TABLE 4.
Take-home messages and questions for future research regarding peripheral pulmonary function tests after haematopoietic stem cell transplantation (HSCT)
| Take-home messages | Questions for future work |
| MBW | |
| 1) MBW at baseline | |
| Baseline MBW abnormality may be encountered in a substantial proportion of both children and adults, reinforcing the importance of its measurement at that time point. Future work should target better understanding of the contributing factors for this, including, but not limited to, the underlying disease process, prior treatment (e.g. chemotherapy), infection and smoking/vaping status. | • What proportion of paediatric and adult subjects have abnormality at baseline in MBW, in comparison to spirometry? • What are the risk factors for baseline abnormality in MBW and how do they compare to those for spirometry? Could they be related to oncological treatment, conditioning regimen (although all MBW most likely performed prior to conditioning) or nontreatment related insults that occurred prior to transplantation? • Are any of these risk factors modifiable? • Does the presence of peripheral airway abnormality at baseline put patients at risk of developing pulmonary cGVHD (or is the development of pulmonary cGVHD independent of prior pulmonary status)? • Does the presence of baseline peripheral airway abnormality put patients who develop pulmonary cGVHD at higher risk of adverse outcomes? |
| 2) Rate of MBW abnormality after HSCT | |
| There is a consistent suggestion within the studies to date in both paediatric and adult cohorts, that cross-sectional MBW values are more frequently abnormal than spirometry post-HSCT, occurring in all nine studies that evaluated this. Rates of abnormality were relatively variable between studies. | • How does selection bias affect the rates of abnormality reported? • Is abnormality in MBW indices associated with increased risk of current/subsequent pulmonary cGVHD? • What is the clinical relevance of a single abnormal value in an MBW index post-HSCT and is this affected by the magnitude of abnormality? Investigation of what drives the abnormality and how specific it is for pulmonary cGVHD is important in future work. |
| 3) Rate of MBW abnormality after HSCT in BOS subjects | |
| Across all studies, MBW indices were abnormal in cohorts of subjects with pulmonary cGVHD, including in those where testing was performed at the time of diagnosis. The strong sensitivity and specificity reported in two studies was encouraging, noting that specificity reduced at lower LCI thresholds in one study, implying that milder abnormality in LCI may either represent other pathological processes or earlier pulmonary cGVHD that does not fulfil conventional diagnostic criteria. Interestingly, MBW indices were more abnormal in histologically proved BO versus BOS. | • Does incorporating MBW into standardised criteria improve our ability to diagnose BO/BOS? • What is the optimal threshold for pulmonary cGVHD diagnosis? • What is the effect of treatment for pulmonary cGVHD on MBW indices? • What is/are the underlying disease process(es) leading to peripheral pulmonary function abnormality? |
| 4) Rate of MBW abnormality after HSCT in cGVHD subjects | |
| Although those with and without pulmonary cGVHD are often grouped together, MBW indices appear to be abnormal in a significant proportion of subjects with cGVHD. Additionally, the results of the one study specifically investigating whether those without apparent extrapulmonary cGVHD had a detectable level of pulmonary function impairment suggests this is the case. | • What proportion of subjects with cGVHD have evidence of pulmonary involvement based on MBW that does not fulfil current NIH criteria? • How specific is MBW in that setting and to what degree do non-cGVHD pulmonary complications also elevate MBW? |
| 5) Changes in MBW indices over time in post-HSCT population | |
| The change in MBW indices over time in the overall post-HSCT population has been studied in small cohorts only. These data suggest that deterioration may occur and be detectable with the right index as early as the first year. Sacin may be the most sensitive index to detect this. It is currently unclear to which extent the peripheral lung function deteriorates over the first 5 years following HSCT, the time during which subjects are at greatest risk of developing pulmonary cGVHD. | • What is the natural trajectory of MBW indices among the overall post-HSCT population over the first 5 years following HSCT (the time during which subjects are at greatest risk of developing pulmonary cGVHD)? • Is Sacin the most sensitive index to detect pulmonary cGVHD? • What is the prognostic value of a change in MBW indices? |
| 6) Changes in MBW indices over time in BOS and cGVHD subjects | |
| While it appears that baseline MBW may not be predictive of BOS development, earlier deterioration in MBW indices may occur and in fact be predictive of subsequent BOS development. Rate of decline in those with cGVHD appears greater than in subjects without cGVHD. | • What is a clinically important change (or MCID) in MBW indices in this population? • Does a clinically important change in MBW indices occur prior to a change in spirometry or the fulfilment of NIH BOS diagnostic criteria? • How frequently should MBW monitoring occur post-HSCT? • Among patients with extrapulmonary cGVHD, is a deterioration of MBW indices associated with subsequent NIH BOS diagnosis? |
| Oscillometry | |
| 1) Cross-sectional measurements of oscillometry prior to and following HSCT | |
| Oscillometry appears to be within normal range in the majority at baseline and, while limited information is available, appears generally to remain normal following HSCT. However, among those who develop BOS, oscillometry indices are frequently abnormal and abnormality may be detectable in BOS 0p. | • What proportion of paediatric and adult subjects have abnormality at baseline in oscillometry, in comparison to spirometry and MBW? What are risk factors for baseline oscillometric abnormality? • Is abnormality in oscillometric indices associated with increased risk of current/subsequent pulmonary cGVHD? |
| 2) Change in oscillometry indices over time | |
| Limited data is available regarding change in oscillometric indices over time. Indices may not deteriorate in the overall post-HSCT population, but likely do among subjects developing pulmonary cGVHD and potentially those with extrapulmonary cGVHD. The timing of this deterioration is presently unclear but may be prior to NIH diagnosis. | • What is the trajectory of oscillometry after HSCT in the overall population? • What is a clinically important change (or MCID) in oscillometric indices after HSCT? • Do oscillometric indices change prior to spirometric and/or MBW indices among subjects who subsequently develop BOS according to NIH criteria? |
BO: bronchiolitis obliterans; BOS: bronchiolitis obliterans syndrome; BOS 0p: BOS stage 0p; cGVHD: chronic graft-versus-host disease; LCI: lung clearance index; MBW: multiple breath washout; MCID: minimal clinically important difference; NIH: National Institutes of Health; Sacin: index of acinar ventilation heterogeneity.