TABLE 2.
Summary of findings in 13 individual studies reporting on multiple breath washout (MBW) after haematopoietic stem cell transplant (HSCT)
| Cohort | Summary of findings | |
| Spirometry, other conventional PFTs | MBW | |
| Paediatric subjects | ||
| Uhlving et al. [42, 72] | Pulmonary function after HSCT (mean (sd; % abnormal)) was significantly different from healthy controls: FEV1 −0.56 z-score (1.40; 9%), FEV1/FVC 0.33 z-score (0.93; 0%) | Pulmonary function after HSCT (mean (sd; % abnormal)) was significantly different from healthy controls: LCI 7.23 (0.85; 34%), Sacin 0.080 (0.041; 25%) and Scond 0.029 (0.012; 52%) Scond was, after adjustment, correlated with cGVHD |
| Rayment et al. [46, 73] | Overall: median FEV1 was 80.7% pred (IQR: 72.2–92.8%) and median FEV1/FVC was 85% (IQR: 82–90%) No cGVHD: median FEV1/FVC 0.88 (IQR: 0.82–0.90) Extrapulmonary cGVHD: median FEV1/FVC 0.86 (IQR: 0.85–0.90) Pulmonary cGVHD: median FEV1/FVC 0.71 (IQR: 0.46–0.80) |
Overall: median LCI was 7.8 (IQR: 7.1–9.6) with 31% being over 9.0 No cGVHD: median LCI 7.7 (IQR: 7.1–8.0) Extrapulmonary cGVHD: median LCI 7.5 (IQR: 6.9–7.6) Pulmonary cGVHD: median LCI 11.8 (IQR: 9.6–18.7) Area under ROC curve for LCI to identify pulmonary cGVHD was 0.97 (95% CI 0.80–0.99) with a threshold of 9.0 giving a sensitivity of 100%, specificity of 90% and PPV of 75% |
| Schindera et al. [43] and Usemann et al. [74–76] | Spirometry was available for 4/5 subjects: FEV1 and FVC were abnormal in one subject | MBW was available for 4/5 subjects: Sacin was abnormal in all subjects and LCI was abnormal in two |
| Jayasuriya et al. [47, 60, 71, 77, 78] | Cross-sectional: FEV1 was abnormal in 21%, FEF25–75 in 17% Follow-up: no significant change in spirometry z-score (FEV1 median change 0.16 (range: −0.77–0.71)) |
Cross-sectional: MBW abnormal in 18 subjects. Median (range; % abnormal) Scond 0.034 (0.004–0.089; 75%), LCI 7.52 (5.03–23.59; 58%) and Sacin 0.105 (0.056–0.463; 33%) Follow-up: no significant change in LCI z-score (median 0.18 (range: −3.93–2.05)) |
| Kavouridou et al. [56] | NA | Mean±sd LCI pre-HSCT: 7.09±0.8; mean±sd LCI post-HSCT: 7.47±1.41 Mean±sd LCI pre-HSCT in BOS subjects: 6.60±0.16; mean±sd LCI post-HSCT in BOS subjects: 9.93±2.79 All four BOS subjects had ≥1 unit LCI increase at 1 year post-HSCT, no subjects with <1 unit increase developed BOS |
| Uhlving et al. [57] and Jensen et al. [79] | Baseline: FEV1 abnormal in 13% and DLCO in 70% 1-year follow-up: FEV1 and FVC at baseline were associated with FEV1 and FVC at 12 months FEV1 at 3 months and FVC at all time points were lower than at baseline GVHD: FEV1 significantly lower in GVHD than non-GVHD subjects BOS/BO: all patients with abnormal FEV1 at 3 months developed BOS |
Baseline: LCI abnormal in 48% 1-year follow-up: LCI at baseline and 3 months was not associated with LCI at 12 months; LCI did not change over time GVHD: LCI was significantly higher in GVHD than non-GVHD subjects BOS/BO: abnormal LCI at baseline and 3 months was not associated with development of BOS; absolute median (range) LCI in BOS: 7.9 (6.4–11.8) at baseline, 7.9 (7.4–14.0) at 3 months, 8.4 (6.3–13.0) at 6 months, 8.4 (6.8–13.0) at 9 months and 8.8 (7.7–14.7) at 12 months |
| Wong et al. [54], Hardaker et al. [80–82] and Robinson et al. [83] | cGHVD was associated with significant deterioration in FEV1 and FEF25–75 compared to those without cGVHD At 3 years post-HSCT, BOS 0p subjects (n=8) had FEV1 worse than subjects unaffected by BOS 0p/BOS that approached significance |
cGVHD was associated with significant deterioration in LCI and Sacin compared to those without cGVHD BOS was associated with significant abnormality in LCI, Scond and Sacin; MBW abnormality was detected at first available test in one BOS subject and 26 and 207 days prior to BOS diagnosis in the remaining two At 3 years post-HSCT, BOS 0p subjects (n=8) had significantly worsened LCI and Sacin, as compared to subjects unaffected by BOS 0p/BOS |
| Walther et al. [55] | Baseline: pulmonary function was normal in all 14 subjects Respiratory failure (n=3): FEV1 53.4, 36.5 and 23.9% pred |
Respiratory failure (n=3): LCI not available Persistent BOS (n=5): LCI 12.59, 14.69, 14.90, 19.30 and 20.90 Recovered BOS (n=6): LCI 6.51, 7.79 and 8.02 |
| Khalid et al. [58] | Case 1: baseline unavailable, reduced airflow at time of BOS diagnosis (7 months after HSCT), obstructive pattern on spirometry and hyperinflation on body plethysmography 2 years after repeat HSCT Case 2: spirometry normal at baseline, obstructive pattern 7 months post-HSCT at time of BO diagnosis, which remained stable for the following 2 years Case 3: unavailable |
Case 1: at 2 years post-HSCT, LCI was greatly increased (at approximately 18) and phase III-slope abnormality was present MBW abnormality worsened after another approximately 4 months; LCI and phase-III slope indices normalised after bilateral lung transplantation Case 2: MBW at 3.5 years post-HSCT was abnormal with LCI approximately 13, which subsequently deteriorated to 22.0 2 years later (at which point spirometry was relatively stable) Case 3: LCI at 1 month post-HSCT was 11.4, increasing to a maximum of approximately 12.5, then decreasing to approximately 9 with treatment |
| Adult subjects | ||
| Nyilas et al. [44] and Baumeler et al. [84, 85] | Overall mean pulmonary function (sd, % abnormal): FEV1 91% pred (20.6; 36%), FEV1/FVC 72% pred (10.5; 36%) cGVHD: FEV1 94.4% pred (18.3; 21%), FEV1/FVC 78.4 (5.3; 0%) BOS: FEV1 89% pred (18; 28%), FEV1/FVC 63% pred (7; 100%) BO: FEV1 71% pred (18; 74%), FEV1/FVC 65% pred (13; 57%) |
Overall mean pulmonary function (sd, % abnormal): LCI 9.6 (2.8; 74%), Sacin 0.17 (0.14; 59%) and Scond 0.029 (0.02; 4%) cGVHD: LCI 9.1 (2.2; 76%), Sacin 0.14 (0.1; 57%) and Scond 0.02 (0.02; 0%) BOS: LCI 9.7 (2.2; 85%), Sacin 0.17 (0.1; 68%) and Scond 0.03 (0.02; 6%) BO: LCI and Sacin were significantly more abnormal in this group than among subjects in the other groups; LCI 11.4 (3.3; 96%), Sacin 0.3 (0.2; 82%) and Scond 0.04 (0.03; 14%) |
| De Giacomi et al. [45, 86, 87] | NA | There was evidence of worsened Sacin and Scond as compared to healthy controls regardless of the presence of chronic GVHD in other organ systems in subjects without BO In subjects with BO Sacin was 551% (sd 360) and worse than in controls (p<0.001); Sacin with a 321% cut-off had an 89% sensitivity and 93% specificity in identifying patients with BO |
| Lahzami et al. [48, 88] and Pechey et al. [89] | Initial testing (mean±sd or median (range)): FEV1 was 87±20% pred, FEV1/FVC 80 (45–89) FEV1 was independently associated with time post-HSCT Follow-up: no significant change in spirometry outcomes |
Initial testing (mean±sd or median (range)): LCI 12.1 (8.0–22.2), Sacin 0.24 (0.08–1.72) and Scond 0.07±0.03; Sacin was independently associated with time post-HSCT; Sacin was correlated with chronic GVHD grade Follow-up: LCI significantly increased from mean±sd 11.6±2.5 to 13.5±3.5 and Sacin increased from median 0.28 (range: 0.06–0.69) to 0.41 (0.08–1.07); only change in Sacin correlated with change in GVHD grade |
| Htun et al. [50, 90] | Baseline: mean±sd FEV1 101±15% pred, FEV1/FVC 79±6.6 Follow-up: FEV1 did not change |
Baseline: mean±sd LCI 8.6±1.1, Sacin 0.10±0.05 and Scond 0.03±0.02 Follow-up: Sacin significantly increased by 42% and was associated with age and time since HSCT; LCI and Scond did not change |
| Schoeffel et al. [49, 59] | Baseline: mean±sd FEV1 was 105±13% pred, FEV1/FVC was normal Follow-up: FVC declined |
Baseline: Sacin and Scond were abnormal in 43% Follow-up: there were no changes in LCI, Sacin or Scond BOS subjects: Sacin and Scond were abnormal at time of BOS diagnosis; respiratory function at the visit prior to diagnosis was not different from baseline |
BO: bronchiolitis obliterans; BOS: bronchiolitis obliterans syndrome; BOS 0p: BOS stage 0p; cGVHD: chronic graft-versus-host disease; DLCO: diffusing capacity of the lung for carbon monoxide; FEF25–75: forced expiratory flow between 25% and 75% of vital capacity; FEV1: forced expiratory volume in the 1 s; FVC: forced vital capacity; GVHD: graft-versus-host disease; IQR: interquartile range; LCI: lung clearance index; NA: not available; PFT: pulmonary function test; PPV: positive predictive value; ROC: receiver operating characteristic; Sacin: index of acinar ventilation heterogeneity; Scond: index of ventilatory inhomogeneity in the conducting airways.