BACKGROUND:Human adenovirus (HAdV) among pediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients can result in asymptomatic infection with risk for disease progression. There are limited data defining HAdV infection, disease, and case-fatality rates in a HAdV polymerase chain reaction (PCR) surveillance testing era. The current study aimed to define these outcomes using a priori definitions applied by a central review committee. METHODS:Pediatric allo-HCT recipients were followed up for 180 days after HCT at 10 pediatric institutions. Blood and stool specimens were collected 0-7 days prior to allo-HCT for serum HAdV immunoglobulin G and stool HAdV PCR testing. Clinical data, including HAdV PCR testing results, informed central review committee-designated outcomes of HAdV infection, including DNAemia, disease, and deaths (case-fatality rate). Outcomes were reported by HAdV surveillance testing status and by pretransplant research specimen results. RESULTS:The cohort included 819 allo-HCT recipients; 649 (79.2%) were under HAdV surveillance. The HAdV infection and DNAemia incidence among surveilled patients was 27.1% and 16.0%, respectively. The incidence of proven or probable HAdV disease was 10.9% for the cohort and, 12.6% for those under surveillance. The HAdV infection incidence was highest (13 of 25 [52.0%]) in patients with pre-HCT HAdV immunoglobulin G and stool PCR positivity. The attributable case-fatality rate for those with proven or probable disease was 13.5%. CONCLUSIONS:HAdV infection and disease are common among pediatric allo-HCT recipients. HAdV disease is associated with a substantial HAdV-attributable mortality rate. Clinical trials assessing novel HAdV in pediatric allo-HCT recipients are needed. Pretransplant serology and stool PCR testing could identify high-risk patients for trial enrollment.

BackgroundUreaplasma spp. are a rare cause of invasive disease outside of the neonatal period. Recent studies have shown that immunosuppression with B-cell depleting therapies, such as rituximab or obinutuzumab, can increase the risk of invasive infection. We present a case in which a patient receiving B-cell depleting therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis and pauci-immune nephritis was diagnosed with disseminated, invasive Ureaplasma infection.Case SummaryA 17-year-old female with documented B-cell depletion presented to the emergency department from the pediatric infectious disease clinic with persistent shoulder pain. Within the first month of admission, the patient developed multifocal abscesses with joint involvement and an echodensity resembling a possible vegetation, all of which were unresponsive to broad-spectrum antibiotics. A broad-spectrum polymerase chain reaction test detected Ureaplasma urealyticum in aspirated joint fluid from multiple anatomic sites. Clinical improvement occurred after initiation of combination therapy with intravenous doxycycline and levofloxacin.ConclusionWe describe a patient with documented iatrogenic B cell depletion presenting with a disseminated, multifocal invasive Ureaplasma infection including osteoarthritis, cellulitis, and soft tissue abscess. Following a 6-week course of levofloxacin, the patient’s C-reactive protein, fever, and pain resolved without further evidence of disease. This case report highlights the importance of considering disseminated, invasive Ureaplasma spp. when evaluating B-cell depleted patients with challenging multifocal symptom complexes. In addition, this case report highlights the critical role of molecular diagnosis in identifying this fastidious pathogen.

Pediatric solid organ transplant (SOT) recipients with splenic dysfunction are at increased risk for infections, and tailored guidance on the management of asplenia/hyposplenism among SOT recipients is often lacking. The purpose of this article is to provide practice recommendations via a frequently asked questions (FAQs) format that focuses on three main domains: the identification of asplenia/hyposplenism among SOT recipients/candidates, prophylactic strategies for mitigating the risk of invasive disease associated with splenic dysfunction in the context of transplantation, and the provision of appropriate patient counseling on the risks associated with asplenia/hyposplenism. Answers to the FAQs are based on international expert opinion informed by practices for managing splenic dysfunction and associated data in other populations with asplenia. Gaps in the existing literature and relevant research aims are emphasized.

The global burden of acute lower respiratory tract infections, including viral etiologies, equated to 725 557 deaths in 2021 in children under 4 years of age. Community-acquired respiratory viral infections (RVI) also carry a high burden among pediatric solid organ transplant recipients (PSOTR), accounting for 14.5% of hospitalizations in the first year post-transplant in an American cohort. This mini review on behalf of the International Pediatric Transplant Association (IPTA) infectious diseases committee discusses novel preventative and prophylactic strategies and includes pertinent updates for vaccine-preventable RVI including influenza, SARS-CoV-2, and RSV in PSOTR.

Abstract Background Adult hematopoietic cell transplant (HCT) recipients are at high risk of influenza complications but have suboptimal immune responses to influenza vaccines. Our previous phase II trial in adult HCT recipients demonstrated that two doses of high-dose trivalent influenza vaccine (HD-TIV) were associated with higher hemagglutination inhibition (HAI) antibody responses than two doses of standard-dose quadrivalent influenza vaccine (SD-QIV), with similar safety profiles. This sub-study aims to characterize immunogenicity and safety of this vaccination strategy in consecutive influenza seasons. Methods A subset of participants from our initial study were re-enrolled in a consecutive season using the same dosing regimen. HAI titers were measured at baseline and 4–6 weeks post-vaccination for each dose in both years. We calculated the geometric mean fold rise (GMFR) in HAI titers and used linear mixed-effects models to determine adjusted geometric mean ratios (aGMRs). Injection-site and systemic reactions were documented for 7 days post-vaccination. Results A total of 43 participants were re-enrolled (n=20 for SD-QIV and n=23 for HD-TIV). Baseline characteristics were similar between groups (Table 1). In the second year, post-dose 1 GMFRs for both SD-QIV and HD-TIV were higher compared to post-dose 1 titers in the first year across all antigens (Table 2). HAI titers were higher for all post-vaccination visits and dose groups in the second year compared to the first year (Figure 1). aGMR comparisons between HD-TIV and SD-QIV favored HD-TIV for A/H1N1, A/H3N2, and B/Victoria antigens in both years, with statistical significance for A/H1N1 after a single dose in the second year (aGMR, 3.21; 95% CI,1.06–9.70). Injection-site and systemic reactions were generally similar between groups in year 2 (Figure 2).Figure 1.Point estimates and 95% confidence intervals for geometric mean HAI titers at visits 1, 2, and 3 in year 1, as well as visits 1, 2, and 3 in the repeater year (denoted by “R”), stratified by influenza antigens (A/H1N1, A/H3N2, B/Victoria, and B/Yamagata), and by dose group (standard-dose quadrivalent influenza vaccine [SD-QIV] and high-dose trivalent influenza vaccine [HD-TIV]). Note that B/Yamagata is not included in HD-TIV. Conclusion In the second year, a single dose of HD-TIV or SD-QIV was more immunogenic than two doses of the same formulation in the first year, with HD-TIV demonstrating superior immunogenicity against A/H1N1. The safety profile across both vaccine formulations were similar.Figure 2.Relative frequencies of any injection-site and systemic reactions within 7 days of each vaccination for both vaccine groups (standard-dose quadrivalent influenza vaccine [SD-QIV] vs high-dose trivalent influenza vaccine [HD-TIV]) following each vaccine dose. Disclosures Edgar T. Overton, MD, ViiV Healthcare: Employment Michael Ison, MD MS, GlaxoSmithKline: Grant/Research Support|UpToDate: Royalties Steven A. Pergam, MD, MPH, Cidara: Participate in company sponsored clinical trial|F2G: Participate in company sponsored clinical trial|Global Life Technologies: Grant/Research Support|Symbio: Participate in company sponsored clinical trial Natasha B. Halasa, MD, MPH, Merck: Grant/Research Support

Abstract Background Human Adenovirus (HAdV) can cause life-threatening illness in pediatric allo-HCT recipients, but studies to define incidence and outcomes of HAdV in allo-HCT patients are limited. Use of PCR-based HAdV surveillance varies by HCT center, in part because there are no approved HAdV-directed therapies. This study describes the epidemiology of HAdV infection and disease in pediatric allo-HCT patients who did and did not undergo HAdV surveillance. Methods An allo-HCT cohort was assembled from July 2018 to June 2021 at ten US pediatric HCT centers. Patients were followed for 180 days from HCT to document presence of HAdV infection and disease and were considered under surveillance if ≥ 2 HAdV blood tests were run in the first 14 days post-HCT. Published HAdV disease and attributable death definitions were applied to patients with positive HAdV PCR tests from any site and adjudicated by a central review committee. HAdV events were designated asymptomatic infection or possible, probable, or proven disease. HAdV DNAemia and disease incidence, time to event, and mortality and attributable case fatality rates were described. Results The cohort included 831 allo-HCT recipients: 645 under surveillance & 186 not (Table 1). 15.5% of patients under surveillance had DNAemia; median time to DNAemia was 31.0 days from HCT (Table 2). Probable/proven disease was documented in 11.9% and 3.8% of patients under and not under surveillance, with median time to disease 37.0 days and 66.0 days from HCT, respectively (Table 3). Overall mortality rates were 7.6% and 8.6% in patients under and not under surveillance (Table 4). Attributable case fatality rates for those with probable or proven disease were 13.0% and 14.3% in those under and not under surveillance, respectively. Conclusion HAdV infection and disease events were frequent; however, incidence was higher in patients under surveillance, suggesting detection bias. HAdV disease was identified as a frequent cause of death. Attributable case fatality rates were similar regardless of surveillance, suggesting early detection did not improve outcomes. Future analyses of these data will determine patient factors that identify allo-HCT patients at high risk for HAdV infection and disease to target for novel prophylaxis or pre-emptive therapy studies. Disclosures Michael D. Green, MD, MPH, ADMA: Advisor/Consultant|Bristol Myers Squibb: Advisor/Consultant|ITB-MED: Advisor/Consultant|kamada: Honoraria Monica I. Ardura, DO, MSCS, Karius: Advisor/Consultant|Miravista: Grant/Research Support Jeffrey Auletta, MD, Ascella Health: Advisor/Consultant Diego R. Hijano, MD, MSc, FDA: Grant/Research Support|Merck: Grant/Research Support|National Institute of Health: Grant/Research Support William J. Muller, MD, Ansun Biopharma: Grant/Research Support|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|DiaSorin: Advisor/Consultant|DiaSorin: Honoraria|Eli Lilly and Company: Grant/Research Support|Enanta Pharmaceuticals: Advisor/Consultant|Enanta Pharmaceuticals: Grant/Research Support|F. Hoffmann-LaRoche Ltd (Roche): Grant/Research Support|Finley Law Firm, P.C.: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Melinta Therapeutics, Inc.: Grant/Research Support|Merck Sharpe & Dohme: Grant/Research Support|Moderna: Grant/Research Support|Nabriva Therapeutics, plc: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer: Grant/Research Support|ProventionBio: Advisor/Consultant|Sanofi: Advisor/Consultant|Sanofi: Honoraria|Tetraphase Pharmaceuticals, Inc.: Grant/Research Support Michael Grimley, MD, SymBio Pharmaceuticals Limited: Advisor/Consultant Lara A. Danziger-Isakov, MD, MPH, Aicuris: clinical research contract, paid to institutio|Ansun BioPharma: clinical research contract, paid to institution|Astellas: Advisor/Consultant|Astellas: clinical research contract, paid to institutio|Merck: clinical research contract, paid to institutio|Pfizer: Grant/Research Support|Takeda: clinical research contract, paid to institutio Brian T. Fisher, DO, MPH/MSCE, Allovir: Grant/Research Support|Astellas: Data Safety Monitoring Board|Merck: Grant/Research Support|Pfizer: Grant/Research Support

Posttransplant lymphoproliferative disorder (PTLD) can mimic infectious processes in the head and neck. A high index of suspicion for PTLD must be maintained in pediatric transplant patients, and minimal response to antibiotics/corticosteroids should prompt timely biopsy of suspicious tissue to expedite the diagnosis and treatment of PTLD.

We describe our approach to addressing a nationwide supply issue for blood culture bottles. Aerobic blood culture bottles received from our distributor during 1-15 July 2024 were <1% of typical usage. Through education and ordering restrictions of blood culture, designed to minimize risk, orders were reduced by 49% over a 1-week period.

Background Pediatric hematopoietic cell transplant (HCT) recipients are at high risk for morbidity from influenza virus infection. We demonstrated in a primary phase 2 randomized controlled trial that 2 post-HCT doses of high-dose trivalent influenza vaccine (HD-TIV) given 4 weeks apart were more immunogenic than 2 doses of standard-dose quadrivalent influenza vaccine (SD-QIV). Herein, we present the immunogenicity and safety of influenza vaccination in a consecutive season post-HCT using the same dosing regimen.Methods A subcohort of study participants reenrolled and had hemagglutinin inhibition titers measured at baseline and 4 weeks after each vaccine dose in year 2. We estimated geometric mean fold rise in hemagglutinin inhibition titer from baseline for each group and used linear mixed effects models to estimate adjusted geometric mean ratios (comparing HD-TIV vs SD-QIV) for each antigen at each time point. We described systemic and injection site reactions.Results A total of 65 subcohort patients participated (33 SD-QIV, 32 HD-TIV). Postvaccine geometric mean fold rise and adjusted geometric mean ratio estimates were higher for both groups following a single influenza vaccine dose in year 2 as compared with 2 doses of the same formulation in year 1. Both groups had similar frequencies of injection site and systemic reactions.Conclusions A single dose of HD-TIV or SD-QIV was more immunogenic in year 2 than 2 doses of the same formulation in year 1. Reactogenicity was comparable between groups. One dose of influenza vaccine may be sufficient after a 2-dose schedule in the prior year post-HCT.Clinical Trials Registration NCT02860039 (ClinicalTrials.gov). A single dose of high-dose trivalent influenza vaccine or standard-dose quadrivalent influenza vaccine was more immunogenic in year 2 than 2 doses of the same formulation in year 1 after hematopoietic cell transplant. One dose of influenza vaccine may be sufficient after a 2-dose schedule in the prior year.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

BackgroundPediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk for morbidity and mortality from human adenovirus (HAdV). HAdV can be detected in an asymptomatic state, referred to as infection or with signs or symptoms of illness, referred to as disease. Standardized case definitions are needed to distinguish infection from disease and allow for consistent reporting in both observational cohort studies and therapeutic clinical trials.MethodsA working group of experts in virology, transplant infectious disease, and HCT was assembled to develop HAdV infection and disease definitions with the degree of certainty (i.e., possible, probable, and proven). Definitions were further refined through an iterative process and independently applied by two central review committees (CRCs) to 20 pediatric allo-HCT recipients with at least one HAdV-positive PCR.ResultsInitial HAdV infection and disease definitions were developed and updated through an iterative process after reviewing clinical and virological details for 81 subjects with at least one positive HAdV PCR detected in a clinical specimen. Independent application of final definitions to 20 HAdV positive allo-HCT recipients by two CRCs yielded similar number of HAdV infection or disease events but with variation of degree of certainty for some events.ConclusionsApplication of definitions by a CRC for a study of HAdV infection and disease is feasible and can provide consistency in the assignment of outcomes. Definitions need further refinement to improve reproducibility and to provide guidance on determining clinical improvement or worsening after initial diagnosis of HAdV infection or disease. Definitions for HAdV infection and diseases in pediatric patients with allo-HCT were developed and applied by CRCs for subjects with HAdV-positive PCRs. The application of definitions determined it feasible, reproducible, and can serve as a framework for outcomes of studies assessing the effectiveness of HAdV-targeted therapies.image

Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in pediatric transplantation. However, currently utilized CMV prevention paradigms have limitations, leading to research aimed at novel strategies for mitigation of CMV infection. Cell-mediated immunity (CMI) is crucial in controlling CMV infection and the use of CMV-specific CMI assays to guide prevention and treatment of CMV infection in both solid organ transplant and hematopoietic cell transplant recipients shows great promise. In this article, we review the immune response to CMV infection to highlight the rationale for CMI assays, describe available commercial assays and strategies for their use, and summarize relevant literature regarding the use of CMI assays in transplant recipients.

Of 319 children with invasive candidiasis, 67 (21%) transitioned from intravenous to enteral antifungal therapy. Eight (12%) transitioned back to intravenous antifungal therapy, one due to perceived treatment failure defined by clinical progression or worsening. Global treatment response at study completion was successful in 66 participants who transitioned to enteral therapy.

The herpesviruses are the most common infectious agents associated with both primary and secondary cytokine storm syndromes (CSS). While Epstein-Barr Virus (EBV) is most frequently reported in association with CSS, cytomegalovirus (CMV) and many other herpesviruses (e.g., herpes simplex virus, varicella zoster virus, and human herpesviruses 6 and 8) are clearly associated with CSS in children and adults. Immunocompromised hosts, whether due to primary immunodeficiency or secondary immune compromise (e.g., solid organ or stem cell transplantation), appear to be at particularly increased risk of herpesvirus-associated CSS. In this chapter, the association of the non-EBV herpesviruses with CSS will be discussed, including predisposing factors and treatment considerations.

Abstract Background Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown. Methods This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3–17 years old who were 3–35 months post-allogeneic HCT, with each formulation administered twice, 28–42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28–42 days following each dose, and 138–222 days after the second dose. Using linear mixed effects models, we estimated adjusted geometric mean HAI titer ratios (aGMR: HD-TIV/SD-QIV) to influenza antigens. Early and late periods were defined as 3–5 and 6–35 months post-HCT, respectively. Results During 3 influenza seasons (2016–2019), 170 participants were randomized to receive HD-TIV (n = 85) or SD-QIV (n = 85). HAI titers maintained significant elevations above baseline for both vaccine formulations, although the relative immunogenic benefit of HD-TIV to SD-QIV waned during the study. A 2-dose series of HD-TIV administered late post-HCT was associated with higher GMTs compared to the early post-HCT period (late group: A/H1N1 aGMR = 2.16, 95% confidence interval [CI] = [1.14–4.08]; A/H3N2 aGMR = 3.20, 95% CI = [1.60–6.39]; B/Victoria aGMR = 1.91, 95% CI = [1.01–3.60]; early group: A/H1N1 aGMR = 1.03, 95% CI = [0.59–1.80]; A/H3N2 aGMR = 1.23, 95% CI = [0.68–2.25]; B/Victoria aGMR = 1.06, 95% CI = [0.56–2.03]). Conclusions Two doses of HD-TIV were more immunogenic than SD-QIV, especially when administered ≥6 months post-HCT. Both groups maintained higher titers compared to baseline throughout the season. Clinical Trials Registration NCT02860039.