Sharon F. Chen

Background: Solid Organ Transplant ( SOT ) provides a survival advantage for individuals with end organ failure. Little is known about the specific effects of immunosuppression on the competence of the immune system during the post‐transplant period especially in the pediatric population, and current immunosuppression and prophylaxis practices are not well informed by immune data. Methods: Blood samples from pediatric patients < 18 years old were collected prior to and 6‐ and 12 months after liver transplant. Peripheral blood mononuclear cells ( PBMCs ) were stimulated with PMA /Ionomycin and the phenotype and function of T cell subsets and NK cells were systematically characterized using cytometry by time‐of‐flight ( CyTOF ). Results: In a cohort of 4 pediatric liver transplant patients, levels of CD4 + and CD8 + T cells, Tregs and NK cells at 6‐ and 12 months following liver transplant were similar to levels before transplant. Upon stimulation, pro‐inflammatory, antiviral, and inhibitory T cell cytokines and enzymes were not reduced at 6 months post‐transplant and remained stable at 12 months. IL ‐2 production, a tacrolimus target, from CD4 + and CD8 + T cells did not correlate with tacrolimus levels. Conclusion: T cell function was not reduced by 6 months following liver transplant. This suggests that it might be safe to discontinue viral prophylaxis or initiate vaccinations sooner than previously suspected. Tregs functional marker expression was intact by 6 months post‐transplant suggesting lower risk of rejection in this cohort. Tacrolimus level may not be a good indication for immunocompetence and T cell functional assays may be more predictive of susceptibility to infection.

Background: Coccidioidomycosis is a fungal infection endemic to the southwestern United States. Central nervous system (CNS) coccidioidomycosis is a severe manifestation that requires lifelong antifungal therapy. While fluconazole is currently recommended as the initial therapy in pediatric patients, a rise in reports of fluconazole failure has led to use of alternative treatment approaches. In this paper, we evaluated our institutional preference to use intravenous (IV) liposomal amphotericin B (L-AmB) as part of the initial therapy for pediatric CNS coccidioidomycosis. Methods: We conducted a retrospective case series of pediatric patients diagnosed with CNS coccidioidomycosis between 2010 and 2024. Clinical presentation, diagnostics, treatment strategies, and outcomes were analyzed. Results: Among 10 patients, 6 had mild initial symptoms of fevers and/or headaches, while 4 had more severe initial presentations, including focal deficits, seizures, or altered mental status. All severe cases received immediate IV L-AmB and fluconazole (+IV L-AmB); 75% were discharged with improvement. The 2 mild cases that received early +IV L-AmB had uncomplicated courses, while 2 of the 4 mild cases initially treated with fluconazole alone progressed to severe disease. Over an average follow-up of 4.5 years, 5 patients were fully functional without neurologic deficits, 2 had mild residual deficits, and 3 died. Relapse occurred in all but 1 patient. Patients receiving early +IV L-AmB trended toward shorter hospitalizations, lower disease progression rates, and delayed disease relapse. Conclusions: Our institutional experience with IV L-AmB in combination with fluconazole for the initial management of pediatric CNS coccidioidomycosis suggests that +IV L-AmB may help reduce disease progression and improve symptom resolution with mild and transient side effects, although the findings of this case series should be interpreted cautiously due to the small cohort size, limited generalizability, and potential confounding factors.

Introduction: Pediatric plastic bronchitis (PB) is a rare complication of surgically palliated congenital heart disease (CHD). Fibrin casts obstruct airways and can cause respiratory distress. There are no therapeutics approved by the United States Food and Drug Administration to treat PB, but inhaled tissue plasminogen activator (tPA) has been anecdotally used to relieve symptoms. We conducted a phase II open‐label clinical trial to test the safety of inhaled tPA in pediatric PB.Methods: Patients with an acute exacerbation of PB requiring hospitalization were enrolled to test the safety of an inhaled tPA regimen (5 mg every 6 h). The primary end point was to assess the safety and tolerability of repeated doses of nebulized, inhaled tPA in pediatric patients with acute PB. Safety parameters consisted of clinical laboratories to assess bleeding, which were measured prior to, during, and after tPA treatment. To benchmark efficacy using spirometry and oxygen saturation, children with Fontan‐palliated CHD without a history of PB, with and without protein losing enteropathy (PLE), and healthy children were enrolled in a control arm that did not receive tPA.Results: Of the 10 patients with PB screened for enrollment, eight qualified for immediate treatment with inhaled tPA. A total of 29 non‐PB participants (PLE, n = 8 [10–18 yo]; CHD, n = 9 [8–17 yo]; and healthy, n = 12 [7–16 yo]) were enrolled. There were no differences in pretreatment clinical blood laboratory values of hemostasis and those during and after treatment with the study drug (primary safety outcome). However, there were four episodes of self‐limiting epistaxis related to the study drug. Inhaled tPA statistically improved oxygen saturation although this was moderate and likely not clinically significant; inhaled tPA did not alter spirometry values.Conclusion: In this small, phase II study, repeated doses of inhaled tPA in patients with an acute exacerbation of PB did not result in disrupted systemic coagulation or hematological homeostasis or serious bleeding. However, patients should be monitored for localized bleeding. Larger, randomized trials are needed to provide more comprehensive assessments of bleeding risk and to further assess efficacy.Trial Registration: ClinicalTrials.gov identifier: NCT02315898

Background: Disseminated mycobacterium poses a significant risk for patients with NEMO deficiency. Hematopoietic stem cell transplant (HSCT) corrects the NEMO defect in hematopoietic cells thus treating the immunodeficiency.Methods: We present a patient with NEMO deficiency who successfully underwent HSCT despite a disseminated Mycobacterium szulgai infection.Results: Despite successful engraftment and resolution of the mycobacterium infection, he developed inflammatory disease leading to his death.Conclusion: HSCT does not cure all aspects of the NEMO protein defect and posttransplant inflammatory diseases involving nonhematopoietic cell types may manifest clinically.

Little is known about infectious complications of lumbar puncture (LP) in children. We reviewed records of children with bacterial meningitis, intraspinal abscess, and vertebral osteomyelitis over a 3-year period to identify infections following LP. Four children with bacterial meningitis and 1 child with vertebral osteomyelitis were identified and their clinical presentations were described. These cases were scored by infectious disease experts, using a Likert scale, for the possibility of iatrogenic causation; these scores were variable, reflecting uncertainty. The bacterial meningitis cases had repeat LPs, and the latter cerebrospinal fluid analyses were diagnostic of bacterial meningitis; the interval between the initial “index” LP (I-LP) and symptom onset was 8 to 10 hours in most cases. Pediatricians should be aware of this possibility, and have a low threshold to repeat LP if there is a clinical change after the I-LP that could be consistent with meningitis.

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.

Background: Solid organ transplant (SOT) recipients are at increased risk of vaccine‐preventable illness due to the high degree of immunosuppression required following transplantation. The current recommendation is to vaccinate with live attenuated vaccines, including Measles, Mumps, and Rubella (MMR) and Varicella (VAR) vaccines, at least 4 weeks prior to transplant. However, data to support the time interval between vaccine and transplant are limited.Methods: We conduct a literature review of the natural history of the viruses and length of viremia following live‐attenuated viral vaccines, and we describe a series of 5 cases from 2 pediatric transplant centers in which live attenuated viral vaccines were administered within 21 days prior to SOT.Results: None of the 5 children who received MMR or VAR 8‐21 days prior to liver (2) and heart (3) transplant suffered from vaccine‐related viral illness after transplant, even in the presence of significant immunosuppression with T‐cell‐depleting agents.Conclusion: These cases support that shorter intervals of live vaccine administration prior to transplant may be safe, allowing the vaccination of a larger cohort of SOT candidates. Increasing pretransplant vaccinations is crucial since, in most cases, live viral vaccines are contraindicated posttransplantation, and the most effective vaccine approaches utilize prime‐boost strategies, priming before and boosting after transplant.