertaken between 1st January 2008 and 31 December 2022: stemless shoulder arthroplasty with cemented polyethylene glenoids (slTSA), stemmed shoulder arthroplasty with modified central peg polyethylene glenoids (stTSA), and cementless reverse shoulder arthroplasty (rTSA). The cumulative percent revision (CPR) was determined using Kaplan-Meier estimates of survivorship and hazard ratios (HR) from Cox proportional hazard models adjusted for age, gender, humeral head/glenosphere size, polyethylene type, and surgeon volume. Possible interactions were examined. A sub-analysis from 1 January 2017 captured additional patient demographics, ASA score, BMI and glenoid morphology. ResultsThe CPR at 7 years was 4.0%(95% confidence interval (CI) 3.1, 5.1) for slTSA (n=3,041), 3.8%(95%CI 2.7, 5.5) for stTSA (n=1,259) and 4.1%(95%CI 3.7, 4.6) for rTSA (n=12,341). slTSA had a higher rate of revision compared to rTSA after the first 9 months (p<0.001). rTSA had a lower revision rate compared to stTSA from 3 months on (p=0.004). After adjusting for other confounders, prosthesis type and gender were associated with revision rates (p<0.001) whereas surgeon volume was not. Additionally, gender and prosthesis type strongly interacted (p=0.013) and the combined model exhibited greater predictive performance when including this interaction. Women had lower rates of revision than men for both stTSA and rTSA, but not slTSA. Most revisions were for infection in men, especially rTSA. After 3 months, the rate of revision for slTSA vs rTSA for women was increased (p<0.001) and revision rates for men did not significantly differ. However, in a sub-analysis of procedures in males since 2017 with additional adjustments, slTSA had a lower revision rate than stTSA (p=0.010). ConclusionsThe optimum shoulder arthroplasty revision rates vary for both the gender and implant type for the diagnosis of OA. A model combining optimum prostheses and gender predicted revision better than optimum implants alone. After 3 months, rTSA was associated with lower revision rates compared to slTSA in women, whereas there were no significant differences between optimum prostheses in men. However, surgeons may also consider lower revision risk of optimum slTSA at sub analysis and increased cumulative incidence of infection for rTSA requiring revision to resolve decision making for male patients.

Incidence, description, and timing of serious and opportunistic infections in patients with hairy cell leukemia

AbstractHairy cell leukemia is an uncommon B‐cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. However, purine analogs are known to be highly immunosuppressive and the infection burden in this patient population with current therapies is unknown. We therefore conducted a retrospective cohort study following 149 patients. Median follow‐up time was 6.9 years. Thirty‐six percent developed an opportunistic or serious infection requiring hospitalization. Most cases were bacterial and most coincided with neutropenia and/or CD4 T‐lymphopenia. No single treatment agent was significantly associated with increased or decreased incidence of infection. Reassuringly, the cumulative incidence of infections plateaued 2 months after initial treatment suggesting clinically significant immune recovery. Only one patient in our cohort passed away due to infection. Estimated 10‐year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

Host-feeding preferences and temperature shape the dynamics of West Nile virus: A mathematical model to predict the impacts of vector-host interactions and vector management on [formula omitted]

West Nile virus (WNV) is prevalent across the United States, but its transmission patterns and spatio-temporal intensity vary significantly, particularly in the Eastern United States. For instance, Chicago has long been a hotspot for WNV cases due to its high cumulative incidence of infection, with the number of cases varying considerably from year to year. The abilities of host species to maintain and disseminate WNV, along with eco-epidemiological factors that influence vector-host contact rates underlie WNV transmission potential. There is growing evidence that several vectors exhibit strong feeding preferences towards different host communities. In our research study, we construct a process based weather driven ordinary differential equation (ODE) model to understand the impact of one vector species (Culex pipiens), its preferred avian and non-preferred human hosts on the basic reproduction number (R0). In developing this WNV transmission model, we account for the feeding index, which is defined as the relative preference of the vectors for taking blood meals from a competent avian host versus a non-competent mammalian host. We also include continuous introduction of infected agents into the model during the simulations as the introduction of WNV is not a single event phenomenon. We derive an analytic form of R0 to predict the conditions under which there will be an outbreak of WNV and the relationship between the feeding index and the efficacy of adulticide is highly nonlinear. In our mechanistic model, we also demonstrate that adulticide treatments produced significant reductions in the Culex pipiens population. Sensitivity analysis demonstrates that feeding index and rate of introduction of infected agents are two important factors beside the efficacy of adulticide. We validate our model by comparing simulations to surveillance data collected for the Culex pipiens complex in Cook County, Illinois, USA. Our results reveal that the interaction between the feeding index and mosquito abatement strategy is intricate, especially considering the fluctuating temperature conditions. This induces heterogeneous transmission patterns that need to be incorporated when modelling multi-host, multi-vector transmission models.

Hybrid immunity protection against severe acute respiratory syndrome coronavirus 2 and severe coronavirus disease 2019 in kidney transplantation: A retrospective, comparative cohort study

Hybrid immunity, resulting from a combination of severe acute respiratory syndrome coronavirus 2 infection and vaccination, offers robust protection against coronavirus disease 2019 in the general population. However, its impact on immunocompromised patients remains unexplored. We investigated the effect of hybrid immunity against the Omicron variant in a population of kidney transplant recipients receiving the fourth dose mRNA monovalent vaccination. By extracting data from the clinical records and performing individual interviews, participants were categorized into the hybrid cohort (previously infected and vaccinated individuals) and the vaccine cohort (vaccinated-only individuals). The study comprised 1114 participants, 442 in the hybrid and 672 in the vaccine cohorts. From April 2022 to August 2023, 286 infections, 38 hospitalizations and 9 deaths were reported. The cumulative incidence of infection was 12.1% (95% confidence interval [CI], 9.03-16.03) for the hybrid cohort and 36.54% (95% CI, 32.81-40.54) for the vaccine cohort after 300 days of follow-up. Hybrid immunity was associated to a 72% lower risk of infection (adjusted hazard ratio, 0.28; 95% CI, 0.21-0.38) and a 96% lower risk of hospitalization (adjusted hazard ratio, 0.04; 95% CI, 0.01-0.32). No deaths occurred in the hybrid cohort. Hybrid immunity was associated with a lower incidence of severe acute respiratory syndrome coronavirus 2 infection and severe coronavirus disease 2019, underscoring its importance for risk stratification in this vulnerable patient population.

Evaluating the Public Health and Health Economic Impacts of Baloxavir Marboxil and Oseltamivir for Influenza Pandemic Control in China: A Cost-Effectiveness Analysis Using a Linked Dynamic Transmission-Economic Evaluation Model.

Pandemic influenza poses a recurring threat to public health. Antiviral drugs are vital in combating influenza pandemics. Baloxavir marboxil (BXM) is a novel agent that provides clinical and public health benefits in influenza treatment. We constructed a linked dynamic transmission-economic evaluation model combining a modified susceptible-exposed-infected-recovered (SEIR) model and a decision tree model to evaluate the cost-effectiveness of adding BXM to oseltamivir in China's influenza pandemic scenario. The cost-effectiveness was evaluated for the general population from the Chinese healthcare system perspective, although the users of BXM and oseltamivir were influenza-infected persons. The SEIR model simulated the transmission dynamics, dividing the population into four compartments: susceptible, exposed, infected, and recovered, while the decision tree model assessed disease severity and costs. We utilized data from clinical trials and observational studies in the literature to parameterize the models. Costs were based on 2021 CN¥ and not discounted due to a short time-frame of one year in the model. One-way, two-way, and probabilistic sensitivity analyses were also conducted. The integrated model demonstrated that adding BXM to treatment choices reduced the cumulative incidence of infection from 49.49% to 43.26% and increased quality-adjusted life years (QALYs) by 0.00021 per person compared with oseltamivir alone in the base-case scenario. The intervention also amounted to a positive net monetary benefit of CN¥77.85 per person at the willingness to pay of CN¥80,976 per QALY. Sensitivity analysis confirmed the robustness of these findings, with consistent results across varied key parameters and assumptions. Adding BXM to treatment choices instead of only treating with oseltamivir for influenza pandemic control in China appears to be cost-effective compared with oseltamivir alone. The dual-agent strategy not only enhances population health outcomes and conserves resources, but also mitigates influenza transmission and alleviates healthcare burden.

Risk of breakthrough infection and hospitalisation after COVID-19 primary vaccination by HIV status in four Italian regions during 2021

BackgroundAs of 2024, vaccination remains the main mitigation measure against COVID-19, but there are contradictory results on whether people living with HIV (PLWH) are less protected by vaccines than people living without HIV (PLWoH). In this study we compared the risk of SARS-CoV-2 infection and COVID-19 hospitalisation following full vaccination in PLWH and PLWoH.MethodsWe linked data from the vaccination registry, the COVID-19 surveillance system and from healthcare/pharmacological registries in four Italian regions. We identified PLWH fully vaccinated (14 days post completion of the primary cycle) and matched them at a ratio of 1:4 with PLWoH by week of vaccine administration, age, sex, region of residence and comorbidities. Follow-up started on January 24, 2021, and lasted for a maximum of 234 days. We used the Kaplan-Meier estimator to calculate the cumulative incidence of infection and COVID-19 hospitalisation in both groups, and we compared risks using risk differences and ratios taking PLWoH as the reference group.ResultsWe matched 42,771 PLWH with 171,084 PLWoH. The overall risk of breakthrough infection was similar in both groups with a rate ratio (RR) of 1.10 (95% confidence interval (CI):0.80–1.53). The absolute difference between groups at the end of the study period was 8.28 events per 10,000 person-days in the PLWH group (95%CI:-18.43-40.29). There was a non-significant increase the risk of COVID-19 hospitalisation among PLWH (RR:1.90; 95%CI:0.93–3.32) which corresponds to 6.73 hospitalisations per 10,000 individuals (95%CI: -0.57 to 14.87 per 10,000).ConclusionsOur findings suggest PLWH were not at increased risk of breakthrough SARS-CoV-2 infection or COVID-19 hospitalisation following a primary cycle of mRNA vaccination.

An effectiveness study of vaccination and quarantine combination strategies for containing mpox transmission on simulated college campuses

The ongoing transmission of mpox in specific countries and regions necessitates urgent action. It is essential to implement targeted containment strategies that concentrate on high-risk populations and critical locations, such as college campuses, to effectively curb the spread of mpox. This study is dedicated to evaluating the performance of various vaccination and quarantine strategies in curbing the spread of mpox and estimating the outbreak risk. To accomplish this, we constructed a stochastic, agent-based, discrete-time susceptible-latent-infectious-recovered (SLIR) model, to examine mpox transmission on a simulated college campus. Our findings reveal that relying solely on PEP is insufficient in containing mpox effectively. To bolster the population immunity and protect the vulnerable, pre-exposure vaccination among high-risk populations prior to an outbreak is imperative. Our study demonstrates that a pre-exposure vaccination rate of 50% in high-risk populations can led to a remarkable 74.2% reduction of infections. This translated to a mere 1.0% cumulative infection incidence in the overall population. In cases where the desired vaccination coverage is not attainable, enhancing case detection and isolation measures can serve as an effective emergency response to contain mpox outbreaks. For pre-exposure vaccination coverage of 20% or lower, a 40% isolation ratio is necessary to keep the cumulative number of infections in check. However, when the coverage exceeds 30%, a reduced isolation ratio of 20% becomes sufficient to manage the outbreak effectively. These insights underscore the importance of strategic pre-exposure vaccination in conjunction with robust surveillance and isolation protocols to safeguard public health and prevent the escalation of mpox outbreaks.

Impact of Early Rejection Treatment on Infection Development in Kidney Transplant Recipients: A Propensity Analysis.

The impact of renal allograft rejection treatment on infection development has not been formally defined in the literature. We conducted a retrospective cohort study of 185 rejection (case) and 185 nonrejection (control) kidney transplant patients treated at our institution from 2014 to 2020 to understand the impact of rejection on infection development. Propensity scoring was used to match cohorts. We collected data for infections within 6 months of rejection for the cases and 18 months posttransplant for controls. In 370 patients, we identified 466 infections, 297 in the controls, and 169 in the cases. Urinary tract infections (38.9%) and cytomegalovirus viremia (13.7%) were most common. Cumulative incidence of infection between the case and controls was 2.17 (CI 1.54-3.05); p < 0.001. There was no difference in overall survival (HR 0.90, CI 0.49-1.66) or graft survival (HR 1.27, CI 0.74-2.20) between the groups. There was a significant difference in overall survival (HR 2.28, CI 1.14-4.55; p = 0.019) and graft survival (HR 1.98, CI 1.10-3.56; p = 0.023) when patients with infection were compared to those without. As previously understood, rejection treatment is a risk factor for subsequent infection development. Our data have defined this relationship more clearly. This study is unique, however, in that we found that infections, but not rejection, negatively impacted both overall patient survival and allograft survival, likely due to our institution's robust post-rejection protocols. Clinicians should monitor patients closely for infections in the post-rejection period and have a low threshold to treat these infections while also restarting appropriate prophylaxis.

Clinical and economic impact of ventricular assist device infections: a real-world claims analysis

Background VAD therapy has revolutionized the treatment of end-stage heart failure, but infections remain an important complication. The objective of this study was to characterize the clinical and economic impacts of VAD-specific infections. Methods A retrospective analysis of a United States claims database identified members ≥ 18 years with a claim for a VAD implant procedure, at least 6 months of pre-implant baseline data, and 12 months of follow-up between 1 June 2016 and 31 December 2019. Cumulative incidence of infection was calculated. Infection and non-infection cohorts were compared regarding mortality, healthcare utilization, and total cost. Regression models were used to identify risk factors associated with infections and mortality. Results A total of 2,259 patients with a VAD implant were included, with 369 experiencing infection (12-month cumulative incidence 16.1%). Patients with infection were 2.1 times more likely to die (p < 0.001, 95% CI [1.5–2.9]). The mean 12-month total cost per US patient was $354,339 for the non-infection cohort and $397,546 for the infection cohort, a difference of $43,207 (p < 0.0001). Conclusions VAD infections were associated with higher mortality, more healthcare utilization, and higher total cost. Strategies to minimize VAD-specific infections could lead to improved clinical and economic outcomes.

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation

AbstractTeclistamab and other B-cell maturation antigen (BCMA)–targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.

Infectious Complications in Patients with Relapsed or Refractory (R/R) Non-Hodgkin's Lymphoma (NHL) Treated with the Anti-CD20xCD3 Bispecific Antibody (BsAb) Mosunetuzumab

Introduction:NHL treatment with anti-CD20 antibodies is associated with an increased risk of infections. Mosunetuzumab (mosun) is a novel anti-CD20xCD3 BsAb that has been examined in clinical trials for different NHL subtypes and was recently approved for treating R/R follicular lymphoma. While the open-label clinical trial of mosun reported that 17% of the patients experienced infectious complications, a detailed analysis of the incidence and types of infections in patients receiving this treatment has not been reported. Methods: This is a single-center, IRB-approved, retrospective analysis of patients with R/R NHL receiving mosun, either on a study protocol (NCT02500407) at the recommended phase 2 dose or as commercial use. Patients who completed at least 1 treatment cycle and had at least 30 days of follow-up were included in this analysis. Patient demographics, information on the lymphoma, and infection variables were collected by chart review. All infection-specific variables were collected from the start of mosun therapy until the initiation of the next line of therapy or the last follow-up, whichever came first. The data cut-off was on 7/22/23. Infectious events were graded according to common terminology criteria for adverse events (CTCAE) version 5.0. Baseline characteristics were analyzed for infection risk by performing a Cox regression analysis. Results: Between October 2016 and July 2023, 48 patients were treated with mosun at our center, and 44 met the study inclusion criteria. Four patients had only received one dose or did not have sufficient follow at the time of the analysis. Baseline characteristics are summarized in Table 1. After a median follow-up of 6.8 months (range 0.7-59.7), we recorded 37 infection episodes in 16/44 patients (36.4%). Amongst these, the frequencies of viral, bacterial, and fungal infections were 54.1% (20/37), 43.2% (16/37), and 2.7% (1/37), respectively. The most common infection types were upper respiratory tract infections 42.1% (20/37), skin and soft tissue infections16.2% (6/37), including 3 shingles episodes), genitourinary infections 10.8% (4/37), and lower respiratory tract infections 10.8% (4/37). Of all the infections, 9/37 (24.3%) were Grade 3 or higher; of these, 2/37 (5.4%) were Grade 5 (1 biliary sepsis, 1 COVID pneumonia). The cumulative incidence of infection was 25% over the follow-up period (figure 1). The median time to the first infection was 144 days (range 29-1821). Among the patients who experienced infections, the infection rate was 1.54 every 100 days at risk within the first three months. The infection rate was 1.69 every 100 days at risk between three and six months and 0.37 every 100 days at risk beyond six months for patients with infection. We evaluated the type of lymphoma (i.e., aggressive vs. indolent), patients' age, number of prior therapies before BsAb administration, prior CAR-T therapy, prior autologous SCT, baseline hypogammaglobulinemia, and baseline cytopenia's as risk factors of infection with a univariate Cox regression analysis. We found that none of these characteristics were associated with the risk of infection with statistical significance. However, in a multivariate Cox regression analysis, patients who received CAR-T therapy before starting a BsAb were at a slightly higher risk of developing an infection (OR = 6.13; 95% CI: 0.90, 41.74, p = 0.063). Conclusion: Infection risk in patients with R/R NHL treated with mosun either on protocol or for commercial use appears to be higher than in the clinical trial experience reported in the literature. Viral infections were especially common, including respiratory infections and shingles episodes. Our findings highlight the need for careful monitoring and implementation of preventive strategies to decrease the infection burden in these vulnerable patients.

Investigation of Age-Specific Differences in Survival and Cause of Death Among Diffuse Large B-Cell Lymphoma Patients with and without HIV in the Modern Era of Antiretroviral Therapy: A Population-Based Analysis from 2010 to 2017

Introduction Despite improved prognosis with combined antiretroviral therapy (cART) among patients with human immunodeficiency virus (PWHIV) diagnosed with diffuse large B-cell lymphoma (DLBCL), population-based studies suggest inferior survival rates compared to patients without HIV. Uncertainty remains about the persistence of this survival difference across age groups. Examining outcomes across ages may help identify higher-risk groups in the current era of cART, providing insights for designing and conducting age-specific interventions. Methods A retrospective population-based cohort was conducted using US population-based cancer registry data among patients aged 15-79 years with newly diagnosed DLBCL from 2010 to 2017, with follow-up through 2019. The 2010-2017 period reflects the availability of integrase inhibitors and the introduction of distinct lymphoma subtypes to the World Health Organization classification system in cancer registries. HIV status was reported at lymphoma diagnosis. Patients were classified into three age groups: adolescents and young adults (AYAs, 15-39 years), adults (40-59 years), and older adults (60-79 years). Overall survival (OS) was defined from diagnosis to death of any cause. Probabilities were estimated using the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox regression models were fitted to assess all-cause mortality, adjusting for cancer stage, race/ethnicity, sex, year of diagnosis, and age. We estimated the cumulative incidence of infections and HIV-related deaths using the competing risk method. Results Patient characteristics: A total of 26,905 DLBCL patients were identified (1,030 PWHIV and 25,758 patients without HIV). Compared to patients without HIV, PWHIV were younger (median age at diagnosis 48 years vs. 62 years), predominantly male (85% vs. 56%), more likely to be non-Hispanic Black (38% vs. 8%) and Hispanic (24% vs. 18%), and more likely to have advanced-stage disease at diagnosis (71% vs. 56%) (Table 1). OS in DLBCL PWHIV vs. patients without HIV:Within each age group, OS was significantly lower among PWHIV with DLBCL compared to patients without HIV(Table 1 and Figure 1). With a median follow-up of 67 months, 5-year OS was particularly low among AYAs (53% vs. 87%, p&amp;lt;0.0001) and adults (48% vs. 74%, p&amp;lt;0.0001). Similarly, older adults experienced lower 5-year OS rates (45% vs. 57%, p&amp;lt;0.0001). Multivariable Cox models suggest that PWHIV has an increased risk of all-cause mortality within each age group (Figure 1). OS in different age groups by HIV status: For PWHIV, age was not a significant factor for increased all-cause mortality, with 5-year OS rates ranging from 45% in adults to 53% in AYAs (p=0.170). Conversely, in DLBCL patients without HIV, AYAs had superior 5-year OS rates (87%, p&amp;lt;0.001) compared to adults (74%) and older adults (57%). Cause of death by HIV status: Among both PWHIV and without HIV, lymphoma/leukemia-related mortality was the most common cause of death reported in death certificates (47% and 73% respectively). However, the 5-year cumulative incidence of infection mortality was higher among PWHIV (range 3-4% across age groups) compared to patients without HIV (1% across age groups). For PWHIV, other HIV-related mortality had a 5-year cumulative incidence ranging from 9% to 14% across age groups. Results stratified by cancer stage (early- or advanced-stage disease) were consistent with those presented above. Conclusion This study highlights worse outcomes among PWHIV diagnosed with DLBCL compared to patients without HIV within each age group at the population level in the modern era of cART, notably among AYAs. Unlike the findings in DLBCL patients without HIV, age was not significantly associated with mortality among PWHIV with DLBCL. Future studies should explore age-specific demographic, biological, or healthcare system factors mediating these outcome disparities. The considerable HIV-related mortality suggests refining HIV surveillance approaches among PWHIV with DLBCL in prospective studies or clinical trials. Identifying the optimal integration of chemotherapy and cART may improve outcomes in this vulnerable population.

Role of Polyomavirus BK and Adenovirus in the Development of Urinary Tract Complications in Pediatric Hematopoietic Stem Cell Transplantation

One of the major challenges in pediatric hematopoietic stem cell transplantation (HSCT) is the susceptibility to viral infections and reactivations that can lead to potentially life-threatening complications and increase the transplant-related mortality (TRM). Polyomavirus BK (BKPyV) and Adenovirus (AdV) represent the predominant causes of urinary tract complications, in particular hemorrhagic cystitis (HC), in HSCT recipients. Treatment options for BKPyV and AdV infections are limited and there is no accepted standard of care for the prevention and treatment of these HSCT complications. The aim of our retrospective study was to analyze the incidence of BKPyV and AdV infection in urinary and plasma samples of pediatric patients undergoing HSCT for both malignant and non-malignant disease at a single pediatric Hematology-Oncology unit. Endpoints were the cumulative incidence of infection, measured on blood and urine samples, in the first 100 days after HSCT, prevalence of asymptomatic and symptomatic infection, and correlation between BKPyV and AdV DNAemia and DNAuria and the development of HC. A total of 79 patients were analyzed. Thirty-seven (47%) patients were positive for BKPyV on urine samples and 20 (30%) on blood samples within the first 30 days after transplantation. As for AdV, 11 (9%) patients were positive on urine samples and 18 (15%) on blood samples. In our pediatric cohort, BKPyV DNAuria was a frequent event after HSCT, while BKPyV DNAemia was observed less frequently, and was accompanied by higher viruria values (p-value &amp;lt;0,001, with a median viral load in the urine of 3.8 x 10 9 copies/mL). Conversely, AdV positivity in urine is rare, while AdV DNAemia was more frequent, due to the modality of BKPyV and AdV distribution (urothelium is the main reservoir for BKPyV, while intestinal lymphocytes represents the main reservoir for AdV). Of the 37 patients with BKPyV DNA on urine samples, 11 (30%) developed a symptomatic infection with grade II (5 patients, 40%) and grade III (6 patients, 60%) HC. We did not observe any correlation between BKPyV DNA urinary levels and the development of HC, as higher viral loads have not been shown to be good predictors of occurrence or severity of HC. Cumulative incidence (CI) of BKPyV infection was higher in haploidentical HSCT (51%) and matched unrelated donors (MUD) (48%) than in HSCT from matched familiar donors (31%). Similarly, CI of AdV reactivation was higher in haploidentical HSCT (16%) than MUD (6%) and matched familiar donors (9%). Choice of donor, the type of immunosuppression used and the intensity of conditioning regimen represented predictors of both blood and urine DNA positivity for both viruses. In our cohort, positivity for BKPyV on blood and/or urine did not increase the risk of transplant-related mortality and did not affect the overall survival after HSCT. On the basis of our data, we now perform screening of BKPyV viruria only in symptomatic patients or in transplant recipients with specific risk factors (type of donor, severity of immunosuppression). Similarly, search for BKPyV DNAemia is reserved to subjects with a high viral load on urine. Likewise, search for AdV on urine samples is performed on symptomatic patients with high-load AdV DNAemia.

Risk of Infections in Multiple Myeloma in the Era of Novel Agents, a Population-Based Study Based on 8672 Multiple Myeloma Patients Diagnosed 2008-2021 from the Swedish Myeloma Registry

Introduction Despite modern therapies, infections are still a major cause of morbidity and mortality in patients with myeloma (MM). We therefore performed a large population-based study to evaluate the risk of bacterial, viral and fungal infections among 8672 Swedish symptomatic MM patients diagnosed 2008-2021 compared to 34,567 matched controls. Materials and methods Symptomatic patients reported to the Swedish Myeloma Registry and four matched controls per patient were analysed with occurrence and date of all infections in the centralized Swedish Patient registry that captures information on individual patient-based discharge diagnosis from inpatient and outpatient care. The Swedish MM patients were followed until death or until 31 st December 2022. Statistical analysis Cox proportional hazard models, with the occurrence of infection as a time dependant co-variate and cumulative incidence with competing risk models were used to estimate the risk of infections in MM compared to controls. All models were adjusted for sex, age and year of diagnosis. The effect of gender, age and calendar period of were evaluated separately. Hazard ratio (HR) and confidence intervals (95% CI) were calculated for the risk of different infections. All p-values were two-sided and a value below 0.05 was considered statistically significant. All analyses were performed with R version 4.3.1 and ethics approved. Results In this population-based study, 8672 Swedish symptomatic MM patients diagnosed 2008-2021 and 34,567 matched controls were included. The majority of patients (73 %) were 65 years or older at diagnosis, 57% were male, and 30 % treated with up-front autologous stem cell transplantation (auto-SCT). The median time of follow-up was 5 years. Overall, MM patients had a 5-fold (HR=4.73; [95% CI=4.59-4.89]) risk of developing any infection compared to matched controls. Bacterial infection had a 4-fold increased risk (HR=4.40; [4.24-4.57]), viral infection 6-fold (HR=6.11; [5.76-6.49]), and fungal infection 6-fold (HR=6.14; [5.56-6.79]) compared to controls. More specifically, MM patients had an increased risk (p&amp;lt;0.05) of the following bacterial infections compared to controls: meningitis (HR=19.6; [ 10.0-38.1]), septicaemia (HR=8.05; [7.52-8.62]), pneumonia (HR=7.72; [7.21-8.27]), endocarditis (HR=4.9; [3.70-6.48]), cellulitis (HR=3.13;[2.57-3.80]), osteomyelitis (HR=2.89; [1.95-2.92]), pyelonephritis (HR=2.3; [2.03-2.59]), and for the viral infections influenza (HR=9.40; [8.19-10.8]) and herpes zoster (HR=9.33; [8.19-10.6]) (Table 1). The risk of infections compared to controls was 4 to 5-fold the first year after diagnosis and remained elevated up to 5 years after the myeloma diagnosis. Figure 1 illustrates the cumulative incidence of infections compared to controls over time. MM patients diagnosed 2018 to 2021 had a slightly lower risk of infection, (HR=0.87 ([0.82-0.93] p&amp;lt; 0.05) compared to patients diagnosed 2008-2012, whilst the risk of infections was slightly higher 2013-2017 compared to the first time period (HR=1.06 ([1.00-1.11], p&amp;lt; 0.05). The cumulative risk of infection compared to controls remained 5-fold in patients diagnosed 2008-2012 (HR=5.03; [4.78-5.29], p&amp;lt;0.05) and 2013-2017 (HR=4.82; [4.59-5.06], p&amp;lt;0.05), and 4-fold (HR=3.93, [3.66-4.21], p&amp;lt;0.05) in patients diagnosed 2018-2021. Females had a significantly lower risk of infections compared to males (p&amp;lt;0.001). Older age at diagnosis increased the risk of a first infection (p&amp;lt;0.001). Discussion This study constitutes the largest population-based study to date on the risk of infections compared to the normal population in the era of modern MM therapies. Infections still represent a major threat to myeloma patients, with an equally about five-fold increased risk for bacterial, viral and fungal infections during the first year and up to 5 years after the myeloma diagnosis, even in more recent years.

Correlation between specific antibody response to wild-type BNT162b2 booster and the risk of breakthrough infection with omicron variants: Impact of household exposure in hospital healthcare workers

BackgroundThe emergence of omicron variants exhibiting antigenic changes has led to an increase in breakthrough infection among individuals with a wild-type SARS-CoV-2 vaccine booster. The correlation between post-booster spike-specific antibodies and omicron infection risk remains unclear. MethodsThis prospective cohort study included SARS-CoV-2-naive healthcare workers with three-dose BNT162b2. Post-booster spike-specific IgG and interferon-γ levels were measured. Breakthrough infection was documented during a 10-month omicron-predominant period. Household and healthcare contacts were followed to identify subsequent infections. The IgG titers were additionally measured at the end of follow-up, and the titers at exposure were estimated from the two-point titers. ResultsOf 333 participants, 89 developed infection, of whom 37 (41.6 %) were household contacts. Kaplan-Meier curves indicated that higher IgG titers were significantly correlated with lower cumulative infection incidence (p = 0.029), whereas the interferon-γ levels were not (p = 0.926). Multivariate Cox analysis showed that increasing IgG titers were associated with a reduced hazard ratio (HR) of 0.26 (95% CI, 0.12–0.55). Household exposure posed a greater infection risk than healthcare exposure (HRs, 11.24 [6.88–18.40] vs. 2.82 [1.37–5.44]). The difference in geometric mean IgG titers of infected and uninfected participants was significant among household contacts (20,244 AU/mL vs. 13,842 AU/mL, p = 0.031). Estimation of IgG titers at exposure showed a significantly higher infection incidence in those exposed with titers of <3,000 AU/mL than in those with higher titers (79.2 % vs. 32.3 %, p < 0.001). ConclusionsSpike-specific antibodies induced by a wild-type SARS-CoV-2 vaccine booster are suggested to be effective in protecting against omicron infection. Household exposure would be a significant source of infection for hospital healthcare workers.

The changing spectrum of infection with BCMA and GPRC5D targeting bispecific antibody (bsAb) therapy in patients with relapsed refractory multiple myeloma.

There is a paucity of granular data on infection risk with B-cell maturation antigen (BMCA) and GPRC5D bispecific antibodies (bsAb) in relapsed/refractory multiple myeloma (RRMM). The aim of our multi-institutional study was to characterize the incidence, etiologies, and risk factors of infections from the start of therapy to the last follow-up or 90 days after study exit. A total of 66 patients received BCMA bsAb monotherapy, 15 GPRC5D bsAb monotherapy, and 15 GPRC5D bsAb combination therapy with daratumumab and/or pomalidomide. While the infection rate per 100 days was 0.57 for BCMA bsAb, it was 0.62 for GPRC5D bsAb combination and 0.13 for GPRC5D bsAb monotherapy; P=0.05. The proportion of infections that were grade ≥3 was higher in the BCMA bsAb group compared to the GPRC5D groups (58% vs. 36%; P=0.04). Grade 5 events were observed in 8% (n=8) of the patients, all treated with BCMA bsAb. The 9 month cumulative incidence of any grade of infection was similar in the BCMA and GPRC5D-combination groups (57% and 62%) and significantly higher than in the GPRC5D-mono group (16%); P=0.012. The cumulative incidence of grade ≥3 infections was highest in the BCMA group reaching 54% at 18 months; P=0.06. Multivariate analysis showed that BCMA bsAb therapy or GPRC5D combination therapy, history of previous infections, baseline lymphopenia, and baseline hypogammaglobulinemia were significantly associated with a higher risk of grade ≥3 infections. Our results indicate that BCMA bsAb and GPRC5D-combination therapies in RRMM are associated with higher cumulative incidence of infection and grade ≥3 infection compared to GPRC5D bsAb mono.

Comparative antibody and cell-mediated immune responses, reactogenicity, and efficacy of homologous and heterologous boosting with CoronaVac and BNT162b2 (Cobovax): an open-label, randomised trial

Few trials have compared homologous and heterologous third doses of COVID-19 vaccination with inactivated vaccines and mRNA vaccines. The aim of this study was to assess immune responses, safety, and efficacy against SARS-CoV-2 infection following homologous or heterologous third-dose COVID-19 vaccination with either one dose of CoronaVac (Sinovac Biotech; inactivated vaccine) or BNT162b2 (Fosun Pharma-BioNTech; mRNA vaccine). This is an ongoing, randomised, allocation-concealed, open-label, comparator-controlled trial in adults aged 18 years or older enrolled from the community in Hong Kong, who had received two doses of CoronaVac or BNT162b2 at least 6 months earlier. Participants were randomly assigned, using a computer-generated sequence, in a 1:1 ratio with allocation concealment to receive a (third) dose of CoronaVac or BNT162b2 (ancestral virus strain), stratified by types of previous COVID-19 vaccination (homologous two doses of CoronaVac or BNT162b2). Participants were unmasked to group allocation after vaccination. The primary endpoint was serum neutralising antibodies against the ancestral virus at day 28 after vaccination in each group, measured as plaque reduction neutralisation test (PRNT50) geometric mean titre (GMT). Surrogate virus neutralisation test (sVNT) mean inhibition percentage and PRNT50 titres against omicron BA.1 and BA.2 subvariants were also measured. Secondary endpoints included geometric mean fold rise (GMFR) in antibody titres; incidence of solicited local and systemic adverse events; IFNγ+ CD4+ and IFNγ+ CD8+ T-cell responses at days 7 and 28; and incidence of COVID-19. Within-group comparisons of boost in immunogenicity from baseline and between-group comparisons were done according to intervention received (ie, per protocol) by paired and unpaired t test, respectively, and cumulative incidence of infection was compared using Kaplan-Meier curves and a proportional hazards model to estimate hazard ratio. The trial is registered with ClinicalTrials.gov, NCT05057169. We enrolled participants from Nov 12, 2021, to Jan 27, 2022. We vaccinated 219 participants who previously received two doses of CoronaVac, including 101 randomly assigned to receive CoronaVac (CC-C) and 118 randomly assigned to receive BNT162b2 (CC-B) as their third dose; and 232 participants who previously received two doses of BNT162b2, including 118 randomly assigned to receive CoronaVac (BB-C) and 114 randomly assigned to receive BNT162b2 (BB-B) as their third dose. The PRNT50 GMTs on day 28 against ancestral virus were 109, 905, 92, and 816; against omicron BA.1 were 9, 75, 8, and 86; and against omicron BA.2 were 6, 80, 6, and 67 in the CC-C, CC-B, BB-C, and BB-B groups, respectively. Mean sVNT inhibition percentages on day 28 against ancestral virus were 83%, 96%, 87%, and 96%; against omicron BA.1 were 15%, 58%, 19%, and 69%; and against omicron BA.2 were 43%, 85%, 50%, and 90%, in the CC-C, CC-B, BB-C, and BB-B groups, respectively. Participants who had previously received two doses of CoronaVac and a BNT162b2 third dose had a GMFR of 12 (p<0·0001) compared with those who received a CoronaVac third dose; similarly, those who had received two doses of BNT162b2 and a BNT162b2 third dose had a GMFR of 8 (p<0·0001). No differences in CD4+ and CD8+ T-cell responses were observed between groups. We did not identify any vaccination-related hospitalisation within 1 month after vaccination. We identified 58 infections when omicron BA.2 was predominantly circulating, with cumulative incidence of 15·3% and 15·4% in the CC-C and CC-B groups, respectively (p=0·93), and 16·7% and 14·0% in the BB-C and BB-B groups, respectively (p=0·56). Similar levels of incidence of, presumably, omicron BA.2 infections were observed in each group despite very weak antibody responses to BA.2 in the recipients of a CoronaVac third dose. Further research is warranted to identify appropriate correlates of protection for inactivated COVID-19 vaccines. Health and Medical Research Fund, Hong Kong. For the Chinese translation of the abstract see Supplementary Materials section.

Addition of aminoglycosides reduces recurrence of infections with multidrug-resistant Gram-negative bacilli in patients with sepsis and septic shock

Aminoglycosides and β-lactams have been recommended for treatment of sepsis/septic shock despite a lack of mortality benefit. Previous studies have examined resistance emergence for the same bacterial isolate using old dosing regimens and during a narrow follow-up window. We hypothesised that combination regimens employing aminoglycosides will decrease the cumulative incidence of infections due to multidrug-resistant (MDR) Gram-negative bacilli (GNB) compared with β-lactams alone. All adult patients admitted to Barnes Jewish Hospital between 2010 and 2017 with a diagnosis of sepsis/septic shock were included in this retrospective cohort study. Patients were divided into two treatment groups, with and without aminoglycosides. Patient demographics, severity of presentation, administered antibiotics, follow-up cultures with susceptibility results for a period of 4-60 days, and mortality were extracted. After propensity score matching, a Fine-Gray subdistribution proportional hazards model summarised the estimated incidence of subsequent infections with MDR-GNB in the presence of all-cause death as a competing risk. A total of 10 212 septic patients were included, with 1996 (19.5%) treated with at least two antimicrobials including one aminoglycoside. After propensity score matching, the cumulative incidence of MDR-GNB infections between 4-60 days was lower in the combination group (incidence at 60 days 0.073, 95% CI 0.062-0.085) versus patients not receiving aminoglycosides (0.116, 95% CI 0.102-0.130). Patients aged ≤65 years and with haematological malignancies had a larger treatment effect in subgroup analyses. Addition of aminoglycosides to β-lactams may protect against subsequent infections due to MDR-GNB in patients with sepsis/septic shock.

Seroprevalence of SARS-CoV-2 and risk factors in Bantul Regency in March-April 2021, Yogyakarta, Indonesia.

COVID-19 case counts in Indonesia inevitably underestimate the true cumulative incidence of infection due to limited diagnostic test availability, barriers to testing accessibility and asymptomatic infections. Therefore, community-based serological data is essential for understanding the true prevalence of infections. This study aims to estimate the seroprevalence of SARS-CoV-2 infection and factors related to the seropositivity in Bantul Regency, Yogyakarta, Indonesia. A cross-sectional study involving 425 individuals in 40 clusters was conducted between March and April 2021. Participants were interviewed using an e-questionnaire developed in the Kobo toolbox to collect information on socio-demographic, COVID-19 suggestive symptoms, history of COVID-19 diagnosis and COVID-19 vaccination status. A venous blood sample was collected from each participant and tested for immunoglobulin G (Ig-G) SARS-CoV-2 antibody titers using the enzyme-linked immunosorbent assay (ELISA). Seroprevalence was 31.1% in the Bantul Regency: 34.2% in semi-urban and 29.9% in urban villages. Participants in the 55-64 age group demonstrated the highest seroprevalence (43.7%; p = 0.00), with a higher risk compared to the other age group (aOR = 3.79; 95% CI, 1.46-9.85, p<0.05). Seroprevalence in the unvaccinated participants was 29.9%. Family clusters accounted for 10.6% of the total seropositive cases. No significant difference was observed between seropositivity status, preventive actions, and mobility. Higher seroprevalence in semi-urban rather than urban areas indicates a gap in health services access. Surveillance improvement through testing, tracing, and treatment, particularly in areas with lower access to health services, and more robust implementation of health protocols are necessary.