Pediatric Pulrnonology 14:141-148 (1992)
Original Articles
Chronic Graft-Versus-Host Disease and Pulmonary Function Ellen B. Kaplan, MD,'.' Ruthven A. Wodell, MD,' Robert W. Wilrnott, MD,* Betty Leifer, MA,3 Martin L. Lesser, P ~ D and , ~ Charles S. August, MD' Summary.Pulmonary complications are a major cause of morbidity and mortality in bone marrow transplant recipients. Earlier series, consisting mainly of adults, have shown evidence of obstructive changes of pulmonary functions in association with chronic graft-versus-host disease (CGVHD). We longitudinally evaluated spirometry in 46 patients who received bone marrow transplants as children or as young adults to determine whether they had similar abnormalities. Group mean FEV,/FVC, and percent predicted FVC, FEV,, and F ,E ,,F, values did not demonstrate obstructive changes in association with CGVHD in this patient population. Our findings suggest that younger patients with CGVHD, as a group, may fare better than older bone marrow transplant recipients with CGVHD. However, due to small sample sizes, it cannot be conclusively stated that the pulmonary function parameters analyzed do not differ in the two patient groups. Pediatr Pulmonol. 1992; 14:141-148. ei 1992 Wiley-Liss, Inc
Key words: Bone marrow transplants;forced expiratory volume, flows, and lung volume; CGVHD and no CGVHD groups.
INTRODUCTION Bone marrow transplantation is now used widely in the treatment of children with certain immunodeficiency syndromes, as well as hematologic and neoplastic disorders. It is also being employed in patients with specific genetic disorders. Pulmonary complications are responsible for considerable morbidity and mortality after bone marrow transplant (BMT).2 Forty to sixty percent of patients, primarily adults, with previous diagnoses of aplastic anemia and leukemia have been reported to have such complicat i o m 3 These include both r e ~ t r i c t i v eand ~ ~ obstructi"e4,s,8-l 8 changes. Cytoreductive regimens (i.e., chemotherapy and irradiation), graft-versus-host disease (GVHD), immunosuppression, infections, transfusions, the underlying disease, other therapies, and/or the transplant itself may contribute to the development of lung disease after BMT. iy.20 Earlier series of BMT recipients, consisting mainly of adults, have shown evidence of obstructive lung changes in association with chronic graft-versus-host disease (CGVHD).X,'7.iX We evaluated the effects of CGVHD on longitudinal pulmonary function in patients who received a BMT as children or as young adults, to determine if similar observations can be made in this younger patient population.
'
0 1992 Wiley-Liss, Inc.
From the Departments of Pediatrics' and Re~earch,~ North Shore University Hospital, Manhasset, New York, Departments of Pediatrics' and Public Health,4 Cornell University Medical College, New York, New York, the Division of Allergy, Immunology, Pulmonology, and Bone Marrow Transplantation, The Children's Hospital of Philadelphia,' and the Department of Pediatrics,' and Clinical Research Center,j University of PennsylvaniaSchool of Medicine, Philadelphia, Pennsylvania. Received April I , 1991; (revision) accepted for publication May 21, 1992. This investigation was supported in part by Public Health Service Research grants RR00040 and RR00047 from the General Research Center Branch, Division of Research Facilities and Resources, Bethesda. Maryland, grant RR00240 from the General Clinical Research Center Program of the National Center for Research Resources, National Institutes of Health, and The Tomorrow Fund of the Children's Hospital of Philadelphia. Address correspondence and reprint requests to Dr. E.B. Kaplan, at her present address, Division of Pulmonary Medicine, Children's Hospital Medical Center, Elland and Bethesda Aves. ,Cincinnati, OH 45229-2899. Robert W. Wilmott's present address i s Division of Pulmonary Medicine, Children's Hospital Medical Center, Elland and Bethesda Aves., Cincinnati, OH 45229-2899. Charles S . August's present address i s Division of Hematology/ Oncology. Miami Children's Hospital, 6125 S.W. 3 1 s t Street, Miami,
FL 33155.
-
142
Kaplan et al.
Diagnostic Methods MATERIALS AND METHODS Study Groups Routine pre- and post-transplant evaluations werc conin The Children’s Hospital of Philadelphia’s Clinducted Fony-six patients (29 males and 17 females) treated for ical Research Center. The evaluations, which included acute leukemia (n = 29), lymphoma (n = 3). and aplaspulmonary function testing. were conducted prc-transtic anemia (n = 14) at The Children’s Hospital of Philadelphia were studied longitudinally between 1977 and plant and at approximately 3 , 6 , 9 , 12, 18, and 24 months January I , 1988. Patients who had pulmonary function post-transplant followed by yearly intervals thereafter tests during the post-transplant time periods were in- (before 1984), or at 4, 8, 12, 18, and 24 months postcluded in the data analysis. Their age at the time of BMT transplant followed by yearly intervals thereafter (after ranged from 2.7 to 24.4 years. Forty of 46 (87%) patients 1984). Should a patient have had more than one test were under 18 years of age at the time of BMT. Six during a study period, the better test was selected for data patients were at least 18 years old, including five who analysis. Hence, for purposes of this study, no patient were 18.0to 21.1 years of age, and one who was 24.4 at had more than one pulmonary function test analyzed durthe time of transplant. Ages at the time of individual ing a designated time period. Pulmonary function was pulmonary function testings ranged from 5.2 to 29.4 assessed at 3-6, 6-9, 9-12, 12-18, and 18-24 months, and 6-7 years post-transplant. years. Forty-five patients were allogeneic BMT recipi- and at 2-3,34,4-5,5-6, The diagnoses of acute and chronic GVHD were made ents. One patient received a syngeneic transplant. Two patients received a second marrow infusion including one according to clinical and histopathologic criteria of Shulpatient who failed to engraft and one who initially en- man,4 Glucksberg,22and Sale and colleagues.” All diaggrafted and then rejected the graft. The time of transplant noses were confirmed histopathologically by biopsies of was considered to be the time of the first marrow infu- involved organs, usually skin, lip (minor salivary sion. Sixteen patients developed CGVHD. Patients were glands), or liver. All patients designated as having categorized as having CGVHD beginning at the time CGVHD had “extensive” or “generalized” disease ininterval in which it developed and from that period on- volving skin (scleroderma, lichen planus), oropharynx ward. Therefore, if at a given time a patient had not yet (sicca syndrome with chronic ulceration), keratoconjuncdeveloped CGVHD, then that patient was analyzed in the tivitis sicca, and immune dysfunction (hypogammaglob“no CGVHD’ group for that time point; later, when that ulemia, splenic hypofunction). All of these patients repatient developed CGVHD, he/she was listed in the ceived prolonged courses of prednisone therapy at doses “CGVHD” group. Patients who may have had inactive or ranging from 1 to 2 mglkglday. Most received intennitsubsequent resolution of their CGVHD were included in tent courses of azathioprine. which were usually limited by myelosuppression. During the time these patients the “CGVHD” group. were studied, cyclosporine-A had not yet come into general use as therapy for GVHD. Bone Marrow Transplant
BMT was performed under active protocols at The Children’s Hospital of Philadelphia during the years of the study. In general, children with aplastic anemia were prepared with cyclophosphamide using total doses of 200 mg/kg and with total body irradiation (TBI) at 300 cGy. Children with leukemia received cyclophosphamide at total doses of 120 mg/kg or cytosine arabinoside at doses of 36 gm/m2, combined with TBI at doses ranging from 800 cGy (single dose) to 1,320 cGy (eight fractions). One patient with acute lymphoblastic leukemia received melphalan (total dose, 210 mg/m2) as the principal alkylating agent. TBI was administered in the Department of Radiation Therapy of The Hospital of The University of Pennsylvania with a 6 meV linear accelerator at a dose rate of 8-1 0 cGylmin as previously described.2’ Informed consent for the BMT and the subsequent follow-up studies was obtained for all recipients and donors, according to a protocol approved by The Children’s Hospital of Philadelphia’s Committee for the Protection of Human Subjects.
Pulmonary Function Tests Spirometric studies were performed on the HewlettPackard 47804 pulmonary system (Hewlett-Packard Co., Waltham, MA) with a Fleisch pneumotachograph, or on a Collins spirometer (Collins, Inc., Braintree, MA). Lung volumc measurements were obtained with a Collins body plethysmograph (Collins, Inc.) or by the multiple breath nitrogen wash-out method. A wedge-type (Med Science) or a rolling seal spirometer and x-y recorder were used for some of the flow volume loop determinations during the early years of thc The forced vital capacity (FVC), forced expiratory volume in I second (FEV,), and forced expiratory tlow at 25-75% of the FVC (FEF2sp75)were expressed as percent predicted values. Predicted values were calculated from the equations of Hsu and Knudson.2s.26 Additionally, the absolute value of FEV, was expressed as a percent of the absolute value of the FVC. FVC data was not reported during the earlier years of the study. Thus,
CGVHD and Pulmonary Function TABLE 1-Forced
143
Vital Capacity (FVC) Values’ ~
Time Post-BMT
Original Articles
Chronic Graft-Versus-Host Disease and Pulmonary Function Ellen B. Kaplan, MD,'.' Ruthven A. Wodell, MD,' Robert W. Wilrnott, MD,* Betty Leifer, MA,3 Martin L. Lesser, P ~ D and , ~ Charles S. August, MD' Summary.Pulmonary complications are a major cause of morbidity and mortality in bone marrow transplant recipients. Earlier series, consisting mainly of adults, have shown evidence of obstructive changes of pulmonary functions in association with chronic graft-versus-host disease (CGVHD). We longitudinally evaluated spirometry in 46 patients who received bone marrow transplants as children or as young adults to determine whether they had similar abnormalities. Group mean FEV,/FVC, and percent predicted FVC, FEV,, and F ,E ,,F, values did not demonstrate obstructive changes in association with CGVHD in this patient population. Our findings suggest that younger patients with CGVHD, as a group, may fare better than older bone marrow transplant recipients with CGVHD. However, due to small sample sizes, it cannot be conclusively stated that the pulmonary function parameters analyzed do not differ in the two patient groups. Pediatr Pulmonol. 1992; 14:141-148. ei 1992 Wiley-Liss, Inc
Key words: Bone marrow transplants;forced expiratory volume, flows, and lung volume; CGVHD and no CGVHD groups.
INTRODUCTION Bone marrow transplantation is now used widely in the treatment of children with certain immunodeficiency syndromes, as well as hematologic and neoplastic disorders. It is also being employed in patients with specific genetic disorders. Pulmonary complications are responsible for considerable morbidity and mortality after bone marrow transplant (BMT).2 Forty to sixty percent of patients, primarily adults, with previous diagnoses of aplastic anemia and leukemia have been reported to have such complicat i o m 3 These include both r e ~ t r i c t i v eand ~ ~ obstructi"e4,s,8-l 8 changes. Cytoreductive regimens (i.e., chemotherapy and irradiation), graft-versus-host disease (GVHD), immunosuppression, infections, transfusions, the underlying disease, other therapies, and/or the transplant itself may contribute to the development of lung disease after BMT. iy.20 Earlier series of BMT recipients, consisting mainly of adults, have shown evidence of obstructive lung changes in association with chronic graft-versus-host disease (CGVHD).X,'7.iX We evaluated the effects of CGVHD on longitudinal pulmonary function in patients who received a BMT as children or as young adults, to determine if similar observations can be made in this younger patient population.
'
0 1992 Wiley-Liss, Inc.
From the Departments of Pediatrics' and Re~earch,~ North Shore University Hospital, Manhasset, New York, Departments of Pediatrics' and Public Health,4 Cornell University Medical College, New York, New York, the Division of Allergy, Immunology, Pulmonology, and Bone Marrow Transplantation, The Children's Hospital of Philadelphia,' and the Department of Pediatrics,' and Clinical Research Center,j University of PennsylvaniaSchool of Medicine, Philadelphia, Pennsylvania. Received April I , 1991; (revision) accepted for publication May 21, 1992. This investigation was supported in part by Public Health Service Research grants RR00040 and RR00047 from the General Research Center Branch, Division of Research Facilities and Resources, Bethesda. Maryland, grant RR00240 from the General Clinical Research Center Program of the National Center for Research Resources, National Institutes of Health, and The Tomorrow Fund of the Children's Hospital of Philadelphia. Address correspondence and reprint requests to Dr. E.B. Kaplan, at her present address, Division of Pulmonary Medicine, Children's Hospital Medical Center, Elland and Bethesda Aves. ,Cincinnati, OH 45229-2899. Robert W. Wilmott's present address i s Division of Pulmonary Medicine, Children's Hospital Medical Center, Elland and Bethesda Aves., Cincinnati, OH 45229-2899. Charles S . August's present address i s Division of Hematology/ Oncology. Miami Children's Hospital, 6125 S.W. 3 1 s t Street, Miami,
FL 33155.
-
142
Kaplan et al.
Diagnostic Methods MATERIALS AND METHODS Study Groups Routine pre- and post-transplant evaluations werc conin The Children’s Hospital of Philadelphia’s Clinducted Fony-six patients (29 males and 17 females) treated for ical Research Center. The evaluations, which included acute leukemia (n = 29), lymphoma (n = 3). and aplaspulmonary function testing. were conducted prc-transtic anemia (n = 14) at The Children’s Hospital of Philadelphia were studied longitudinally between 1977 and plant and at approximately 3 , 6 , 9 , 12, 18, and 24 months January I , 1988. Patients who had pulmonary function post-transplant followed by yearly intervals thereafter tests during the post-transplant time periods were in- (before 1984), or at 4, 8, 12, 18, and 24 months postcluded in the data analysis. Their age at the time of BMT transplant followed by yearly intervals thereafter (after ranged from 2.7 to 24.4 years. Forty of 46 (87%) patients 1984). Should a patient have had more than one test were under 18 years of age at the time of BMT. Six during a study period, the better test was selected for data patients were at least 18 years old, including five who analysis. Hence, for purposes of this study, no patient were 18.0to 21.1 years of age, and one who was 24.4 at had more than one pulmonary function test analyzed durthe time of transplant. Ages at the time of individual ing a designated time period. Pulmonary function was pulmonary function testings ranged from 5.2 to 29.4 assessed at 3-6, 6-9, 9-12, 12-18, and 18-24 months, and 6-7 years post-transplant. years. Forty-five patients were allogeneic BMT recipi- and at 2-3,34,4-5,5-6, The diagnoses of acute and chronic GVHD were made ents. One patient received a syngeneic transplant. Two patients received a second marrow infusion including one according to clinical and histopathologic criteria of Shulpatient who failed to engraft and one who initially en- man,4 Glucksberg,22and Sale and colleagues.” All diaggrafted and then rejected the graft. The time of transplant noses were confirmed histopathologically by biopsies of was considered to be the time of the first marrow infu- involved organs, usually skin, lip (minor salivary sion. Sixteen patients developed CGVHD. Patients were glands), or liver. All patients designated as having categorized as having CGVHD beginning at the time CGVHD had “extensive” or “generalized” disease ininterval in which it developed and from that period on- volving skin (scleroderma, lichen planus), oropharynx ward. Therefore, if at a given time a patient had not yet (sicca syndrome with chronic ulceration), keratoconjuncdeveloped CGVHD, then that patient was analyzed in the tivitis sicca, and immune dysfunction (hypogammaglob“no CGVHD’ group for that time point; later, when that ulemia, splenic hypofunction). All of these patients repatient developed CGVHD, he/she was listed in the ceived prolonged courses of prednisone therapy at doses “CGVHD” group. Patients who may have had inactive or ranging from 1 to 2 mglkglday. Most received intennitsubsequent resolution of their CGVHD were included in tent courses of azathioprine. which were usually limited by myelosuppression. During the time these patients the “CGVHD” group. were studied, cyclosporine-A had not yet come into general use as therapy for GVHD. Bone Marrow Transplant
BMT was performed under active protocols at The Children’s Hospital of Philadelphia during the years of the study. In general, children with aplastic anemia were prepared with cyclophosphamide using total doses of 200 mg/kg and with total body irradiation (TBI) at 300 cGy. Children with leukemia received cyclophosphamide at total doses of 120 mg/kg or cytosine arabinoside at doses of 36 gm/m2, combined with TBI at doses ranging from 800 cGy (single dose) to 1,320 cGy (eight fractions). One patient with acute lymphoblastic leukemia received melphalan (total dose, 210 mg/m2) as the principal alkylating agent. TBI was administered in the Department of Radiation Therapy of The Hospital of The University of Pennsylvania with a 6 meV linear accelerator at a dose rate of 8-1 0 cGylmin as previously described.2’ Informed consent for the BMT and the subsequent follow-up studies was obtained for all recipients and donors, according to a protocol approved by The Children’s Hospital of Philadelphia’s Committee for the Protection of Human Subjects.
Pulmonary Function Tests Spirometric studies were performed on the HewlettPackard 47804 pulmonary system (Hewlett-Packard Co., Waltham, MA) with a Fleisch pneumotachograph, or on a Collins spirometer (Collins, Inc., Braintree, MA). Lung volumc measurements were obtained with a Collins body plethysmograph (Collins, Inc.) or by the multiple breath nitrogen wash-out method. A wedge-type (Med Science) or a rolling seal spirometer and x-y recorder were used for some of the flow volume loop determinations during the early years of thc The forced vital capacity (FVC), forced expiratory volume in I second (FEV,), and forced expiratory tlow at 25-75% of the FVC (FEF2sp75)were expressed as percent predicted values. Predicted values were calculated from the equations of Hsu and Knudson.2s.26 Additionally, the absolute value of FEV, was expressed as a percent of the absolute value of the FVC. FVC data was not reported during the earlier years of the study. Thus,
CGVHD and Pulmonary Function TABLE 1-Forced
143
Vital Capacity (FVC) Values’ ~
Time Post-BMT
