Late Infection Research Articles

Increased postpartum anxiety symptoms after perinatal SARS-CoV-2 infection in a large, prospective pregnancy cohort in New York City

Numerous studies reported an increase of postpartum mood symptoms during the COVID-19 pandemic. Yet, the link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and perinatal mental health is less well understood. We investigated the associations between prenatal SARS-CoV-2 infection and postpartum depressive and anxiety symptoms, including examinations of infection timing and pandemic timeline. We included 595 participants from Generation C, a prospective pregnancy cohort in New York City (2020–2022). Prenatal SARS-CoV-2 infection was determined via laboratory or medical diagnosis. Depression and anxiety symptoms were measured 4–12 weeks postpartum using the Edinburgh Postnatal Depression Scale (EPDS) and Generalized Anxiety Disorder questionnaire (GAD), respectively. Quantile regressions were conducted with prenatal SARS-CoV-2 infection as exposure and continuously measured EPDS and GAD scores as outcomes. We reran the analyses in those with COVID-19-like symptoms in the trimester during which infection occurred. 120 (20.1%) participants had prenatal SARS-CoV-2 infection. After adjusting for socio-demographic, obstetric and other maternal health factors, prenatal SARS-CoV-2 infection was associated with higher median postpartum anxiety scores (b = 0.55, 95% CI = 0.15; 0.96). Late gestation infection (b = 1.15, 95% CI = 0.22; 2.09) and symptomatic infection (b = 1.15, 95% CI = 0.12; 2.18) were also associated with higher median postpartum anxiety scores. No associations were found with depressive symptoms. The associations were not moderated by time since the start of the pandemic. This study suggests that prenatal SARS-CoV-2 infection increases the risk of postpartum anxiety symptoms among participants reporting median anxiety symptoms. Given that this association was not affected by pandemic timing and that SARS-CoV-2 transmission continues, individuals infected with SARS-CoV-2 during pregnancy should be monitored for postpartum anxiety symptoms.

SARS-CoV-2-infected hiPSC-derived cardiomyocytes reveal dynamic changes in the COVID-19 hearts

BackgroundThe ongoing coronavirus disease 2019 (COVID-19) pandemic has had an enormous impact on our societies. Moreover, the disease’s extensive and sustained symptoms are now becoming a nonnegligible medical challenge. In this respect, data indicate that heart failure is one of the most common readmission diagnoses among COVID-19 patients.MethodsIn this study, we used human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes to develop an in vitro model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and studied the dynamic changes occurring in cardiomyocytes after SARS-CoV-2 infection.ResultsTo this end, we have created an effective time series SARS-CoV-2 infection model exhibiting different functional patterns of up- and downregulated proteins, and demonstrating that SARS-CoV-2 mainly affects (i) the lipid and the energy metabolism of hiPSC-derived cardiomyocytes during the early infection stage, and (ii) the DNA repair ability of cardiomyocytes during the late infection stage. By analyzing the proteome changes occurring at different infection timepoints, we were able to observe that the simulated disease (COVID-19) course developed rapidly, and that each of the studied timepoints was characterized by a distinct protein expression pattern.ConclusionsOur findings highlight the importance of early detection and personalized treatment based on the disease stage. Finally, by combing the proteomics data with virus-host interaction network analysis, we were able to identify several potential drug targets for the disease.

Major complications after total hip arthroplasty with the direct anterior approach at a high-volume Ontario tertiary care centre.

The rate of major surgical complications for high-volume orthopedic surgeons using the direct anterior approach (DAA) in Ontario, Canada, is not known. The purpose of this study was to investigate the rate of major surgical complications after total hip arthroplasty (THA) using DAA performed by experienced orthopedic surgeons at a high-volume tertiary care centre in Ontario. We conducted a retrospective cohort review of primary THA through DAA performed by 2 experienced fellowship-trained surgeons at an academic hospital in London, Ontario, between Jan. 1, 2012, and May 1, 2019. We excluded the first 100 cases to allow for surgeon learning curves. We recorded major surgical complications (intraoperative events, postoperative periprosthetic fractures, dislocation requiring closed or open reduction, implant failure [aseptic loosening or subsidence], early (< 6 wk) deep wound infection requiring irrigation and débridement, late (≥ 6 wk) deep wound infection requiring irrigation and débridement, and wound complications [wound dehiscence, stitch abscess, erythema, hematoma or seroma]) within 1 year of THA. A total of 875 primary DAA THA procedures were included. The rates of surgical complications were 0.9% for intraoperative events, 1.5% for postoperative periprosthetic fractures, 0.8% for implant failure, 0.7% for early deep wound infection, 0.1% for late deep wound infection and 3.2% for wound complications; there were no cases of dislocation. The rate of revision for implant failure within 1 year was 0.1%. Male sex was associated with a greater risk of implant failure (p = 0.01), and having a higher body mass index was associated with both increased rates of infection (p < 0.01) and having a wound complication (p < 0.01). Intraoperative events, postoperative periprosthetic fractures, implant failure, deep wound infection and wound complications accounted for the major surgical complications within 1 year of THA through DAA. The low revision rate suggests that DAA is a safe approach for THA.

Intravenous vitamin C against acute respiratory distress syndrome: A narrative review

BackgroundThe use of intravenous vitamin C (IV-Vit-C) in the context of acute respiratory distress syndrome (ARDS) has been a topic of interest and research. ARDS is a severe and life-threatening form of respiratory failure that can be triggered by various factors, including infections, trauma, and inflammatory conditions. Some studies and clinical trials have explored the potential benefits of high-dose intravenous vitamin C in the treatment of ARDS, particularly in the context of severe respiratory illnesses such as those caused by viral infections. MethodsTwo literature reviews are performed by using the google scholar data base (scholar.google.com), one searching for “CITRIS-ALI”, and the other searching for “COVID-19 Vitamin C”, without any time restrictions, and selecting specific works, and citing or cited works, deemed appropriate. All the works included in the c19early.org data base are then indirectly considered through their statistical summary of improvements. ResultsMost of the studies support the use of IV-Vit-C against ARDS in general, including the COVID-19 induced ARDS. From the statistical analysis of 66 COVID-19 Vit-C studies, both IV and oral, there is a 18 % improvement in prophylaxis (RR 0.82 CI 0.69–0.97), a 37 % improvement in early treatment (RR 0.63, CI 0.41–0.98), and 21 % improvement in late treatment (RR 0.79, CI 0.70–0.88). Specific to this latter result are 39 studies of the 66. ConclusionsWhile IV-Vit-C was not a cure for COVID-19, it was a pragmatic but effectual means to reduce the COVID-19 mortality in cases of late infections and ARDS. IV and oral Vit-C may be considered one of the tools treating general ARDS.

Transcriptional insights of citrus defense response against Diaporthe citri

Citrus melanose, caused by Diaporthe citri, is one of the most important and widespread fungal diseases of citrus. Previous studies demonstrated that the citrus host was able to trigger the defense response to restrict the spread of D. citri. However, the molecular mechanism underlying this defense response has yet to be elucidated. Here, we used RNA-Seq to explore the gene expression pattern at the early (3 days post infection, dpi) and late (14 dpi) infection stages of citrus leaves in response to D. citri infection, and outlined the differences in transcriptional regulation associated with defense responses. The functional enrichment analysis indicated that the plant cell wall biogenesis was significantly induced at the early infection stage, while the callose deposition response was more active at the late infection stage. CYP83B1 genes of the cytochrome P450 family were extensively induced in the callus deposition-mediated defense response. Remarkably, the gene encoding pectin methylesterase showed the highest upregulation and was only found to be differentially expressed at the late infection stage. Genes involved in the synthesis and regulation of phytoalexin coumarin were effectively activated. F6’H1 and S8H, encoding key enzymes in the biosynthesis of coumarins and their derivatives, were more strongly expressed at the late infection stage than at the early infection stage. Collectively, our study profiled the response pattern of citrus leaves against D. citri infection and provided the transcriptional evidence to support the defense mechanism.

Antimicrobials use and infection hospital contacts as proxies of infection exposure at ages 0–2 years and risk of infectious mononucleosis

Infectious mononucleosis (IM) often results from late primary infection with Epstein–Barr virus (EBV). Exposure to EBV at ages 0–2 years from, e.g., siblings therefore protects against IM. Using Danish registers, we therefore followed children born in 1997 through 2015 from age 3 years for a hospital contact with an IM diagnosis as outcome with the number of antimicrobial prescriptions filled before age 3 years as a proxy of infection pressure and the main exposure in stratified Cox regressions. The main analyses used sibships as strata primarily to adjust for health-seeking behaviour with further possible adjustments for age, sex, calendar period and sibship constellation. In these analyses we followed 7087 children, exposed on average to 3.76 antimicrobials prescriptions. We observed a crude hazard ratio for IM per unit increase in cumulative antimicrobial use of 1.00 (95% confidence interval 0.99, 1.02), with similar results in adjusted analyses. The hypothesis that children with the largest use of antimicrobials at ages 0–2 years would subsequently have the lowest risk of IM within a sibship was not corroborated by the data. Furthermore, sibship-matched analyses provided no support for some common early-life immune system characteristics being predictive of IM.

A major facilitator superfamily transporter PlMFS1 contributes to growth, oosporogenesis, and pathogenesis of Peronophythora litchii

Major facilitator superfamily (MFS) transporters are secondary active membrane transporters that play an important role in solute interchange and energy metabolism. Peronophythora litchii causes the most destructive disease on lichi, litchi downy blight. PlM90 was reported as a key oosporogenesis regulator. Here, we identified an MFS transporter gene PlMFS1, which is up-regulated during oospore formation at the late infection stage, while down-regulated in the PlM90 mutant. To investigate PlMFS1 function, we generated PlMFS1 knockout mutants using CRISPR/Cas9-mediated genome editing technology. Compared with the wild-type strain SHS3, PlMFS1 deletion impaired mycelium growth, zoospore release, oospore production and pathogenicity. Furthermore, PlMFS1 deletion significantly affected P. litchii utilization of fructose, lactose and maltose, and may be the PlMFS1 mechanism involved in mycelial growth. PlMFS1 gene deletion also led to deceased laccase activity, laccase-encoding gene downregulation and impaired P. litchii pathogenicity. To our knowledge, this is the first report of an MFS transporter involved in sugar utilization, sexual reproduction, asexual reproduction and pathogenesis in oomycetes.

Zika virus infection triggers caspase cleavage of STAT1.

Zika virus (ZIKV) is a re-emerging flavivirus. Similar to other flaviviruses, ZIKV antagonizes the host interferon (IFN) signaling pathway to establish infection. Understanding the molecular mechanism by which ZIKV antagonizes IFN-induced antiviral signaling may lead to a new antiviral strategy by cracking the IFN antagonism. Flaviviruses have been reported to employ NS5-dependent and -independent mechanisms to block STAT2-mediated signaling, whereas whether flaviviruses target STAT1 remains controversial. Herein, we found that ZIKV infection triggered caspase-dependent cleavage of STAT1 at the aspartic acid 694 during late infection, whereas murine STAT1 (mSTAT1) was resistant to cleavage. Intriguingly, ectopically expressed cleavage-resistant human STAT1.D694A or complementation of cleavable mSTAT1.D695G exerted comparable anti-ZIKV activity with their counterparts, challenging the role of caspase-mediated STAT1 cleavage in the IFN antagonism in ZIKV-infected cells. These data may also imply a dominant role of the antagonism of STAT2 but not STAT1 in ZIKV-infected cells.

Late and Persistent Symptoms Suggestive of Surgical Site Infections After Cesarean Section: Results from a Prospective Cohort Study in Rural Rwanda.

Background: Women in low-resource settings will likely develop late surgical site infections (SSIs), diagnosed after post-operative day (POD) 10. We measured SSI prevalence and predictors of late and persistent SSIs-suggestive symptoms among women who delivered via cesarean section (c-section). Patients and Methods: Women who underwent c-sections at Kirehe District Hospital (KDH) between September 2019 and February 2020 were prospectively enrolled. Data were collected on POD1, POD11, and POD30. Logistic regression identified factors associated with persistent and late SSI symptoms. Results: In total, 808 women were study enrolled. Of these, 646 women physically attended the POD11 clinic visit follow-up, while 671 received the POD30 telephone-based follow-up review. Thirty-three (5.0%) women were diagnosed with an SSI on POD11, and 39 (5.3%) had an SSI diagnosis during POD11 to POD30, giving a cumulative prevalence of 10.3% late SSI rate. Of 671, 400 (59.9%) reported at least one SSI-associated symptom between POD11 and POD30. The reported symptoms included pain (56.6%), fever (19.4%), or incision drainage (16.6%). Of these, 200 women reported still having at least one of these symptoms on POD30. Of the 400 women with late SSI symptoms, 232 (58.0%) did not seek care, and of these, 80 (48.5%), 59 (35.8%), and 15 (8.9%) could not afford transport fare, did not believe symptoms were severe for a medical visit, and were not able to travel, respectively. Lower odds of late SSI-suggestive symptoms were reported among women with health insurance (adjusted odds ratio [aOR], 0.06; p = 0.013), whereas higher late SSI-suggestive symptoms odds were among women with wealthier socioeconomic status (aOR, 2.88; p = 0.004). Conclusions: Women in rural Rwanda are at risk of late and persistent SSI-suggestive symptoms. Financial barriers and the perception that their symptoms were not serious enough for the medical visit need education on early care seeking and interventions to mitigate financial barriers for optimizing perinatal care.

Impact of Letermovir Prophylaxis for Cytomegalovirus Reactivation on Post-Transplant Outcomes 100 Days before and after Allogeneic Hematopoietic Cell Transplantation

Background: Cytomegalovirus (CMV) infection is a major infectious complication following allogeneic hematopoietic cell transplantation (allo-HCT). Although letermovir (LMV) prophylaxis dramatically reduces the incidence of early clinically significant CMV (csCMV) infection, it remains unclear whether it has a beneficial effect on nonrelapse mortality (NRM) and overall survival (OS). Additionally, because the incidence of csCMV infection increases after completing LMV prophylaxis, the impact of late csCMV infection beyond 100 days after transplantation on posttransplant outcomes should also be verified. Study Design: We included adult patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS) aged ≥16 years who underwent allo-HCT between 2017 and 2019. These patients' data were obtained from the registry database of the Japanese Society for Transplantation and Cellular Therapy (JSTCT). Results: Donor CMV seronegativity (D-CMV −)/recipient CMV seronegativity (R-CMV −) was recorded in 558 cases (9.3%), and R-CMV +/D-CMV + or - was recorded in 4,562 cases (78.0%). The median age was 51 (range, 16-80) years. The median follow-up length was 389 (range, 0-1,334) days. LMV prophylaxis was administered to 1,640 patients (LMV group), and the median duration of LMV prophylaxis was 85 (range, 2-152) days. LMV prophylaxis significantly reduced the incidence of early csCMV infection compared with those not administered LMV prophylaxis (15.4% vs. 54.1%; p&amp;lt;0.01, hazard ratio [HR], 0.30; p&amp;lt;0.01)). However, LMV prophylaxis did not have any beneficial effect on the 1-year NRM (HR, 0.93; p=0.40) and OS (HR, 0.96; p=0.49) in multivariate analysis. The possible causes were breakthrough csCMV infection within 100 days after transplantation during LMV prophylaxis and late csCMV infection after 100 days after transplantation after completion of LMV prophylaxis. Breakthrough csCMV infection during LMV prophylaxis developed in 74 (4.5%) of the 1,640 patients who had received LMV prophylaxis. Breakthrough csCMV infection occurred at a median of 33 (range, 6-139) days after transplantation. R-CMV +, prior transplantation, cord blood (CB) transplants, anti-thymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCY) use for GVHD prophylaxis, and grade II-IV acute GVHD were associated with an increased risk of breakthrough csCMV infection. The breakthrough csCMV infection group showed inferior NRM (HR, 3.44; p&amp;lt;0.01) and OS (HR, 1.93; p=0.02) compared with those without infection among LMV prophylaxis group. After completing LMV prophylaxis, 252 patients had late csCMV infection at a median of 134 (range, 101-405) days after transplantation. In multivariate analysis, R-CMV +, older age, CB transplantation, ATG and/or PTCY use for GVHD prophylaxis, grade II-IV acute GVHD, and LMV prophylaxis before day 100 after transplantation were associated with an increased risk of late csCMV infection. Late csCMV infection showed inferior NRM (HR, 1.83; p&amp;lt;0.01) and OS (HR, 1.58; p&amp;lt;0.01) in multivariate analysis. Conclusion: LMV prophylaxis efficiently suppressed the development of early csCMV infection; however, this effect did not translate into improved posttransplant outcomes. Breakthrough csCMV infection during LMV prophylaxis and the development of late csCMV infection after completing LMV prophylaxis worsened transplant outcomes in the LMV prophylaxis group. Further improvements in posttransplant CMV management will be required to address these issues.

Cladribine and Cyclophosphamide Lymphodepletion Prior to Brexucabtagene Autoleucel in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia and Mantle Cell Lymphoma

Introduction : Fludarabine and cyclophosphamide (Flu/Cy) lymphodepletion (LD) prior to chimeric antigen T-cell (CAR T) infusion favorably impacts CAR T expansion and efficacy. A national shortage of Flu prompted our center to explore substitute Flu with Cladribine (Cla) as part of Cla/Cy LD. Here, we report our experience with this regimen prior to brexucabtagene autoleucel (brexu-cel) for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and mantle cell lymphoma (MCL). Methods : We performed a retrospective, single-center analysis of consecutive patients who received brexu-cel for RR B-ALL and MCL at Moffitt Cancer Center (1/2022 and 4/2023). The Cla/Cy LD regimen utilized Cy at 500 mg/m 2 x 3 days for MCL or 900 mg/m 2 x 1 day for B-ALL (two patients received MCL dosing) and substituted Flu 30 mg/m 2 with Clad 5 mg/m 2 x 3 days. We compared best overall response (BOR), including measurable residual disease (MRD) status by the clonoSEQ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) ± PCR for B-ALL, event-free survival (EFS, event = progression or death) and overall survival (OS) in those receiving standard Flu/Cy vs Clad/Cy LD. CRS and ICANS were graded as per ASTCT criteria. For patients with a sustained response ≥6 months and who did not undergo stem cell transplant, we assessed serial absolute neutrophil counts (ANC), CD4, CD8, CD19 counts and IgG levels post-CAR T. The HEMATOTOX score (HS, Rejeski et al, 2021) was used to stratify patients for risk of post-CAR T cytopenias. Results : We analyzed 63 patients who received brexu-cel: 23 with ALL (10 Cla/Cy) and 40 with MCL (7 Cla/Cy). Rates of CRS grade ≥ 3 (12% vs Flu/Cy 4%; p=0.29) and ICANS grade ≥ 3 (24% vs Flu/Cy 40%; p = 0.25) did not differ with LD. Two ALL (1 Flu/Cy, 1 Clad/Cy) and one MCL (Flu/Cy) patients died prior to day 28 reassessment. BOR did not differ by LD and histology (Figure 1). MRD negativity in ALL was also comparable (Cla/Cy 5/7, Flu/Cy 10/11, p=0.52). Among ALL patients, 5 received alloSCT consolidation (1 Cla/Cy). Progression was noted in 3/8 Cla/Cy and 6/11 Flu/Cy patients (p=1.0). Fifteen ALL patients experienced early infections (6/10 Cla/Cy, 9/13 FluCy, p=0.69), including bacterial (5), viral (4), and fungal (3). Three deaths (2 Cla/Cy) occurred before day 100, all due to refractory fungemia post anakinra. Two later deaths were attributed to relapse (both Flu/Cy). Among MCL patients, progression was noted in 16 (1 Cla/Cy). Seven MCL patients experienced early infection (all Flu/Cy), including bacterial (6), fungal (2), and viral (1). Two deaths occurred before day 100, 1 related to CRS and fungemia post anakinra (Flu/Cy), and another from stroke (Cla/Cy). Four (all Flu/Cy) have developed a second cancer (2 MDS/AML, 1 prostate, 1 liver), and 1 each died in remission from late infection (sepsis) and intracranial hemorrhage (both Flu/Cy). Cla/Cy patients had higher median ANCs at 28, 90, and 180 days (Table 1). When only patients with HS ≥ 2 were considered, 28-day ANC remained higher after Cla/Cy LD (1.57 vs Flu/Cy 0.67; p=0.04), numerically higher at 90 days (2.36 vs Flu/Cy 1.82; p=0.38) and again significantly higher at 180 days (3.96 vs Flu/Cy 1.2; p=0.05). Median CD4 was higher for Cla/Cy patients at day 28 (0.232 vs Flu/Cy 0.121; p=0.04), and numerically higher at day 90 (0.244 vs Flu/Cy 0.152; p=0.31) and 180 (0.254 vs Flu/Cy 0.161; p=0.21). Median CD8 was similar at day 28 (0.197 vs 0.155; p=0.46), 90 (0.435 vs Flu/Cy 0.167; p=0.65), and 180 (0.557 vs 0.220; p=0.14). There was no difference in IgG levels at day 28 (502 vs Flu/Cy 466; p=0.87), 90 (385 vs Flu/Cy 393; p=0.76), or 180 (424 vs Flu/Cy 426; p=0.94). Median CD19 was greater for Cla/Cy at day 90 (median 0.095 vs 0.000; p&amp;lt;0.01) and numerically higher at day 180 (0.213 vs Flu/Cy 0.000; p=0.29). Median duration of followup was 245d for ALL (FluCy 361d, ClaCy 194d) and 746d for MCL (FluCy 812d, ClaCy 215d). Median DOR, EFS, and OS did not differ by LD (Figure 1). Conclusions : Cla/Cy LD prior to brexu-cel is feasible in ALL and MCL patients with comparable efficacy. Toxicity rates including CRS, ICANS and early infections were similar to those seen with Flu/Cy, but there was a trend towards earlier recovery of neutrophils, B-, and T-cells with Cla/Cy. The trend was demonstrable even in patients at high risk of prolonged post-CAR T neutropenia as identified by the HS. Longer follow-up and correlative analyses are warranted to further explore differences between Cla/Cy and Flu/Cy.

Final Analysis of the Randomized Phase II/III Study of Standard R-CHOP Versus CHOP Combined with Dose-Dense Weekly Rituximab for DLBCL: JCOG0601

Background: Despite several attempts of randomized phase III trial to overcome R-CHOP in overall survival (OS), R-CHOP has been continued to be a standard of care in previously untreated DLBCL. We conducted a randomized phase II/III study (JCOG0601, jRCTs031180139) that investigated the efficacy of dose-dense weekly rituximab combined with standard CHOP regimen (RW-CHOP) during the early treatment period for previously untreated DLBCL and published the results (Ohmachi K, et al. Blood Adv. 2021). Here in, we report the long-term efficacy and safety of the JCOG 0601 trial after 8 years follow-up from the end of accrual. Methods: Patients aged 20-79 years with previously untreated CD20-positive DLBCL (stage I-IV, performance status 0-2) were randomized to standard R-CHOP (CHOP-21 with eight doses of rituximab, once every 3 weeks) or RW-CHOP (CHOP-21 with eight doses of weekly rituximab). The primary endpoint of phase III part was progression-free survival (PFS). Required sample size was 422 patients, an accrual period of 7 years, and a follow-up period of 3 years with the primary analysis. An additional follow-up period was added to assess long-term outcomes, for a total of 8 years of follow-up. Results: Between December 2007 and December 2014, 422 patients were enrolled, but primary analysis was performed on 421 patients after one patient withdrew consent: 213 in the R-CHOP arm and 208 in the RW-CHOP arm. The baseline characteristics were as follows (R-CHOP arm vs. RW-CHOP arm): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and International Prognostic Index score ≤2, 77.0% vs. 87.5%. At a primary analysis, there was no significant difference in PFS between the arms. At the time of final analysis with a median follow-up of 9.6 years (range: 0.3-14.9) among all patients, meaningful differences were not found in PFS and OS as well as the primary analysist (hazard ratio [HR] in PFS of RW-CHOP against R-CHOP, 0.94; 95% confidence interval [CI], 0.67 to 1.32, one-sided log-rank, P = 0.36 and HR in OS, 0.94; 95% CI, 0.63 to 1.41). Median PFS and OS were not estimable in both arms. Estimated 10 years PFS and OS of all patients was 66.9% (95% CI, 62.1 to 71.3) and 78.0% (95% CI, 73.6 to 81.7). After the first relapse or refractoriness, 126 patients received post-protocol salvage therapy: 66 in the R-CHOP arm and 60 in the RW-CHOP arm. In each arm, 3 patients received high-dose chemotherapy followed by autologous stem cell transplantation. One patient in the R-CHOP arm proceeded to allogeneic stem cell transplantation from a sibling donor. Ann Arbor stage I to II disease tended to have more favor prognosis than Ann Arbor stage III to IV disease, and no sustained relapse was observed in either stage. Of the 401 patients who underwent central pathological review, 125 were diagnosed with germinal center B-cell-like (GCB) type and 216 with non-GCB type by immunohistochemistry analysis. There was no remarkable difference in PFS between the arms for GCB type and non-GCB type. Death occurred in 95 patients: 56 from DLBCL, 2 from treatment-related cardiac toxicity, 9 from treatment-related mortality caused by salvage treatment, 14 from secondary malignancies, and 11 from other diseases or reasons. There were 34 secondary malignancies in 31 patients (14.6%) in the R-CHOP arm, and 39 cases in 35 patients (16.8%) in the RW-CHOP arm. The most common secondary malignancies were lung cancer (2.6%), colon cancer (1.9%), prostate cancer (1.7%) and gastric cancer (1.9%). Three cases of acute myeloid leukemia (0.7%) and three of myelodysplastic syndromes (0.7%) were observed. The median age of patients who developed secondary malignancy was 72 years (range: 49-84) at the onset. The median time from study enrollment to the onset of secondary malignancy was 4.5 (range: 0.1-13.1) years and the incidence was time dependent. There were no unexpected adverse events, including late opportunistic infections. Conclusion: This final-follow up data demonstrated again no superiority of RW-CHOP in PFS and OS. Standard R-CHOP remains a standard of care for untreated DLBCL.

Reconstitution Dynamics and Impact on Clinical Outcomes of Mucosal-Associated Invariant T-Cells in Pediatric Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

Background Understanding the reconstitution of all immune system components after allogeneic hematopoietic stem cell transplantation (HSCT) is crucial to optimize the prevention of infections, leukemia relapse and graft-versus-host disease (GvHD), thus improving patient's outcome. Mucosal-associated invariant T (MAIT) cells have received major interest in the field for their ability to respond to fungal and bacterial infections and control mucosal homeostasis in the GvHD context. However, the impact of MAIT cell recovery on T-cell immunity and on patient outcomes after HSCT remains not fully characterized. Patients and study design We retrospectively analyzed 156 consecutive patients (median age 8.5 years, range 0.6-24.7) affected by malignant hemopathies undergoing HSCT between April 2019 to May 2022, fully engrafted at day+30 after receiving the graft from an unrelated matched (MUD) or mismatched (mMUD) donor (n=52 and n=11, respectively) or from an HLA-haploidentical (Haplo) donor (n= 93) after alpha-beta T-/CD19-cell depletion. Conditioning regimen was myeloablative, TBI- (n=120) or chemo-based (n=36) in all patients. GvHD prophylaxis included short course methotrexate, anti-thymocyte globulin, cyclosporin with or without abatacept 10mg/kg at day -1,+5,+14,+28,+42,+60 for patients transplanted from mMUD or MUD, respectively. Haplo-HSCT patients did not receive any post-HSCT pharmacological prophylaxis. Patient characteristics are listed in Table 1. We investigated T and, in particular, MAIT cell recovery up to 2 years after HSCT and their correlation with clinical outcomes. Results With a median follow-up of 27 months (range 2-49), the overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM) of the entire cohort were 78,5% (95%CI 70-84), 70% (95%CI 62-77) and 6% (95%CI 3-11), respectively. The cumulative incidence (CI) of relapse was 23% (95%CI 17-31). CI of grade II-IV acute GvHD (aGvHD) was 19.7% (95%CI 14-27), while CI of chronic GvHD (cGvHD) was 15% (95%CI 10-22) with a CI of moderate-severe cGvHD of 10% (95% CI 6-16), resulting in a cGvHD-free, relapse-free survival (GRFS) of 63% (95%CI 54-69). CI of post-HSCT CMV reactivation was 35% (95%CI 28-43); 13 and 22 patients experienced pre-engraftment or late blood stream infections (BSI) (CI 8%, 95%CI 5-13 and 14%, 95%CI 9-20, respectively). While total abT cells reached normal levels between 1 and 2 years post-transplantation, MAIT cells showed prolonged impaired reconstitution up to 2 years post-HSCT. Compared to UD-HSCT, MAIT cell recovery after Haplo-HSCT was significantly delayed. Interestingly, across all time points analyzed, we observed that a large fraction of MAIT cells were negative for CD161, a marker canonically expressed on MAIT cells. We also found that MAIT cells showed prolonged functional impairment as demonstrated by the increased expression of the activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, as well as by the suboptimal response to ex vivo T-cell activation 1 year post HSCT. OS, DFS and NRM were not influenced by the absolute number and proportion of MAIT cells when assessed 30 days post-HSCT. Interestingly, higher absolute count of MAIT at +30 was associated with higher CI of aGvHD (27% vs 11%, p=0.04) in univariate analysis. Furthermore, an higher proportion of MAIT cells at the same time point, as well as the use of mMUD as donor, were associated as independent factors with a higher CI of all grades of cGvHD (25% vs 8%, p=0.01 and 74% vs 12%, p&amp;lt;0.001, respectively) and moderate-severe cGvHD (17% vs 4% p=0.024 and 59% vs 8% p=0.017, respectively), resulting in lower GRFS in patients with an higher proportion of MAIT cells at +30 (72% vs 52%, p=0.019) (Fig. 1). Univariate analysis also showed that patients with higher absolute values of MAIT had a lower CI of late BSI (17% vs 35%, p=0.05) but experienced more frequently CMV reactivation (44% vs 26%, p= 0.029) which occurred more in Haplo- and mMUD-recipients compared to MUD-patients (41.2% and 45.4% vs 21.2%, p=0.029). Conclusions Our study shows that MAIT cell recovery is significantly impaired in terms of absolute number and function in patients receiving HSCT. Evaluation of MAIT cells at early time points after HSCT may represent a useful parameter to identify patients at risk of late BSI, cGvHD and CMV reactivation. Additional studies are needed to further assess the biological function of MAIT cells.

1312. Incidence and Microbiology of Prosthetic Joint Infection According to Time Following Total Knee Arthroplasty: A Retrospective Cohort Study Among US Veterans

Abstract Background Despite the frequency of total knee arthroplasty (TKA) and clinical impact of prosthetic joint infections (PJIs), the incidence and microbiology of these infections in the United States remains unclear. Our objective was to determine the incidence of PJI occurring ≤ 3 months (early), between &amp;gt; 3 and ≤ 12 months (delayed), and &amp;gt; 12 months (late) after primary TKA and to identify the organisms isolated from microbiologic cultures during each of these periods. Methods We conducted a retrospective study of patients in the Veterans Aging Cohort Study- National Cohort who underwent elective primary TKA in the VA between October 1, 1999 to September 30, 2019. The primary outcome was incident hospitalization with PJI. We estimated incidence rates (events/10,000 person-months) with 95% confidence intervals (CIs) of early, delayed, and late PJI. Poisson regression was used to estimate the incidence rate ratio (IRR) with 95% CI of early and delayed PJI compared to late PJI. The Kaplan-Meier method was used to demonstrate the cumulative incidence of PJI at 3, 12 and 24 months. We measured the frequency of Gram-positive, Gram-negative, fungal, polymicrobial, and culture-negative PJI occurring within each of the three time periods and compared frequencies of interest using Pearson’s chi-squared tests. Results Among 82,401 VHA patients who underwent primary TKA, a total of 1,605 incident PJIs (1.9%) were identified. The incidence rate of PJI was higher in the first 12 months after primary TKA surgery, with an IRR of 20.4 (95% CI, 18.2-222.8) for early and 4.2 (95% CI, 3.7-4.8) for delayed periods when compared to late. The cumulative incidence of PJI at 3 months was 0.77% (95% CI, 0.71-0.83%), at 12 months was 1.25% (95% CI 1.17-1.33%), and at 24 months was 1.56% (95% CI 1.48-1.65%) (Figure 1). Staphylococcus aureus was the most common organism isolated (33.2%) across the periods. Gram-negative bacteria were isolated in 11.1% of all infections, and 15.1% of early PJIs (Table 1). Kaplan Meier failure curves for prosthetic joint infection for the overall study period (upper panel) as well as the first 24 months (lower panel) following primary total knee arthroplasty. Abbreviations: PJI, prosthetic joint infection; CI, confidence interval.Table 1.Organisms isolated from synovial fluid or operative tissue cultures of early, delayed and late prosthetic joint infections after primary total knee arthroplasty. aAmong the 1,605 PJIs in the Overall Cohort, the microbiology data for 103 were missing and 1,502 PJIs with available microbiology data were included in these results. bPolymicrobial defined by multiple genera of organisms identified cIncludes: Micrococcus species, diphtheroids dIncludes: Salmonella, Pasteurella, Citrobacter, Morganella, Acinetobacter, Pasteurella, Burkholderia species, and Gram-negative organisms not otherwise specified eAll fungal infections were identified as Candida species fNumbers may not sum to group totals or percentages as polymicrobial infections with more than one organism were possible Abbreviations: PJI, prosthetic joint infection. Conclusion Incidence rates of early and delayed PJI were significantly higher than late PJI following primary TKA. Gram-negative organisms were more prevalent in early compared to delayed or late PJI. Empiric Gram-negative antibiotic therapy should be considered with a suspected PJI within 3 months after elective primary TKA. Disclosures Alisa Stephens-Shields, PhD, Gilead Sciences: Advisor/Consultant Charles Nelson, MD, Stryker: Advisor/Consultant|Zimmer-Biomet: Advisor/Consultant|Zimmer-Biomet: Grant/Research Support

830. Risk factors for late Pneumocystis jirovecii pneumonia in kidney transplant recipients: A Case-Control Study of United States Renal Data System Data

Abstract Background Organ transplant recipients are at increased risk of potentially life-threatening opportunistic infections, including Pneumocystis jirovecii pneumonia (PJP). Given the use of effective prophylaxis, PJP has become less common, especially during the first-year post-transplant. Recent data has shown that the risk of infection has shifted within the first 2 years after discontinuing prophylaxis. We aimed to determine risk factors for late posttransplant PJP using a national database. Methods Using the United States Renal Data System database, we performed a retrospective case-control study of patients who underwent kidney transplant from 1998 through 2019. To evaluate risk factors for late PJP, we performed logistic regression analysis by comparing characteristics between infected patients and their matched uninfected controls. Results We identified 407 cases with PJP and matched to 1628 controls (1:4). 60 (14.7%) of the cases occurred within one year post transplant and 347 (85.3%) patients were diagnosed after one year of transplant. In the late period, the median time between transplant and PJP diagnosis was 68.7 (IQR 28 -134.2) months. Seventy cases (20.1%) occurred between 12 and 24 months. In multivariate analysis (table 1), risk factors for late infection included a higher Elixhauser Comorbidity Index (ECI), history of cytomegalovirus disease, older donor age, use of antilymphocyte agents, history of re-transplant and a longer time of hemodialysis prior to transplant. Of note, in the early period, we found that having a living donor was protective. Multivariate analysis of risk factors for late Pneumocystis jirovecii pneumonia Conclusion Our findings highlight the importance of a timely transplant to mitigate the risk of post-transplant PJP in the late post-transplant period where prophylaxis is not routinely used. These results also raise the consideration of PJP prophylaxis in the late period in patients diagnosed with CMV disease, history of re transplant and recent use of antilymphocyte agents. Disclosures Paschalis Vergidis, MD, MSc, AbbVie: Advisor/Consultant|Ansun: Grant/Research Support|Cidara: Grant/Research Support|Scynexis: Grant/Research Support

Dynamic Interplay of Metabolic and Transcriptional Responses in Shrimp during Early and Late Infection Stages of Enterocytozoon hepatopenaei (EHP)

Enterocytozoon hepatopenaei (EHP) is a microsporidian parasite that infects Litopenaeus vannamei, causing severe hepatopancreatic microsporidiosis (HPM) and resulting in significant economic losses. This study utilizes a combined analysis of transcriptomics and metabolomics to unveil the dynamic molecular interactions between EHP and its host, the Pacific white shrimp, during the early and late stages of infection. The results indicate distinct immunological, detoxification, and antioxidant responses in the early and late infection phases. During early EHP infection in shrimp, immune activation coincides with suppression of genes like Ftz-F1 and SEPs, potentially aiding parasitic evasion. In contrast, late infection shows a refined immune response with phagocytosis-enhancing down-regulation of Ftz-F1 and a resurgence in SEP expression. This phase is characterized by an up-regulated detoxification and antioxidant response, likely a defense against the accumulated effects of EHP, facilitating a stable host–pathogen relationship. In the later stages of infection, most immune responses return to baseline levels, while some immune genes remain active. The glutathione antioxidant system is suppressed early on but becomes activated in the later stages. This phenomenon could facilitate the early invasion of EHP while assisting the host in mitigating oxidative damage caused by late-stage infection. Notably, there are distinctive events in polyamine metabolism. Sustained up-regulation of spermidine synthase and concurrent reduction in spermine levels suggest a potential role of polyamines in EHP development. Throughout the infection process, significant differences in genes such as ATP synthase and hexokinase highlight the continuous influence on energy metabolism pathways. Additionally, growth-related pathways involving amino acids such as tryptophan, histidine, and taurine are disrupted early on, potentially contributing to the growth inhibition observed during the initial stages of infection. In summary, these findings elucidate the dynamic interplay between the host, Litopenaeus vannamei, and the parasite, EHP, during infection. Specific phase differences in immune responses, energy metabolism, and antioxidant processes underscore the intricate relationship between the host and the parasite. The disruption of polyamine metabolism offers a novel perspective in understanding the proliferation mechanisms of EHP. These discoveries significantly advance our comprehension of the pathogenic mechanisms of EHP and its interactions with the host.

Riding apoptotic bodies for cell-cell transmission by African swine fever virus.

African swine fever virus (ASFV), a devastating pathogen to the worldwide swine industry, mainly targets macrophage/monocyte lineage, but how the virus enters host cells has remained unclear. Here, we report that ASFV utilizes apoptotic bodies (ApoBDs) for infection and cell-cell transmission. We show that ASFV induces cell apoptosis of primary porcine alveolar macrophages (PAMs) at the late stage of infection to productively shed ApoBDs that are subsequently swallowed by neighboring PAMs to initiate a secondary infection as evidenced by electron microscopy and live-cell imaging. Interestingly, the virions loaded within ApoBDs are exclusively single-enveloped particles that are devoid of the outer layer of membrane and represent a predominant form produced during late infection. The in vitro purified ApoBD vesicles are capable of mediating virus infection of naive PAMs, but the transmission can be significantly inhibited by blocking the "eat-me" signal phosphatidyserine on the surface of ApoBDs via Annexin V or the efferocytosis receptor TIM4 on the recipient PAMs via anti-TIM4 antibody, whereas overexpression of TIM4 enhances virus infection. The same treatment however did not affect the infection by intracellular viruses. Importantly, the swine sera to ASFV exert no effect on the ApoBD-mediated transmission but can partially act on the virions lacking the outer layer of membrane. Thus, ASFV has evolved to hijack a normal cellular pathway for cell-cell spread to evade host responses.

Human HLA prolongs the host inflammatory response in Streptococcus suis serotype 2 infection compared to mouse H2 molecules.

Streptococcus suis (S. suis) is widely acknowledged as a significant zoonotic pathogen in Southeast Asia and China, which has led to a substantial number of fatalities in both swine and humans. Despite the prevalent use of mice as the primary animal model to study S. suis pathogenesis, the substantial differences in the major histocompatibility complex (MHC) between humans and mice underscore the ongoing exploration for a more suitable and effective animal model. In this study, humanized transgenic HLA-A11/DR1 genotypes mice were used to evaluate the differences between humanized HLA and murine H2 in S. suis infection. Following intravenous administration of S. suis suspensions, we investigated bacterial load, cytokine profiles, pathological alterations, and immune cell recruitment in both Wild-type (WT) and humanized mice across different post-infection time points. Relative to WT mice, humanized mice exhibited heightened pro-inflammatory cytokines, exacerbated tissue damage, increased granulocyte recruitment with impaired resolution, notably more pronounced during the late infection stage. Additionally, our examination of bacterial clearance rates suggests that HLA-A11/DR1 primarily influences cell recruitment and mitochondrial reactive oxygen species (ROS) production, which affects the bacterial killing capacity of macrophages in the late stage of infection. The reduced IL-10 production and lower levels of regulatory T cells in humanized mice could underlie their compromised resolution ability. Intervention with IL-10 promotes bacterial clearance and inflammatory regression in the late stages of infection in transgenic mice. Our findings underscore the heightened sensitivity of HLA-A11/DR1 mice with impaired resolution to S. suis infection, effectively mirroring the immune response seen in humans during infection. The humanized HLA-A11/DR1 mice could serve as an optimal animal model for investigating the pathogenic and therapeutic mechanisms associated with sepsis and other infectious diseases.

Abstract 13879: Characterizing Post-Cardiac Surgery Infection Risk: A Statewide Experience

Introduction: Patients undergoing cardiac surgery are at risk for developing early (in-hospital or within 30-days) and late (up to 180 days after surgery) postoperative infections. Current national database infection metrics are limited in scope and duration of follow-up. Aim: Evaluate rates and types of early and late postoperative infections and mortality. Methods: Medicare claims from 8335 Michigan fee-for-service beneficiaries undergoing isolated coronary artery bypass grafting (CABG) (n=4162), isolated surgical aortic valve replacement (SAVR) (n=618), CABG + SAVR (n=627), or transcatheter aortic valve replacement (TAVR) (n= 2946) between 2017-2020 at 33 Michigan hospitals were linked to The Society of Thoracic Surgeons data. Nine infection types were tracked within 180 days following surgery. The relationship between infections and 180-day and 365-day mortality was evaluated. Results: The average age was 74.2 ± 9.1 years, 36.5% were female, 5.0% were Black and 1.4% were Hispanic. The in-hospital infection rate was 8.9%, while 17.8% within 180 days after surgery. Infection rates varied by hospital (9.1%-33.9%), year (2017 vs 2020: 20.1% vs 16.0%), and procedure type (CABG: 18.2%, SAVR: 14.9%, CABG+SAVR: 19.6%, TAVR: 17.4%). Most common infections were urinary tract infection (8.7%), pneumonia (7.0%) and sepsis (5.2%). The overall mortality rate was 5.9% at 180-days (and varied by infection type, Table ) and 9.0% at 365 days. Patients with an infection had higher associated 180-day mortality compared to those with no infection (17.7% vs 3.4%, p&lt;0.001). Among infection types, sepsis was associated with the highest 180-day mortality rate. Conclusions: Nearly 20% of Medicare beneficiaries develop an infection within 180 days after cardiac surgery, with rates varying by 24% across hospitals and contributing to higher 180-day mortality. Future efforts should identify determinants of postoperative infections, especially given their impact on mortality.

Common inflammatory markers in the screening of knee arthroprosthesis infections

&amp;lt;p&amp;gt;&amp;lt;strong&amp;gt;Aim&amp;lt;br /&amp;gt;&amp;lt;/strong&amp;gt; To evaluate the sensitivity and specificity of serum C-reactive protein (CRP) in early and late total knee arthroplasty (TKA)&amp;lt;br /&amp;gt;infections.&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Methods&amp;lt;br /&amp;gt;&amp;lt;/strong&amp;gt; Blood tests to determine CRP levels (cut-off 10 mg/L) were conducted before surgery, at 1st day, 7th day and 15th day after surgery and at 1, 3, 6,12, 24 and 36 months. Patients had routine follow-up visits and radiological evaluations at 14 days and at 1, 3, 6, 12, 24 and 36 months. Infections were recorded and classified according to Widmer classification. The &amp;amp;chi;2 test or Fisher (in subgroups smaller than 10 patients) exact test was used to compare categorical variables. The statistical significance was set at p &amp;amp;lt; 0.05.&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Results&amp;lt;br /&amp;gt;&amp;lt;/strong&amp;gt; A total of 19 infections were diagnosed during the followup. According to Widmer, five were classified as early post-operative and 14 as late chronic. All patients with early infections had suspected symptoms such as fever, swelling and pain. During the first month, 59 patients who had high CRP level but negative microbiological culture were considered as false positive representing a CRP sensitivity of 80% and a specificity of 67.6%. Fourteen patients had late chronic infection.&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Conclusion&amp;lt;br /&amp;gt;&amp;lt;/strong&amp;gt; This study suggests that a synovial fluid aspiration should be performed in patients with persistent inflammation&amp;lt;br /&amp;gt;symptoms with or without radiographic signs of loosening. Moreover, it recommends the use of different serum and synovial tests for periprosthetic joint infection (PJI) diagnosis.&amp;lt;/p&amp;gt;