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Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and non-malignant diseases. Despite increasing survival rates, long-term morbidity following HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction following HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction following HCT. In this review, we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and to help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Lastly, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae following HCT.

Introduction Pulmonary graft versus host disease is a pathological process arising in peripheral airways causing significant morbidity and mortality post-Bone Marrow Transplantation (BMT). Current screening and diagnosis focuses on spirometry change from baseline to identify Bronchiolitis Obliterans Syndrome (BOS), and an at-risk pre-BOS stage BOS0p (≥10% fall FEV1). Sensitive peripheral airway function tools exist but remain under-utilized and utility is unclear. Aim To investigate longitudinal peripheral airway function change, detected by Multiple Breath Washout (MBW) and Forced Oscillation Technique (FOT), in pediatric BMT subjects with/without BOS and BOS0p. Methods Children aged ≥3 years were recruited. Testing occurred at baseline, monthly during 1st year and 6-monthly to 3yrs: MBW (LCI, Scond and Sacin, ExhalyserD®, Ecomedics), FOT (Rrs and Xrs at 5Hz, AX, Fres, tremoFlo®, Thorasys) and, if feasible, spirometry, plethysmography and DLCO. Groups (BOS, BOS0p, unaffected) compared at baseline, 12, 24 and 36 months. Results Of 24 recruited subjects (mean±SD (range) age 10.2±4.2 (3.3-18.1) years at BMT, 54% AML/ALL diagnosis, 71% male), 1 withdrew and 6 died (5 within 12 months). BOS and BOS0p alone were detected in 3 (12.5%) and 8 (33.3%), respectively. BOS was associated with pattern of marked abnormality, significant increases from baseline were observed in LCI, Scond, Sacin, Xrs, AX and Fres. One subject developed BOS3 at 105 days (1st feasible post-BMT test). MBW/FOT abnormality was detected 26 and 207 days prior to BOS≥1 in other cases. LCI trajectory increased with increasing BOS severity. At 3 years, statistically significant differences between BOS0p vs unaffected were observed for LCI (p=0.009), Sacin(p=0.03), Xrs (p=0.004) and approached significance for AX (p=0.09) and Fres (p=0.09). Conclusion BOS and its earlier at-risk stage BOS0p were associated with significant peripheral airway abnormality detectable on MBW and FOT. MBW and FOT abnormality predated BOS≥1 in 2/3 BOS cases.

Introduction: Peripheral airway abnormalities are common in children post Bone Marrow Transplantation (BMT). Lung Clearance Index (LCI) was abnormal in 50% of a paediatric post BMT cohort at our institution.(1) Little is known about the progression of peripheral airway function in children post BMT. Adult data has reported increasing LCI values over time post BMT.(2) Aim: To evaluate the change in lung function (including peripheral airway function) over time in our paediatric post BMT cohort. Methods: Follow up assessment of the previously studied cohort, performed 12-24 months after initial testing. Protocol included Multiple Breath Washout (SF 6 based), conventional lung function and Liverpool respiratory questionnaire (LRQ). Lung function data presented as median (range) for z scores or raw values. SF6 LCI ULN – 7.38. Maximum score for LRQ 128. Statistical analysis: Wilcoxon signed rank test. Results: 17 tested to date: 76% males; age 15.3(5.6-20.0) years, 6.3 (1.6- 12.8) years post BMT and 1.2(0.9-1.8) years since last assessment. Proportion with abnormal LCI was similar at baseline and on follow up testing (47%vs 35%, p=0.3) as were FEV1 z-scores (18% vs 18%). No significant change in LCI over time: 0.18 (-3.93 to 2.05). No significant change in spirometry z-score change over time; FEV1 0.16 (-0.77 to 0.71); FVC -0.08 (-0.80 to 0.81); FEV1/FVC 0.20 (-0.45 to 0.43); FEF25-75; -0.03 (-0.69 to 0.53). No significant change in LRQ score over time; 0(-28 to 30). Conclusion: Across the overall cohort respiratory symptoms, peripheral airway function and spirometry did not worsen. However within individual subjects considerable variation was observed.