Application of cell-free DNA fungal polymerase chain reaction for invasive fungal disease evaluation in pediatric oncology and stem cell transplant patients.

BACKGROUND: Molecular diagnostics may enable early, noninvasive detection of invasive fungal disease (IFD) in immunocompromised patients. Cell-free deoxyribonucleic acid (cfDNA) fungal polymerase chain reaction (PCR) assays were recently incorporated into institutional prolonged febrile neutropenia pathways. We aimed to evaluate the performance of plasma cfDNA PCR panels (mold and Candida panels) in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients with clinical concern for IFD. METHODS: This single-center, observational study assessed plasma cfDNA fungal PCR performance for noninvasive IFD detection in hospitalized pediatric oncology and HSCT patients. The primary outcome was IFD diagnosis per published consensus definitions within 1 month. Positive and negative agreement between plasma cfDNA fungal PCR and consensus definitions were calculated. We also described test turnaround time and patient survival. RESULTS: From October 2021 to 2022, 54 patients underwent 60 evaluations with 11 proven/probable IFD cases. Comparing plasma cfDNA fungal PCRs to consensus definitions for proven/probable IFD, there was 73% positive agreement and 96% negative agreement. Two proven/probable cases with negative PCRs were caused by organisms not included on either panel. Median time to cfDNA fungal PCR result was 35 hours (interquartile range: 19-69) in eight proven/probable cases detected by cfDNA fungal PCR. There were 17 deaths among 54 patients, and IFD contributed to 45% of deaths in patients with proven/probable IFD. CONCLUSIONS: Plasma cfDNA fungal PCRs detected relevant molds or yeast in most cases classified as proven/probable IFD. However, this targeted approach missed some cases. More studies are required to determine optimal utilization of molecular diagnostics in pediatric patients.

Utilization of Hepatitis C Virus-Infected Donor Hearts in Two Children and Two Young Adults: Initial Experience at a Pediatric Transplant Center.

BACKGROUND: Although adult transplant centers are successfully transplanting organs from hepatitis C virus (HCV)-infected donors with detectable viral load by nucleic acid testing (NAT+) into HCV-negative recipients, this practice has not yet been adopted widely by the pediatric heart transplant community. METHODS: We present a case series of four patients who received heart transplants from HCV NAT+ donors at a pediatric transplant center, including two pediatric patients < 18 years of age. RESULTS: All recipients tolerated a 12-week course of glecaprevir/pibrentasvir and achieved a sustained virologic response with no HCV or liver complications with over 1 year of follow-up (range 1.4-2.5 years). All four have had good post-heart transplant outcomes with normal graft function and good functional status without rejection or cardiac allograft vasculopathy at time of last follow-up. CONCLUSIONS: This case series details the successful multidisciplinary implementation of a protocol to accept cardiac allografts from HCV NAT+ donors for transplantation into HCV negative recipients at our pediatric transplant center. With the limited donor pool in pediatrics and the morbidity associated with prolonged durations on the transplant waitlist, pediatric centers should consider utilizing organs from HCV NAT+ donors to broaden the donor pool. Future work should evaluate other organs beyond heart and optimal timing and duration of direct acting antiviral therapy.

Vaccine-Associated Measles Encephalitis in Immunocompromised Child, California, USA.

We report a fatal case of vaccine-associated measles encephalitis in an immunocompromised child in California, USA. The infection was confirmed by whole-genome RNA sequencing of measles virus from brain tissue. We observed biased matrix-gene hypermutation consistent with persistent measles virus central nervous system infection.

Vaccine Associated Measles Complicated by Suspected Measles Inclusion Body Encephalitis in a Pediatric Leukemia Patient and Stem Cell Transplant Recipient: A Focus on Clinical Evolution and Management.

BACKGROUND: Immunocompromised individuals are at increased risk for severe disease and complications from viral infections, highlighting the importance of vaccination. However, in extremely rare situations, vaccine associated viral infections can be associated with disseminated disease and complications in immunocompromised hosts. CASE: Herein, we present a case of a 1-year-old child diagnosed with acute myeloid leukemia less than 2 weeks after receiving live viral vaccines who developed acute vaccine-strain measles virus disease, later complicated by central nervous system involvement following hematopoietic stem cell transplantation. A brain biopsy specimen was positive for vaccine-strain measles virus detected by reverse transcriptase polymerase chain reaction. MANAGEMENT AND OUTCOME: She was treated with intravenous ribavirin, inosine pranobex, intrathecal interferon-alpha and donor lymphocyte infusion following measles-mumps-rubella vaccine boost. Despite these measures, the patient suffered neurologic decline and dysautonomia, expiring after compassionate extubation. Management and ideal risk mitigation strategies are discussed within the context of existing literature for this rare complication.

Impact of cell-free DNA fungal polymerase chain reaction panels on healthcare-associated infection mould investigations.

Launch of in-house sensitive cell-free deoxyribonucleic acid (cfDNA) mould polymerase chain reaction (PCR) assays increased detection of moulds meeting suspected healthcare-associated infection (HAI) criteria. Definition was based on time from admission and mould detection in culture or via molecular methods. We created a modified mould HAI algorithm incorporating clinical context into the case definition, which allowed for better capture of possible mould HAIs, decreased number of investigations, and improved utilization of Infection Prevention and Control (IPC) resources.

Laying the Groundwork for a Fulfilling Career in Pediatric Infectious Diseases: The Transition From Fellowship to Faculty.

There are limited resources for guidance on the transition from fellowship into a new faculty role in pediatric infectious diseases. This review aims to address this gap and provides a framework for a successful transition that is composed of four essential pillars-(1) stepping into your role, (2) finding your niche, (3) building your network, and (4) self-care-all of which are supported by strong mentorship/sponsorship and continual realignment with one's personal mission statement. In addition to providing general principles and guidance, this review also outlines specific steps that a junior faculty member can take to expand their influence and build a successful, fulfilling career in pediatric infectious diseases.

"For COVID" or "With COVID": Classification of SARS-CoV-2 Hospitalizations in Children.

OBJECTIVES: Pediatric hospitalization rates are used as a marker of coronavirus disease 2019 (COVID-19) disease severity in children but may be inflated by the detection of mild or asymptomatic infection via universal screening. We aimed to classify COVID-19 hospitalizations using an existing and novel approach and to assess the interrater reliability of both approaches. METHODS: This retrospective cohort study characterized severity of illness and likelihood of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as the cause of hospitalization in pediatric patients <18 years of age. Subjects had positive SARS-CoV-2 nasopharyngeal testing or were diagnosed with multisystem inflammatory syndrome in children and were hospitalized between May 10, 2020 (when universal screening of all admissions began) and February 10, 2021, at a university-based, quaternary care children's hospital in Northern California. Hospitalizations were categorized as either likely or unlikely to be caused by SARS-CoV-2 (novel approach), and disease severity was categorized according to previously published classification of disease severity. RESULTS: Of 117 hospitalizations, 46 (39.3%) were asymptomatic, 33 (28.2%) had mild to moderate disease, 9 (7.7%) had severe illness, and 15 (12.8%) had critical illness (weighted κ: 0.82). A total of 14 (12%) patients had multisystem inflammatory syndrome in children. A total of 53 (45%) admissions were categorized as unlikely to be caused by SARS-CoV-2 (κ: 0.78). CONCLUSIONS: Although COVID-19 has considerable associated morbidity and mortality in children, reported hospitalization rates likely lead to overestimation of the true disease burden.

Client and staff experiences assessing adverse childhood experiences in a clinical setting: Results from the First Nations ACE Study.

BACKGROUND: Conducting culturally-relevant research with Indigenous populations requires a balance of approaches that benefit Indigenous communities, while perceiving and mitigating the potential risk of harm when engaging in research-related activities. Reducing the burden of research is especially useful for research with Indigenous populations as ongoing systemic marginalization and discrimination through historical colonial practices may result in a higher likelihood of experiencing harm from research activities. One way to ensure that stakeholder experiences with the research processes are not burdensome, and to understand how study implementation practices are perceived across research teams, supporting organizations, and individual participants is to build this into the study method. OBJECTIVE: The current study describes stakeholder experiences within a broader research study, entitled the First Nations ACE Study, which examined early childhood experiences and health outcomes for Indigenous people seeking treatment for substance use. PARTICIPANTS AND SETTING: Five treatment centre staff participated in ongoing consultations with the research team and described their experiences within a Community-Based Participatory Research (CBPR) study. METHOD: A document review of client satisfaction questionnaires of seventy-five participants provided quantitative feedback on experiences in addition to qualitative interviews with staff. RESULTS: Overall, experiences of both treatment centre staff and clients were generally positive. Additional results described the importance of continuous stakeholder participation, and ongoing study adaptations to remain aligned with CBPR approaches as pressure for expediency and convenience have the potential to encroach upon CBPR values. The study method was described to mitigate participant and staff burden, as well as risk of participant harm. CONCLUSIONS: Directions for future research are discussed, including discussion of modifications that will be made to future iterations of the presented research study.

Oral Antibiotics for Treating Children With Community-Acquired Pneumonia Complicated by Empyema.

No consensus exists on management of children with community-acquired pneumonia complicated by empyema (CAP-Em). We evaluated outpatient oral (O-Abx) compared with parenteral antibiotics (OPAT) in children with CAP-Em. We also evaluated inflammatory markers to guide length of treatment. We conducted a retrospective cohort study of patients discharged (2006-2016) with CAP-Em. Primary outcome measured was treatment success (no change in antibiotics or readmission to hospital for treatment of CAP-Em). White blood cell (WBC) count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) serial measurements were identified. Success was achieved in 133/144 (92.4%) O-Abx and 7/12 (58%) OPAT patients (P = .0031). WBC and CRP decreased early; and ESR increased initially (admit and switch to O-Abx) and decreased by end of treatment. O-Abx is the modality of choice for treatment of CAP-Em after hospital discharge. WBC and CRP are useful to monitor success of O-Abx switch; and ESR provides guidance for length of treatment.

A feasibility study to determine if minimally trained medical students can identify markers of chronic parasitic infection using bedside ultrasound in rural Tanzania.

BACKGROUND: Parasitic infections pose a significant health risk in developing nations and are a major cause of morbidity and mortality worldwide. In the Republic of Tanzania, the CDC estimates that 51.5% of the population is infected with one or more intestinal parasites. If diagnosed early, the consequences of chronic parasitic infection can potentially be avoided. METHODS: Six first-year medical students were recruited to enroll patients in the study. They underwent ten hours of formal, hands-on, ultrasound which included basic cardiac, hepatobiliary, renal, pulmonary and FAST scan ultrasound. A World Health Organization protocol with published grading scales was adapted and used to assess for pathology in each patient's liver, bladder, kidneys, and spleen. RESULTS: A total of 59 patients were enrolled in the study. Students reported a sensitivity of 96% and specificity of 100% for the presence of a dome shaped bladder, a sensitivity and specificity of 100% for bladder thickening, a sensitivity and specificity of 100% for portal hypertension and ascites. The sensitivity was 81% with a specificity of 100% for presence of portal vein distention. The sensitivity was 100% with a specificity of 90% for dilated bowel. CONCLUSIONS: Ultrasound has shown a promise at helping to identify pathology in rural communities with limited resources such as Tanzania. Our data suggest that minimally trained first year medical students are able to perform basic ultrasound scans that can identify ultrasonographic markers of parasitic infections.

Immune biomarker differences and changes comparing HCV mono-infected, HIV/HCV co-infected, and HCV spontaneously cleared patients.

BACKGROUND: Immune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response. METHODS: Fifty immune biomarkers were analyzed at baseline (BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error. RESULTS: Compared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment. CONCLUSIONS: Clear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets.