Pediatric Hematopoietic Stem Cell Transplantation Recipients Research Articles

COVID-19 disease in children and adolescents following allogeneic hematopoietic stem cell transplantation: A report from the Turkish pediatric bone marrow transplantation study group.

Data on the risk factors and outcomes for pediatric patients with SARS-CoV-2 infection (COVID-19) following hematopoietic stem cell transplantation (HSCT) are limited. The study aimed to analyze the clinical signs, risk factors, and outcomes for ICU admission and mortality in a large pediatric cohort who underwent allogeneic HSCT prior to COVID-19 infection. In this nationwide study, we retrospectively reviewed the data of 184 pediatric HSCT recipients who had COVID-19 between March 2020 and August 2022. The median time from HSCT to COVID-19 infection was 209.0 days (IQR, 111.7-340.8; range, 0-3845 days). The most common clinical manifestation was fever (58.7%). While most patients (78.8%) had asymptomatic/mild disease, the disease severity was moderate in 9.2% and severe and critical in 4.4% and 7.6%, respectively. The overall mortality was 10.9% (n: 20). Deaths were attributable to COVID-19 in nine (4.9%) patients. Multivariate analysis revealed that lower respiratory tract disease (LRTD) (OR, 23.20, p: .001) and lymphopenia at diagnosis (OR, 5.21, p: .006) were risk factors for ICU admission and that HSCT from a mismatched donor (OR, 54.04, p: .028), multisystem inflammatory syndrome in children (MIS-C) (OR, 31.07, p: .003), and LRTD (OR, 10.11, p: .035) were associated with a higher risk for COVID-19-related mortality. While COVID-19 is mostly asymptomatic or mild in pediatric transplant recipients, it can cause ICU admission in those with LRTD or lymphopenia at diagnosis and may be more fatal in those who are transplanted from a mismatched donor and those who develop MIS-C or LRTD.

Clonal Hematopoiesis Is Common in Long-Term Survivors of Pediatric Hematopoietic Cell Transplantation, Including Umbilical Cord Blood Transplantation

Background 1. Approximately 20.000 to 200.000 hematopoietic stem and progenitor cells (HSPCs) contribute to steady-state adult hematopoiesis. During ageing, the overall diversity of the HSPC pool decreases, which is in part driven by the selective expansion of HSPC clones with driver mutations, a process called clonal hematopoiesis (CH). CH is an age-related condition that predisposes to hematologic malignancy, cardiovascular disease, and all-cause mortality. Hematopoietic stem cell transplantation (HCT) recipients are at increased risk of CH, but the mechanisms driving the emergence and expansion of CH clones are largely unknown. Furthermore, the prevalence of CH in pediatric HCT recipients, in whom the long-term consequences of CH are particularly relevant, remains to be defined. Aim To determine the prevalence and risk factors of CH in long-term survivors of HCT at pediatric age. Methods We included survivors of HCT at pediatric age, with a minimum survival of 5 years after HCT. CH was assessed by targeted, error-corrected sequencing of mutations in 27 cancer driver genes in whole blood, at a variant allele frequency detection threshold of 1%. HSC age was calculated by the sum of the age of the donor and the interval after HCT. In case the age of a donor was unknown (n=53), the median age for donors of the same donor relation were used (i.e., 12.6 years for sibling donors and 28.7 for matched unrelated donors). Clinical characteristics were compared using the Wilcoxon signed ranked test for continuous variables and Chi-squared or Fisher's exact test for categorical variables. Results Here, we report the interim results of the first 120 HCT survivors in this study. The median age of the survivors was 20.4 years (range 6.7-51.8), and the median interval after HCT was 11.8 years (range 5.2-38.2). Indications for HCT were hemato-oncology (n=95), bone marrow failure (n=22), or immune deficiency (n=3). The median calculated age of the HSCs was 31 years (range 5.2-61.8). CH was present in 13.3% of survivors (n=16). Mutated genes were DNMT3A (n=15), TET2 (n=4) and MPL (n=1), with three individuals having more than one driver mutation. The median variant allele frequency of the CH clones was 2.2%, but allele frequencies up to 30% were found. No differences were observed in recipient age or interval after HCT between individuals with or without CH (Figure 1A). However, the age of the HSCs was significantly higher in individuals with CH compared to those without (38.6 versus 26.3 years, p = 0.01, Figure 1B). Surprisingly, we detected CH in two recipients of umbilical cord blood grafts, at an interval of 11 and 15 years after HCT. Conclusion Clonal hematopoiesis is common in long-term survivors of pediatric HCT. After HCT, the prevalence of CH is related to the age of the transplanted HSCs, rather than the age of the survivor. The presence of CH in cord blood HSCs within two decades after HCT suggests that HCT-related factors may drive the de novo emergence and/or outgrowth of donor-derived CH. Ongoing research is aimed at investigating how factors such as stem cell source and post-transplant complications affect clonal expansion after HCT. Furthermore, we are investigating the prevalence of CH in an age-matched control cohort using the same detection pipeline, enabling direct comparison of the prevalence of CH in HCT survivors compared to the general population.

Risk factors and clinical characteristics of acute and chronic cutaneous graft-versus-host disease in pediatric patients undergoing hematopoietic stem cell transplantation.

Acute and chronic cutaneous graft-versus-host disease (GVHD) are common complications following hematopoietic stem cell transplantation (HSCT) in pediatric patients. In this retrospective study, we explored the risk factors and clinical characteristics of acute and chronic cutaneous GVHD in a case series of children undergoing HSCT at a tertiary referral hospital. We found that 36% of acute cutaneous GVHD was severe and these patients were more likely to have an unrelated donor, and that children with acute cutaneous GVHD who progressed to chronic cutaneous GVHD had a higher proportion of malignant diseases, total body irradiation, and bronchiolitis obliterans compared to those who did not progress to chronic cutaneous GVHD. Our study highlights the importance of identifying and monitoring these high-risk patients to improve the clinical management and outcomes of cutaneous GVHD in pediatric HSCT recipients.

Financial burden and recommended multilevel solutions among caregivers of pediatric hematopoietic stem cell transplant recipients.

The healthcare costs of patients who receive hematopoietic stem cell transplantation (HSCT) are substantial. At the same time, the increasing use of pediatric HSCT leaves more caregivers of pediatric HSCT recipients at risk for financial burden-an understudied area of research. Financial burden experienced by caregivers of recipients who received autologous or allogeneic transplants was assessed using an explanatory mixed-methods design including a one-time survey and semi-structured interviews. Financial burden was assessed through an adapted COmprehensive Score for financial Toxicity (COST) as well as questions about the types of out-of-pocket costs and cost-coping behaviors. Chi-squared or Fisher's exact tests were used to assess differences in costs incurred and coping behaviors by financial toxicity and financial toxicity by demographic factors. Interviews were audio recorded, transcribed, and analyzed using directed content analysis. Of 99 survey participants, 64% experienced high financial toxicity (COST 22). Caregivers with high financial toxicity were more likely to report costs related to transportation and diet. High financial toxicity was associated with nearly all cost-coping behaviors (e.g., borrowed money). High financial toxicity was also associated with increased use of hospital financial support and transportation assistance. Qualitative analysis resulted in four categories that were integrated with quantitative findings: (1) care-related out-of-pocket costs incurred, (2) cost-coping behaviors, (3) financial support resources used, and (4) multilevel recommendations for reducing financial burden. Considering the substantial, long-term financial burden among pediatric HSCT patients and their caregivers, this population would benefit from adapted and tailored financial burden interventions.

Prognostic factors and predictive scores for 6-months mortality of hematopoietic stem cell transplantation recipients admitted to the pediatric intensive care unit.

Despite advances in hematopoietic stem cell transplantation (HSCT), a considerable number of pediatric HSCT patients develops post-transplant complications requiring admission to the pediatric intensive care unit (PICU). The objective of this study was to evaluate clinical findings, PICU supportive therapy and outcome as well as predictive factors for 6-months survival after discharge of HSCT patients from PICU. This retrospective single-center analysis investigated patient characteristics, microbiological findings, reasons for admission and death of 54 cases accounting for 94 admissions to the PICU of the University Children's Hospital Tuebingen from 2002 to 2017. We compared clinical characteristics between children with and without 6-months survival after discharge from PICU following HSCT. Finally, we assessed the potential prognostic value of the oncological Pediatric Risk of Mortality Score (O-PRISM), the Pediatric Sequential Organ Failure Assessment Score (pSOFA) and the pRIFLE Criteria for Acute Kidney Injury for 6-months survival using Generalized Estimating Equations (GEE) and Receiver Operating Characteristic curves. Respiratory insufficiency, gastroenterological problems and sepsis were the most common reasons for PICU admission. Out of 54 patients, 38 (70%) died during or after their last PICU admission, 30% survived for at least six months. When considering only first PICU admissions, we could not determine prognostic factors for 6-months mortality. In contrast, under consideration of all PICU admissions in the GEE model, ventilation (p=0.03) and dialysis (p=0.007) were prognostic factors for 6-months mortality. Furthermore, pSOFA (p=0.04) and O-PRISM (p=0.02) were independent risk factors for 6-months mortality considering all PICU admissions. Admission of HSCT patients to PICU is still associated with poor outcome and 69% of patients died within 6 months. Need for respiratory support and dialysis are associated with poor outcome. Prediction of 6-months survival is difficult, especially during a first PICU admission. However, on subsequent PICU admissions pSOFA and O-PRISM scores might be useful to predict mortality. These scores should be prospectively evaluated in further studies to verify whether they can identify pediatric HSCT recipients profiting most from transferal to the PICU.

Treatment of steroid-refractory graft versus host disease in children

Systemic steroids are still the first-line approach in acute graft-versus-host disease (aGvHD), and the backbone of chronic GvHD management. Refractoriness to steroid represent a major cause of morbidity and non-relapse mortality after hematopoietic stem cell transplantation (HSCT). In both backgrounds, several second-line immunosuppressive agents have been tested with variable results in terms of efficacy and toxicity. Solid evidence regarding these approaches is still lacking in the pediatric setting where results are mainly derived from adult experiences. Furthermore, the number of treated patients is limited and the incidence of acute and chronic GvHD is lower, resulting in a very heterogeneous approach to this complication by pediatric hematologists. Some conventional therapies and anti-cytokine monoclonal antibodies used in the adult setting have been evaluated in children. In recent years, the increasing understanding of the biological mechanisms underpinning the pathogenesis of GvHD justified the efforts toward the adoption of targeted therapies and non-pharmacologic approaches, with higher response rates and lower immunosuppressive effects. Moreover, many questions regarding the precise timing and setting in which to integrate these new approaches remain unanswered. This Review aims to critically explore the current evidence regarding novel approaches to treat SR-GvHD in pediatric HSCT recipients.

Long-term parental distress after pediatric hematopoietic stem cell transplantation for nonmalignant diseases.

Survival rates have continued to increase for pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. Despite the crucial role of caregivers in this high-intensity treatment, knowledge about long-term parental impact is lacking. This cross-sectional study assessed parental distress and everyday problems in parents of patients 2years and older after pediatric HSCT for a nonmalignant disease using Distress Thermometer for Parents (DT-P), and compared outcomes to matched Dutch parents of healthy children and Dutch parents of children with a chronic condition (CC). Median follow-up was 5.3years (interquartile range [IQR]: 2.9-8.6). Underlying diseases were inborn errors of immunity (N=30), hemoglobinopathies (N=13), and bone marrow failure (N=27). Mothers of pediatric HSCT recipients (N=70) reported comparable overall distress levels to mothers of healthy children, but experienced more distress related to parenting problems, specifically managing their child's emotions, discussing disease consequences, and fostering independence. Fathers of HSCT recipients (N=45) reported higher overall distress levels and had more emotional distress compared to fathers of healthy children. Overall, parental distress and everyday problems of parents of HSCT recipients are comparable to those of parents of children with CC. However, there is ongoing parental burden, both emotional and in parenting, long-term after HSCT compared to parents of healthy children, and the type of burden differs between mothers and fathers. These results indicate that individualized parental supportive care should not remain restricted to the acute hospitalization phase, but also be actively offered during long-term follow-up after pediatric HSCT.

High rate of adenovirus detection in gastrointestinal biopsies of symptomatic stem cell transplant recipients.

The gastrointestinal (GI) tract is a major human adenovirus (HAdV) replication site in patients undergoing hematopoietic stem cell transplantation (HSCT), yet the prevalence and correlates of HAdV GI infection in this setting have remained poorly recognized, especially among adult HSCT recipients. We retrospectively studied the prevalence and risk factors of HAdV GI-tissue infection in HSCT recipients (73 adults and 15 children) with GI symptoms who underwent GI-tissue biopsy between January-2012 and December-2017. The presence of HAdV in the GI tissues was determined by real-time PCR. HAdV GI-tissue infection was detected in 21 (23.9%) patients, with similar infection rates identified in adults and children. GI-tissue detection was more common at late (>100 days) compared to early times post-transplantation (50%vs. 12.9%, p<.001). The presence of bloody diarrhea, Arab ethnicity (p=.014) and concurrent cytomegalovirus GI-tissue detection (p=.025) were significantly correlated with HAdV GI-tissue infection, while chronic graft versus host disease was of borderline association (p=.055). Our findings reveal a high rate and new clinical-demographic correlates of HAdV GI-tissue infection in adult and pediatric HSCT recipients with GI symptoms. The findings highlight the need for future prospective studies to assess the relatedness of HAdV infection to the GI symptoms, and the prevalence, impact, and treatment of HAdV GI infection in HSCT recipients.

Effect of Antibiotics and Gut Microbiota on the Development of Sepsis in Children with Hematopoietic Stem Cell Transplants

Abstract Objective To describe the association between antibiotic use, gut microbiota composition, and the development of sepsis in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) to treat acute lymphoblastic leukemia. Methods A cohort of pediatric patients was followed up between days −30 (pre-HSCT) and +30 (post-HSCT), and sequential stool samples were collected for analysis of the taxonomic composition of bacterial communities by comparing the sequences of the 16s ribosomal RNA gene. Clinically, patients were divided into those with or without sepsis according to their clinical and laboratory data. Gut microbiota was categorized as potentially pathogenic or commensal and was described according to antibiotic use in patients with and without sepsis. Results A cohort of eight patients provided 34 stool samples at different time points during their pre- and post-HSCT periods. There was a greater diversity in the microbial composition in patients who did not develop sepsis. In contrast, patients who developed sepsis had low microbiota diversity, a slight dominance of the genus Bacteroides and order Enterobacterales, and a low abundance of the genus Akkermansia. The use of antibiotics was associated with a low relative abundance of commensal bacteria, a high relative abundance of potentially pathogenic microbiota, and a risk of sepsis. Conclusion Our results suggest that gut microbiota sequencing in pediatric HSCT recipients could predict the clinical course and guide direct interventions to improve patient outcomes. Accordingly, short-spectrum, tailored antibiotic therapy could be provided to patients with fever pre- and post-HSCT to prevent dysbiosis and reduce the risk of sepsis.

Droplet Digital PCR Development for Adenovirus Load Monitoring in Children after Hematopoietic Stem Cell Transplantation

Human adenovirus (AdV) reactivation after hematopoietic stem cell transplantation (HSCT) is associated with life-threatening clinical manifestations. Although real-tme quantitative PCR (qPCR) has been widely used to measure AdV loads, it has not been standardized for AdV. Droplet digital PCR (ddPCR) is a novel pathogen detection technology that enables the absolute quantification of viral loads. ddPCR would enable a more accurate AdV DNA detection compared with qPCR. In this study, ddPCR was developed for AdV DNA and its performance characteristics compared with those of qPCR. AdV DNAemia incidence during the first 12 weeks after allogenic HSCT was then retrospectively examined by qPCR and ddPCR in 97 HSCT procedures using the preserved 545 DNA samples. ddPCR exhibited better reproducibility and sensitivity, as well as equivalent quantifiability, compared with qPCR. AdV DNA among HSCT patients was detected in 11 (2.0%) and 49 (9.0%) of 545 samples by qPCR and ddPCR, respectively. AdV DNA levels >1000 copies/mL were observed in five cases by qPCR and/or ddPCR. However, two patients developed fulminant hepatitis and died; other patients remained asymptomatic with subsequently undetectable AdV DNA. In conclusion, ddPCR was more sensitive and reproducible in detecting AdV DNA among pediatric HSCT recipients than qPCR. ddPCR offers the potential to provide a more accurate DNAemia detection, determine cutoff values for treatment initiation, and enable antiviral efficacy assessment.

Elevated ADA2 Enzyme Activity at the Onset of Chronic Graft-versus-Host Disease in Children

Adenosinergic signaling has potent, context-specific effects on immune cells, particularly on the dysregulation of lymphocytes. This in turn may have a role in immune activation and loss of tolerance in such diseases as chronic graft-versus-host disease (chronic GVHD). We assessed whether changes in the enzymatic activity of adenosine deaminase 2 (ADA2), an enzyme that depletes adenosine in the extracellular space via conversion to inosine, may be associated with the onset of chronic GVHD. ADA2-specific enzyme activity was measured in plasma samples from 230 pediatric hematopoietic stem cell transplantation (HSCT) recipients enrolled on the Applied Biomarkers of Late Effects of Childhood Cancer (ABLE)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) 1202 study and compared between patients developing chronic GVHD and those not developing chronic GVHD within 12 months of transplantation. ADA2 and its relationships with 219 previously measured plasma-soluble proteins, metabolites, and immune cell populations were evaluated as well. Plasma ADA2 enzyme activity was significantly elevated in pediatric HSCT recipients at the onset of chronic GVHD compared to patients without chronic GVHD and was not associated with prior history of acute GVHD or generalized inflammation as measured by C-reactive protein concentration. ADA2-specific enzyme activity met our criteria as a potential diagnostic biomarker of chronic GVHD (effect ratio ≥1.30 or ≤.75; area under the receiver operating characteristic curve ≥.60; P < .05) and was positively associated with markers of immune activation previously identified in pediatric chronic GVHD patients. These results support the potential of ADA2 enzyme activity, in combination with other biomarkers and subject to future validation, to aid the diagnosis of chronic GVHD in children post-HSCT.

Third-Party and Patient-Specific Donor-Derived Virus-Specific T Cells Demonstrate Similar Efficacy and Safety for Management of Viral Infections after Hematopoietic Stem Cell Transplantation in Children and Young Adults

Infections with double-stranded DNA viruses are a common complication after hematopoietic stem cell transplantation (HSCT) and cause significant morbidity and mortality in the post-transplantation period. Both donor-derived (DD) and third-party (TP) virus-specific T cells (VSTs) have shown efficacy and safety in viral management following HSCT in children and young adults. Owing to a greater degree of HLA matching between the recipient and stem cell donor, DD VSTs potentially persist longer in circulation compared to TP VSTs, because they are collected from a well-matched donor. However, TP VSTs are more easily accessible, particularly for smaller transplantation centers that do not have VST manufacturing capabilities, and more economical than creating a customized product for each transplant recipient. We conducted the present study to compare clinical efficacy and safety outcomes for DD VSTs and TP VSTs in a large cohort of pediatric and young adult HSCT recipients and to determine whether DD VSTs are associated with improved outcomes owing to potentially longer persistence in the recipient's circulation. This retrospective cohort study included 145 patients who received VSTs at Cincinnati Children's Hospital Medical Center (CCHMC) between 2017 and 2021 for the treatment of adenovirus, BK virus, cytomegalovirus, and/or Epstein-Barr virus. Viruses were detected using quantitative polymerase chain reaction. Patients received VSTs on a DD (NCT02048332) or TP (NCT02532452) protocol, and VST products for both protocols were manufactured in an identical fashion. The primary study outcome was clinical response to VSTs, evaluated 4 weeks after VST administration, defined as decrease in viral load to under the inclusion thresholds, or resolution of symptoms of invasive viral infection, without the need for additional conventional antiviral medication following VST administration. Secondary outcomes included graft-versus-host-disease, transplant-associated thrombotic microangiopathy, renal function, hospital length of stay, and overall survival at 30 days and 100 days after VST administration and 1 year after HSCT. Statistical analysis was performed using the Fisher exact test or chi-square test. An unpaired t test was used to compare continuous variables. The study group comprised 77 patients in the DD cohort and 68 patients in the TP cohort. Eighteen patients in the TP cohort underwent HSCT at CCHMC, and the other 50 underwent HSCT at other institutions and presented to CCHMC solely for VST administration. There was no statistically significant difference in clinical response rates between DD and TP cohorts (65.6% versus 62.7%; odds ratio [OR], 1.162; 95% confidence interval [CI], .619 to 2.164; P=.747). There were no significant differences in secondary outcomes between the 2 cohorts. The percentage of patients requiring multiple infusions for a clinical response did not differ significantly between the DD and TP cohorts (38.2% versus 32.5%; OR, .780; 95% CI, .345 to 1.805; P=.666). We found no significant difference in clinical response rate between DD VSTs and TP VSTs and a similar safety profile. Our data suggest that TP VSTs may be sufficient to control viral infection until immune reconstitution occurs despite the potential for more rapid VST clearance compared to DD VSTs. The lack of significant differences between DD VSTs and TP VSTs is an important finding, indicating that it is not necessary for every transplant center to manufacture customized DD VSTs, and that TP VSTs are a satisfactory substitute.

2158. Monitoring of Varicella specific T-cell mediated immunity in pediatric allogenic hematopoietic stem cell transplant recipients

Abstract Background Varicella-zoster virus (VZV) infection is known to occur in 13-55% of patients within the first year after hematopoietic stem cell transplant (HSCT). The dynamics of recovery of VZV-specific T cell- mediated immunity (CMI) and its role for prevention and control of VZV reactivation are rarely reported in pediatric allogenic HSCT recipients. Methods From April 2019 to February 2020, subjects aged younger than 19 years who underwent allogenic HSCT with at least 1 year of follow up at Asan Medical Center Children`s Hospital were prospectively enrolled. All of them underwent VZV-specific enzyme-linked immune absorbent spot (ELISPOT) assays just before HSCT and then at 1, 3 months following HSCT. Extension study, which measures VZV-specific CMI before and after VZV vaccination at 24 months post-HSCT, is currently underway. Results A total of 32 HSCT recipients with a median age of 11years were enrolled. 37.5% underwent haploidentical HSCT and VZV R+ were in 78.1%. Antiviral prophylaxis was applied to all HSCT recipients, of which 65.6% were applied up to 365 days after HSCT. During this study period, only 1 patient (3.1%) experienced herpes zoster at 23 months following HSCT, whose VZV-specific ELISPOT assay showed 0, 1, and 0 spot-forming cells (SFC)/2.0x105 cells before HSCT, 1 and 3 months following HSCT, respectively. The presence of VZV-specific CMI ≥ 1 SFC/ 2.0 × 105 cells was observed in 62.5 % before HSCT, 65.6 % at 1 month, 59.4 % at 3 months, and 70% at 24 months after HSCT, respectively. However, only 18.8 % ,12.5 % and 21.9 % recovered VZV-specific CMI with ≥ 5 SFC/ 2.0 × 105 cells at 1, 3 and 24 months following HSCT. Meanwhile, all the 4 recipients who got the 1st VZV vaccination at 24 months following HSCT showed recovery of VZV-specific CMI with ≥ 5 SFC/ 2.0 × 105 cell. Recovery of VZV-specific CMI after HSCT was not associated with VZV serostatus, chickenpox history, type of HSCT, conditioning regimens, and GVHD. Conclusion Only a few pediatric allogenic HSCT recipients recovered VZV-specific CMI with ≥ 5 SFC/ 2.0 × 105 cell up to 2 years following HSCT. In addition, the association between VZV-specific CMI and VZV reactivation could not be analyzed because no one experienced VZV reactivation within 1 year after HSCT. More long-term large-scale multicenter study is mandatory to supplement these parts. Disclosures All Authors: No reported disclosures.

Prevention and management of human cytomegalovirus in pediatric HSCT recipients: A review.

Cytomegalovirus (CMV), like other herpesviruses, has the unique ability to establish latent infection with subsequent reactivation during periods of stress and immunosuppression. Herpesviruses cause potentially devastating disease, particularly in hematopoietic stem cell transplant (HSCT) recipients. CMV is especially of concern in HSCT recipients given the high community seroprevalence, high risk of reactivation and high risk of transmission from HSCT donors to recipients causing primary infection after transplantation. The risk of CMV infection and severity of CMV disease varies depending on the underlying disease of the HSCT recipient, donor and recipient CMV status prior to HSCT, type of conditioning therapy in preparation for HSCT, allogeneic versus autologous HSCT, donor graft source, timing of infection in relation to HSCT, and other patient comorbidities. Different strategies exist for prevention (e.g., preemptive therapy vs. universal prophylaxis) as well as management of CMV disease (e.g., antiviral therapy, augmenting immune reconstitution, cytotoxic T-cell therapy). The purpose of this narrative review is to discuss diagnosis, prevention, and management of CMV infection and disease at different stages of HSCT, including key points illustrated through presentations of complex cases and difficult clinical scenarios. Traditional and novel strategies for CMV management will be discussed in the context of these unique clinical cases.

Pleuroparenchymal fibroelastosis after hematopoietic stem cell transplantation in children: a propensity score-matched analysis.

To investigate the incidence, risk factors, and clinical outcomes of pleuroparenchymal fibroelastosis (PPFE) in pediatric hematopoietic stem cell transplantation (HSCT) recipients. This single-center, retrospective, case-control study included 738 consecutive patients who underwent chest CT more than 3 months after HSCT. We identified patients who fulfilled the diagnostic criteria for PPFE and assessed their clinical characteristics and radiologic findings. Propensity score-matched analysis was performed using four covariates (age, sex, HSCT type, and primary disease). The risk factors and clinical outcomes of PPFE were analyzed using the Fine and Gray regression model and stratified log-rank test in the matched groups. PPFE was identified in 4% (31/738, 8.3 ± 3.1 years, 15 males) of the pediatric HSCT recipients with a median time of 2.7 years after HSCT, and it occurred following allogeneic (5%, 15/317), autologous (4%, 15/379), or both (2%, 1/42). Matching yielded 30 and 130 cases in the PPFE and control groups, respectively. The PPFE group showed more frequent late-onset noninfectious pulmonary complications (LONIPCs) and pneumonia more than 3 months after HSCT (p < 0.05). Multivariable analysis showed a significantly higher risk of PPFE in HSCT recipients who had pneumonia more than 3 months after HSCT (hazard ratio = 10.78 [95% confidence interval: 4.29, 27.13], p < 0.001). The PPFE group showed higher mortality (73%, 22/30) and poorer median overall survival (6.8 years [95% confidence interval: 4.1, 9.5]) than the control group (p < 0.001). PPFE represents a severe type of LONIPC after HSCT. HSCT recipients with pneumonia after HSCT may have an increased risk of PPFE. • The incidence of pleuroparenchymal fibroelastosis is not negligible (4%), and it can occur after either allogeneic or autologous hematopoietic stem cell transplantation. • Pleuroparenchymal fibroelastosis after hematopoietic stem cell transplantation showed poor outcome with a high mortality rate of 73% and median overall survival of 6.8 years. • After hematopoietic stem cell transplantation, pneumonia may increase the risk of pleuroparenchymal fibroelastosis development in children. • Lung biopsy should not be indicated in patients with pleuroparenchymal fibroelastosis findings on chest CT as it can cause refractory pneumothorax without helping the diagnosis.

Antibody Response against Vaccine Antigens in Children after TCRαβ-Depleted Haploidentical Stem Cell Transplantation: Is It Similar to That in Recipients with Fully Matched Donors?

Recipients of hematopoietic stem cell transplantation (HSCT) with HLA-mismatched donors are more immune suppressed than those with fully matched donors. The immunologic response to vaccines also may differ in HLA-mismatched haploidentical HSCT recipients. In this study, we aimed to evaluate the antibody response to vaccines in pediatric TCRαβ-depleted haploidentical HSCT recipients. This longitudinal study included a study group of 21 children who underwent haploidentical HSCT without CD19 depletion and with TCRαβ depletion and a control group of 38 children who underwent fully matched donor HSCT. Antibody levels were quantified by serologic tests before vaccination and after each dose against tetanus, diphtheria, pneumococcus, hepatitis B, hepatitis A, measles, rubella, mumps, and varicella. The median recipient age was significantly lower (P=.037) and the median donor age was significantly higher (P=.000) in the haploidentical group compared with the fully matched group. At the months 1, 3, 6, 9 and 12 post-transplantation, the median CD4, CD8, and CD19 cell counts and lymphocyte counts were similar in the haploidentical and fully matched groups. The median natural killer cell count was higher in the haploidentical group at the months 1, 3, and 6 post-transplantation (P=.001, .006, and .004, respectively). The median time to first vaccination was similar in the 2 groups (12.5 [range, 11 to 14] months for the haploidentical group and 11 [range, 9 to 13] months for the fully matched group; P=.441). Seroprotection rates were 100% in both groups after the second and third doses of diphtheria vaccine, the third dose of tetanus vaccine, the third dose of hepatitis B vaccine, the second and third doses of pneumococcal conjugate vaccines (PCV13), and pneumococcal polysaccharide vaccine (PSPV23), although lower after the initial doses and before vaccination. Seroprotection for hepatitis A, rubella, and varicella was >90% in the fully matched group and 100% for the haploidentical group after the second doses. Measles and mumps seroprotection rates were >80% in the haploidentical group and approximately 70% for the fully matched group after the second dose. Antibody response and seroprotection rates against vaccine antigens were similar in the haploidentical group and the fully matched when revaccination was started at 12 months post-transplantation. These findings support the idea that TCRαβ-depleted haploidentical HSCT recipients can be revaccinated according to the same vaccination schedule as fully matched HSCT recipients. Revaccination earlier after transplantation and vaccine responses for recipients of different types of HSCT should be evaluated in future studies.

The Impact of High CMV Viral Load and Refractory CMV Infection on Pediatric HSCT Recipients with Underlying Non-Malignant Disorder.

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for an increasing number of nonmalignant indications. Its use is restricted by severe transplant-related complications, including CMV infection; despite various prophylactic and therapeutic strategies, CMV reactivation has remarkable morbidity and mortality. The analysis included 94 children with nonmalignant disorder who underwent allogeneic HSCT in the Department of Pediatric Hematology, Oncology, and Bone Marrow Transplantation in Wrocław during years 2016–2020. Twenty-seven (29%) children presented with CMV infection, including ten (10/27; 37%) with high level CMV viremia (10,000 copies/mL). Six patients experienced subsequent CMV reactivation. The first-line ganciclovir-based (GCV) treatment was insufficient in 40% (11/27) of children. Overall survival (OS) was significantly lower in children with high CMV viremia compared to those with low levels/no CMV [1yrOS High CMV = 0.80 (95% CI 0.41–0.95) vs. 1yrOS others = 0.96 (95% CI 0.89–0.99)]. Similarly, patients with resistant and recurrent infections had greater risk of death. CMV reactivation at any level relevantly prolonged the hospital stay. CMV reactivation with high viremia load and resistant/recurrent CMV infections lead to a significant decrease in OS in children with nonmalignant disorders treated with HSCT. Our data proves there is an urgent need to introduce an effective anti-CMV prophylaxis in this cohort of patients.

Vaccine Adherence and Postvaccination Serological Status of Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single-center Experience.

Despite developing consensus guidelines addressing immunization after hematopoietic stem cell transplantation (HSCT), studies showed deviations from recommended immunization practices commonly occur. Difference between the ideal scenario presented in guidelines and real-life scenarios is one of the most recognized barriers to implementing recommended practices. Therefore, this study aimed to evaluate pediatric allogeneic HSCT recipients' adherence to revaccination schedule and evaluate the serological status after immunization. Transplant and vaccination records of children who were followed up at least 2 years after HSCT, postvaccination antibody results of vaccine-preventable diseases were evaluated retrospectively. Total of 173 patients have enrolled in this study. Median revaccination onset time was post-transplant 15 months. Adherence to revaccination program was 30% for inactive and 11.4% for live vaccines. Oral polio vaccine was given to 22 patients, and Bacille-Calmette-Guerin vaccine was applied to 3. Seropositivity after revaccination was >90% for Hepatitis B, Hepatitis A, pertussis, and measles, and it was 88.5% for rubella, 80% for mumps and varicella. Measles seropositivity was low in children with hemoglobinopathy. In subgroup assessments of pertussis, patients vaccinated with low antigen-containing pertussis vaccine (Tdap) had higher seropositivity of adenylate cyclase toxin. Our findings revealed the importance of careful monitoring of current practices in pediatric HSCT recipients.

Clinical Characteristics and Outcomes of COVID-19 in Pediatric and Early Adolescent and Young Adult Hematopoietic Stem Cell Transplant Recipients: A Cohort Study

Adult hematopoietic stem cell transplantation (HSCT) recipients are at a high risk of adverse outcomes after COVID-19. Although children have had better outcomes after COVID-19 compared to adults, data on risk factors and outcomes of COVID-19 among pediatric HSCT recipients are lacking. We describe outcomes of HSCT recipients who were ≤21 years of age at COVID-19 diagnosis and were reported to the Center for International Blood and Marrow Transplant Research between March 27, 2020, and May 7, 2021. The primary outcome was overall survival after COVID-19 diagnosis. We determined risk factors of COVID-19 as a secondary outcome in a subset of allogeneic HSCT recipients. A total of 167 pediatric HSCT recipients (135 allogeneic; 32 autologous HSCT recipients) were included. Median time from HSCT to COVID-19 was 15 months (interquartile range [IQR] 7-45) for allogeneic HSCT recipients and 16 months (IQR 6-59) for autologous HSCT recipients. Median follow-up from COVID-19 diagnosis was 53 days (range 1-270) and 37 days (1-179) for allogeneic and autologous HSCT recipients, respectively. Although COVID-19 was mild in 87% (n = 146/167), 10% (n = 16/167) of patients required supplemental oxygen or mechanical ventilation. The 45-day overall survival was 95% (95% confidence interval [CI], 90-99) and 90% (74-99) for allogeneic and autologous HSCT recipients, respectively. Cox regression analysis showed that patients with a hematopoietic cell transplant comorbidity index (HCT-CI) score of 1-2 were more likely to be diagnosed with COVID-19 (hazard ratio 1.95; 95% CI, 1.03-3.69, P = .042) compared to those with an HCT-CI of 0. Pediatric and early adolescent and young adult HSCT recipients with pre-HSCT comorbidities were more likely to be diagnosed with COVID-19. Overall mortality, albeit higher than the reported general population estimates, was lower when compared with previously published data focusing on adult HSCT recipients.

#45 Antibiotic Exposure and Risk of Cytomegalovirus Viremia Among Pediatric Hematopoietic Stem Cell Transplant Recipients at a Single Institution

Abstract Background Cytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HCT), and antibiotic exposure after HCT is increasingly recognized as a risk for negative clinical outcomes. Recent studies identified an association between receipt of antibiotics with an anaerobic spectrum of activity and infection with cytomegalovirus (CMV) after HCT in adults. We sought to evaluate the association between anaerobic antibiotic exposure and CMV viremia in a well-characterized cohort of pediatric HCT recipients. Method We conducted a single-center retrospective cohort study of HCT recipients &amp;lt;18 years of age who underwent HCT at Duke University between 2000 and 2016. Routine pre-emptive surveillance testing for CMV was performed; CMV viremia was defined as a positive whole blood hybrid capture CMV DNA assay or quantitative plasma CMV PCR. We used log-logistic regression to evaluate associations between anaerobic antibiotic exposure (vancomycin, metronidazole, meropenem, piperacillin-tazobactam) and CMV viremia-free survival at 100 days after HCT. The first model considered anaerobic antibiotic exposure in the first 14 days after HCT as a binary variable. The second model considered anaerobic antibiotic exposure in the first 100 days as a time-varying variable; once a subject was exposed to a specific antibiotic, they were considered exposed for the remainder of the study period. Both models adjusted for year of HCT, age, race, HCT type and donor cell source, underlying diagnosis, conditioning regimen, CMV serostatus, and treatment for graft-versus-host-disease. Results Among 966 children, median (interquartile range) age was 6.5 (3.1, 11.5) years. Hematologic malignancy was the indication for transplantation in 417 (43%) subjects. Of 770 allogeneic HCT, 566 (74%) were from an umbilical cord blood donor and 204 (26%) were from a bone marrow donor. The majority of HCT were recipient CMV-seronegative and donor CMV-seronegative (R-/D-; 537, 56%), with 24 (2%) R-/D+, 270 (28%) R+/D-, and 135 (14%) R+/D+ transplants. Within the first 100 days after HCT, 692 (72%) children received vancomycin, 363 (38%) received metronidazole, 231 (24%) received meropenem, and 121 (13%) received piperacillin-tazobactam. Exposure to vancomycin (OR=0.86; 95% CI: 0.59, 1.26), metronidazole (OR=0.76; 95% CI: 0.53, 1.10), meropenem (OR=1.19; 95% CI: 0.74, 1.90), or piperacillin-tazobactam (OR=1.03; 95% CI: 0.55, 1.92) in the first 14 days after HCT was not associated with the risk of CMV viremia-free survival at 100 days. Similarly, we found no increased risk of CMV viremia with anaerobic antibiotic exposure in the first 100 days after HCT (vancomycin OR=0.90; 95% CI: 0.60, 1.34; metronidazole OR=0.80; 95% CI: 0.53, 1.21; meropenem OR=0.98; 95% CI: 0.60, 1.62; piperacillin-tazobactam OR=0.69; 95% CI: 0.38, 1.23). Conclusion In this study of pediatric HCT recipients, we did not find evidence of an association between anaerobic antibiotic exposures and CMV viremia risk. However, future pediatric and adult studies are warranted to evaluate this previously reported association in other populations, including studies evaluating for a possible role of the gut microbiome in modifying CMV viremia risk after HCT.