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(Chest. 2001;120:1900-1906.)
© 2001 American College of Chest Physicians

Lung Function Abnormalities After Bone Marrow Transplantation in Children*

Has the Trend Recently Changed?

Isa Cerveri, MD; Paola Fulgoni, MD; Giovanna Giorgiani, MD; Maria Cristina Zoia, MD; Massimiliano Beccaria, MD; Carmine Tinelli, MD and Franco Locatelli, MD

* From the Clinic of Respiratory Diseases (Drs. Cerveri, Fulgoni, Zoia, and Beccaria), Department of Pediatrics (Drs. Giorgiani and Locatelli), and Unit of Biometrics (Dr. Tinelli), Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico "San Matteo", Pavia, Italy.

Correspondence to: Isa Cerveri, MD, Clinica Malattie Apparato Respiratorio, IRCCS Policlinico "San Matteo", via Taramelli 5, 27100 Pavia, Italy; e-mail: isa{at}mbox.systemy.it


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To evaluate early and late lung function abnormalities and their predictors in a large sample of children who underwent bone marrow transplantation (BMT) for leukemias in the 1990s, highlighting changes with respect to the 1980s.

Designs: Prospective cohort.

Setting: A university department of pediatrics.

Participants: Seventy-five consecutive children who underwent BMT were enrolled in the study (median age, 11 years; range, 6 to 19 years; 45 male and 30 female children). Twenty-three children received autologous BMT, and 52 children received allogeneic BMT; 50 children completed the study.

Measurements: Clinical examinations and lung function tests were performed before BMT, and 3 to 6 months, 12 months, and 24 months after BMT.

Results: Before BMT, at 3 to 6 months after BMT, and at 24 months after BMT, 44%, 85%, and 62% of children, respectively, had altered lung function in the absence of persistent respiratory symptoms. Between 3 months and 6 months after BMT, a restrictive pattern was the most frequent abnormality. The only predictive factors for late abnormalities were transplantation performed in the advanced disease phase (odds ratio [OR], 6.75; p = 0.005) and bronchopulmonary infections (OR, 3.9; p < 0.05).

Conclusions: These data suggest that a significant proportion of children who undergo BMT, especially if for leukemia in advanced phase, have early and late pulmonary abnormalities. These abnormalities, especially the late ones, seem to be more severe than patients reported in studies analyzing children undergoing BMT in the 1980s. This could be due to the more intensive front-line treatment protocols employed for treatment of children with acute leukemia in the 1990s.

Key Words: bone marrow transplantation • lung function


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Over the past decades, bone marrow transplantation (BMT) has proven to be potentially curative in children with neoplastic diseases, and increasing attention has been paid to the incidence and severity of complications related to this treatment. The lungs have been found to be particularly at risk because of their susceptibility to the toxic effects of chemotherapy and radiotherapy,1 2 3 the frequent occurrence of pulmonary complications in the early posttransplant period,4 5 and immune-mediated lung damage, associated with chronic graft-vs-host disease (GVHD).6

Several reports1 7 8 9 10 11 have focused specifically on lung function abnormalities and on their risk factors in children. Most of them are retrospective studies that enrolled patients who had been treated in the late 1980s when therapeutic protocols were different from the more recent protocols. Unfortunately, the results of these studies, and also of the longitudinal ones, were not unequivocal. This is probably because of small sample sizes, heterogeneous disorders treated in the study populations, and different lung function parameters tested. The majority of patients in the study by Beinert et al1 were affected by chronic myeloid leukemia (CML); the sample of Kaplan et al7 also included patients with aplastic anemia and lymphoma; and patients with lymphoma were enrolled in the series of Nysom et al.2 Some studies8 10 evaluated pulmonary function only after autologous BMT, while other studies1 7 11 only after allogeneic BMT.

In the 1990s, front-line protocols for acute leukemias were intensified, so that most children who received a BMT in this decade could be expected to have more pulmonary abnormalities than children treated 10 to 15 years ago; nevertheless, advances in transplant immunobiology, supportive care, and prevention of GVHD might have reduced or modified pulmonary complications. These modifications and the constantly increasing improvement of survival rate in children undergoing BMT make the monitoring of late pulmonary sequelae ever more necessary.

This prospective study on the incidence and severity of early and late lung damage in children who underwent BMT for leukemia in the last decade provides accurate information on the current status. Moreover, we have specifically analyzed disease-related, patient-related, and transplant-related factors that currently predict the occurrence of lung function impairment in BMT recipients.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Selection and Study Protocol
Between January 1992 and December 1997, 75 consecutive children with leukemia, who received allogeneic BMT (52 patients) or autologous BMT (23 patients) at the Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico S. Matteo, Pavia, Italy, were enrolled in this study. Data were analyzed as of December 30, 1999. All children were > 6 years old and survived for at least 3 months after transplantation. Younger children were not included in the study because they have difficulty in performing lung function tests correctly. The patients’ characteristics are reported in Table 1 . The patients’ parents gave written informed consent to this study, which was designed and carried out in accordance with the Helsinki II declaration and approved by the medical ethics committee of our hospital.


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  		Table 1.. Patient Characteristics*

 
Children with acute leukemia receiving transplantation in the first complete remission (CR) and those with CML in the first chronic phase (early-disease group) were considered separately from all other patients (advanced-disease group). This classification was made with the aim of obtaining information on the impact of duration of chemotherapy on lung function after transplantation, and bears no relationship to the usual classification of patients receiving BMT, used to identify risk of treatment failure, in which children receiving transplantation in the second CR of acute leukemia are considered good-risk patients. The median duration of chemotherapy before transplantation was 5 months (range, 3 to 8 months) and 28 months (range, 6 to 54 months) in the early-disease and advanced-disease groups, respectively. The majority of patients with acute lymphoblastic leukemia (ALL) received BMT in the second hematologic remission, having experienced a medullary relapse, whereas children with acute myeloid leukemia (AML) underwent transplantation in the first CR. Before BMT, patients with ALL and AML had been previously treated using protocols established by the Italian Association for Pediatric Hematology/Oncology (AIEOP), whereas those patients CML received hydroxyurea.

In children with ALL, first-line chemotherapy treatment was administered according to the AIEOP ALL 87, ALL 88, ALL 91, and ALL 95 protocols.12 13 14 These last three protocols have a Berlin-Frankfurt-Munster-like backbone. Enrolled patients usually underwent a three-drug remission induction with prednisone, vincristine, and asparaginase at standard dosages; intermediate-risk and high-risk patients also received anthracyclines. Multiple-agent chemotherapy with appropriate CNS prophylaxis, including cyclophosphamide, cytosine arabinoside (Ara-C), etoposide, systemic high-dose and intrathecal methotrexate, and/or cranial irradiation was continued for 2 years. Only four patients received cranial irradiation before BMT. Patients with ALL who had hematologic relapse before BMT were treated with the same cytotoxic agents employed for first-line chemotherapy until they achieved a new complete remission.

Patients with AML were treated according to the cooperative AIEOP protocols.15 In particular, all children received identical induction therapy, including anthracyclines and Ara-C according to the classical 3 + 7 scheme, followed by a second course of 2 days of anthracyclines and 5 days of Ara-C. One or two courses of consolidation therapy with high-dose Ara-C, etoposide, and anthracyclines were administered before either autologous BMT or allogeneic BMT.

The conditioning regimens used varied according to the type of leukemia, previous treatment, and disease status at time of transplantation. A conditioning regimen consisting of fractionated total body irradiation (TBI) [12 cGy in six divided fractions over 3 days, with a dose rate of 5 to 7 cGy/min) and chemotherapy (ie, melphalan, thiotepa, cyclophosphamide) was employed in 50 patients, whereas the remaining 25 children received a chemotherapy-based preparation. All children who received autologous BMT were prepared with a TBI-containing regimen. The majority of patients who did not receive TBI received busulfan and cyclophosphamide, with or without melphalan, as their conditioning regimen.

Acute GVHD was classified according to previously reported criteria16 and was treated with steroids as first-line therapy and with horse antilymphocyte globulin in resistant cases. For the purpose of this analysis, patients were classified as having acute GVHD when they experienced grade II-IV acute GVHD. Chronic GVHD was diagnosed according to the criteria published by Shulman et al17 and usually treated with cyclosporine-A and steroids.

Cytomegalovirus (CMV) serologic status was studied before transplantation in all children receiving allogeneic BMT and in their donors. In detail, of the patients studied, 24 of the 32 related BMT recipients and 14 out of 20 patients unrelated BMT recipients were CMV seropositive. Expression of pp65 CMV matrix protein (ie, antigenemia) was monitored in all patients who received an allograft, in order to detect reactivation of CMV infection.18 Results were reported as the number of pp65-positive cells per 2 x 105 cells examined. CMV infection was defined as identification of one or more CMV pp65-positive cells in the peripheral blood. Patients with reactivation of CMV infection were treated, according to a strategy of preemptive therapy, with ganciclovir or foscarnet.18 Using this approach, no patient had clinically overt CMV disease.

Acute bronchitis was defined as an acute episode of airway inflammation with cough and mucopurulent phlegm requiring treatment; pneumonia was defined as the occurrence of an acute pulmonary infection with physical and radiographic signs of parenchymal shadowing. Attempts were made to isolate bacterial, fungal, and viral agents from secretions obtained by deep coughing and/or BAL in all patients with bronchial and pulmonary infections.

Clinical examinations and lung function tests were performed in the week before BMT and 3 to 6 months, 12 months, and 24 months after transplantation. Twenty patients died during the follow-up (16 of leukemia relapse, 2 of interstitial pneumonia of unknown origin, and 1 each of fungal meningitis and chronic GVHD); 3 more children were unavailable for follow-up because they lived abroad. Finally, two patients whose leukemia recurred in the first 2 years after BMT were withdrawn from the study at time of their relapse. In detail, of the 25 patients who did not reach the end of the study protocol, 18 patients became unavailable between 3 months and 12 months, and 7 patients became unavailable between 12 months and 24 months after transplantation.

Respiratory Symptoms
The presence of persistent cough and/or phlegm and dyspnea, not part of an acute respiratory event, was recorded at the 2-year follow-up: the details were provided directly by the patients or their parents.

Pulmonary Function Tests
Measurements of lung volumes were obtained by a water-sealed spirometer (Pulmonet III; Sensor Medics; Anaheim, CA). Measurements were performed according to the European Community for Coal and Steel statements19 and American Thoracic Society recommendations.20 The best of three FVC measurements was recorded, as well as FEV1, FEV1/FVC ratio, and maximal expiratory flow at 25% of FVC.

Diffusion capacity of the lung for carbon monoxide (DLCO) was determined using the single-breath method (Transferscreen-II; Jaeger; Wuerzburg, Germany) and corrected for hemoglobin content. Since the correction of DLCO for alveolar volume did not influence the results of our analysis, only uncorrected DLCO values are reported. Measurements were made according to the European Community for Coal and Steel19 and American Thoracic Society21 guidelines. Since this test is more difficult to perform and requires greater cooperation than FVC, DLCO data are unavailable for six patients.

Functional data were expressed as a SD score (actual result - predicted value/population SD) and defined as pathologic when < - 1.64, a value corresponding to the fifth percentile. SD scores were reported as mean values ± SD. Taking into account the pubertal stage of each subject, evaluated using the method of Tanner,22 the SD score was corrected according to the tables published by Rosenthal et al.23 Reference values were those reported in a published cross-sectional study23 24 on lung function in healthy schoolchildren aged 4 to 19 years. Three patterns of respiratory function abnormalities were defined as follows: (1) restrictive, FVC SD score < - 1.64 with FEV1/FVC SD score ratio > - 1.64; (2) obstructive, FEV1 SD score < - 1.64 with FEV1/FVC SD score ratio <= - 1.64; and (3) isolated diffusion impairment, DLCO SD score < - 1.64 and other parameters in the normal range. Patients were then classified as those with normal lung function (absence of any of the above-mentioned patterns) and those with a pathologic pattern.

Statistical Analysis
Repeated-measures analysis of variance was used to test for statistically significant changes in scores over time. Differences in frequencies between lung function abnormalities and several clinical and treatment parameters were evaluated by means of {chi}2 statistics or Fisher’s Exact Test, as appropriate. The odds ratio (OR) was calculated by Woolf’s method. We considered both normal and pathologic respiratory function (grouping all three above-mentioned patterns) as dependent variables. As independent variables, we analyzed the following factors: sex; age; time interval between diagnosis and BMT; conditioning regimen (TBI-containing and chemotherapy-based regimens); baseline lung function; use of systemic high-dose methotrexate during chemotherapy; type of BMT; type of donor employed (only for children receiving an allograft); period when BMT was performed (from 1992 to 1994, and from 1995 to 1997); disease status at transplantation; bronchial and pulmonary infections during follow-up; type of GVHD prophylaxis employed; acute and chronic GVHD occurrence; patient and donor CMV serology; and reactivation of CMV infection.

A p value < 0.05 was considered to be statistically significant. All tests were two sided. Analyses were performed with statistical software (Statistica for Windows; StatSoft; Tulsa, OK; and Stata Statistical Software, release 6.0; Stata Corporation; College Station, TX).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
During the follow-up period, 49% of patients had bronchopulmonary infections, these being more frequent after allogeneic BMT. Thirty-five percent of patients had a reactivation of CMV infection; acute GVHD developed in 40% of patients, and chronic GVHD developed in 27% of patients.

Before transplantation, mean FVC and, even more markedly, DLCO SD scores were negative, although still within the normal range (- 0.3 ± 1.1 and - 1.2 ± 1.2, respectively). Between 3 months and 6 months after BMT, FVC and DLCO mean values were significantly lower (- 1.8 ± 1.7 and - 2.6 ± 1.3, respectively; p < 0.0001 in both cases) than the pretransplant values. Subsequently, both FVC and DLCO mean values tended to recover progressively, although at 12 months and 24 months after BMT, they still remained more negative than the pretransplant values (repeated-measures analysis of variance, p < 0.0001 and p < 0.0001, respectively; Fig 1 ).



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  		Figure 1.. FVC (top) and DLCO (bottom) values expressed as the mean ± SD of the SD score in all patients who completed the follow-up (before BMT, 3 to 6 months, 12 months, and 24 months after BMT).

 
When lung function abnormalities were grouped according to the previously defined patterns, 44% of subjects had pathologic lung function before transplantation. At the first evaluation, 3 to 6 months after BMT, the percentage of patients with a pathologic pattern had risen to 85%. Two years after transplantation, although no patient complained of persistent respiratory symptoms, 62% of the children still had a pathologic pattern. At the time of BMT, the most common pathologic finding was an isolated impairment of DLCO, whereas at both 3 to 6 months and 1 year after transplantation, a restrictive pattern was the most frequent abnormality. Two years after transplantation, the percentage of patients with a restrictive pattern had almost halved, while the percentage of patients with an obstructive defect remained substantially unchanged (Fig 2 ).



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  		Figure 2.. Distribution of different respiratory function patterns in all patients before BMT, and 3 to 6 months, 12 months, and 24 months after BMT.

 
Before BMT, there was no difference in the incidence of pathologic abnormalities between children undergoing transplantation in the early-disease phase and those receiving transplantation in the advanced-disease phase (46% vs 43%, respectively). Three to six months after transplantation, the prevalence of pathologic abnormalities was comparable (83% vs 88%). In the cohort of patients undergoing transplantation in the early-disease phase, the percentage of subjects (40%) with a pathologic pattern 2 years after BMT was comparable to that observed before transplantation. By contrast, at the same time point, a negligible percentage (18%) of children undergoing transplantation in the advanced-disease stage had recovered normal respiratory function (Fig 3 ). Therefore, in patients who reached the second year of observation, there was a pronounced, statistically significant difference in the percentage of subjects with a pathologic pattern of lung function between children undergoing transplantation in advanced-disease phase and children undergoing transplantation in the early-disease phase (82% vs 40%, respectively; p = 0.005). Two years after transplantation, 81% of patients with early respiratory infections, 73% of patients with CMV reactivation, and 62% of patients with chronic GVHD had a pathologic pattern of lung function.



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  		Figure 3.. Distribution of pathologic pattern in patients undergoing transplantation in early-disease phase and in those undergoing transplantation in advanced-disease phase before BMT, and 3 to 6 months, 12 months, and 24 months after BMT.

 
The most significant variable predicting late (ie, 2 years after BMT) pulmonary impairment was stage of disease (advanced-disease vs early-disease phase) [OR, 6.75; p = 0.005]. Development of bronchopulmonary infections in the first 3 to 6 months after BMT also played a relevant role in producing late pulmonary function abnormalities (OR, 4.3; p = 0.04). None of the other factors analyzed had any impact on development of long-term pulmonary abnormalities. In particular, baseline lung function, type of BMT, type of conditioning regimen employed, history of CMV reactivation, and presence of chronic GVHD did not influence decline in lung function.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This prospective study shows that children with leukemia receiving BMT in the 1990s were at substantial risk of experiencing short-term and long-term respiratory abnormalities, the latter being present despite the absence of persistent respiratory symptoms. These abnormalities, especially the late ones, seem to be more severe than those reported in the literature concerning children undergoing transplantation in the 1980s. The only factors predictive of late abnormalities were undergoing transplantation in the advanced-disease phase and having had bronchopulmonary infections.

A great proportion of patients already showed evidence of some lung dysfunction before BMT, suggesting that pretransplant treatment with cytotoxic agents may favor the occurrence of lung damage prior to BMT. Previously published studies in children receiving BMT in the 1980s showed baseline lung function close to normal10 or only slightly reduced.1 25 Our results could be explained by the global intensification in front-line chemotherapy protocols for acute leukemias adopted in the 1990s.

Trends in lung function after BMT were similar to those described in the previous articles, but abnormalities were more severe and tended to be permanent in a higher percentage of patients than in the past. Functionally restrictive impairment was the most common pathologic abnormality observed 3 to 6 months after transplantation. At 24 months, the different pathologic patterns were more homogeneously distributed. It is very difficult to correlate different types of lung injury with the recorded patterns because different bronchopulmonary structures may be damaged simultaneously and because different types of injuries can act contemporaneously; the resulting patterns are probably related to the prevalent lesion.26 A pulmonary restrictive syndrome has been reported frequently in BMT recipients, especially in those who received TBI during the preparative regimen and received an allograft.27 Radiotherapy to the chest, and cytotoxic drugs, such as cyclophosphamide, busulfan, and melphalan, are known to cause lung injury in BMT patients. The type of cytotoxic agents used, the dose of both chemotherapy and radiation administered, as well as fractionation and dose rate of TBI may influence development of lung abnormalities.28 29

In our study, the incidence of pathologic obstructive abnormalities was low, and we were unable to confirm the observation of Schultz et al6 on the role of chronic GVHD in promoting development of obstructive lung abnormalities in children receiving BMT. The number of children with chronic GVHD in our cohort (eight patients) was much lower than that in the series reported by Schultz et al,6 this possibly precluding the chance of identifying the detrimental effect played by the donor immune system on recipient lungs. Moreover, a lower percentage of our patients received methotrexate as part of GVHD prophylaxis. Improvement of GVHD prophylaxis, more accurate donor selection, and more effective therapy of acute GVHD may have contributed to the reduction in the incidence of chronic GVHD.

Lung function was significantly worse in patients who underwent transplantation in advanced-disease stages. Our data confirm and extend previously published analyses8 25 documenting that the total amount of chemotherapy administered before BMT plays a synergistic role with transplant in determining long-lasting pulmonary damage. Among the major agents potentially responsible for lung damage are high-dose methotrexate and cyclophosphamide, usually employed in the treatment of patients with ALL.30

Bronchopulmonary infections occurring early after BMT have already been documented to favor late pulmonary function abnormalities in our previous cross-sectional study31 of a group of young adults receiving BMT during childhood for hematologic malignancies. It is reasonable to speculate that lung damage associated with occurrence of respiratory infections could have a detrimental, synergistic effect with chemoradiotherapy in producing long-lasting pulmonary function anomalies. The large sample size, the fact that only one disease was selected for study and that the BMT procedures were performed in a single institution, the relatively short and recent period of enrollment, and the prospective evaluation all give power to our study.

Although part of the lung abnormalities are not amenable to cure, early detection and prompt adoption of prophylactic and therapeutic measures may reverse or prevent progression of lung disease. Although lung function abnormalities 2 years after BMT are not clinically overt, consideration of lung function should become a part of the prognostic counseling provided to each patient offered the option of BMT. Children surviving BMT now have a long life expectancy and will undergo unavoidable age-related deterioration in respiratory function. They may, later in life, also have to cope with many other risk factors potentially affecting respiratory function, such as smoke, pollution, and infections that could affect their possibly limited pulmonary function reserve. They must, therefore, avoid any contact with smoke and other sources of air pollution. Moreover, they should choose an occupation that does not expose them to the risk of other agents potentially capable of further worsening their lung function.


   Footnotes
 
Abbreviations: AIEOP = Italian Association for Pediatric Hematology/Oncology; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; Ara-C = cytosine arabinoside; BMT = bone marrow transplantation; CML = chronic myeloid leukemia; CMV = cytomegalovirus; CR = complete remission; DLCO = diffusion capacity of the lung for carbon monoxide; GVHD = graft-vs-host disease; TBI = total body irradiation; OR = odds ratio

This work was partly supported by grants from Associazione Italiana per la Ricerca sul Cancro and Istituto di Ricovero eCura a Carattere Scientifico, Policlinico San Matteo (#8105) to Dr. Locatelli, and is part of Current Research Project No.

681RCR96/02 by Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo, Pavia, Italy.

Received for publication January 9, 2001. Accepted for publication July 9, 2001.


   References
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 Abstract
 Introduction
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 Results
 Discussion
 References
 

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