Documented Infection Research Articles

Cilgavimab and tixagevimab as pre-exposure prophylaxis in vaccine non-responder kidney transplant recipients during a period of prevalent SARS-CoV-2 BA.2 and BA.4/5 variants—a prospective cohort study (RESCUE-TX)

The response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination is severely impaired in patients on maintenance immunosuppression after kidney transplantation. We conducted a prospective cohort study of 194 kidney transplant recipients (KTR) who exhibited no response to SARS-CoV-2 vaccinations (i.e., SARS-CoV-2 spike protein antibodies ≤264 U/mL) and had no prior documented infection. Patients received 300mg of cilgavimab/tixagevimab as SARS-CoV-2 pre-exposure prophylaxis (PrEP) between March 4, 2022, and May 3, 2022 and were contrasted to a matched cohort of 186 KTRs also without immunization again defined as SARS-CoV-2 spike protein antibodies ≤264 U/mL and no documented prior infection. The primary outcome was the serum kinetics of cilgavimab/tixagevimab, the secondary endpoints were time to SARS-CoV-2 breakthrough infection, severity of disease and variant specific live viral invitro neutralization tests of patient sera. Longitudinal serum level monitoring showed a half-life of 91 days for both antibodies (95% CI 86-95 days for cilgavimab and 85-96 days for tixagevimab) in KTRs. Invitro neutralization tests showed effectiveness against the BA.2 omicron subvariant but not BA.5. The cumulative incidence of SARS-CoV-2 infections until May 15, 2022, (BA.2 dominance) was 15/194 vs 36/186 in the PrEP and control group respectively (OR=0.35, 95% CI 0.18-0.66) but was not different thereafter (BA.4/5 dominance). The number of severe infections during the BA.2 period was lower in the prophylaxis than in the control group (OR=0.37, 95% CI 0.17-0.79). This study showed that SARS-CoV-2 PrEP with cilgavimab/tixagevimab demonstrated clinical effectiveness against variants that are neutralised (BA.2) but not against BA.4/5. This study was funded by the Medical University of Vienna and an unrestricted grant from AstraZeneca (ESR-21-21585).

Impact of Extracorporeal Membrane Oxygenation (ECMO) on Serum Concentrations of Cefepime

ECMO is becoming widely used as a life-saving measure for critically ill patients. However, there is limited data on pharmacokinetics and the dosing of beta-lactam antibiotics in ECMO. In this study, we evaluated the serum concentrations of cefepime in patients on ECMO to determine the impact of ECMO circuitry and to guide therapeutic dosing. Methods: Patients 19 years or older admitted to the ICU, treated with ECMO and beta-lactam antibiotics for presumed or documented infection, were enrolled. Three blood samples (peak, midpoint, trough) were obtained before ECMO (pre-ECMO) and during ECMO (intra-ECMO) at a steady state. Results: Eight patients met inclusion criteria; six received cefepime. All patients were male. Average ± SD age was 45.8 ± 14.7. Four patients received ECMO for severe SARS-CoV-2 infection, and one each for Pneumocystis pneumonia and influenza A infection. Mean ± SD APACHE II and SOFA scores prior to ECMO were 24.6 ± 7.1 and 11.0 ± 3.9, respectively. All but one of the patients received venovenous (VV) ECMO. Cefepime 1 g every 6 h intravenously over 2 min was administered to all patients before and during ECMO. Cefepime concentrations were fit to non-compartment analysis (NCA) and area under the serum concentration–time curve averaged ± SE 211.9 ± 29.6 pre-ECMO and 329.6 ± 32.3 mg*h/L intra-ECMO, p = 0.023. No patients displayed signs of cefepime neurotoxicity. Patients received ECMO for 43.1± 30 days. All patients expired. Cefepime dosed at 1 g every 6 h intravenously appears to achieve therapeutic levels for critically ill patients on ECMO.

Recent Endemic Coronavirus Infection Associates With Higher SARS-CoV-2 Cross-Reactive Fc Receptor Binding Antibodies.

Recent documented infection with an endemic coronavirus (eCoV) associates with less severe coronavirus disease 2019 (COVID-19), yet the immune mechanism behind this protection has not been fully explored. We measured both antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in SARS-CoV-2 naïve individuals classified into two groups, either with or without presumed recent eCoV infections. There was no difference in neutralizing antibodies and T cell responses against SARS-CoV-2 antigens between the two groups. SARS-CoV-2 naïve individuals with recent presumed eCoV infection, however, had higher levels of Fc receptor (FcR) binding antibodies against eCoV spikes (S) and SARS-CoV-2 S2. There was also a significant correlation between eCoV and SARS-CoV-2 FcR binding antibodies. Recent eCoV infection boosts cross-reactive antibodies that can mediate Fc effector functions, and this may play a role in the observed heterotypic immune protection against severe COVID-19.

Males are at higher risk of colonization and infection with multi-drug-resistant organisms than females

Global rise of multidrug-resistant organisms (MDRO) is alarming and antimicrobial resistance (AMR) poses a significant public health threat globally. Although certain risk factors are known including recent antimicrobial therapy, inappropriate use and hospitalization, the focus on gender-specific aspects in MDRO is scarce. Our aim was to show gender-specific differences in colonization and infections of multiple MDRO and their detection sites. For this multicentre, retrospective cohort study surveillance data between 2015 and 2020 was collected in 86 hospitals of the Helios group, Germany. The following multidrug-resistant bacteria were analysed according to sample site: MRSA, Enterococcus spp., Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa and Acinetobacter baumannii. Out of the 7,081,708 cases in the database, 187,656 patients were found to be colonized with MDRO (2.65%). A documented infection with MDRO was identified in 33,023 patients (0.466%), with the origin of infection known in 24,231 cases. Male gender was a risk factor for both infection and colonization of any MDRO (p< .001). Males exhibited a higher likelihood of MDRO detection in superficial skin/soft tissue, blood cultures (p < .001), and respiratory samples (p = .002). Additionally, gender-specific differences in MDRO detection site and pathogens were found with slightly higher proportion of MRSA infection in deep skin/soft tissue and respiratory samples for females. Our study reinforces the existing hypothesis that male gender is a risk factor for MDRO, supported by our large dataset. It highlights the need to acknowledge gender-specific MDRO susceptibility in clinical practice.

Nurse-Driven Interventions Reduce Central Line-Associated Bloodstream Infection Close to Zero in One Pediatric Oncologic Facility: A Single-Center Retrospective Observational Study.

Central line-associated bloodstream infections (CLABSIs) are critical infectious complications among pediatric hematology-oncology patients, and the management of central venous catheters (CVCs) by healthcare personnel can significantly influence the incidence of these infections. This study evaluates the impact of nurse-led changes in CVC management on the incidence of CLABSIs. This single-center, retrospective observational study was conducted at an urban, tertiary referral, and academic center serving pediatric patients. The study cohort comprised 239 patients and 323 CVCs seen between 2012 and 2022. CLABSI was defined according to the Centers for Disease Control and Prevention definitions. Oncology nurse leaders developed CVC-specific educational modules for CLABSI prevention. All the relevant information during the CVC maintenance period was noted in the patient's CVC logbook. A total of 24 (7%) cases of confirmed CLABSI were identified. The incidence of CVC-related infections was 0.32 cases per 1000 catheter days (95%CI: 0.19-0.45). The incidence decreased by 40% between the first and second three-year study period. Documented exit-site infection was reported in 32 (10%) cases. The correlation between exit-site infection and CLABSI was found in 9 (28%) cases. Our CVC-related infection rates are significantly lower than the incidence reported by the Italian Association of Pediatric Hematology and Oncology, which settles at 3-5 cases per 1000 catheter days. Our data confirm the effectiveness of local CVC management guidelines in preventing CVC-related infectious complications.

Assessment of De-Escalation of Empirical Antimicrobial Therapy in Medical Wards with Recognized Prevalence of Multi-Drug-Resistant Pathogens: A Multicenter Prospective Cohort Study in Non-ICU Patients with Microbiologically Documented Infection.

Antimicrobial resistance poses a major threat to human health worldwide and the implementation of antimicrobial stewardship programs (ASPs), including antimicrobial de-escalation (ADE), is a multifaceted tool for minimizing unnecessary or inappropriate antibiotic exposure. This was a prospective observational study of 142 non-Intensive Care Unit (ICU) patients with microbiologically documented infection who were initially administered empirical antimicrobial therapy and admitted to the medical wards of 6 tertiary-care hospitals in Greece from January 2017 to December 2018. Patients were divided into two groups, the ADE and non-ADE group, based on whether ADE was applied or not, respectively. Exploratory end-points were ADE feasibility, safety and efficacy. ADE was applied in 76 patients at a median time of 4 days (IQR: 3, 5). An increased likelihood of ADE was observed in patients with urinary tract (OR: 10.04, 95% CI: 2.91, 34.57; p < 0.001), skin and soft tissue (OR: 16.28, 95% CI: 1.68, 158.08; p = 0.016) and bloodstream infections (OR: 2.52, 95% CI: 1, 6.36; p = 0.05). Factors significantly associated with higher rates of ADE were clarithromycin administration, diagnosis of urinary tract infection (UTI), isolation of E. coli, age and symptoms type on admission. Mortality was lower in the ADE group (18.4% vs. 30.3% p < 0.1) and ADE was not significantly associated with the probability of death (p = 0.432). ADE was associated with favorable clinical outcomes and can be performed even in settings with high prevalence of multi-drug resistant (MDR) pathogens without compromising safety.

Widespread exposure to SARS-CoV-2 in wildlife communities

Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events to animals. While SARS-CoV-2 has a potential broad wildlife host range, most documented infections have been in captive animals and a single wildlife species, the white-tailed deer. The full extent of SARS-CoV-2 exposure among wildlife communities and the factors that influence wildlife transmission risk remain unknown. We sampled 23 species of wildlife for SARS-CoV-2 and examined the effects of urbanization and human use on seropositivity. Here, we document positive detections of SARS-CoV-2 RNA in six species, including the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, and Eastern red bat between May 2022–September 2023 across Virginia and Washington, D.C., USA. In addition, we found that sites with high human activity had three times higher seroprevalence than low human-use areas. We obtained SARS-CoV-2 genomic sequences from nine individuals of six species which were assigned to seven Pango lineages of the Omicron variant. The close match to variants circulating in humans at the time suggests at least seven recent human-to-animal transmission events. Our data support that exposure to SARS-CoV-2 has been widespread in wildlife communities and suggests that areas with high human activity may serve as points of contact for cross-species transmission.

Chimeric Antigen Receptor T-Cell Postinfusion Fever: Infection Profile, Clinical Parameters, and Biomarkers Trends to Assist Antibiotic Stewardship.

This study aimed to describe documented infections associated with postinfusion fever after CAR T-cell therapy and to evaluate daily changes in vital signs, laboratory results, and the National Early Warning Score (NEWS) in patients with and without confirmed bacterial infections following fever onset, with the objective of assisting in antibiotic stewardship. This was a retrospective, observational study including all consecutive adult patients who received CAR T-cell therapy. Documented infection in the first fever episode after infusion, and clinical and analytic trend comparison of patients with bacterial documented infections and those without documented infections, are described. Among 152 patients treated with CAR T-cell therapy, 87 (57.2%) had fever within 30 days of infusion, with a median time from infusion to fever of 3 (interquartile range, 2-5) days. Of these 87 patients, 82 (94.3%) received broad-spectrum antibiotics. Infection was documented in 9 (10.3%) patients and only 4 (4.6%) had bacterial infections. Clinical signs and biomarkers were similar in patients with bacterial documented infection and in those without documented infection at fever onset. Fever, tachycardia, and high C-reactive protein levels remained high during the first 3 days after CAR T-cell infusion, even when no infection was documented. Fever is a common symptom following CAR T-cell infusion and is largely treated with broad-spectrum antibiotics. However, confirmed bacterial documented infections after the first fever post-CAR T-cell infusion are very unusual. Because clinical parameters and biomarkers are not useful for identifying infectious fever, other methods should be assessed to ensure the proper use of antibiotics.

West Nile and Usutu viruses are efficiently inactivated in platelet concentrates by UVC light using the THERAFLEX UV-Platelets system.

West Nile virus (WNV) and Usutu virus (USUV) are mosquito-borne flaviviruses (Flaviviridae) that originated in Africa, have expanded their geographical range during the last decades and caused documented infections in Europe in the last years. Acute WNV and USUV infections have been detected in asymptomatic blood donors by nucleic acid testing. Thus, inactivation of both viral pathogens before blood transfusion is necessary to ensure blood product safety. This study aimed to investigate the efficacy of the THERAFLEX UV-Platelets system to inactivate WNV and USUV in platelet concentrates (PCs). Plasma-reduced PCs were spiked with the virus suspension. Spiked PC samples were taken after spiking (load and hold sample) and after UVC illumination on the Macotronic UV illumination machine with different light doses (0.05, 0.1, 0.15 and 0.2 (standard) J/cm2). Virus loads of WNV and USUV before and after illumination were measured by titration. Infectivity assays showed that UVC illumination inactivated WNV and USUV in a dose-dependent manner. At a UVC dose of 0.2 J/cm2, the WNV titre was reduced by a log10 factor of 3.59 ± 0.43 for NY99 (lineage 1) and 4.40 ± 0.29 for strain ED-I-33/18 (lineage 2). USUV titres were reduced at the same UVC dose by a log10 factor of 5.20 ± 0.70. Our results demonstrate that the THERAFLEX UV-Platelets procedure is an effective technology to inactivate WNV and USUV in contaminated PCs.

Self-Reported Everyday Functioning After COVID-19 Infection

Changes in everyday functioning are crucial to assessing the long-term impact of COVID-19 infection. To examine the impact of COVID-19 infection on everyday functioning 18 months after infection among veterans with and without histories of COVID-19 infection. This cohort study used data from the US Veterans Affairs (VA) and included 186 veterans who had COVID-19 between October 2020 and April 2021 (ie, COVID-19 cohort) and 186 matched comparators who did not have documented COVID-19 infections (ie, control cohort). This match balanced the risk of COVID-19 based on 39 variables measured in the 24 months before infection or match, using principles of target trial emulation. Data were analyzed from December 2022 to December 2023. First documented COVID-19. The differences in self-reported everyday functioning 18 months after COVID-19 infection were estimated and compared with their matched comparators. Within-matched pair logistic and linear regressions assessed differences in outcomes and were weighted to account for sampling and nonresponse. Among the 186 matched pairs of participants, their weighted mean age was 60.4 (95% CI, 57.5 to 63.2) years among veterans in the COVID-19 cohort (weighted sample, 91 459 of 101 133 [90.4%] male; 30 611 [30.3%] Black or African American veterans; 65 196 [64.4%] White veterans) and 61.1 (95% CI, 57.8 to 64.4) years among their comparators in the control cohort (91 459 [90.4%] male; 24 576 [24.3%] Black or African American veterans; 70 157 [69.4%] White veterans). A high proportion of veterans in the COVID-19 cohort (weighted percentage, 44.9% [95% CI, 34.2% to 56.2%]) reported that they could do less than what they felt they could do at the beginning of 2020 compared with the control cohort (weighted percentage, 35.3%; [95% CI, 25.6% to 46.4%]; within-matched pair adjusted odds ratio [OR], 1.52 [95% CI, 0.79 to 2.91]). There was no association of documented COVID-19 infection with fatigue, substantial pain, limitations in either activities of daily living and instrumental activities of daily living, severely curtailed life-space mobility, employment, or mean health-related quality of life on a utility scale. In this cohort study of veterans with and without documented COVID-19, many reported a substantial loss of everyday functioning during the pandemic regardless of whether or not they had a documented infection with COVID-19. Future work with larger samples is needed to validate the estimated associations.

Mortality in patients with hematological malignancies, febrile neutropenia, and septic shock.

Patients with severe neutropenia who develop septic shock (SS) have high mortality. This study aimed to evaluate the risk factors and mortality of SS in patients with HM and febrile neutropenia. We included all patients with hematological malignancies (HM) who presented fever and severe neutropenia, admitted to an oncological tertiary care center in Mexico City for one year. Two hundred ninety-two episodes of fever and severe neutropenia were documented; 68 patients (23.2%) developed SS. Documented clinical infection was different between SS and non-SS patients (94.1% vs. 63.4%, p < 0.001); pneumonia was the most frequent infection (36.8% vs. 23.2%, p = 0.02). Also, in SS vs. non-SS, there were more positive cultures (69.1% vs. 38.4%, p < 0.001), higher frequency of Gram-negative bacteria (89.3% vs. 63.9%, p < 0.001), particularly Escherichia coli (68% vs. 44.2%) and Klebsiella spp. (23.4% vs. 15.1%). There were no differences when multidrug-resistant (MDR) microorganisms were compared. In the multivariate analysis, associated risk factors for SS were: prolonged neutropenia, a documented site of infection, and having received highly myelosuppressive chemotherapy. Risk factors for mortality at 30 days were: older patients, prolonged neutropenia, and SS. Severe and prolonged neutropenia was associated with SS development and mortality at 30 days. ICU management should be offered to all critically ill patients with HM if long-term survival of the underlying malignancy is expected.

A Systematic Review of Three Biomarkers to Aid in the Assessment of Outcomes for Children and Young People with Cancer that are Febrile Neutropenic

For paediatric patients with cancer, febrile neutropenia (FN) is the most common complication of treatment. It requires inpatient hospitalisation and treatment with empirical broad-spectrum antibiotics. Approximately 20-30% of febrile neutropenic patients have a documented infection, thus needing antibiotics. For the rest, it is suggested that the cause of FN could be a viral or fungal infection, the malignancy itself, drug related or the result of a blood transfusion reaction as examples, therefore not requiring antibiotics. With no risk-stratification tool in use in practice to distinguish between patients who are at high or low risk of bacterial infections, recent studies have focused on identifying clinical and laboratory markers for this. This systematic review will focus on three biomarkers, C-reactive protein (CRP), presepsin (sCD14-ST) and lactate, to find their sensitivities and specificities for diagnosing bacterial infections and thus help determine the risk of poor outcomes for patients with FN. This review has systematically searched for relevant primary research papers. These studies have been critically appraised using a validated critical appraisal tool. Data from these studies were then extracted using a data extraction form, and evidence summarised. The findings have been interpreted, and the implications to practice and research are discussed. 1051 febrile neutropenic episodes from 743 children from different countries were analysed. In the majority of studies (75%), acute lymphoblastic leukaemia was the most frequent diagnosis. Eight of the studies in this review are looking at CRP. Two studies are looking at lactate, and five review presepsin. Lactate is a sensitive and specific biomarker with a lactate level ≥ 2mmol/L and &gt;2.5mmol/L showed sensitivities of 81% and 80% and specificities of 83% and 92.1%, respectively. Presepsin and CRP had mixed results for its sensitivity and specificity. Lactate and CRP are useful biomarkers for assessing the outcomes of children with FN and could be added to a CDR. This review cannot confirm that presepsin is a useful biomarker for practice and, therefore, cannot justify adding it to a CDR.

Impact of Antibacterial Prophylaxis on Morbidity-Mortality of Patients with Myeloid Neoplasms Treated with Non-Intensive Venetoclax Combinations

Background and aims: The addition of Venetoclax (VEN) to the treatment of myeloid neoplasms, particularly newly diagnosed and relapse/refractory (R/R) Acute Myeloid Leukemia (AML), has shown improved responses compared to hypomethylating agents (HMA) in unfit patients. Nevertheless, side effects derived from deep cytopenias (infections) could potentially be a caved of such strategy. The use of antibacterial prophylaxis in this setting is controversial and its employment heterogeneous across centers, making difficult to draw conclusions from real-world studies. In this study we aimed to ascertain whether the use of antibacterial prophylaxis has an impact on the incidence of bacterial infections, hospitalization rates, infection severity, and mortality due to the infection. Finally, we also aimed to identify potential risk factors for bacterial infections. Methods: Retrospective data collection of patients with de novo, R/R or secondary AML, High Risk Myelodisplastic Syndrome and accelerated phases of Myeloproliferative Neoplasms treated with HMA or low dose cytarabine + VEN between January 2018 and May 2023 in 10 Spanish centers. Baseline characteristics and infectious episodes [presented as Microbiologically Documented Bacterial Infections (MDBI) or Clinically Documented infections without Isolation (CDI)], or febrile neutropenia without isolation or focus (FN) were recorded. Confirmed or suspected infections of parasites/fungi/viruses were excluded in this study. For each event, antibacterial prophylaxis, days of hospitalization, severity, disease status and dead due to infectious events/FN were collected. Results: In total, 165 patients have been included (clinical characteristics summarized in Table 1). VEN was initially used as 28 days/cycle and it had to be adjusted in 78 (48.75%) patients, mainly due to cytopenias and infections. The univariate analysis showed that infectious events and FN occurred more frequently in patients with high ELN risk than in those with Intermediate/favorable (OR; 2.71, 95% CI; 1.03-7.11, p = 0.041). In our cohort, 175 infections (MDBI/CDI) or FN occurred in 113 patients (68.5%) with an incidence of 26.1/100 cycles. These episodes correspond to 70 (40%) cases of MBI, 59 cases of CDI (33.7%) and 46 (26.3%) cases FN, with a median of 1 episode per patient (range 1-5). Most events occurred in the first (85; 48.9%) and second cycle (43; 24.7%) with a median of cycles at the moment of the event of 2 (p25-p75: 1-3) and a median time from VEN start to episode of 44 days (p25-p75: 18-105) because infections/FN usually led to delays on subsequent cycles. Considering the total number of events in patients with at least first disease evaluation available at the time of infection, only 48 (31%) had cytologic response (&amp;lt;5% blasts). Table 1 shows type of episode/isolation/focus. Antibacterial prophylaxis was used in 48 patients (29.5%), primarily with quinolones (levofloxacin 74%, ciprofloxacin 23%) according to physician decision. Incidence of infections (MDBI/CDI) or FN was lower in patients with antibacterial prophylaxis (OR; 0.37, 95% CI; 0.18-0.74, p = 0.05). Additionally, the median number of infections was lower in prophylaxis group (0.77 vs 1.18; p= 0.004). However, no differences were observed between both groups regarding hospitalization incidence or infection severity (defined as need of vasoactive drugs, high-flow oxygen therapy or deaths caused by the infectious episode). Microbiological isolations were significantly higher in non-prophylaxis group with infections (45.6% vs 23.7%, p 0.015). Incidence of multidrug-resistant organisms was 10.2% among all patients, with no differences between groups neither in Clostridioides difficile incidence (3.6%). In the competitive risk survival analysis, cumulative incidence of death from MBI/CDI or FN cause showed no differences between patients receiving or not antibacterial prophylaxis ( p= 0.98) (Figure 1). Conclusions: Our data suggest that avoiding antibacterial prophylaxis in non-intensive VEN-based treatments may result in a higher incidence of FN and infectious events, but it does not lead to impaired outcomes in terms of severity and/or mortality related to infections. Having a greater availability of microbiological isolations could enable more targeted antibiotic therapy, avoiding drug resistance. Additional data from the prophylaxis cohort will be included in the presentation.

Autoimmune Neutropenia of Infancy Is Almost Exclusively Caused By IgG Antibodies

Background The relevance of IgM antibodies in autoimmune mediated hemocytopenias remains a matter of debate. For autoimmune neutropenia, conflicting results were published. This study was performed as part of the Giessen Neutropenia Registry, which prospectively included children with suspected autoimmune neutropenia. Methods Children with suspected autoimmune neutropenia were prospectively enrolled and data central to their suspected diagnosis were collected over 3 years. Sera were tested for the presence of autoantibodies against neutrophils by granulocyte immunofluorescence test (GIFT) and granulocyte agglutination test (GAT). The presence of IgG and IgM antibodies was assessed in a subgroup of patients with positive initial GIFT in whom spontaneous remission of their neutropenia was documented. Results A total of 406 children were included in the study. A remission was reported for 114 patients during the study period. Of those, 96 children (84%) had an initial positive GIFT. Their median age at diagnosis was 11 months (7-17.5), and their mean neutrophil count was 293 (±267)/µL, ranging from 0 to 975. In total 75/96 (78%) of children had at least one documented infection at diagnosis. In 29/96 (30%), a bone marrow aspirate was available. At the documented time point of remission, children were 27 months (18-41) old. In the initial sample send for diagnosis, IgG antibodies against neutrophils were detected in 94/96 children (98%), and IgM antibodies were detected in 2/96 (2%). We did not observe children with autoantibodies of both Ig classes. Conclusion To our knowledge, this is the first study to demonstrate the contribution of IgG or IgM antibodies in a well-defined clinical cohort with a typical course including, spontaneous disease remission. IgG antibodies were present in 98%. Only very rarely, IgM antibodies can be detected. We conclude that in general, screening for IgG autoantibodies is appropriate as a first diagnostic step. In cases with strong clinical suspicion but negative GIFT with anti-IgG, anti-IgM testing may be considered.

Fever with Significant Procalcitonin Increase Following Gemtuzumab Ozogamicin Infusion in Hematologic Malignancy Patients without Evidence of Infection

In patients diagnosed with hematologic malignancies, including acute myeloid leukemia (AML), infections remain a major cause of non-relapse mortality. The accurate detection and management of infections during the treatment of these diseases are crucial for successful outcomes. Procalcitonin (PCT) has been proposed as a valuable tool for identifying severe bacterial infections, even in patients with hematologic malignancies. Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, is used in certain subsets of AML patients, such as core binding factor (CBF) leukemia and AML with favorable-risk, as well as in cases of refractory AML. However, GO administration comes with its own set of risks, including liver dysfunction, veno-occlusive disease (VOD), bone marrow suppression, bleeding, and infusion reactions. Among these reactions, those causing high fever and shivering can be particularly challenging to differentiate from sepsis or severe infections. Nevertheless, there have been no reports evaluating the utility of PCT in discriminating infections during GO-induced infusion reactions. To shed light on the impact of GO administration on PCT levels, we undertook a retrospective analysis. Over the period between 2014 and 2022, we administered GO (3.0 mg/sqm per dose) to 42 patients with hematologic malignancies, a total of 97 times (median 2 doses per patient, range 1-6 doses per patient). Of the recipients, 23 had undergone allogeneic stem cell transplantation, while 19 were non-transplant patients. Prior to GO administration, all patients received premedication comprising corticosteroids, antihistamines, and acetaminophen. Among the 97 instances of GO administration, 40 (41.2%) resulted in fever (≥37.5 ℃) within 24 hours. For 19 cases, we conducted a complete set of PCT measurements and blood cultures within 24 hours of GO administration and analyzed the PCT levels and clinical parameters. These 19 cases corresponded to 19 individual patients, of whom nine had CBF leukemia, including t(8;21) AML or inv(16) AML, and ten had non-CBF leukemia. Out of these patients, 12 experienced fever (≥37.5 ℃), while seven did not. The findings indicated that patients with fever (≥37.5 ℃) exhibited significantly higher PCT levels compared to afebrile patients (p=0.018). Furthermore, PCT levels showed a significant positive correlation with C-reactive protein levels (p=0.003). However, among the 19 patients, only one patient with a positive PCT result had a documented infection identified through blood cultures or imaging studies.Other factors, such as patient gender (p=0.467), underlying disease (p=0.224), disease remission status at GO administration (p=0.492), transplant status (p=0.556), and the number of GO administrations (p=0.906), did not significantly influence PCT levels. It is essential to acknowledge that this analysis is based on a limited number of cases from a single institution. Nevertheless, approximately 40% of patients experienced fever within 24 hours of GO administration, despite receiving premedication.Furthermore, the presence of fever after GO administration was associated with a significant increase in PCT levels, even in the absence of identifiable infection. This raises the possibility of false positives for PCT in the context of GO-induced infusion reactions, underscoring the need for cautious interpretation of PCT values for infection differentiation in patients undergoing regimens that include GO. Further research with larger patient cohorts is warranted to validate these findings and improve our understanding of the implications of PCT measurements in this clinical setting.

Shotgun Sequencing of Multi-Site Oral and Colonic Microbiota in Patients with AML: Site-Specific Patterns and Microbiota Decompartmentalization

Gut microbiota is a source of pathogens in immunocompromised patients. While most microbiota studies in patients with AML receiving induction chemotherapy have focused on the gut microbiota, the few on salivary microbiota suggest less severe dysbiosis. As the saliva does not have its own intrinsic microbiota and takes fractions of the microbiota from the different oral tissues it bathes, the extent to which the salivary microbiota reflects microbial changes in other oral sites is unknown. To fill this knowledge gap, we characterized the microbiota in longitudinal salivary, supragingival plaque, and fecal samples of AML patients receiving inpatient chemotherapy. 31 patients have been enrolled in this prospective single-center study. Baseline stool, saliva, and plaque samples were collected at baseline and repeated weekly until 5 weeks after starting chemotherapy or discharge from the hospital, whichever occurred first. Time was divided into 3 intervals: admission to day 10 of chemotherapy, days 11-20, and day 21 and later. 111 samples (stool: 39, saliva: 36, plaque: 36) from 16 patients have been sequenced to date. Samples underwent shotgun sequencing targeting 10M paired-end reads/sample. MetaPhlAn4 was used for taxonomic assignment. Alpha diversity was quantified by Shannon index and beta diversity by Bray-Curtis dissimilarity. 9 patients were male and 7 were female. Median age was 64 (range 34-82). 15 patients were newly diagnosed and 1 was relapsed/refractory. Chemotherapy regimens included CLAG-M (n=10), ATRA+ATO (n=3), Vyxeos (n=1), Venetoclax+Azacitidine (n=1), and intermediate-dose Ara-C (n=1). The 3 most frequently used antibacterial antibiotics were cefepime (n=14), IV vancomycin (n=12), and levofloxacin (n=11). Median hospitalization length was 19 days (range 6-31). Neutropenic fever occurred in 13 patients. Documented infections included bacteremia (n=8), skin/soft tissue (n=5), intestinal (n=4), urinary tract (n=4), and pneumonia (n=1). Four bacterial species isolated from blood cultures of patients with fever were detected by sequencing 1-2 weeks before bacteremia: Gemella Haemolysans in saliva, plaque, and stool, Streptococcus mitis in saliva and stool, Rothia mucilaginosa in saliva and plaque, and Citrobacter freundii in stool. Microbiota diversity from the 3 sites showed markedly different dynamics ( Fig. 1). Plaque microbiota diversity remained stable throughout, with levels as high as fecal microbiota in intervals 1 and 2, and higher than both fecal and salivary microbiota in interval 3. Salivary microbiota diversity was the lowest among sites in intervals 1 and 2 and experienced only a slight reduction in interval 3. In contrast, fecal microbiota diversity was high compared to the other sites in intervals 1 and 2 but dropped in interval 3 to the lowest among all sites. With all 3 intervals combined, salivary microbiota had lower diversity (median 1.9, range 0.04-3.9) than plaque (median 2.7, 0.2-4.3; P=0.01) and fecal microbiota (median 2.9, 0.3-3.7; P=0.048). The 3 sites largely segregated on hierarchical clustering using species abundances ( Fig. 2). However, microbiota in several low-diversity samples from different sites in the same patient coalesced: Veillonella parvula and R. mucilaginosa were detected in all 3 sites, V. dispar in stool and plaque, and S. parasanguinis in stool and saliva. Each overlap was present in 5 or more patients. This first shotgun sequencing analysis of longitudinal salivary, plaque, and fecal microbiota in AML patients offers several novel findings. First, plaque microbiota diversity is stable despite exposure to antibiotics, whereas fecal microbiota diversity is not. Second, while healthy adults show no overlap between oral and colonic microbiota, low-diversity fecal samples from AML patients contained species of their own oral microbiota, particularly at later time points. These data suggest ectopic colonization of the gut by oral flora. Future mechanistic studies of plaque biofilms may reveal community-protective mechanisms that sustain oral plaque microbial diversity and contribute oral flora to the gut. Mitigating gut dysbiosis in AML patients by manipulating plaque biofilms could be a novel approach to improve patient outcomes.

Vaccination, time lost from work, and COVID-19 infections: a Canadian healthcare worker retrospective cohort study.

The COVID-19 pandemic highlighted hurdles for healthcare delivery and personnel globally. Vaccination has been an important tool for preventing severe illness and death in healthcare workers (HCWs) as well as the public at large. However, vaccination has resulted in some HCWs requiring time off work post-vaccination to recover from adverse events. We aimed to understand which HCWs needed to take time off work post-vaccination, for which vaccine types and sequence, and how post-vaccination absence impacted uptake of booster doses in a cohort of 26,267 Canadian HCWs. By March 31, 2022, more than 98% had received at least two doses of the approved COVID-19 vaccines, following a two-dose mandate. We found that recent vaccination and longer intervals between doses were associated with significantly higher odds of time-loss, whereas being a medical resident and receiving the BNT162b2 vaccine were associated with lower odds. A history of lab-confirmed SARS-CoV-2 infection was associated with lower odds of receiving a booster dose compared with no documented infection, aOR 0.61 (95% CI: 0.55, 0.68). Similarly, taking sick time following the first or second dose was associated with lower odds of receiving a booster dose, aOR 0.83 (95% CI: 0.75, 0.90). As SARS-CoV-2 becomes endemic, the number and timing of additional doses for HCWs requires consideration of prevention of illness as well as service disruption from post-vaccination time-loss. Care should be taken to ensure adequate staffing if many HCWs are being vaccinated, especially for coverage for those who are more likely to need time off to recover.

Relationship Between Real-time TDM-guided Pharmacodynamic Target Attainment of Continuous Infusion Beta-lactam Monotherapy and Microbiologic Outcome in the Treatment of Critically Ill Children With Severe Documented Gram-negative Infections.

To explore the relationship between real-time therapeutic drug monitoring (TDM)-guided pharmacodynamic target attainment of continuous infusion (CI) beta-lactam monotherapy and microbiological outcome in the treatment of critically ill children with severe documented Gram-negative infections. Observational, monocentric, retrospective study of critically ill patients receiving CI piperacillin-tazobactam, ceftazidime, or meropenem in monotherapy for documented Gram-negative infections optimized by means of a real-time TDM-guided strategy. Average steady-state beta-lactam concentrations (Css) were calculated for each patient, and the beta-lactam Css/minimum inhibitory concentration (MIC) ratio was selected as a pharmacodynamic parameter of efficacy. The Css/MIC ratio was defined as optimal if ≥4, quasi-optimal if between 1 and 4, and suboptimal if <1. The relationship between Css/MIC and microbiological outcome was assessed. Forty-six TDM assessments were carried out in 21 patients [median age 2 (interquartile range: 1-8) years]. Css/MIC ratios were optimal in 76.2% of cases. Patients with optimal Css/MIC ratios had both a significantly higher microbiological eradication rate (75.0% vs. 0.0%; P = 0.006) and lower resistance development rate (25.0% vs. 80.0%; P = 0.047) than those with quasi-optimal or suboptimal Css/MIC ratios. Quasi-optimal/suboptimal Css/MIC ratio occurred more frequently when patients had infections caused by pathogens with MIC values above the European Committee on Antimicrobial Susceptibility Testing clinical breakpoint (100.0% vs. 6.3%; P < 0.001). Real-time TDM-guided pharmacodynamic target attainment of CI beta-lactam monotherapy allowed to maximize treatment efficacy in most critically ill children with severe Gram-negative infections. Attaining early optimal Css/MIC ratios of CI beta-lactams could be a key determinant associated with microbiological eradication during the treatment of Gram-negative infections. Larger prospective studies are warranted for confirming our findings.

Duration of human papillomavirus persistence and its relationship with recurrent cervical dysplasia.

To evaluate how the duration of human papillomavirus (HPV) persistence influences the risk of developing recurrent high-grade cervical dysplasia (CIN2+). Data of patients with persistent HPV infection (at least at 6 months) after primary conization were extracted from a multi-institutional Italian database, retrospectively. Kaplan-Meier and Cox proportional hazards models were used to evaluate associations between duration of HPV persistence with the 5-year risk of developing recurrent CIN2+. Overall, 545 patients met the inclusion criteria. Positive margins were detected in 160 (29.3%) patients. Overall, 247 (45.3%) and 123 (22.6%) patients had a documented infection from HPV16/18, and other high-risk HPV types. 187 (34.3%), 73 (13.4%), and 40 (7.3%) were diagnosed with persistent HPV infection at 12, 18, and 24 months, respectively. Patients with HPV persistence at 6 months experienced a risk of recurrence of 7.46%. Twelve-month HPV persistence strongly correlates with the risk of developing the recurrent disease (risk of recurrence: 13.1%). While, having HPV persistence >12 months did not correlate with an increased risk of recurrence (hazard ratio: 1.34 (95% confidence interval: 0.78-2.32); P = 0.336, log-rank test). HPV persistence is one of the most important factors predicting the risk of CIN2+ recurrence. The risk of CIN2+ recurrence increased with the increase of HPV persistence for up to 1 year. The persistence of HPV after the first year does not appear as a risk factor.

Factors affecting length and complexity of hospital stay in pediatric dog bite patients

BackgroundDog bite injuries are a source of significant morbidity and expense in the USA, and rates of hospitalization have been rising. Children are at increased risk of dog bites compared...