Presentation, management, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

BACKGROUND: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.  Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. METHODS: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. RESULTS: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. CONCLUSION: In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

Anti-spike antibody durability after SARS-CoV-2 vaccination in adolescent solid organ transplant recipients.

BACKGROUND: Adolescent solid organ transplant recipients (aSOTRs) who received three doses of the COVID-19 mRNA vaccine experience high seroconversion rates and antibody persistence for up to 3 months. Long-term antibody durability beyond this timeframe following three doses of the SARS-CoV-2 mRNA vaccine remains unknown. We describe antibody responses 6 months following the third vaccine dose (D3) of the BNT162b2 mRNA vaccination among aSOTRs. METHODS: Participants in a multi-center, observational cohort who received the third dose of the vaccine were analyzed for antibodies to the SARS-CoV-2 spike protein receptor-binding domain (Roche Elecsys anti-SARS-CoV-2-S positive: ≥0.8, maximum: >2500 U/mL). Samples were collected at 1-, 3-, and 6-months post-D3. Participants were surveyed at each timepoint and at 12-months post-D3. RESULTS: All 34 participants had positive anti-RBD antibody titers 6 months post-D3. Variations in titers occurred between 3 and 6 months post-D3, with 8/28 (29%) having decreased antibody levels at 6 months compared to 3 months and 2/28 (7%) reporting increased titers at 6 months. The remaining 18/28 (64%) had unchanged antibody titers compared to 3-month post-D3 levels. A total of 4/34 (12%) reported breakthrough infection within 6 months and 3/32 (9%) reported infection after 6-12 months following the third dose of the SARS-CoV-2 mRNA vaccine. CONCLUSIONS: The results suggest that antibody durability persists up to 6 months following three doses of the SARS-CoV-2 mRNA in aSOTRs. Demography and transplant characteristics did not differ for those who experienced antibody weaning. Breakthrough infections did occur, reflecting immune-evasive nature of novel variants such as Omicron.

Survey of pediatric transplant center practices regarding COVID-19 vaccine mandates for transplant candidates and living donors and use of COVID-19-positive deceased organs.

BACKGROUND: COVID-19 vaccine is recommended for individuals ages ≥6 months; however, whether vaccination should be mandated for transplant candidates and living donors remains controversial. This study assessed COVID-19 policies at US pediatric solid organ transplant centers. METHODS: A 79-item survey was emailed between March and April 2022 to 200 UNOS Medical Directors detailing center COVID-19 vaccine policies for transplant candidates and living donors and use of grafts from COVID-19-positive deceased donors. RESULTS: The response rate was 77% (154/200). For children aged 5-15 years, 23% (35/154 centers) have a COVID-19 vaccine mandate, 27% (42/154) anticipate implementing a future mandate, and 47% (72/154) have not considered or do not anticipate implementing a mandate. For children ≥16 years, 32% (50/154 centers) have a COVID-19 vaccine mandate, 25% (39/154) anticipate implementing a future mandate, and 40% (62/154) have not considered or do not anticipate implementing a mandate. The top two reasons for not implementing a COVID-19 vaccine mandate were concerns about penalizing a child for their parent's decision and worsening inequities in transplant. Of 85 kidney and liver living donor centers, 32% (27/85) require vaccination of donors. Twenty percent (31/154) of centers accept organs from COVID-19-positive deceased donors. CONCLUSIONS: There is great variation among pediatric SOT centers in both the implementation and details of COVID-19 vaccine mandates for candidates and living donors. To guide more uniform policies, further data are needed on COVID-19 disease, vaccine efficacy, and use of grafts from donors positive for COVID-19 in the pediatric transplant population.

Absolute Monocyte Count as Early and Safe Marker for Antibiotic Cessation in Febrile Neutropenia Without Etiology in Pediatric Oncology Patients.

BACKGROUND: There is no practice standard regarding antibiotic duration in children with cancer and unexplained febrile neutropenia (FN). We hypothesized that absolute monocyte count (AMC) and absolute phagocyte count (APC= ANC + AMC + bands) are more sensitive, earlier, and safe markers of antibiotic cessation compared with absolute neutrophil count (ANC). METHODS: A retrospective review of FN episodes (FNEs) in pediatric oncology patients was conducted between 2009 and 2016. Included patients were afebrile for 24 hours and without an identified infectious source at antibiotic cessation. Primary endpoints, including recurrent fever, readmission, bloodstream infection, microbiologically documented infection, and adverse outcomes, were assessed 10 days after antibiotic cessation and compared among different bone marrow recovery parameters (ANC, AMC, APC). Secondary endpoints included length of FN stay, antibiotic-free days, and cost. RESULTS: Three hundred ninety-one FNEs in 235 patients were included. Three groups were compared based on ANC (cells/µL) at the time of antibiotic cessation: < 200 in 102 (26%), 200 to 500 in 111 (28%), and >500 in 178 (46%). No statistically significant differences in primary endpoints were identified among the 3 ANC groups; however, a trend toward unfavorable outcomes in the ANC ≤200 cells/µL group compared with the ANC >200 cells/µL was observed. Primary endpoints based on AMC >100 cells/µL at the time of antibiotic cessation showed statistically significant favorable outcomes compared AMC ≤100 cells/µL (80%, 88%, 90%, 89%, and 93% risk reduction in recurrent fever, readmission, new bloodstream infection, new microbiologically documented infection, and adverse events, respectively). Similar favorable results were seen when APC >300 cells/µL was used as a threshold for antibiotic cessation. The median length of stay for FN if discharged when AMC >100 cells/µL was 3 days shorter and associated with fewer unfavorable outcomes, thus resulting in fewer hospital days, fewer antibiotic days, and decreased cost. CONCLUSION: Our results suggest that AMC >100 cells/µL (regardless of ANC) or APC >300 cells/µL may be safe thresholds for empiric antibiotic cessation and result in reduced unfavorable clinical outcomes within 10 days postdischarge, reduced antibiotic days of therapy and reduced health care costs. Further prospective studies are needed to validate AMC as an accurate surrogate marker for antibiotic cessation in FNEs in children with cancer.

Early stool microbiome and metabolome signatures in pediatric patients undergoing allogeneic hematopoietic cell transplantation.

BACKGROUND: The contribution of the gastrointestinal tract microbiome to outcomes after allogeneic hematopoietic cell transplantation (HCT) is increasingly recognized. Investigations of larger pediatric cohorts aimed at defining the microbiome state and associated metabolic patterns pretransplant are needed. METHODS: We sought to describe the pretransplant stool microbiome in pediatric allogenic HCT patients at four centers. We performed shotgun metagenomic sequencing and untargeted metabolic profiling on pretransplant stool samples. Samples were compared with normal age-matched controls and by clinical characteristics. We then explored associations between stool microbiome measurements and metabolite concentrations. RESULTS: We profiled stool samples from 88 pediatric allogeneic HCT patients, a median of 4 days before transplant. Pretransplant stool samples differed from healthy controls based on indices of alpha diversity and in the proportional abundance of specific taxa and bacterial genes. Relative to stool from healthy patients, samples from HCT patients had decreased proportion of Bacteroides, Ruminococcaeae, and genes involved in butyrate production, but were enriched for gammaproteobacterial species. No systematic differences in stool microbiome or metabolomic profiles by age, transplant indication, or hospital were noted. Stool metabolites demonstrated strong correlations with microbiome composition. DISCUSSION: Stool samples from pediatric allogeneic HCT patients demonstrate substantial dysbiosis early in the transplant course. As microbiome disruptions associate with adverse transplant outcomes, pediatric-specific analyses examining longitudinal microbiome and metabolome changes are imperative to identify causal associations and to inform rational design of interventions.

Immunity to varicella, measles, and mumps in patients evaluated for lung transplantation.

Vaccine-preventable viral infections are associated with increased risk of morbidity and mortality in post-transplant patients on immunosuppression regimens. Therefore, we studied rates of immunity against vaccine-preventable viruses in lung transplantation (LTx) candidates and their associations with underlying lung disease and clinical characteristics. We retrospectively studied 1025 consecutive adult patients who underwent first-time evaluation for LTx at a single center between January 2016 and October 2018. Viruses studied included varicella zoster (VZV), measles, and mumps. Young age (17-48 years old) was negatively associated with immunity for VZV (OR 4.54, p < .001), measles (OR 15.45, p < .001) and mumps (OR 3.1, p < .001), as compared to those 65+. Many LTx candidates with cystic fibrosis (CF) had undetectable virus-specific antibody titers including: 13.5% for VZV, 19.1% for measles, and 15.7% for mumps with significant odds of undetectable titers for VZV (OR 4.54, p < .001) and measles (OR 2.32, p = .010) as compared to those without CF. Therefore, a substantial number of patients undergoing LTx evaluation had undetectable virus-specific antibody titers. Our results emphasize the importance of screening for immunity to vaccine-preventable infections in this population and the need for revaccination in selected patients to boost their humoral immunity prior to transplantation.

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients.

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUCSS) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range, 60 to 233 µg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).

Pediatric Febrile Neutropenia: Change in Etiology of Bacteremia, Empiric Choice of Therapy and Clinical Outcomes.

BACKGROUND: The optimal choice of initial antibiotic therapy for patients with high-risk febrile neutropenia (FN) in children is unclear and varies by the institution on the basis of local antibiograms and epidemiology of specific pathogens. The authors evaluated the appropriateness of antibiotics for the empiric treatment of FN in pediatric patients with cancer in our institution on the basis of changes in the epidemiology of organisms isolated from blood cultures (BCx). METHODS: The authors conducted a retrospective medical record review of pediatric patients who received any oncology care (including patients with cancer and patients who had stem cell transplant) at University of Chicago Medicine Comer Children's Hospitals (March 2009 to December 2016) with a diagnosis of FN who had at least 1 BCx obtained. They reviewed pathogens isolated from BCx and determined whether they were pathogens or contaminants using the Infectious Diseases Society of America (IDSA) guidelines and the team's decision to treat. They investigated the microbiologic spectrum and susceptibility patterns of pathogens causing bacteremia in pediatric FN and whether the empiric therapy chosen may have affected clinical outcomes. RESULTS: A total of 667 FN episodes were identified in 268 patients. BCx were negative in 497 (74.5%) and were determined to be contaminants in 27 (4%). In 143 episodes (21.5%), the BCx were positive for a pathogenic species. Polymicrobial bacteremia was identified in 25 episodes; a total of 176 pathogens were isolated. The majority of pathogens (95/176, 54%) were Gram-positive (GP), whereas 64 of 162 (36%) were Gram-negative (GN), 5 were fungal, and 4 were mycobacterial. The most common GP pathogens were viridans group streptococci (VGS) (n=34, 19.3%), coagulase-negative staphylococci (n=25, 14%), and methicillin-susceptible Staphylococcus aureus (n=12, 6.8%). Of aerobic GN bacilli, 15 (8.5%) were AmpC producers and 3 (1.7%) carried extended-spectrum beta-lactamases. There was no increase in the prevalence of multidrug-resistant GN isolates during the study period. Patients with VGS and multidrug-resistant GN bacteremia were more likely to be admitted to the pediatric intensive care unit [odds ratio (OR), 3.24; P=0.017; and OR, 2.8; P=0.07, respectively]. There were trends toward a higher prevalence of GP pathogens causing bacteremia and the emergence of VGS with decreased penicillin sensitivity. The prevalence of bacteremia with VGS was higher in acute myelogenous leukemia and neuroblastoma (OR, 2.3; P<0.01) than in patients with other solid tumors. CONCLUSIONS: Empiric antibiotic treatment should be tailored to patients' risk for VGS and multidrug-resistant organisms. Individual hospitals should monitor the pathogens causing FN among patients with cancer to guide choice of empiric therapy.

Training in transplant infectious diseases: A survey of infectious diseases and transplant infectious diseases fellows in the United States and Canada.

BACKGROUND: Infectious diseases (ID) specialists with experience in managing infections in transplant recipients and other immunocompromised hosts are increasingly needed as these fields expand. METHODS: To evaluate experiences and identify trainee-described needs in transplant infectious diseases (TID) training, the American Society of Transplantation, Infectious Diseases Community of Practice (AST IDCOP) surveyed ID fellows across the United States and TID fellows in the United States and Canada and received responses from 203 ID fellows and 13 TID fellows. RESULTS: Among ID fellows, the amount of TID training during ID fellowship was rated between less than ideal and adequate. Reasons cited included limited frequency of didactic activities and limited exposure to transplant patients during training. In particular, ID fellows at low-volume transplantation centers expressed interest in more TID training time, away training opportunities, and specific TID didactics. Educational resources of high interest among trainees were case-based interactive websites, mobile phone applications with TID guidelines, and a centralized collection of relevant articles. Pediatric ID fellows reported lower satisfaction scores with TID training, while TID fellows were overall satisfied or more than satisfied with their training experience. CONCLUSION: Findings from this survey will inform local and national TID educational initiatives.

Anellovirus loads are associated with outcomes in pediatric lung transplantation.

Anelloviruses are DNA viruses ubiquitously present in human blood. Due to their elevated levels in immunosuppressed patients, anellovirus levels have been proposed as a marker of immune status. We hypothesized that low anellovirus levels, reflecting relative immunocompetence, would be associated with adverse outcomes in pediatric lung transplantation. We assayed blood samples from 57 patients in a multicenter study for alpha- and betatorquevirus, two anellovirus genera. The primary short-term outcome of interest was acute rejection, and longer-term outcomes were analyzed individually and as "composite" (death, chronic rejection, or retransplant within 2 years). Patients with low alphatorquevirus levels at 2 weeks post-transplantation were more likely to develop acute rejection within 3 months after transplant (P = .013). Low betatorquevirus levels at 6 weeks and 6 months after transplant were associated with death (P = .047) and the composite outcome (P = .017), respectively. There was an association between low anellovirus levels and adverse outcomes in pediatric lung transplantation. Alphatorquevirus levels were associated with short-term outcomes (ie, acute rejection), while betatorquevirus levels were associated with longer-term outcomes (ie, death, or composite outcome within 2 years). These observations suggest that anelloviruses may serve as useful biomarkers of immune status and predictors of adverse outcomes.

Airway plaque presenting after alteration of immunosuppression in a pediatric patient remote from heart transplantation.

Success after solid organ transplantation is dependent on the proper balance of immunosuppression to prevent rejection of the allograft while limiting the risk of developing infections and malignancy. We present a 9-year-old girl, remote from transplant, who presented with airway plaque after a change in immunosuppression to include the mTOR inhibitor sirolimus. Differential diagnosis included direct medication side effect, infection, and neoplasia.

Antifungal prophylaxis in pediatric lung transplantation: an international multicenter survey.

Fungal infections create a significant risk to pediatric lung transplant recipients. However, no international consensus guidelines exist for fungal infection prevention strategies. It was the aim to describe the current strategies of antifungal prophylaxis in pediatric lung transplant centers. A self-administered, web-based survey on current practices to prevent fungal infection was circulated to centers within the IPLTC. Twenty-one (88%) IPLTC centers participated, predominantly from Europe and the US. More than 50% of respondents perform adult and pediatric lung transplant operations. Twenty-four percent use universal prophylaxis, 28% give prophylaxis to all patients but stratify the antifungal coverage based on pretransplant risk, and 48% target prophylaxis to only the children with CF or pretransplantation fungal colonization. Commonly, centers aim to target Aspergillus and Candida infection. Monotherapy with either voriconazole or inhaled amphotericin B is used in the majority of centers. Institutions utilize prophylactic therapy for variable time periods (40% 3-6 months; 30% ≥12 months). Alternative drugs were prescribed for lack of tolerance, toxicity, or positive surveillance culture. TDM (itraconazole/voriconazole) was used in 86% of centers. The survey revealed a wide range of antifungal prophylaxis strategies as current international practice in pediatric lung transplant recipients.

Current and Emerging Antiviral Agents in the Prevention and Treatment of Cytomegalovirus in Pediatric Transplant Recipients.

Despite current prophylaxis regimens, cytomegalovirus (CMV) is common in hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT) and remains a significant cause of morbidity and mortality. Newer antiviral medications are reshaping the landscape for prevention and treatment of CMV DNAemia, infection, and disease. Letermovir is approved for CMV prevention in adult HCT patients and is attractive due to the absence of marrow suppression seen with ganciclovir/valganciclovir. Letermovir should not be routinely used for CMV treatment due to its low threshold for resistance. Maribavir is approved for the treatment of refractory or resistant CMV disease in HCT and SOT recipients ≥12 years of age, though it has no current role in CMV prevention. More research is needed to fully elucidate the roles, efficacy, and safety of these newer agents in prevention and treatment of CMV in pediatric transplant recipients.

Omicron Infections in Vaccinated Pediatric Solid Organ Transplant Recipients.

SARS-CoV-2 infection during the Omicron period was frequent amongst a cohort of vaccinated pediatric solid organ transplant recipients (pSOTRs) despite robust anti-receptor-binding domain (anti-RBD) antibody response, suggesting poor neutralizing capacity against Omicron subvariants. Breakthrough infections among pSOTRs were overall limited in severity.

RSV prevention and treatment in pediatric lung transplant patients: a survey of current practices among the International Pediatric Lung Transplant Collaborative.

RSV infection can be severe after pediatric lung transplantation. Strategies to prevent and treat RSV in this population are underreported. To assess the current practices, we surveyed the members of the IPLTC regarding RSV prevention and treatment strategies. Twenty-eight programs were surveyed; 18 (64.3%) responded at least partially. A median of 53 transplants (range, 8-355) occurred since inception. RSV testing occurs in asymptomatic (6/17) and symptomatic (17/17) patients. Diagnostic method is polymerase chain reaction at 13 sites and DFA at 8. Transplant candidates were received prophylaxis at 10 sites, with nine following national (5) or local (4) guidelines. All use palivizumab IM and/or IV. Recipients were received prophylaxis with palivizumab at eight centers (eight IM, one IV). Fourteen were treated for RSV (seven all patients; seven age-related). Medications include inhaled (6), oral (4), or IV (4) ribavirin, plus IVIG (9), steroids (8), and IV (2) or IM (3) palivizumab. Prevention and treatment barriers include insurance/hospital concerns, such as institutional reluctance to use inhaled ribavirin. RSV prevention and treatment strategies are diverse at pediatric lung transplant programs. Many centers offer prophylaxis (9/17) and treatments (14/17), but strategies are not uniform.

The impact of COVID-19 on the pediatric solid organ transplant population.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly impacted all aspects of healthcare including solid organ transplantation. In this review, we discuss the specific impact of COVID-19 on the pediatric solid organ transplant population including access to grafts for pediatric transplant candidates as well as COVID-19 disease manifestations in pediatric transplant recipients. We address the current knowledge of prevention and management of COVID-19 in pediatric transplant recipients and provide additional information regarding social distancing, infection prevention and return to school.

Return to School and COVID-19 Vaccination for Pediatric Solid Organ Transplant Recipients in the United States: Expert Opinion for 2021-2022.

The COVID-19 pandemic continues to generate challenges for pediatric solid organ transplant (SOT) recipients and their families. As rates of COVID-19 fluctuate, new SARS-CoV-2 variants emerge, and adherence to and implementation of mitigation strategies vary from community to community, questions remain about the best and safest practices to prevent COVID-19 in vulnerable patients. Notably, decisions about returning to school remain difficult. We assembled a team of specialists in pediatric infectious diseases, transplant infectious diseases, public health, transplant psychology, and infection prevention and control to re-address concerns about school re-entry, as well as COVID-19 vaccines, for pediatric SOT recipients in the United States in 2021. Based on available literature and guidance from national organizations, we generated expert statements specific to pediatric SOT recipients focused on school attendance in 2021.