The time-dependent changes in serum immunoglobulin after kidney transplantation and its association with infection.

Introduction: Kidney transplant recipients often experience significant alterations in their immune system, which can lead to increased susceptibility to infections. This study aimed to analyze time-dependent changes in serum immunoglobulin and complement levels and determine the risk factors associated with infection. Methods: A retrospective analysis of serum samples from 192 kidney transplant recipients who received transplantations between August 2016 and December 2019 was conducted. The serum samples were obtained at preoperative baseline (T0), postoperative 2 weeks (T1), 3 months (T2), and 1 year (T3). The levels of serum C3, C4, IgG, IgA, and IgM were measured to evaluate immune status over time. Results: The analysis revealed significant decreases in IgG and IgA levels at T1. This period was associated with the highest occurrence of hypogammaglobulinemia (HGG) and hypocomplementemia (HCC), as well as an increased incidence of severe infection requiring hospitalization and graft-related viral infections. Using a time-dependent Cox proportional hazards model adjusted for time-varying confounders, HGG was significantly associated with an increased risk of infection requiring hospitalization (HR, 1.895; 95% CI: 1.871-1.920, P-value<0.001) and graft-related viral infection (HR, 1.152; 95% CI: 1.144-1.160, P-value<0.001). Discussion: The findings suggest that monitoring serum immunoglobulin levels post-transplant provides valuable insights into the degree of immunosuppression. Hypogammaglobulinemia during the early post-transplant period emerges as a critical risk factor for infection, indicating that serum immunoglobulins could serve as feasible biomarkers for assessing infection risk in kidney transplant recipients.

Outcomes and risk factors for infection after endovascular treatment in patients with acute ischemic stroke.

AIMS: Infection is a common complication following acute ischemic stroke (AIS) and significantly contributes to poor functional outcomes after stroke. This study aimed to investigate the effects of infection after endovascular treatment (post-EVT infection) on clinical outcomes and risk factors in patients with AIS. METHODS: We retrospectively analyzed AIS patients treated with endovascular treatment (EVT) between January 2016 and December 2022. A post-EVT infection was defined as any infection diagnosed within 7 days after EVT. The primary outcome was functional independence, defined as a modified Rankin scale (mRS) score of 0-2 at 90 days. A multivariable logistic regression analysis was conducted to determine independent predictors of post-EVT infection and the associations between post-EVT infection and clinical outcomes. RESULTS: A total of 675 patients were included in the analysis; 306 (45.3%) of them had post-EVT infections. Patients with post-EVT infection had a lower rate of functional independence than patients without infection (31% vs 65%, p = 0.006). In addition, patients with post-EVT infection achieved less early neurological improvement (ENI) after EVT (25.8% vs 47.4%, p < 0.001). For safety outcomes, the infection group had a higher incidence of any intracranial hemorrhage (23.9% vs 15.7%, p = 0.01) and symptomatic intracranial hemorrhage (10.1% vs 5.1%, p = 0.01). Unsuccessful recanalization (aOR 1.87, 95% CI 1.11-3.13; p = 0.02) and general anesthesia (aOR 2.22, 95% CI 1.25-3.95; p = 0.01) were identified as independent predictors for post-EVT infection in logistic regression analysis. CONCLUSION: AIS patients who develop post-EVT infections are more likely to experience poor clinical outcomes. Unsuccessful recanalization and general anesthesia were independent risk factors for the development of post-EVT infection.

Higher infection risk for JAK inhibitors tofacitinib and baricitinib compared to subcutaneous biological DMARDs.

INTRODUCTION: Rheumatoid arthritis (RA) is usually treated with disease modifying antirheumatic drugs (DMARDs), including biological DMARDs (bDMARDs) and more recently, Janus kinase inhibitors (JAKi). Randomized trials suggest similar infection risks for JAKi and bDMARDs, but real-world data are scarce. METHODS: From a nationally representative prescription database, adult RA patients starting a new JAKi or bDMARD between August 1st, 2018, and January 31st, 2021, were included. Prescriptions of antibiotic, antiviral or antifungal medication were used as proxy for infections. Infection incidence rates (IR) were compared between JAKi and bDMARDs and infection risks were estimated using multilevel Poisson regression adjusted for follow-up time and potential confounders and stratified for age < 65 and ≥ 65 years. RESULTS: In 14,989 patients, we identified 20,050 treatment episodes with either JAKi or bDMARDs. The infection IR was significantly higher in JAKi (48/100 patient years) compared bDMARDs (35/100 patient years, adjusted incidence rate ratio (IRR) 1.22, 95% CI 1.12-1.33). More herpes zoster infections were seen in JAKi compared to bDMARDs (adjusted IRR 2.65, 95% CI 1.94-3.60). No significant differences in infection IRs were found comparing JAKi baricitinib and tofacitinib. In older patients, infection IRs were higher, but IRRs were similar between age groups. CONCLUSION: In comparison to bDMARDs, JAKi are associated with a slightly higher infection risk and a higher risk of herpes zoster specifically. In older patients, infection IRs are higher but similar infection risks for JAKi and bDMARDs are observed. No differences in infection risk between tofacitinib and baricitinib were found. Key Points • Compared to bDMARDs, JAKi are associated with a slightly higher infection risk for all ages • An increased risk of herpes zoster in patients who use JAK inhibitors was confirmed • No significant differences in infection incidence were found between tofacitinib and baricitinib.

Association between serum IgG concentrations and the incidence of infections in patients with chronic lymphocytic leukemia and secondary immunodeficiency under treatment with Privigen.

OBJECTIVE: To investigate the association between serum immunoglobulin G (IgG) concentrations and the incidence of infections in patients with chronic lymphocytic leukemia (CLL) and secondary immunodeficiency receiving treatment with Privigen. MATERIALS AND METHODS: Data was analyzed from a non-interventional study conducted in 31 centers in Germany and 1 in Austria. Adult CLL patients with hypogammaglobulinemia and recurrent infections were allowed to enter the study upon signing informed consent, if a prior decision for treatment with Privigen had been made. All infections requiring an antimicrobial treatment were subject to analysis. Patients were stratified according to their mean post-baseline serum IgG trough levels in a group with lower IgG trough levels (≤ 5.0 g/L), and a group with higher IgG trough levels (> 5.0 g/L). RESULTS: Overall, 89 patients and 840 treatment cycles were analyzed. Up to 11 treatment cycles (average duration 29 days) were documented in each patient. In the group with higher IgG trough levels (> 5.0 g/L, N = 72), significantly fewer infections were observed than in the group with lower IgG trough levels (≤ 5.0 g/L, N = 17), including fewer severe and serious infections. The Privigen dosage was a major determinant of the post-baseline serum IgG levels. Overall tolerability of Privigen was assessed as very good or good in 91% of patients. CONCLUSION: This analysis confirms the association of serum IgG trough levels with the incidence of infections and highlights the importance of careful monitoring of IgG levels during treatment of secondary immunodeficiencies in CLL patients.

Infectious complications in pediatric patients undergoing CD19+CD22+ chimeric antigen receptor T-cell therapy for relapsed/refractory B-lymphoblastic leukemia.

Chimeric antigen receptor T-cell (CAR-T) therapy is effective in the treatment of relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL); however, patients who receive CAR-T therapy are predisposed to infections, with considerable detrimental effects on long-term survival rates and the quality of life of patients. This study retrospectively analyzed infectious complications in 79 pediatric patients with R/R B-ALL treated with CAR-T cells at our institution. Overall, 53 patients developed 88 infections. Nine patients experienced nine infections during lymphodepletion chemotherapy, 35 experienced 41 infections during the early phase (days 0-+ 30 after infusion), and 29 experienced 38 infections during the late phase (day + 31-+ 90 after infusion). Pathogens were identified in 31 infections, including 23 bacteria, seven viruses, and one fungus. Four patients were admitted to the intensive care unit for infection and one died. In a univariate analysis, there were ten factors associated with infection, including tumor load, lymphodepleting chemotherapy, neutrophil deficiency and lymphocyte reduction, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), etc. In a multivariate analysis, CRS ≥ grade 3 was identified as a risk factor for infection (hazard ratio = 2.41, 95% confidence interval: 1.08-5.36, P = 0.031). Therefore, actively reducing the CRS grade may decrease the risk of infection and improve the long-term quality of life of these patients.

Brain border-associated macrophages: common denominators in infection, aging, and Alzheimer's disease?

Mammalian brain border-associated macrophages (BAMs) are strategically positioned to support vital properties and processes: for example, the composition of the brain's perivascular extracellular matrix and cerebrospinal fluid flow via the glymphatic pathway. BAMs also effectively restrict the spread of infectious microbes into the brain. However, while fighting infections, BAMs sustain long-term transcriptomic changes and can be replaced by inflammatory monocytes, potentially leading to a gradual loss of their beneficial homeostatic functions. We hypothesize that by expediting the deterioration of BAMs, multiple infection episodes might be associated with accelerated brain aging and the putative development of neurodegenerative diseases. Our viewpoint is supported by recent studies suggesting that rejuvenating aged BAMs, and counterbalancing their detrimental inflammatory signatures during infections, might hold promise in treating aging-related neurological disorders, including Alzheimer's disease (AD).

Tryptophan catabolism via the kynurenine pathway regulates infection and inflammation: from mechanisms to biomarkers and therapies.

BACKGROUND: L-Tryptophan (L-Trp), an essential amino acid, is the only amino acid whose level is regulated specifically by immune signals. Most proportions of Trp are catabolized via the kynurenine (Kyn) pathway (KP) which has evolved to align the food availability and environmental stimulation with the host pathophysiology and behavior. Especially, the KP plays an indispensable role in balancing the immune activation and tolerance in response to pathogens. SCOPE OF REVIEW: In this review, we elucidate the underlying immunological regulatory network of Trp and its KP-dependent catabolites in the pathophysiological conditions by participating in multiple signaling pathways. Furthermore, the KP-based regulatory roles, biomarkers, and therapeutic strategies in pathologically immune disorders are summarized covering from acute to chronic infection and inflammation. MAJOR CONCLUSIONS: The immunosuppressive effects dominate the functions of KP induced-Trp depletion and KP-produced metabolites during infection and inflammation. However, the extending minor branches from the KP are not confined to the immune tolerance, instead they go forward to various functions according to the specific condition. Nevertheless, persistent efforts should be made before the clinical use of KP-based strategies to monitor and cure infectious and inflammatory diseases.

Infection and telomere length: a systematic review protocol.

INTRODUCTION: Telomeres are a measure of cellular ageing with potential links to diseases such as cardiovascular diseases and cancer. Studies have shown that some infections may be associated with telomere shortening, but whether an association exists across all types and severities of infections and in which populations is unclear. Therefore we aim to collate available evidence to enable comparison and to inform future research in this field. METHODS AND ANALYSIS: We will search for studies involving telomere length and infection in various databases including MEDLINE (Ovid interface), EMBASE (Ovid interface), Web of Science, Scopus, Global Health and the Cochrane Library. For grey literature, the British Library of electronic theses databases (ETHOS) will be explored. We will not limit by study type, geographical location, infection type or method of outcome measurement. Two researchers will independently carry out study selection, data extraction and risk of bias assessment using the ROB2 and ROBINS-E tools. The overall quality of the studies will be determined using the Grading of Recommendations Assessment, Development and Evaluation criteria. We will also evaluate study heterogeneity with respect to study design, exposure and outcome measurement and if there is sufficient homogeneity, a meta-analysis will be conducted. Otherwise, we will provide a narrative synthesis with results grouped by exposure category and study design. ETHICS AND DISSEMINATION: The present study does not require ethical approval. Results will be disseminated via publishing in a peer-reviewed journal and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42023444854.

Effects of long-term HbA1c variability on serious infection risks in patients with type 2 diabetes and the influence of age, sex and ethnicity: A cohort study of primary care data.

AIMS: Long-term HbA1c (glycated haemoglobin) variability is associated with micro- and macrovascular complications in Type 2 diabetes (T2D). We explored prospective associations between HbA1c variability and serious infections, and how these vary by HbA1c level, age, sex and ethnicity. METHODS: 411,963 T2D patients in England, aged 18-90, alive on 01/01/2015 in the Clinical Practice Research Datalink with ≥ 4 HbA1c measurements during 2011-14. Poisson regression estimated incidence rate ratios (IRRs) for infections requiring hospitalisation during 2015-19 by HbA1c variability score (HVS) and average level, adjusting for confounders, and stratified by age, sex, ethnicity and average level. Attributable risk fractions (AF) were calculated using reference categories for variability (HVS < 20) and average level (42-48 mmol/mol). RESULTS: An increased infection risk (IRR > 1.2) was seen with even modest variability (HVS ≥ 20, 73 % of T2D patients), but only at higher average levels (≥64 mmol/mol, 27 % patients). Estimated AFs were markedly greater for variability than average level (17.1 % vs. 4.1 %). Associations with variability were greater among older patients, and those with lower HbA1c levels, but not observed among Black ethnicities. CONCLUSIONS: HbA1c variability between T2D patients' primary care visits appears to be associated with more serious infections than average level overall. Well-designed trials could test whether these associations are causal.

Diabetic Foot Infections and Amputations Are All Too Common-Here's What Could Move the Needle.

This Medical News article discusses how multidisciplinary care teams, new drugs and devices, and practical solutions to socioeconomic factors could reduce diabetic foot infections and amputations.

Physiologic disruption and metabolic reprogramming in infection and sepsis.

Effective responses against severe systemic infection require coordination between two complementary defense strategies that minimize the negative impact of infection on the host: resistance, aimed at pathogen elimination, and disease tolerance, which limits tissue damage and preserves organ function. Resistance and disease tolerance mostly rely on divergent metabolic programs that may not operate simultaneously in time and space. Due to evolutionary reasons, the host initially prioritizes the elimination of the pathogen, leading to dominant resistance mechanisms at the potential expense of disease tolerance, which can contribute to organ failure. Here, we summarize our current understanding of the role of physiological perturbations resulting from infection in immune response dynamics and the metabolic program requirements associated with resistance and disease tolerance mechanisms. We then discuss how insight into the interplay of these mechanisms could inform future research aimed at improving sepsis outcomes and the potential for therapeutic interventions.