Background

Acute and chronic lung injury after hematopoietic stem cell transplantation (HSCT) is recognized as major clinical problems by the pediatric hematopoietic stem cell transplant community. However, the literature describing incidence, risk factors and optimal therapies is limited, consisting mostly of retrospective analyses and case series, despite recognition of the clinical importance of this problem. Atsuta et al. reported on late mortality and causes of death among long term survivors of allogeneic HSCT in adults and children and determined that standardized mortality ratios (SMR) for pulmonary complications were highly elevated (283-fold) in children ages 0-15 years, much higher than in patients older than 15. Similarly, Bhatia et al. reported a 5.6-fold increased risk of late death due to pulmonary dysfunction in HSCT recipients. In addition, Inaba et al. found that 40% of children had at least one abnormal parameter in pulmonary function tests performed prior to HSCT, rising to 64% of children after HSCT. Common causes of early and late lung injury include infections, immunological injury such as bronchiolitis obliterans (BO), interstitial pneumonia syndrome (IPS), diffuse alveolar hemorrhage (DAH) and acute toxicities related to drugs and radiation used in HSCT. Retrospective and registry series have limited granularity, accuracy and completeness of data collection to describe incidence and risk factors for lung injury, and lack of associated biological samples further limits research on mechanisms of cell injury. A prospective cohort with collection of biological samples is a pressing need to prevent and treat lung injury after HSCT in children. HSCT is increasingly being used as a curative treatment for non-malignant disorders such as sickle cell anemia, immune deficiencies and metabolic disorders, diseases with potential for specific pre- transplant pulmonary morbidities such as pulmonary hypertension, pre-existing infections, or deposition of abnormal substrates such as glycosaminoglycan, making the need for prospective studies even more compelling.

Many complications of HSCT lack rigorous clinical definitions, and are often subject to individual clinical judgement, perhaps explaining differing frequencies reported in different case series. Prospective detailed clinical characterization of complications is crucial for development of evidence-based definitions of specific disease entities such as IPS, DAH and BO, and for subsequent mechanistic studies and development of evidence-based treatment guidelines.

Early and accurate diagnosis of lung injury is key to improving survival. A major challenge in monitoring lung function in children is the inability of younger children to reliably perform spirometry. Some children as young as 6 years old can perform reproducible spirometry, but even teenagers, particularly when feeling unwell, can fail to perform adequately for evaluation. Reliable measurement of lung function in children younger than 6 years is particularly challenging, and conventional imaging has low specificity and sensitivity and requires anesthesia. The lack of availability of spirometry in a significant proportion of pediatric patients has been identified as a major obstacle to diagnosis and management of bronchiolitis obliterans in children. Identification of novel strategies for assessment of lung function in young children is an urgent need. Potential modalities that could be tested include oscillometry, multiple breath washout testing and imaging using hyperpolarized xenon and magnetic resonance imaging.