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Post-Transplant Complications

Pulmonary function after autologous bone marrow transplantation in children: a long-term prospective study

Summary:

We performed serial pulmonary function tests (PFTs) consisting of spirometry and diffusing capacity in 26 children after BMT. The median follow-up was 10 years. The influence of total body irradiation (TBI) on long-term pulmonary function was of particular interest. In the 20 children who had received TBI, after an initial decrease the PFTs showed recovery, but the mean lung volumes were still significantly decreased 5 years after BMT at 10% below baseline. The proportions of children with restrictive impairment 5 and 10 years after BMT were 20 and 21%, respectively. Only one child was diagnosed with obstructive impairment. The proportions of children with isolated diffusing impairment at 5 and 10 years were 7/20 (35%) and 7/13 (54%), respectively. Six children had received chemotherapy only and showed isolated diffusing impairment as the only long-term sequela in 4/5 and 1/3 at 5 and 10 years. Our main finding was that there was little change in PFTs 1–10 years after BMT. TBI was associated with persistently decreased lung volumes in a proportion of patients, whereas chemotherapy also might have been of importance for the development of impaired gas exchange.

Main

Pulmonary complications are a major cause of morbidity and mortality in the early period after BMT, both in children and adults. Long-term pulmonary sequelae of BMT are well-recognized in adults, but less is known about the long-term effects of this procedure on lung function in children.1,2 Since pediatric lung function has to be assessed in the context of continuous growth, children and adults should be studied separately. BMT may impair lung growth by affecting both thoracic and parenchymal growth. Also, impairment of skeletal growth may result in changing body proportions after BMT and erroneous predictions when using references from normal children. Finally, the change from pediatric to adult reference standards at the transition from late adolescence to early adulthood has to be considered. Most previous pediatric studies on the long-term pulmonary effects of BMT have had a retrospective, cross-sectional design, and the few longitudinal studies that have been performed have mostly been of short duration.3,4,5,6,7 Little is therefore known about whether the pulmonary impairment that is evident in most studies within the first few years after BMT leads to progressive loss of pulmonary function, to ultimate stabilization, or to improvement in the long term. Due to the absence of chronic GVHD after autologous BMT, the spectrum of late complications may differ from that seen after allogeneic BMT.8 We present a longitudinal study of pulmonary function after autologous BMT in a group of children which, being an extension of a previous study at our center, constitutes the longest follow-up published to date.9 The influence of TBI on long-term pulmonary function was of particular interest.

Patients and methods

Patients

Between October 1985 and August 1997, 50 children below the age of 18 years with acute leukemia or lymphoma were treated with autologous (n=49) or syngeneic BMT (n=1) at the University Hospital of Uppsala. The present study comprised the 26 children who were followed up for at least 60 months after BMT with repeated pulmonary function tests, and who had received no radiation to the thorax other than TBI (except for one girl with a CNS relapse, who had received craniospinal irradiation with a risk of scatter to the lungs). Some clinical characteristics are summarized in Table 1. The reasons for exclusion were: 19 children relapsed within 60 months after BMT, with a median time to relapse of 6 months (range 2–48 months); one boy declined to attend the routine check-ups; one boy refused to perform the scheduled pulmonary function tests; in one girl a second malignancy (Ewing sarcoma) had developed 60 months after BMT; two children with Hodgkin's disease had received radiation to the thorax during their primary therapy.

Table 1 Clinical characteristics of 26 children undergoing autologous BMT

The children with ALL had received treatment according to the Swedish Child Leukemia Group protocol that applied at the time of diagnosis, and the children with AML had received treatment according to the current AML protocol of the Nordic Society for Pediatric Hematology and Oncology (NOPHO).10,11 Details of the conditioning regimens have been thoroughly recorded elsewhere.12 In short, children with ALL and lymphoblastic lymphoma (LBL) were conditioned with prednisolone, teniposide, daunorubicin, vincristine, cyclophosphamide, and cytarabine, plus TBI. In most children (n=16), TBI was given in a single fraction as two opposed 5 MV X-ray anterior–posterior fields with lung shielding. The total absorbed dose in the center of the patient was 7.5 Gy (dose rate 15 cGy/min). The four children most recently undergoing transplantation were treated with fractionated TBI, consisting of 12 Gy in six fractions over 3 days (dose rate 15 cGy/min). The maximum dose to the lungs in the children who received single-fraction TBI was 7.5 Gy±5%, and that in the children who received fractionated TBI was 12 Gy±5%. These 20 children are referred to as the +TBI group. Children with AML (n=5) were given busulfan and cyclophosphamide (BUCY regimen), whereas the child with large cell anaplastic lymphoma received BCNU, etoposide, cytarabine, and cyclophosphamide. These six children are referred to as the −TBI group. All children received oral acyclovir and cotrimoxazole for 3 months after BMT prophylactically. Except for the girl with a CNS relapse, who received cytarabine intrathecally every sixth week for 2 years after BMT, no further chemotherapy was given after BMT. A clinical examination and chest radiography were performed before BMT and 3, 6, 9, and 12 months after BMT, and then annually. During follow-up, any symptoms (including respiratory symptoms) reported by the children or their families were recorded, but were not actively asked for. Pulmonary function tests were performed before BMT and 6, 12, 24, 36, 60, and 120 months after BMT. In addition, a few patients were tested 3 months after BMT. Figures 1, 2 and 3 show the exact number of children tested at each point in time in the +TBI group. The number of patients in the –TBI group who performed spirometry and DLCO at each point in time were 4, 4, 5, 5, 4, 6, 3 and 2, 3, 5, 5, 4, 5, 3, respectively. The median duration of follow-up was 120 months (range 60–120 months). Seven children were too young to undergo pulmonary function tests before BMT and for a varying period of time after BMT (younger than 6 years). In the other patients, these tests were not carried out at every follow-up, but the number of dropouts was small (e.g. 93% of scheduled measurements of TLC were performed). To illustrate any potential bias caused by the fact that the children who lacked a pretransplant value were those who were the youngest at BMT, these children are presented individually in the figures.

Figure 1
figure1

Total lung capacity values in children who received TBI in their conditioning regimen before autologous BMT. Values are given as the percentage of that predicted. (—) Connects mean values for patients tested both before and after BMT. () Patients lacking pretransplant measurements. (- - -) Shows the pretransplant value.

Figure 2
figure2

FEV1/VC in children who received TBI in their conditioning regimen before autologous BMT. See also the legend to Figure 1.

Figure 3
figure3

DLCO values in children who received TBI in their conditioning regimen before autologous BMT. See also the legend to Figure 1.

Methods

Lung volumes

Lung volumes were measured with a Jaeger constant volume body plethysmograph with a pneumotachograph connected to an Epson PC-AT. The subjects were asked to breathe at a rate of 25 breaths/min during the measurements of the thoracic gas volume. The functional residual capacity (FRC) was defined as the mean end-expiratory thoracic gas volume of at least three measurements. The vital capacity (VC) obtained immediately after the FRC measurements was used for calculating the total lung capacity (TLC) and residual volume (RV).

Spirometry

Spirometry, including the recording of flow–volume curves, was carried out with a Jaeger Master lab pneumo with a pneumotachograph connected to an Epson PC-AT. At least two measurements of VC with slow expiratory and at least three forced vital capacity (FVC) maneuvers were performed. The following variables were calculated: VC, FVC, forced expiratory volume in one second (FEV1), FEV1 in percent of VC (FEV1/VC), maximum expiratory flow (MEF), and forced expiratory flows at 75, 50, and 25% of FVC (FEF75, FEF50, and FEF25). Here, only FEF25 is presented as a measure of peripheral obstruction.

Diffusing capacity

The diffusing capacity of the lung for carbon monoxide (DLCO) was measured as a single breath test with a Jaeger Master lab Transfer and a pneumotachograph. CO was detected by an infrared cell and helium was measured by a katharometer. After expiration to RV, a gas mixture of helium (10%), oxygen (21%), and carbon monoxide (0.30%) in nitrogen was rapidly inhaled to TLC. After holding their breath for 9 s, the subjects were asked to exhale rapidly and a sample of 0.8 l exhaled gas was taken (0.5 l in small children) after the start of expiration, and analyzed for helium and carbon monoxide. Only measurements with an inspired volume of at least 90% of earlier volumes for VC were accepted. DLCO was calculated with allowance for hemoglobin concentrations outside the normal range for age and sex. Since the DLCO test was introduced later than the other PFTs, most children had only been tested after BMT.

The change from pediatric to adult reference standards at the transition from late adolescence to adulthood often results in abrupt changes in predicted normal values. The model of Solymar et al13 used for lung volumes and spirometry is based on pulmonary function tests in boys and girls aged 7–18 years. The present study included children who were above 18 years of age after BMT, however. Since the data in adults, collected and analyzed by one of the authors (HH), showed that age had little influence on lung volumes and spirometry below the age of 30 years, we decided to use only the reference of Solymar et al.14,15 The reference values of Nysom et al16 used for DLCO constitutes an attempt to bridge one pediatric and one adult reference standard.

Definitions of pulmonary impairment and disease

To make lung function variables comparable, they were expressed as a percentage of predicted values in each subject. Restrictive lung disease was defined as TLC <80% of that predicted. Obstructive lung disease was defined as FEV1/VC <70. Diffusing impairment was defined as DLCO <80% of that predicted. Isolated diffusing impairment was defined as DLCO <80% of that predicted with TLC in the normal range. The diagnosis of idiopathic pneumonia syndrome (IPS) was made in patients who developed pulmonary symptoms and findings indicative of IPS on radiographs, but in whom no etiological infectious organism could be verified, despite extensive examinations including bronchioalveolar lavage.17 Tobacco smoking was not recorded systematically.

Height

Height was measured with a Harpenden stadiometer. Standard deviation scores (SDS) for height were calculated, using a Swedish reference according to the formula (actual height−mean height for age and sex)/standard deviation of height for age and sex.18 The sitting height to standing height ratio SDS was calculated using the reference of Gerver et al.19

Statistics

In agreement with previous publications, PFTs are reported as mean values. Confidence intervals (95%) were calculated for all points in time. All other data are reported as the median values (range). Since long-term changes were of particular interest and in order to avoid the problems inherent in multiple significance testing, statistical analyses were restricted to a comparison of pretransplant values with those obtained 60 months after BMT, using the paired t-test. Student's t-test was used to compare the changes in PFTs between groups. Pearson's product moment correlations and Spearman's rank correlations were calculated in analyses of relationships between normally and not normally distributed variables, respectively. Multiple regression analysis was performed to examine the independent contributions of the variables TBI, pretransplant TLC, and age at BMT to the change in TLC. The significance level was set at 5%. All calculations were made with SPSS 11.0.

Ethics

This study was approved by the Ethics Committee of the Medical Faculty, Uppsala University.

Results

Clinical observations

No child had symptoms of lung disease before BMT. No procedure-related deaths occurred during the early post transplant period and major clinical complications were few. Almost all patients had episodes of fever during neutropenia, necessitating antibiotic treatment. Severe infections were sparse, however. Acute pulmonary complications of clinical significance were noted in three patients. One boy with ALL developed pulmonary edema syndrome 10 days after BMT and one boy with LBL developed pneumonia, probably caused by Candida albicans, 14 days after BMT. Both rapidly improved after institution of therapy. One girl developed idiopathic pneumonia syndrome 6 weeks after BMT with marked dyspnea, cough, and fever. Corticosteroid therapy had a prompt effect on the symptoms. She was subsequently diagnosed as having a restrictive lung disease, but the development of her lung function did not differ from that of the other patients. At the latest follow-up, there were no reports of respiratory symptoms and no radiographic signs of pulmonary abnormality were seen.

Lung volumes

Before BMT, one of 15 patients (7%) was diagnosed with restrictive lung disease (TLC <80% of the predicted) in the +TBI group and none (out of 4 tested) in the −TBI group. The proportions of patients diagnosed with restrictive lung disease in the +TBI group 6, 60, and 120 months after BMT were 8/14 (57%), 4/20 (20%), and 3/14 (21%), respectively. The corresponding numbers in the –TBI group were 2/4, 0/6, and 0/3.

The mean and 95% confidence interval before BMT for TLC and VC in the +TBI group were 96.1% (89.6–102.5) and 89.0% of that predicted (82.7–95.3). After a nadir (3–) 6 months after BMT, the mean TLC (Figure 1) and mean VC recovered, and stabilized at a level about 10% below baseline. The mean TLC of 85.6% (80.4–90.8) and the mean VC of 80.5% of that predicted (73.3–87.7), obtained 60 months after BMT, were both significantly lower than the pretransplant values (P<0.01). The change in TLC from BMT to 60 months after BMT (ΔTLC) was –10.5% of that predicted in the +TBI group and 18.8% of that predicted in the –TBI group (P<0.001). Pretransplant TLC (r=−0.52, P=0.022), but not age at BMT (rs=0.38, P=0.11), was significantly correlated with ΔTLC. In the multivariate analysis, only TBI had a significant impact on ΔTLC (R2=0.75; B=25.1, P<0.001, 95% confidence interval −35.9 to −14.2).

Spirometry

The mean and 95% confidence interval for FEV1 in the +TBI group were 88.6% of that predicted before BMT (82.7–94.5). After a nadir (3–) 6 months after BMT, the mean FEV1 improved gradually and stabilized at a level about 5% below baseline. The value of 83.2% of that predicted (74.7–91.7), obtained 60 months after BMT, was not significantly lower than the pretransplant value. During follow-up, only one patient in the +TBI group was diagnosed with obstructive lung disease (FEV1/VC <70) 60 months after BMT. The mean pretransplant FEV1/VC in the +TBI group was 89.0% (85.2–92.8) and did not change during follow-up (Figure 2). The mean pretransplant FEF25 in the +TBI group was 93.6% of that predicted (74.9–112.2). After the first year post BMT, FEF25 stabilized at a level about 20% below baseline. The value of 74.9% of predicted (53.1–96.7) obtained 60 months after BMT was not significantly lower than the pretransplant value.

DLCO

Four out of seven patients tested in the +TBI group had isolated diffusing impairment before BMT, but neither of the two tested children in the −TBI group. At 6 months after BMT, all the seven patients tested in the +TBI group and two of three patients in the –TBI group had DLCO <80% of predicted. The proportions of patients with isolated diffusing impairment 60 and 120 months after BMT in the +TBI group were 7/20 (35%) and 7/13 (54%), respectively. The corresponding proportions in the –TBI group were 4/5 and 1/3, respectively. The mean pretransplant DLCO in the +TBI group was 75.1% of that predicted (56.0–94.2). After a nadir (3–) 6 months after BMT, the mean DLCO increased and stabilized at the baseline value until 60 months after BMT; thereafter it tended to decrease somewhat (Figure 3). The value of 80.6% of that predicted (62.4–98.7), obtained 60 months after BMT, was not significantly different from the pretransplant value.

Effect of fractionation

The change in TLC from BMT to 60 months after BMT (ΔTLC) was –7% of that predicted in those who had received fractionated TBI, and −23% of that predicted in those who had received unfractionated TBI (P=0.017). There was no significant difference in ΔVC (−7% vs −13%) and ΔFEV1 (−5% vs −7%) between different TBI regimens. DLCO was not tested due to the small number of patients.

Standing height and sitting height to standing height ratio in the +TBI group

At 60 and 120 months after BMT, the median height-SDS value was −0.51 s.d. (range −1.8 to 0.97) and –0.98 s.d. (range −2.58 to 1.13), respectively. There was a significant correlation between height SDS and TLC in the +TBI group 120 months (but not 60 months) after BMT (rs =−0.71, P=0.004). Sitting height was measured in 10 patients 120 months after BMT. In these patients, the sitting height to standing height ratio was 0.0 s.d. (range −1.74 to 2.97).

Discussion

In the +TBI group, only one patient was diagnosed with restrictive lung disease before BMT, whereas more than half of the patients were diagnosed with restrictive lung disease 6 months after BMT. Lung function then improved and restrictive lung disease persisted in one-fifth of the patients. A similar pattern was discernable in the –TBI group, although none had persistent restrictive lung disease in this group. On the group level, there was a rapid decline in lung volumes shortly after BMT in the +TBI group, followed by a recovery and stabilization, but not with complete return to the baseline value. In the multivariate analysis, TBI, but not age at BMT or pretransplant TLC, was shown to have a significant impact on the change in TLC. Although our results suggest that TBI decreases TLC, due to the small sample size (especially the –TBI group) and incomplete data, the conclusion that TBI causes restrictive lung disease may not be supported. TBI has previously been associated with decreased lung volumes in adults, but data for children are conflicting.6,7,20,21,22 One reason for this may be the small sample sizes in pediatric studies and the heterogeneity with respect to TBI regimen. Single-fraction TBI has been associated with more marked decrease in lung volumes and less recovery in comparison with fractionated TBI.21 We found no benefit of fractionation in our small sample, however. A possible sparing effect of fractionation may have been counteracted by the 60% higher total dose in those who received fractionated TBI, but our limited data should be interpreted with caution.

FEV1 followed a biphasic pattern roughly similar to that of the lung volumes. Since FEV1 changed in parallel with the lung volumes, the mean FEV1/VC remained unchanged through the follow-up period. Only one patient in the +TBI group had a low FEV1/VC according to definition, suggesting a lack of obstructive disease of the large airways. Investigators generally report a proportionately lower incidence of obstructive compared with restrictive changes in children after BMT.3,6,7 The low incidence in our group of patients may in part be due to the absence of chronic GVHD in our group of autografted children.23 On the other hand, processes in the lung parenchyma that lead to restrictive lung disease may also produce a higher resilience, resulting in a higher FEV1/VC. The trend to persistent decrease in FEF25 (which is not affected to the same degree by a potentially higher resilience), albeit not statistically significant, may suggest obstructive disease of the smaller airways.

DLCO showed a transient decline shortly after BMT in the +TBI group, followed by a return to the (decreased) baseline value. The proportion of patients in the +TBI group with isolated diffusing impairment tended to increase slightly from 5 to 10 years after BMT, but this trend was not analyzed statistically and its importance for the future is unclear at present. A large proportion (of the few patients tested) had isolated diffusing impairment before BMT, and after BMT the proportion of patients with isolated diffusing impairment was persistently high, both in those who had received TBI and in those who had been conditioned with chemotherapy alone. Impaired gas exchange after BMT has been associated with TBI in previous studies.20,21 Investigators have also described diffusing impairment both before BMT and after BMT not including TBI.6,7,24 These and our data suggest that chemotherapy may have a pathogenetic role in the induction of impaired gas exchange. Of the chemotherapeutic agents used in our patients both before and in conjunction with BMT, methotrexate, cyclophosphamide, busulfan, and BCNU have been linked with the development of pulmonary fibrosis, which might lead to thickening of the pulmonary diffusion membrane.25 Another cause of impaired gas exchange is cardiac dysfunction but, as previously reported in this group of patients, cardiac function was well preserved both before and after BMT.26 Tobacco smoking, which may induce diffusing impairment, was not recorded systematically in our study, but due to the young age of the patients, and hence the short potential period for smoking, we do not believe this factor to have played a decisive role.

In a long-term study of a homogeneous group of childen, Nysom et al3 found that lung volumes and DLCO decreased immediately after BMT, but increased or stabilized over the subsequent years. At their last follow-up at a median of 8 years after BMT, there were still signs of restrictive pulmonary disease and impaired gas exchange. The findings in most longitudinal studies, which have had a shorter follow-up, but which in contrast to Nysom et al also include baseline values, seem to follow the same pattern.4,6,7 We were able to show that, after the first year, there was little change at all over a period of 10 years after autologous BMT, and the main impression was that lung function was relatively well preserved in the long term. Like most long-term studies, there was a conspicuous lack of spontaneously reported respiratory symptoms in our patients.3,4,5,7 These data were based on a retrospective chart review, however, and less severe symptoms may have been missed.

One of the many late effects of BMT in childhood is impaired growth and body disproportion27 Since the reference values for TLC are based solely on height, the relationship between height SDS and TLC suggests a clinically significant body disproportion, which may result in erroneous estimations when children given TBI are compared with a reference population.13 Since the median sitting height to standing height ratio was normal in our group of patients, we do not believe that the influence of body proportion mattered here on the group level.

In conclusion, our main finding was that lung volumes and DLCO decreased immediately after BMT, but recovered partly and stabilized over subsequent years, so that there was little change in PFT values 1–10 years post BMT. We found persistent subclinical restrictive lung disease in one-fifth of the patients who had received TBI and persistently impaired gas exchange in one-third to one-half both in those who had received TBI and those who had not. One patient was diagnosed with transient obstructive lung disease. TBI seemed to be the most important factor for the persistently decreased lung volumes, whereas treatment with chemotherapeutic agents might have been of importance for the development of impaired gas exchange. Larger long-term studies are necessary to determine the long-term development of pulmonary function after BMT and the role of TBI.

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Acknowledgements

This study was supported by the Children's Cancer Foundation in Sweden.

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Frisk, P., Arvidson, J., Bratteby, LE. et al. Pulmonary function after autologous bone marrow transplantation in children: a long-term prospective study. Bone Marrow Transplant 33, 645–650 (2004). https://doi.org/10.1038/sj.bmt.1704393

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Keywords

  • pulmonary function
  • autologous
  • children
  • long-term follow-up

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