Search

•There are issues with the criteria for post-hematopoietic stem cell transplantation (HSCT) bronchiolitis obliterans syndrome (BOS) leading to delayed diagnosis.•Several solutions that can be implemented to improve the criteria.•A multidisciplinary group has proposed new criteria for post-HSCT BOS in children.

Autologous hematopoietic stem cell transplant (ASCT) may be curative therapy for pediatric patients with relapsed/refractory Hodgkin lymphoma (HL). Therapy for HL may involve pulmonary toxic modalities. Little information exists regarding pulmonary function in these patients post-ASCT. A retrospective chart review was performed for patients undergoing ASCT from February 2012 to December 2019. Lung disease was defined as a z-score ≤−1.7 in forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), or diffusing capacity of lung for carbon monoxide. Descriptive and limited statistical analyses were performed. Twenty-eight patients were included. Median age at diagnosis was 15 (2 to 19) and was 17 (4 to 21) at ASCT. Twenty-three received radiation before ASCT. Fourteen received brentuximab before, and 9 after, transplant. Nineteen met criteria for lung disease post-ASCT. Sixteen had lung disease before ASCT. Longitudinal trends for pulmonary function testing parameters did not reach statistical significance, however, FEV1, FVC, and TLC trended towards worsening immediately post-transplant. There was no statistically significant change in FEV1, FVC, or TLC at 2 years as compared with pretransplant data, suggesting no substantial difference from baseline. Diffusing capacity of lung for carbon monoxide showed statistically significant improvement at the 2 year timepoint (P=0.03). This data reinforces the importance of close follow-up for these patients. Large cohort studies are necessary to identify risk factors so that possible mitigative strategies or alternate regimens could be used.

We conducted a randomized, placebo‐controlled, double‐blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti‐thymocyte globulin induction would reduce de novodonor‐specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n= 15) or placebo (n= 12). No rituximab‐treated subjects versus five placebo‐treated subjects developed de novoDSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0‐p, obliterative bronchiolitis or listing for retransplant). A post‐hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0‐p showed no difference in outcome (p = .118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888). A multicenter randomized controlled trial in pediatric lung transplantation shows that Rituximab induction reduces the development of de novo donor specific antibody.

We conducted a randomized, placebo-controlled, double-blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti-thymocyte globulin induction would reduce de novodonor-specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n= 15) or placebo (n= 12). No rituximab-treated subjects versus five placebo-treated subjects developed de novoDSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0-p, obliterative bronchiolitis or listing for retransplant). A post-hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0-p showed no difference in outcome (p= .118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888).

Pulmonary complications are a major cause of morbidity and mortality in children undergoing autologous and allogeneic hematopoietic stem cell transplant (HSCT). Pulmonary complications are likely underreported in pediatric patients. Our goal was to describe the incidence and spectrum of pulmonary complications after autologous HSCT (auto-HSCT) in a large cohort of pediatric patients.

Pulmonary complications, pulmonary chronic graft vs host disease (cGVHD) and bronchiolitis obliterans, are a major cause of morbidity and mortality following hematopoietic stem cell transplant (HSCT). Pulmonary function testing is insensitive for detecting changes in small airways (SA). Multiple breath nitrogen washout (MBW) is a technique to detect ventilation heterogeneity; a measure of peripheral SA disease often seen in early manifestations of pulmonary cGVHD. Primary outcome of MBW testing is lung clearance index (LCI), the number of lung turnovers required to clear an inert gas (N2). MBW has several advantages, allowing it to be used in younger age groups. Utilization of LCI as a marker for early disease may allow for prompt diagnosis at a time in which intervention is the most meaningful.

Respiratory complications are common following HSCT in children. The most sensitive tests to evaluate these complications are unknown. Airwave oscillometry has been proposed to be a sensitive test of disorders of the mechanics of the respiratory system, including large and small airway dysfunction and elevated respiratory system stiffness due to pulmonary parenchymal or chest wall damage. We performed oscillometry (Tremofloã C100, Thorasys, Montreal, CA) at baseline and following HSCT in a cohort of 56 children at 3 of 4 centers to date: Cincinnati Children's Hospital, Children's Hospital of Philadelphia, University of Minnesota Children's Hospital, and Boston Children's Hospital.

Bronchiolitis obliterans syndrome is a devastating complication following hematopoietic stem cell transplant (HSCT) which can be treated once detected. Spirometry offers the opportunity for earlier detection of lung function decline in at risk patients, but many patients do not live near their HSCT center and may not be able to return for frequent spirometry monitoring. As part of the TRANSPIRE research study, we are evaluating the feasibility of home spirometry as a remote monitoring strategy in pediatric and young adult HSCT recipients.

Hematopoietic stem cell transplantation (HSCT) is an effective treatment for malignant and non-malignant diseases in pediatric patients but comes with significant risk of toxicity. Pulmonary morbidity affects as many as 25% of children receiving transplant. Better diagnostic and treatment modalities for pulmonary complications are greatly needed as survival after HSCT improves.

Remote interventions are increasingly used in transplant medicine but have rarely been rigorously evaluated. We investigated a remote intervention targeting immunosuppressant management in pediatric lung transplant recipients. Patients were recruited from a larger multisite trial if they had a Medication Level Variability Index (MLVI) ≥2.0, indicating worrisome tacrolimus level fluctuation. The manualized intervention included three weekly phone calls and regular follow-up calls. A comparison group included patients who met enrollment criteria after the subprotocol ended. Outcomes were defined before the intent-to-treat analysis. Feasibility was defined as ≥50% of participants completing the weekly calls. MLVI was compared pre- and 180 days postenrollment and between intervention and comparison groups. Of 18 eligible patients, 15 enrolled. Seven additional patients served as the comparison. Seventy-five percent of participants completed ≥3 weekly calls; average time on protocol was 257.7 days. Average intervention group MLVI was significantly lower (indicating improved blood level stability) at 180 days postenrollment (2.9 ± 1.29) compared with pre-enrollment (4.6 ± 2.10), p= .02. At 180 days, MLVI decreased by 1.6 points in the intervention group but increased by 0.6 in the comparison group (p= .054). Participants successfully engaged in a long-term remote intervention, and their medication blood levels stabilized. NCT02266888.

Remote interventions are increasingly used in transplant medicine but have rarely been rigorously evaluated. We investigated a remote intervention targeting immunosuppressant management in pediatric lung transplant recipients. Patients were recruited from a larger multisite trial if they had a Medication Level Variability Index (MLVI) ≥2.0, indicating worrisome tacrolimus level fluctuation. The manualized intervention included three weekly phone calls and regular follow‐up calls. A comparison group included patients who met enrollment criteria after the subprotocol ended. Outcomes were defined before the intent‐to‐treat analysis. Feasibility was defined as ≥50% of participants completing the weekly calls. MLVI was compared pre‐ and 180 days postenrollment and between intervention and comparison groups. Of 18 eligible patients, 15 enrolled. Seven additional patients served as the comparison. Seventy‐five percent of participants completed ≥3 weekly calls; average time on protocol was 257.7 days. Average intervention group MLVI was significantly lower (indicating improved blood level stability) at 180 days postenrollment (2.9 ± 1.29) compared with pre‐enrollment (4.6 ± 2.10), p = .02. At 180 days, MLVI decreased by 1.6 points in the intervention group but increased by 0.6 in the comparison group (p = .054). Participants successfully engaged in a long‐term remote intervention, and their medication blood levels stabilized. NCT02266888. This multisite trial evaluates a remote intervention targeting medication adherence in pediatric lung transplant recipients, finding that patients and their families can be successfully engaged over a long follow‐up period and that the intervention stabilizes medication blood levels.

Based on reports in adult lung transplant recipients, we hypothesized that community‐acquired respiratory viral infections (CARVs) would be a risk factor for poor outcome after pediatric lung transplant. We followed 61 pediatric lung transplant recipients for 2+ years or until they met a composite primary endpoint including bronchiolitis obliterans syndrome/obliterative bronchiolitis, retransplant, or death. Blood, bronchoalveolar lavage, and nasopharyngeal specimens were obtained with standard of care visits. Nasopharyngeal specimens were obtained from recipients with respiratory viral symptoms. Respiratory specimens were interrogated for respiratory viruses by using multiplex polymerase chain reaction. Donor‐specific HLAantibodies, self‐antigens, and ELISPOTreactivity were also evaluated. Survival was 84% (1 year) and 68% (3 years). Bronchiolitis obliterans syndrome incidence was 20% (1 year) and 38% (3 years). The primary endpoint was met in 46% of patients. CARVwas detected in 156 patient visits (74% enterovirus/rhinovirus). We did not find a relationship between CARVrecovery from respiratory specimens and the primary endpoint (hazard ratio 0.64 [95% confidence interval: 0.25‐1.59], P= .335) or between CARVand the development of alloimmune or autoimmune humoral or cellular responses. These findings raise the possibility that the immunologic impact of CARVfollowing pediatric lung transplant is different than that observed in adults. In contrast to studies in adults, a prospective study of pediatric lung transplant recipients finds no relationship between respiratory viral infections and outcome or the development of allo‐ or autoimmune humoral or cellular responses, raising the possibility that the immunologic impact of viral infections in pediatric lung transplant recipients differs from that in adults.

Based on reports in adult lung transplant recipients, we hypothesized that community-acquired respiratory viral infections (CARVs) would be a risk factor for poor outcome after pediatric lung transplant. We followed 61 pediatric lung transplant recipients for 2+ years or until they met a composite primary endpoint including bronchiolitis obliterans syndrome/obliterative bronchiolitis, retransplant, or death. Blood, bronchoalveolar lavage, and nasopharyngeal specimens were obtained with standard of care visits. Nasopharyngeal specimens were obtained from recipients with respiratory viral symptoms. Respiratory specimens were interrogated for respiratory viruses by using multiplex polymerase chain reaction. Donor-specific HLA antibodies, self-antigens, and ELISPOT reactivity were also evaluated. Survival was 84% (1 year) and 68% (3 years). Bronchiolitis obliterans syndrome incidence was 20% (1 year) and 38% (3 years). The primary endpoint was met in 46% of patients. CARV was detected in 156 patient visits (74% enterovirus/rhinovirus). We did not find a relationship between CARV recovery from respiratory specimens and the primary endpoint (hazard ratio 0.64 [95% confidence interval: 0.25-1.59], P= .335) or between CARV and the development of alloimmune or autoimmune humoral or cellular responses. These findings raise the possibility that the immunologic impact of CARV following pediatric lung transplant is different than that observed in adults.

Bronchiolitis obliterans syndrome (BOS) is a devastating complication of allogeneic bone marrow transplantation (BMT). Detecting early small airway disease to diagnose BOS when it may be reversible could improve long term outcomes. Spirometry can be technically difficult for young and/or ill children. Oscillometry is novel pulmonary function assessment technology which superimposes pressure waves on normal tidal breathing, and the alterations in flow and pressure caused by the external waves are measured. Importantly, oscillometry is not effort dependent.

Pulmonary complications after allogeneic bone marrow transplant (BMT) are significant sources of morbidity and mortality. Pre-BMT pulmonary status may be a predictor of patient outcome, and can be affected by underlying diagnosis, age and prior therapy received.

A retrospective review of pediatric lung transplant recipients at 14 centers in North America and Europe was conducted to characterize the epidemiology and the risk factors for cytomegalovirus (CMV) and to explore the impact of preventative antiviral therapy.

This article reviews current trends in pediatric lung posttransplant management, reveals pitfalls that exist, and introduces additional parameters that may have an impact on long-term survival.