Emergency Myelopoiesis Distinguishes Multisystem Inflammatory Syndrome in Children From Pediatric Severe Coronavirus Disease 2019.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition caused by recent infection with severe acute respiratory syndrome coronavirus 2, but the underlying immunological mechanisms driving this distinct syndrome are unknown. METHODS: We utilized high-dimensional flow cytometry, cell-free (cf) DNA, and cytokine and chemokine profiling to identify mechanisms of critical illness distinguishing MIS-C from severe acute coronavirus disease 2019 (SAC). RESULTS: Compared to SAC, MIS-C patients demonstrated profound innate immune cell death and features of emergency myelopoiesis (EM), an understudied phenomenon observed in severe inflammation. EM signatures were characterized by fewer mature myeloid cells in the periphery and decreased expression of HLA-DR and CD86 on antigen-presenting cells. Interleukin 27 (IL-27), a cytokine known to drive hematopoietic stem cells toward EM, was increased in MIS-C, and correlated with immature cell signatures in MIS-C. Upon recovery, EM signatures decreased and IL-27 plasma levels returned to normal levels. Despite profound lymphopenia, we report a lack of cfDNA released by adaptive immune cells and increased CCR7 expression on T cells indicative of egress out of peripheral blood. CONCLUSIONS: Immune cell signatures of EM combined with elevated innate immune cell-derived cfDNA levels distinguish MIS-C from SAC in children and provide mechanistic insight into dysregulated immunity contributing toward MIS-C, offering potential diagnostic and therapeutic targets.

Israeli neonatal herpes simplex infection: Unique epidemiology and clinical profile.

To gather national level data on Israeli neonatal HSV (NHSV) infection and to evaluate the distinct clinical characteristics of NHSV and neonatal enteroviral meningitis (NEM). Israeli NHSV patients, hospitalized between January 2015 and April 2022 in 22 medical centers were assessed, together with NEM patients, hospitalized at Sheba Medical Center during the same period. NHSV demographic and clinical characteristics were documented and compared to those of NEM. Eighty-five NHSV (73% males) and 130 NEM (62% males) patients were included. The incidence of NHSV was 5.9/100 000 live births, the common phenotype and HSV type were SEM (53%) and HSV1 (91%), respectively. Horizontal transmission was suspected in 50% cases (of which 67% underwent a Jewish ritual circumcision with direct wound sucking, 33% had relatives with highly suspicious herpetic lesions). Compared with NEM, NHSV tends to present with rash (14% vs. 60%, p-value < 0.01) and seizures (0% vs. 6%, p-value 0.02), while fever, irritability and poor feeding appear more frequently in NEM (94% vs. 18%, p-value < 0.01; 37% vs. 1%, p-value < 0.01; 25% vs. 1%, p-value < 0.01 respectively). Of NEM patients, 28% were treated with acyclovir. Our results mark a decrease in the incidence rate of NHSV in Israel and a prominent mode of horizontal infection acquisition. We underscore the unique localized phenotype of NHSV, in contrast to enterovirus, which tends to cause a systemic disease with constitutional symptoms. These findings should be considered when evaluating the need for comprehensive empirical treatment for HSV in the context of neonatal fever, or according to a certain clinical presentation.

Molecular Imaging to Study Antimicrobial Pharmacokinetics In Vivo.

While antimicrobials are among the most prescribed drugs, the use of some older antibiotics is not optimized for efficacy in terms of dosage, route of administration, and duration of therapy. Knowledge gaps exist regarding the heterogeneous microenvironments within different infected tissues consisting of varying bacterial loads, immune responses, and drug gradients. Positron-emission tomography-based imaging, where radiolabeled drugs are visualized within the living body, enables accurate, holistic, and real-time determination of pharmacokinetics to provide valuable, actionable data to optimize antibiotic use. Here we briefly review the concepts, history, and recent progress in the field.

Multi-institutional experience with COVID-19 convalescent plasma in children.

BACKGROUND AND OBJECTIVES: Convalescent COVID-19 plasma (CCP) was developed and used worldwide as a treatment option by supplying passive immunity. Adult studies suggest administering high-titer CCP early in the disease course of patients who are expected to be antibody-negative; however, pediatric experience is limited. We created a multi-institutional registry to characterize pediatric patients (<18 years) who received CCP and to assess the safety of this intervention. METHODS: A REDCap survey was distributed. The registry collected de-identified data including demographic information (age, gender, and underlying conditions), COVID-19 disease features and concurrent treatments, CCP transfusion and safety events, and therapy response. RESULTS: Ninety-five children received CCP: 90 inpatients and 5 outpatients, with a median age of 10.2 years (range 0-17.9). They were predominantly Latino/Hispanic and White. The most frequent underlying medical conditions were chronic respiratory disease, immunosuppression, obesity, and genetic syndromes. CCP was primarily given as a treatment (95%) rather than prophylaxis (5%). Median total plasma dose administered and transfusion rates were 5.0 ml/kg and 2.6 ml/kg/h, respectively. The transfusions were well-tolerated, with 3 in 115 transfusions reporting mild reactions. No serious adverse events were reported. Severity scores decreased significantly 7 days after CCP transfusion or at discharge. Eighty-five patients (94.4%) survived to hospital discharge. All five outpatients survived to 60 days. CONCLUSIONS: CCP was found to be safe and well-tolerated in children. CCP was frequently given concurrently with other COVID-19-directed treatments with improvement in clinical severity scores ≥7 days after CCP, but efficacy could not be evaluated in this study.

Severe Acute Respiratory Syndrome Coronavirus 2 in Infants Younger Than 90 Days Presenting to the Pediatric Emergency Department: Clinical Characteristics and Risk of Serious Bacterial Infection.

OBJECTIVES: There are scant data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in infants younger than 90 days. This study was designed to characterize COVID-19 presentation and clinical course in this age group and evaluate the risk of serious bacterial infection. METHODS: Data on all SARS-CoV-2-polymerase chain reaction-positive infants presenting to the pediatric emergency department (PED) were retrospectively collected, followed by a case-control study comparing those infants presenting with fever (COVID group) to febrile infants presenting to the PED and found to be SARS-CoV-2 negative (control group). RESULTS: Of the 96 PCR-positive SARS-CoV-2 infants who met the inclusion criteria, the most common presenting symptom was fever (74/96, 77.1%) followed by upper respiratory tract infection symptoms (42/96, 43.8%). Four (4.2%) presented with symptoms consistent with brief resolved unexplained event (4.2%).Among the febrile infants, the presenting symptoms and vital signs were similar in the COVID and control groups, with the exception of irritability, which was more common in the control group (8% and 26%; P < 0.01). The SARS-CoV-2-positive infants had decreased inflammatory markers including: C-reactive protein (0.6 ± 1 mg/dL vs 2.1 ± 2.7 mg/dL; P < 0.0001), white blood cell count (9.3 ± 3.4 × 10 9 /L vs 11.8 ± 5.1 × 10 9 /L; P < 0.001), and absolute neutrophils count (3.4 ± 2.4 × 10 9 /L vs 5.1 ± 3.7 × 10 9 /L; P < 0.001). The rate of invasive bacterial infection was similar between groups (1.4% and 0%; P = 0.31). No mortality was recorded. Although not significantly different, urinary tract infections were less common in the COVID group (7% and 16%; P = 0.07). CONCLUSIONS: The SARS-CoV-2 infection in infants aged 0 to 90 days who present to the PED seems to be mostly mild and self-limiting, with no increased risk of serious bacterial infection.

Robust immune responses to SARS-CoV-2 in a pediatric patient with B-Cell ALL receiving tisagenlecleucel.

Recipients of anti-CD19 targeted therapies such as chimeric antigen receptor (CAR)-T cell are considered at high risk for complicated Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection due to prolonged B cell aplasia and immunosuppression. These patients represent a unique cohort and so far, immune responses to SARS-CoV-2 have not been well characterized in this setting. We report a pediatric patient with B-cell acute lymphoblastic leukemia (B-ALL) who had asymptomatic SARS-CoV-2 infection while receiving blinatumomab, followed by lymphodepletion (LD) and tisagenlecleucel, a CD19 targeting CAR-T therapy. The patient had a complete response to tisagenlecleucel, did not develop cytokine release syndrome, or worsening of SARS-CoV-2 during therapy. The patient had evidence of ongoing persistence of IgG antibody responses to spike and nucleocapsid after LD followed by tisagenlecleucel despite the B-cell aplasia. Further we were able to detect SARS-CoV-2 specific T-cells recognizing multiple viral structural proteins for several months following CAR-T. The T-cell response was polyfunctional and predominantly CD4 restricted. This data has important implications for the understanding of SARS-CoV-2 immunity in patients with impaired immune systems and the potential application of SARS-CoV-2-specific T-cell therapeutics to treat patients with blood cancers who receive B cell depleting therapy.

Distinct Cytokine and Chemokine Dysregulation in Hospitalized Children With Acute Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome With Similar Levels of Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 Shedding.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe clinical phenotype of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that remains poorly understood. METHODS: Hospitalized children <18 years of age with suspected coronavirus disease 2019 (COVID-19) (N = 53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the US Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral ribonucleic acid (RNA) levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. RESULTS: The median ages for those with and without MIS-C were 8.7 years (interquartile range [IQR], 5.5-13.9) and 2.2 years (IQR, 1.1-10.5), respectively (P = .18), and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the 2 groups (median 63 848.25 copies/mL versus 307.1 copies/mL, P = .66); 75% of those with MIS-C were antibody positive compared with 44% without (P = .026). Levels of 14 of 37 cytokines/chemokines (interleukin [IL]-1RA, IL-2RA, IL-6, IL-8, tumor necrosis factor-α, IL-10, IL-15, IL-18, monocyte chemoattractant protein [MCP]-1, IP-10, macrophage-inflammatory protein [MIP]-1α, MCP-2, MIP-1ß, eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (false discovery rate <0.05; P < .05). CONCLUSIONS: The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.

Interaction between Streptococcus pneumoniae and Staphylococcus aureus Generates ·OH Radicals That Rapidly Kill Staphylococcus aureus Strains.

Streptococcus pneumoniae rapidly kills Staphylococcus aureus by producing membrane-permeable hydrogen peroxide (H2O2). The mechanism by which S. pneumoniae-produced H2O2 mediates S. aureus killing was investigated. An in vitro model that mimicked S. pneumoniae-S. aureus contact during colonization of the nasopharynx demonstrated that S. aureus killing required outcompeting densities of S. pneumoniae Compared to the wild-type strain, isogenic S. pneumoniae ΔlctO and S. pneumoniae ΔspxB, both deficient in production of H2O2, required increased density to kill S. aureus While residual H2O2 activity produced by single mutants was sufficient to eradicate S. aureus, an S. pneumoniae ΔspxB ΔlctO double mutant was unable to kill S. aureus A collection of 20 diverse methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains showed linear sensitivity (R2 = 0.95) for S. pneumoniae killing, but the same strains had different susceptibilities when challenged with pure H2O2 (5 mM). There was no association between the S. aureus clonal complex and sensitivity to either S. pneumoniae or H2O2 To kill S. aureus, S. pneumoniae produced ∼180 µM H2O2 within 4 h of incubation, while the killing-defective S. pneumoniae ΔspxB and S. pneumoniae ΔspxB ΔlctO mutants produced undetectable levels. Remarkably, a sublethal dose (1 mM) of pure H2O2 incubated with S. pneumoniae ΔspxB eradicated diverse S. aureus strains, suggesting that S. pneumoniae bacteria may facilitate conversion of H2O2 to a hydroxyl radical (·OH). Accordingly, S. aureus killing was completely blocked by incubation with scavengers of ·OH radicals, dimethyl sulfoxide (Me2SO), thiourea, or sodium salicylate. The ·OH was detected in S. pneumoniae cells by spin trapping and electron paramagnetic resonance. Therefore, S. pneumoniae produces H2O2, which is rapidly converted to a more potent oxidant, hydroxyl radicals, to rapidly intoxicate S. aureus strains.IMPORTANCEStreptococcus pneumoniae strains produce hydrogen peroxide (H2O2) to kill bacteria in the upper airways, including pathogenic Staphylococcus aureus strains. The targets of S. pneumoniae-produced H2O2 have not been discovered, in part because of a lack of knowledge about the underlying molecular mechanism. We demonstrated that an increased density of S. pneumoniae kills S. aureus by means of H2O2 produced by two enzymes, SpxB and LctO. We discovered that SpxB/LctO-produced H2O2 is converted into a hydroxyl radical (·OH) that rapidly intoxicates and kills S. aureus We successfully inhibited the toxicity of ·OH with three different scavengers and detected ·OH in the supernatant. The target(s) of the hydroxyl radicals represents a new alternative for the development of antimicrobials against S. aureus infections.

Molecular Imaging of Diabetic Foot Infections: New Tools for Old Questions.

Diabetic foot infections (DFIs) are a common, complex, and costly medical problem with increasing prevalence. Diagnosing DFIs is a clinical challenge due to the poor specificity of the available methods to accurately determine the presence of infection in these patients. However, failure to perform an opportune diagnosis and provide optimal antibiotic therapy can lead to higher morbidity for the patient, unnecessary amputations, and increased healthcare costs. Novel developments in bacteria-specific molecular imaging can provide a non-invasive assessment of the infection site to support diagnosis, determine the extension and location of the infection, guide the selection of antibiotics, and monitor the response to treatment. This is a review of recent research in molecular imaging of infections in the context of DFI. We summarize different clinical and preclinical methods and the translational implications aimed to improve the care of patients with DFI.

Using anaerobic blood cultures for infants younger than 90 days rarely showed anaerobic infections but increased yields of bacterial growth.

AIM: The use of anaerobic blood cultures in infants suspected of bacteraemia is controversial. Our children's hospital uses both aerobic and anaerobic media, regardless of the risk of anaerobic infection, and the aim of this study was to re-evaluate the use of anaerobic cultures in infants. METHODS: We collected retrospective data from 2002 to 2016 on all blood cultures taken from infants younger than 90 days in the Hadassah-Hebrew University Medical Centre, Jerusalem, Israel. The incidence and characteristics of infants with positive anaerobic blood cultures were assessed. RESULTS: During the study period, 51 035 blood cultures were drawn from 44 304 infants. Of these, 1496 (2.9%) were clinically significant positive cultures. Pathogenic obligatory anaerobic bacteraemia was extremely rare, with only 37 positive cultures (0.07%) from all of the cultures drawn. No specific risk factors for obligatory anaerobic bacteraemia could be defined, but as many as 174 (11.6%) clinically significant isolates were only detected in the anaerobic culture bottle. CONCLUSION: True anaerobic bacteraemia was extremely rare in neonates. Nevertheless, using anaerobic culture media may increase the overall yield of bacterial culture growth by isolating anaerobic-facultative bacteria. This should be weighed up against increasing the volume of blood used for the aerobic culture.

A comprehensive comparative analysis of treatment modalities for sinonasal malignancies.

BACKGROUND: Sinonasal malignancies are a rare and heterogeneous group of tumors for which there is a paucity of robust data with which to guide management decisions. The authors used the National Cancer Data Base to better understand the presenting characteristics of these tumors and to compare outcomes by treatment modality. METHODS: The National Cancer Data Base was queried for sinonasal malignancies diagnosed between 2004 and 2012. Overall survival was assessed using multivariate analyses and propensity score matching. RESULTS: A total of 11,160 patients were identified for the initial analysis. The majority were male, aged 40 to 69 years, with tumors of the nasal cavity or maxillary sinus. Squamous cell histology was most common. The majority of patients presented with advanced tumor stage but without locoregional lymph node or distant metastases. Treatment modalities were compared for squamous cell carcinomas. In multivariate analysis, compared with surgery alone, patients who received adjuvant radiotherapy (hazard ratio [HR], 0.658 [P<.001]), adjuvant chemoradiotherapy (HR, 0.696 [P = .002]), or neoadjuvant therapy (HR, 0.656 [P = .007]) had improved overall survival. Patients who received radiotherapy alone (HR, 1.294 [P = .001]) or chemotherapy alone (HR, 1.834 [P<.001]) had worse outcomes. These findings were validated in propensity score matching. It is important to note that neoadjuvant chemoradiotherapy was associated with achieving a negative surgical margin (odds ratio, 2.641 [P = .045]). CONCLUSIONS: Surgery is the mainstay of therapy for patients with sinonasal malignancies, but multimodality therapy is associated with improved overall survival. Cancer 2017;123:3040-49. © 2017 American Cancer Society.

Enterococcal Central Nervous System Infections in Children: A 22 Years' Experience in a Tertiary Center and Review of the Literature.

BACKGROUND: Enterococcal meningitis in children is rare, and its clinical presentation, laboratory characteristics and outcomes are not well defined. METHODS: We conducted a retrospective analysis of Enterococcal meningitis cases during 2002-2023 at our tertiary center. RESULTS: We identified 10 cases in children 2 weeks to 15 years old (median age: 8 months). Seven children were males and 9 had comorbidities, including a ventriculoperitoneal shunt in 5 children. All children with shunt infections presented with nonspecific signs and symptoms. While 8 children presented with fever, only 3 had signs of meningeal irritation and altered consciousness. Cerebrospinal fluid pleocytosis was evident in almost all children with a median of 173 cells/mL. Nine cases were due to Enterococcus faecalis , and 1 case was due to E. faecium . All 5 children with ventriculoperitoneal shunt underwent shunt removal and replacement. All children recovered without documented sequelae. CONCLUSIONS: Enterococcal meningitis is rare, especially in healthy neonates. It typically occurs following neurosurgical interventions and may only present with fever and shunt malfunction, without overt meningeal signs and with mild inflammation. The prognosis is favorable.

Helicobacter cinaedi Bacteremia in Children: A Case Report and Literature Review.

Helicobacter cinaedi is known to cause invasive infections in immunocompromised adults. Here we report the first case of H. cinaedi bacteremia in a child with nephrotic syndrome. The patient presented with a mild transient febrile illness that resolved spontaneously. We discuss the diagnostic challenges associated with this case and the microbiologic approach, including genomic analysis. Furthermore, we review the current case together with all previous pediatric cases (n = 6). Notably, all cases involved neonates or otherwise immunocompromised individuals and were characterized by severe disease with complicated infections (eg, meningitis, cholangitis and arthritis). H. cinaedi bacteremia in children is associated with a wide spectrum of clinical presentations ranging from mild to life-threatening conditions. This bacterium may be difficult to diagnose and require specialized methods.

Return Visits in Infants Younger Than 90 Days Presenting to the Pediatric Emergency Department for Fever.

Fever in infants presenting to pediatric emergency departments (PEDs) often results in significant return visits (RVs). This retrospective study aimed to identify factors associated with RVs in febrile infants aged 0 to 90 days. Data from infants presenting to PED between 2018 and 2021 and returning within 7 days (RV group) were compared to age-matched febrile infants without RVs (control group). Each group had 95 infants with similar demographics and medical history. RVs were primarily due to positive cultures and persistent fever. The control group had higher initial hospitalization rates, longer PED stays, and increased antibiotic treatment. Prevalence of serious bacterial infections (SBIs) did not significantly differ. Higher hospitalization, prolonged PED stays, and initial antibiotic treatment were associated with reduced RV incidence despite similar SBI rates. Return visits in infants <90 days were primarily driven by persistent fever and positive cultures. Addressing these factors through targeted parental education and improved care protocols may reduce RVs.

Implementation of pooled saliva tests for universal screening of cCMV infection.

Congenital cytomegalovirus (cCMV) is the most common intrauterine infection, leading to neurodevelopmental disabilities. Universal newborn infant screening of cCMV has been increasingly advocated. In the absence of a high-throughput screening test, which can identify all infected newborn infants, the development of an accurate and efficient testing strategy has remained an ongoing challenge. Here we assessed the implementation of pooled saliva polymerase chain reaction (PCR) tests for universal screening of cCMV, in two hospitals of Jerusalem from April 2022 through April 2023. During the 13-month study period, 15,805 infants (93.6% of all live newborn infants) were screened for cCMV using the pooled approach that has since become our routine screening method. The empirical efficiency of the pooling was six (number of tested newborn infants per test), thereby sparing 83% of the saliva tests. Only a minor 3.05 PCR cycle loss of sensitivity was observed for the pooled testing, in accordance with the theoretical prediction for an eight-sample pool. cCMV was identified in 54 newborn infants, with a birth prevalence of 3.4 per 1,000; 55.6% of infants identified with cCMV were asymptomatic at birth and would not have been otherwise targeted for screening. The study demonstrates the wide feasibility and benefits of pooled saliva testing as an efficient, cost-sparing and sensitive approach for universal screening of cCMV.

Vascular endothelial growth factor-induced neovascularization rescues cardiac function but not adverse remodeling at advanced ischemic heart disease.

OBJECTIVE: Proangiogenic therapy is a promising avenue for the treatment for chronic heart failure and a potentially powerful modality for reversing adverse cardiac remodeling. There is a concern, however, that adverse remodeling might enter an irreversible stage, and become refractory to treatments. The present study aims to determine whether neovascularization therapy is feasible at end stage heart failure and its capacity to reverse adverse cardiac remodeling during progressive disease stages. METHODS AND RESULTS: Using a conditional transgenic mouse system for generating escalating levels of myocardium-specific vascular deficit and resultant stepwise development of heart remodeling, we show that left ventricular dilatation and fibrosis precede ventricular hypertrophy, but that interstitial fibrosis is progressive and eventually results in heart failure. Vascular endothelial growth factor-mediated neovascularization was efficient even at the end stage of disease, and rescued compromised contractile function. Remarkably, remodeling was also fully reversed by neovascularization during early and late stages. Adverse remodeling could not be rescued, however, at the end stage of the disease, thus defining a point of no return and indentifying a critical level of fibrosis as the key determinant to be considered in intended reversal. CONCLUSIONS: The study supports the notion of a restricted golden time for remodeling reversal but not for vascular endothelial growth factor-induced neovascularization, which is feasible even during advanced disease stages.

A novel rodent model of chronic spinal implant-associated infection.

BACKGROUND CONTEXT: Bacterial infection of spinal instrumentation is a significant challenge in spinal fusion surgery. Although the intraoperative local application of powdered vancomycin is common practice for mitigating infection, the antimicrobial effects of this route of administration are short-lived. Therefore, novel antibiotic-loaded bone grafts as well as a reliable animal model to permit the testing of such therapies are needed to improve the efficacy of infection reduction practices in spinal fusion surgery. PURPOSE: This study aims to establish a clinically relevant rat model of spinal implant-associated infection to permit the evaluation of antimicrobial bone graft materials used in spinal fusion. STUDY DESIGN: Rodent study of chronic spinal implant-associated infection. METHODS: Instrumentation anchored in and spanning the vertebral bodies of L4 and L5 was inoculated with bioluminescent methicillin-resistant Staphylococcus aureus bacteria (MRSA). Infection was monitored using an in vivo imaging system (IVIS) for 8 weeks. Spines were harvested and evaluated histologically, and colony-forming units (CFUs) were quantified in harvested implants and spinal tissue. RESULTS: Postsurgical analysis of bacterial infection in vivo demonstrated stratification between MRSA and phosphate-buffered saline (PBS) control groups during the first 4 weeks of the 8-week infection period, indicating the successful establishment of acute infection. Over the 8-week chronic infection period, groups inoculated with 1 × 105 MRSA CFU and 1 × 106 MRSA CFU demonstrated significantly higher bioluminescence than groups inoculated with PBS control (p = 0.009 and p = 0.041 respectively). Histological examination at 8 weeks postimplantation revealed the presence of abscesses localized to implant placement in all MRSA inoculation groups, with the most pervasive abscess formation in samples inoculated with 1 × 105 MRSA CFU and 1 × 106 MRSA CFU. Quantification of CFU plated from harvested spinal tissue at 8 weeks post-implantation revealed the 1 × 105 MRSA CFU inoculation group as the only group with a significantly greater average CFU count compared to PBS control (p = 0.017). Further, CFU quantification from harvested spinal tissue was greater than CFU quantification from harvested implants across all inoculation groups. CONCLUSION: Our model demonstrated that the inoculation dosage of 1 × 105 MRSA CFU exhibited the most robust chronic infection within instrumented vertebral bodies. This dosage had the greatest difference in bioluminescence signal from control (p < 0.01), the lowest mortality (0% compared to 50% for samples inoculated with 1 × 106 MRSA CFU), and a significantly higher amount of CFUs from harvested spine samples than CFUs from control harvested spine samples. Further, histological analysis confirmed the reliability of this novel rodent model of implanted-associated infection to establish infection and biofilm formation of MRSA for all inoculation groups. CLINICAL SIGNIFICANCE: This model is intended to simulate the infection of instrumentation used in spinal fusion surgeries concerning implant locality and material. This model may evaluate potential antimicrobial and osteogenic biomaterials and investigate the relationship between implant-associated infection and failed fusion.

Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes pediatric COVID-19 (pCOVID-19). The relationship of the systemic tissue injury to the pathophysiology of MIS-C is poorly defined. We leveraged the high sensitivity of epigenomics analyses of plasma cell-free DNA (cfDNA) and plasma cytokine measurements to identify the spectrum of tissue injury and glean mechanistic insights. Compared with pediatric healthy controls (pHCs) and patients with pCOVID-19, patients with MIS-C had higher levels of cfDNA primarily derived from innate immune cells, megakaryocyte-erythroid precursor cells, and nonhematopoietic tissues such as hepatocytes, cardiac myocytes, and kidney cells. Nonhematopoietic tissue cfDNA levels demonstrated significant interindividual variability, consistent with the heterogenous clinical presentation of MIS-C. In contrast, adaptive immune cell-derived cfDNA levels were comparable in MIS-C and pCOVID-19 patients. Indeed, the cfDNA of innate immune cells in patients with MIS-C correlated with the levels of innate immune inflammatory cytokines and nonhematopoietic tissue-derived cfDNA, suggesting a primarily innate immunity-mediated response to account for the multisystem pathology. These data provide insight into the pathogenesis of MIS-C and support the value of cfDNA as a sensitive biomarker to map tissue injury in MIS-C and likely other multiorgan inflammatory conditions.

Implant-Associated Spinal Infections in Children: How Can We Improve Diagnosis and Management?

Implant-associated spinal infection affects up to 10% of all pediatric instrumented spinal fixation surgeries and is associated with patient morbidity and significant impact on the health care system. Children with neuromuscular scoliosis are at increased risk compared with those with idiopathic scoliosis. Early infections (≤90 days from index surgery) are caused by virulent pathogens such as Staphylococcus aureus; more indolent pathogens cause late infections. Early infections are treated with debridement and implant retention with prolonged antibiotics, but implant removal is often needed to treat late infections. Antibiofilm agents and pathogen-specific imaging may improve future outcomes.

Increasing Pediatric Infectious Diseases Consultation Rates for Staphylococcus aureus Bacteremia.

Introduction: Staphylococcus aureus bacteremia (SAB) in children is associated with significant mortality and morbidity, including recurrent bacteremia. Infectious disease consultation (IDC) improves SAB outcomes in adult patients. However, increasing IDC and impact for pediatric patients with SAB is not well described. Methods: This quality improvement project aimed to increase IDC for SAB events at a quaternary pediatric medical center. First, we evaluated the local practices regarding pediatric SAB and engaged stakeholders (July 2018-August 2020). We added an advisory comment supporting IDC for SAB to all blood culture results in September 2020. Using statistical process control charts, we monitored the number of SAB events with IDC before a SAB event without IDC. Finally, we evaluated SAB recurrences before and after initiating the advisory comment. Results: In the baseline period, 30 of 49 (61%) SAB events received an IDC with a mean of 1.4 SAB events with IDC before a SAB event without IDC. Postintervention, 22 of 23 (96%) SAB events received IDC with a mean of 14 events with IDC before 1 event without IDC. The SAB recurrence rate was 8%, with 6 events in 4 children; none of the index cases resulting in recurrence received an IDC (P = 0.0002), and all occurred before any intervention. Conclusions: An electronic advisory comment supporting IDC for SAB significantly increased the rate of pediatric IDC with no further SAB recurrence episodes following intervention. This low-resource intervention may be considered in other pediatric centers to optimize SAB management.