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Pulmonary hypertension associated with bone marrow transplantation
Journal of Cardiology Cases (2010) 2, e23—e27
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Case Report
Pulmonary hypertension associated with bone marrow transplantation Hajime Nakaoka (MD) a, Yasushi Sakata (MD) a, Masaki Yamamoto (MD) b, Tetsuo Maeda (MD) b, Yoh Arita (MD) a, Wataru Shioyama (MD) a, Yoshikazu Nakaoka (MD) a, Yuzuru Kanakura (MD) b, Shizuya Yamashita (MD) a, Issei Komuro (MD, FJCC) a, Keiko Yamauchi-Takihara (MD) a,∗ a b
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
Received 27 November 2009; received in revised form 4 January 2010; accepted 14 January 2010
KEYWORDS Pulmonary arterial hypertension; Bone marrow transplantation; Pulmonary veno-occlusive disease; Chemotherapy; Leukemia
Summary Bone marrow transplantation (BMT) is one of the promising methods of treatment of hematologic malignancy. However, it has a variety of complications since it involves fatal doses of anti-cancer drugs and radiation during the conditioning period. Among the various complications of BMT, pulmonary hypertension is rare and its pathogenesis is poorly understood. A 35-year-old female with acute myeloid leukemia (AML) presented with pulmonary hypertension after BMT. Although she exhibited severe dyspnea on admission, her general condition markedly improved after oxygen therapy and treatment with warfarin and beraprost sodium. Her pulmonary hypertension was diagnosed as pulmonary arterial hypertension (PAH) related to BMT. Although PAH has only rarely been reported as a complication of BMT, we present here for the first time an adult patient with PAH associated with BMT who exhibited marked improvement with medical treatment. This case indicates that attention needs to be paid to the clinical symptoms and physical findings of PAH as a complication of BMT. © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Introduction
∗ Corresponding author at: Health Care Center, Osaka University; Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 1-17 Machikaneyama 560-0043, Japan. Tel.: +81 6 6850 6012; fax: +81 6 6850 6040. E-mail address: [email protected] (K. Yamauchi-Takihara).
Acute myeloid leukemia (AML) involves a hematopoietic transformation characterized by impaired differentiation of hematopoietic stem or progenitor cells, resulting in abnormal growth of a clonal subpopulation of neoplastic cells or blasts. This malignant alteration may lead to a loss of normal hematopoietic function, typically resulting in death within a few weeks to months [1]. Bone marrow transplantation (BMT), one of the key treatments of AML, dramatically
1878-5409/$ — see front matter © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jccase.2010.01.008
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H. Nakaoka et al.
improves the prognosis of AML. It has been used not only for patients with AML but also for patients with a wide variety of hematologic malignancies and benign diseases such as aplastic anemia. However, it features a variety of complications that result from the chemotherapy and radiotherapy applied during the conditioning period. Well-known complications of BMT include graft-versus host disease (GVHD), graft failure, interstitial pneumonitis, B-lymphocyte proliferative disorder, and various infections [2]. In contrast, pulmonary hypertension (PH) is rare as a complication of BMT, and its mechanism of onset remains poorly understood. PH is a rare progressive disease with poor prognosis. PH features a resting mean pulmonary arterial pressure (PAP) ≥25 mmHg, and one of the subgroups of pre-capillary PH, with pulmonary capillary wedge pressure (PCWP) ≤15 mmHg, is classified as pulmonary arterial hypertension (PAH) according to the updated clinical classification of PH reported by the Symposium at Dana Point, California in 2008 [3,4]. One of the prominent changes in this classification from the Venice classification is that pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis are moved from a separate category into a subcategory of PAH [4]. Although PVOD is the most common feature of PH reported in association with BMT, there have been reported few case reports of it [5—9]. We report here a 35-year-old female with AML, who presented with PH after BMT. Although she had severe dyspnea, her general condition markedly improved after oxygen therapy and treatment with warfarin and beraprost sodium. PAH has only rarely been reported as a complication of BMT, and there has been no report of reversible PAH in association with BMT in an adult. We present here for the first time a patient with PAH after BMT who exhibited marked improvement with early medical treatment.
Figure 1
Case report A 35-year-old woman was diagnosed with AML with maturation (AML M2 in FAB classification) in October 2007 at 30-weeks of pregnancy. She was transferred to the Department of Hematology and Oncology and Department of Obstetrics of Osaka University Hospital, and underwent induced labor on October 24. After giving birth to her baby, chemotherapy was begun for induction of remission, followed by three courses of consolidation therapy. On March 28, 2008, she received a BMT from an HLA-identical brother while her disease was in complete remission. Busulphan (36 mg/day) was used for 4 days and cyclophosphamide (2700 mg/day) for 2 days for conditioning for BMT. GVHD prophylaxis was performed using the standard regimen, with cyclosporine and a short course of methotrexate. Serum KL-6 levels before and after BMT were 189 U/mL and 159 U/mL, respectively. She had no complication of BMT, including GVHD, and was discharged two months later (day 68) in a relatively good condition. Soon after leaving the hospital, however, she gradually developed shortness of breath and was re-hospitalized with symptoms of severe heart failure. She was transferred to the Department of Cardiovascular Medicine on July 2, 2008 (day 94). On admission, her heart rate was 108 bpm, her blood pressure was 92/68 mmHg, and oxygen saturation on room air was 93%. Physical examination revealed no abnormal breath or heart sounds and no leg edema. Arterial blood gas analysis on room air revealed a pO2 62.6 mmHg and pCO2 30.6 mmHg. Laboratory data on admission are summarized in Table 1. Brain natriuretic peptide (BNP) was 702 pg/mL and serum uric acid (UA) was 7.2 mg/dL. Although the electrocardiography (ECG) showed sinus tachycardia of 115 bpm, chest radiography revealed no cardiomegaly and no signs of
Chest radiography (A) and chest computed tomography (B) on admission.
PH associated with BMT Table 1 WBC RBC Plt Na K BUN Creatinine T-bilirubin AST ALT ␥-GTP ALP LDH UA CRP
e25
Laboratory data on admission. 4.70 × 103 /L 3.74 × 103 /L 164 × 103 /L 141 mequiv./L 4.7 mequiv./L 15 mg/dL 0.75 mg/dL 0.8 mg/dL 29 U/L 26 U/L 15 U/L 102 U/L 235 U/L 7.2 mg/dL 0.04 mg/dL
BNP PT-INR APTT D-dimer HIV ANA HHV8 Blood analysis pCO2 pO2 HCO3 BE SaO2 pH
702 pg/mL 1.27 28 s 1.80 g/mL Negative ≤1:40 Negative 30.6 mmHg 62.6 mmHg 20.3 mequiv./L −2.6 mequiv./L 91.9% 7.435
WBC, white blood cells; RBC, red blood cells; Plt, platelets; BUN, blood urea nitrogen; T-bilirubin, total bilirubin; AST, aspartate transaminase; ALT, alanine transaminase; ␥-GTP, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; UA, uric acid; CRP, C-reactive protein; BNP, brain natriuretic peptide; PT-INR, prothrombin-international normalized ratio; APTT, activated partial thromboplastin time; HIV, human immunodeficiency virus; ANA, antinuclear antibody; HHV, human herpes virus; BE, base excess.
Figure 2 Echocardiographic images. (A) On admission, right ventricular systolic pressure was 38 mmHg and reverse curvature of the inter-ventricular septum was noted. (B) After one month of treatment, left and right ventricular contraction were normal and her tricuspid valve regurgitation had disappeared.
congestive heart failure (Fig. 1A). The result of the 6-min walking distance (6MWD) test was 237 m with 2 L/min nasal O2 at that time. Echocardiographic (UCG) examination was performed prior to BMT, and showed normal cardiac function and normal right ventricular (RV) pressure. However, her tricuspid regurgitation-pressure gradient was 38 mmHg, the diameter of inferior vena cava was 14 mm and reverse curvature of the inter-ventricular septum was noted at that time. Left ventricular (LV) contraction was normal (Fig. 2A). Chest computed tomography (CT) and lung perfusion scintigraphy yielded no evidence of pulmonary thromboembolism (PTE). High-resolution chest CT revealed no sign of centrilobular ground-grass opacities, septal lines, or lymph node enlargement, which are suggestive for PVOD. In addition, enhanced CT revealed no pulmonary embolism and no deep vein thrombosis (Fig. 1B). The results of right heart catheterization (RHC) are summarized in Table 2. PCWP was normal (mean PCWP: 7 mmHg), cardiac output
2.74 L/min/m2 , mean PAP 35 mmHg, and pulmonary vascular resistance was high (545 dyn s/cm5 ). There was no evidence of family history of PAH, collagen disease, chronic hepatitis, portal hypertension, human
Table 2 PCWP PAP RVP RAP CO SVR PVR
Right heart catheterization data. (7) mmHg 42/28(35) mmHg 46/4/10 mmHg (7) mmHg 4.11 L/min 1888 dyn s/cm5 545 dyn s/cm5
PCWP, pulmonary capillary wedge pressure; PAP, pulmonary artery pressure; RVP, right ventricular pressure; RAP, right atrial pressure; CO, cardiac output; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance.
e26 immunodeficiency virus (HIV) infection, or human herpes virus (HHV)8 infection. She had no evidence of microangiopathic hemolytic anemia, such as an increase in fragmented cells or elevated lactate dehydrogenase, which are frequently seen in thrombotic microangiopathy. PH associated with respiratory disease and chronic thromboembolic pulmonary hypertension were further excluded on clinical grounds. Although the possibility of PAH associated with drugs and toxins or PVOD could not be excluded at that time, she was clinically diagnosed with PAH. Oxygen therapy was started on admission, and furosemide was simultaneously administered for 2 days (20 mg/day). Thereafter, warfarin and beraprost sodium (120 g/day) were started. Her general condition improved soon after initiation of treatment. After one month of treatment, 6MWD had markedly improved to 395 m with 1 L/min nasal O2 , BNP had decreased to 12.9 pg/mL, and UA had also decreased to 4.8 mg/dL. UCG examination revealed normal contraction of the heart, and the abnormal contour of the inter-ventricular septum and her tricuspid valve regurgitation had disappeared (Fig. 2B). Her general condition was stable in New York Heart Association (NYHA) Class II, and she was discharged on August 31, 2008 with 1.5 mg/day warfarin (prothrombin-international normalized ratio: 2.35) and beraprost sodium without oxygen therapy. Her BNP and UA were maintained at low levels (BNP 17.2 pg/mL and UA 4.7 mg/dL) during a year of observation in the out-patient clinic without any signs of heart failure (NYHA Class I).
Discussion In the updated Dana Point classification, BMT is not characterized as associated with PH. However, drugs- and toxins-induced PAH are included in the category of PAH [4]. In addition, chemotherapeutic agents are classified as ‘possible’ risk factors in the updated lists for PAH [10]. Although PVOD has been reported in association with BMT [5—9], attributed in part to direct injury by chemotherapeutic agents and radiation therapy [11,12], PAH as a complication of BMT has only rarely been reported. In the present case, (1) PH occurred after BMT, (2) enhanced chest CT scan and ventilation-perfusion scintigraphy did not reveal pulmonary embolism, and (3) her clinical course did not deteriorate and was instead improved with medical treatment. We therefore diagnosed her PH as PAH related to BMT. However, because we did not perform lung biopsy, we could not exclude the possibility of PVOD, the most common form of PH associated with BMT. Vaksmann et al. described the onset of PAH 5 months post-BMT in an 8-year-old girl conditioned with busulphan, cyclophosphamide, and cytarabine [13]. They found no signs of pulmonary vein involvement that would have suggested veno-occlusive disease. Open-lung biopsy revealed lesions located exclusively in small pulmonary arteries and arterioles with medial hypertrophy and intimal fibrosis associated with plexiform lesions, and the pulmonary veins and venules were normal. Prostacyclin and diltiazem infusion reduced pulmonary vascular resistance without significant modification of systemic vascular resistance or cardiac output, and the patient was discharged from hospital on oral diltiazem
H. Nakaoka et al. and an anticoagulant in NYHA Class II. Our patient was also treated with busulphan and cyclophosphamide, and subsequently with BMT, and her pulmonary hypertension markedly improved with oral prostacyclin and an anticoagulant. PH has been reported as a complication of BMT in several disease groups. Although we excluded PTE in this case, there are reports of PTE in association with BMT [14]. Whether epithelial-alveolar injury induced by chemotherapeutic agents or radiation results in the development of PTE or whether other factors play a role in the pathogenesis of PTE is unknown. PAH of late onset after BMT has been reported in association with GVHD [15]. Bronchiolitis obliterans, interstitial pneumonia, and pulmonary fibrosis are well-recognized complications of BMT. These disorders are strongly associated with GVHD, suggesting that the small airways and lung parenchyma are tissues targeted by immune processes in the post-transplant period. However, serum KL6 level after BMT was maintained as normal and chest CT scan in our patient yielded no evidence of pulmonary complications and no signs of GVHD. Another possible cause of PAH is infection with a vasculotrophic virus, such as HHV8 or HIV [16], which has been postulated to play a role in PAH. A reactivation of the viruses during post-transplant period has been reported. However, there was no evidence of HHV8 or HIV infection in our patient. Holcomb et al. suggested that PH associated with hematologic malignancies has received considerable attention as a potential cause of PVOD [17]. In general, the clinical course of PVOD is progressive, and, though there may be a few patients who respond to medical therapy, long-term survival is poor and remission has never been reported. The cause of PVOD remains unclear, although association of it with multiple conditions has been reported, and most cases of it have been diagnosed at autopsy. The actual incidence of PVOD after BMT is unknown, and it may be more prevalent than commonly believed, given the difficulty in diagnosing it. It is possible that less severe cases of it are diagnosed as other illnesses [9]. We therefore cannot exclude the possibility of chemotherapy-induced injury to the pulmonary vascular endothelium in this patient, various possibilities remain, such as PAH associated with drugs and toxins, a less severe case of PVOD, or other illness. The issue of interest in this case is the underlying pathological cause of the vascular injury. Although we were unable to clearly determine the cause of her PH, early appropriate treatment resulted in improvement of her PH. While the possibility of coincidental overlap with toxicity after BMT cannot be excluded, the clinical context suggests that injury to pulmonary vessels may occur after BMT, and not only in the context of GVHD. There has been no previous report of reversible PAH in association with BMT in an adult. In the early stage of human PAH, the disease has two components: pulmonary vasoconstriction and vascular remodeling. As the disease progresses, the capacity of the pulmonary vascular bed to dilate and recruit unused vasculature is lost. Considering the effectiveness of the medical treatment, the vasoconstriction of small arteries may be the pivotal mechanism for the pathogenesis of PAH in this case. Whatever its pathogenesis, this case indicates that PH should be considered in post-BMT patients with dyspnea
PH associated with BMT without evidence of pulmonary parenchymal disease or bronchiolitis. We have presented here for the first time an adult case of PAH after BMT with marked improvement with medical treatment. This case indicates that attention must be paid to the clinical symptoms and physical findings of PH as a possible complication of BMT.
References [1] Shipley JL, Butera JN. Acute myelogenous leukemia. Exp Hematol 2009;37:649—58. [2] Fischer A, Landais P, Friedrich W, Gerritsen B, Fasth A, Porta F, Vellodi A, Benkerrou M, Jais JP, Cavazzana-Calvo M. Bone marrow transplantation (BMT) in Europe for primary immunodeficiencies other than severe combined immunodeficiency: a report from the European Group for BMT and the European Group for Immunodeficiency. Blood 1994;83:1149—54. [3] Badesch DB, Champion HC, Sanchez MAG, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(Suppl.):S55—66. [4] Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcrox M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(Suppl.):S43—54. [5] Hackman RC, Madtes DK, Petersen FB, Clark JG. Pulmonary venoocclusive disease following bone marrow transplantation. Transplantation 1989;47:989—92. [6] Wingard JR, Mellits ED, Jones RJ, Beschorner WE, Sostrin MB, Burns WH, Santos GW, Saral R. Association of hepatic venoocclusive disease with interstitial pneumonitis in bone marrow transplant recipients. Bone Marrow Transplant 1989;4:685—9. [7] Kuga T, Kohda K, Hirayama Y, Matsumoto S, Nakazawa O, Ando M, Ezoe A, Nobuoka A, Mochizuki C. Pulmonary veno-occlusive disease accompanied by microangiopathic hemolytic anemia 1 year after a second bone marrow transplantation for acute lymphoblastic leukemia. Int J Hematol 1996;64:143—50.
e27 [8] Seguchi M, Hirabayashi N, Fujii Y, Azuno Y, Fujita N, Takeda K, Sato Y, Nishimura M, Yamada K, Oka Y. Pulmonary hypertension associated with pulmonary occlusive vasculopathy after allogeneic bone marrow transplantation. Transplantation 2000;69:177—9. [9] Trobaugh-Lotrario AD, Greffe B, Deterding R, Deutsch G, Quinones R. Pulmonary veno-occlusive disease after autologous bone marrow transplant in a child with stage IV neuroblastoma: case report and literature review. J Pediatr Hematol Oncol 2003;25:405—9. [10] McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Rubin LJ, Tapson VF, Varga J. ACCF/AHA 2009 Expert consensus document on pulmonary hypertension. Circulation 2009;119:2250—94. [11] Doll DC, Yarbro JW. Vascular toxicity associated with antineoplastic agents. Semin Oncol 1992;19:580—96. [12] Kramer MR, Estenne M, Berkman N, Antoine M, de Francquen P, Lipski A, Jacobovitz D, Lafair J. Radiation-induced pulmonary veno-occlusive disease. Chest 1993;104:1282—4. [13] Vaksmann G, Nelken B, Deshildre A, Rey C. Pulmonary arterial occlusive disease following chemotherapy and bone marrow transplantation for leukaemia. Eur J Pediatr 2002;161:247— 9. [14] Uderzo C, Marraro G, Riva A, Bonanomi E, Vaj PL, Marchi PF, Locasciulli A, Masera G. Pulmonary thromboembolism in leukaemic children undergoing bone marrow transplantation. Bone Marrow Transplant 1993;11:201—3. [15] Grigg A, Buchanan M, Whitford H. Late-onset pulmonary arterial hypertension in association with graft-versus-host disease after allogeneic stem-cell transplantation. Am J Hematol 2005;80:38—42. [16] Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, Voelkel NF. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003;349:1113— 22. [17] Holcomb Jr BW, Loyd JE, Ely EW, Johnson J, Robbins IM. Pulmonary veno-occlusive disease: a case series and new observations. Chest 2000;118:1671—9.
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Case Report
Pulmonary hypertension associated with bone marrow transplantation Hajime Nakaoka (MD) a, Yasushi Sakata (MD) a, Masaki Yamamoto (MD) b, Tetsuo Maeda (MD) b, Yoh Arita (MD) a, Wataru Shioyama (MD) a, Yoshikazu Nakaoka (MD) a, Yuzuru Kanakura (MD) b, Shizuya Yamashita (MD) a, Issei Komuro (MD, FJCC) a, Keiko Yamauchi-Takihara (MD) a,∗ a b
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
Received 27 November 2009; received in revised form 4 January 2010; accepted 14 January 2010
KEYWORDS Pulmonary arterial hypertension; Bone marrow transplantation; Pulmonary veno-occlusive disease; Chemotherapy; Leukemia
Summary Bone marrow transplantation (BMT) is one of the promising methods of treatment of hematologic malignancy. However, it has a variety of complications since it involves fatal doses of anti-cancer drugs and radiation during the conditioning period. Among the various complications of BMT, pulmonary hypertension is rare and its pathogenesis is poorly understood. A 35-year-old female with acute myeloid leukemia (AML) presented with pulmonary hypertension after BMT. Although she exhibited severe dyspnea on admission, her general condition markedly improved after oxygen therapy and treatment with warfarin and beraprost sodium. Her pulmonary hypertension was diagnosed as pulmonary arterial hypertension (PAH) related to BMT. Although PAH has only rarely been reported as a complication of BMT, we present here for the first time an adult patient with PAH associated with BMT who exhibited marked improvement with medical treatment. This case indicates that attention needs to be paid to the clinical symptoms and physical findings of PAH as a complication of BMT. © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Introduction
∗ Corresponding author at: Health Care Center, Osaka University; Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 1-17 Machikaneyama 560-0043, Japan. Tel.: +81 6 6850 6012; fax: +81 6 6850 6040. E-mail address: [email protected] (K. Yamauchi-Takihara).
Acute myeloid leukemia (AML) involves a hematopoietic transformation characterized by impaired differentiation of hematopoietic stem or progenitor cells, resulting in abnormal growth of a clonal subpopulation of neoplastic cells or blasts. This malignant alteration may lead to a loss of normal hematopoietic function, typically resulting in death within a few weeks to months [1]. Bone marrow transplantation (BMT), one of the key treatments of AML, dramatically
1878-5409/$ — see front matter © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jccase.2010.01.008
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H. Nakaoka et al.
improves the prognosis of AML. It has been used not only for patients with AML but also for patients with a wide variety of hematologic malignancies and benign diseases such as aplastic anemia. However, it features a variety of complications that result from the chemotherapy and radiotherapy applied during the conditioning period. Well-known complications of BMT include graft-versus host disease (GVHD), graft failure, interstitial pneumonitis, B-lymphocyte proliferative disorder, and various infections [2]. In contrast, pulmonary hypertension (PH) is rare as a complication of BMT, and its mechanism of onset remains poorly understood. PH is a rare progressive disease with poor prognosis. PH features a resting mean pulmonary arterial pressure (PAP) ≥25 mmHg, and one of the subgroups of pre-capillary PH, with pulmonary capillary wedge pressure (PCWP) ≤15 mmHg, is classified as pulmonary arterial hypertension (PAH) according to the updated clinical classification of PH reported by the Symposium at Dana Point, California in 2008 [3,4]. One of the prominent changes in this classification from the Venice classification is that pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis are moved from a separate category into a subcategory of PAH [4]. Although PVOD is the most common feature of PH reported in association with BMT, there have been reported few case reports of it [5—9]. We report here a 35-year-old female with AML, who presented with PH after BMT. Although she had severe dyspnea, her general condition markedly improved after oxygen therapy and treatment with warfarin and beraprost sodium. PAH has only rarely been reported as a complication of BMT, and there has been no report of reversible PAH in association with BMT in an adult. We present here for the first time a patient with PAH after BMT who exhibited marked improvement with early medical treatment.
Figure 1
Case report A 35-year-old woman was diagnosed with AML with maturation (AML M2 in FAB classification) in October 2007 at 30-weeks of pregnancy. She was transferred to the Department of Hematology and Oncology and Department of Obstetrics of Osaka University Hospital, and underwent induced labor on October 24. After giving birth to her baby, chemotherapy was begun for induction of remission, followed by three courses of consolidation therapy. On March 28, 2008, she received a BMT from an HLA-identical brother while her disease was in complete remission. Busulphan (36 mg/day) was used for 4 days and cyclophosphamide (2700 mg/day) for 2 days for conditioning for BMT. GVHD prophylaxis was performed using the standard regimen, with cyclosporine and a short course of methotrexate. Serum KL-6 levels before and after BMT were 189 U/mL and 159 U/mL, respectively. She had no complication of BMT, including GVHD, and was discharged two months later (day 68) in a relatively good condition. Soon after leaving the hospital, however, she gradually developed shortness of breath and was re-hospitalized with symptoms of severe heart failure. She was transferred to the Department of Cardiovascular Medicine on July 2, 2008 (day 94). On admission, her heart rate was 108 bpm, her blood pressure was 92/68 mmHg, and oxygen saturation on room air was 93%. Physical examination revealed no abnormal breath or heart sounds and no leg edema. Arterial blood gas analysis on room air revealed a pO2 62.6 mmHg and pCO2 30.6 mmHg. Laboratory data on admission are summarized in Table 1. Brain natriuretic peptide (BNP) was 702 pg/mL and serum uric acid (UA) was 7.2 mg/dL. Although the electrocardiography (ECG) showed sinus tachycardia of 115 bpm, chest radiography revealed no cardiomegaly and no signs of
Chest radiography (A) and chest computed tomography (B) on admission.
PH associated with BMT Table 1 WBC RBC Plt Na K BUN Creatinine T-bilirubin AST ALT ␥-GTP ALP LDH UA CRP
e25
Laboratory data on admission. 4.70 × 103 /L 3.74 × 103 /L 164 × 103 /L 141 mequiv./L 4.7 mequiv./L 15 mg/dL 0.75 mg/dL 0.8 mg/dL 29 U/L 26 U/L 15 U/L 102 U/L 235 U/L 7.2 mg/dL 0.04 mg/dL
BNP PT-INR APTT D-dimer HIV ANA HHV8 Blood analysis pCO2 pO2 HCO3 BE SaO2 pH
702 pg/mL 1.27 28 s 1.80 g/mL Negative ≤1:40 Negative 30.6 mmHg 62.6 mmHg 20.3 mequiv./L −2.6 mequiv./L 91.9% 7.435
WBC, white blood cells; RBC, red blood cells; Plt, platelets; BUN, blood urea nitrogen; T-bilirubin, total bilirubin; AST, aspartate transaminase; ALT, alanine transaminase; ␥-GTP, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; UA, uric acid; CRP, C-reactive protein; BNP, brain natriuretic peptide; PT-INR, prothrombin-international normalized ratio; APTT, activated partial thromboplastin time; HIV, human immunodeficiency virus; ANA, antinuclear antibody; HHV, human herpes virus; BE, base excess.
Figure 2 Echocardiographic images. (A) On admission, right ventricular systolic pressure was 38 mmHg and reverse curvature of the inter-ventricular septum was noted. (B) After one month of treatment, left and right ventricular contraction were normal and her tricuspid valve regurgitation had disappeared.
congestive heart failure (Fig. 1A). The result of the 6-min walking distance (6MWD) test was 237 m with 2 L/min nasal O2 at that time. Echocardiographic (UCG) examination was performed prior to BMT, and showed normal cardiac function and normal right ventricular (RV) pressure. However, her tricuspid regurgitation-pressure gradient was 38 mmHg, the diameter of inferior vena cava was 14 mm and reverse curvature of the inter-ventricular septum was noted at that time. Left ventricular (LV) contraction was normal (Fig. 2A). Chest computed tomography (CT) and lung perfusion scintigraphy yielded no evidence of pulmonary thromboembolism (PTE). High-resolution chest CT revealed no sign of centrilobular ground-grass opacities, septal lines, or lymph node enlargement, which are suggestive for PVOD. In addition, enhanced CT revealed no pulmonary embolism and no deep vein thrombosis (Fig. 1B). The results of right heart catheterization (RHC) are summarized in Table 2. PCWP was normal (mean PCWP: 7 mmHg), cardiac output
2.74 L/min/m2 , mean PAP 35 mmHg, and pulmonary vascular resistance was high (545 dyn s/cm5 ). There was no evidence of family history of PAH, collagen disease, chronic hepatitis, portal hypertension, human
Table 2 PCWP PAP RVP RAP CO SVR PVR
Right heart catheterization data. (7) mmHg 42/28(35) mmHg 46/4/10 mmHg (7) mmHg 4.11 L/min 1888 dyn s/cm5 545 dyn s/cm5
PCWP, pulmonary capillary wedge pressure; PAP, pulmonary artery pressure; RVP, right ventricular pressure; RAP, right atrial pressure; CO, cardiac output; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance.
e26 immunodeficiency virus (HIV) infection, or human herpes virus (HHV)8 infection. She had no evidence of microangiopathic hemolytic anemia, such as an increase in fragmented cells or elevated lactate dehydrogenase, which are frequently seen in thrombotic microangiopathy. PH associated with respiratory disease and chronic thromboembolic pulmonary hypertension were further excluded on clinical grounds. Although the possibility of PAH associated with drugs and toxins or PVOD could not be excluded at that time, she was clinically diagnosed with PAH. Oxygen therapy was started on admission, and furosemide was simultaneously administered for 2 days (20 mg/day). Thereafter, warfarin and beraprost sodium (120 g/day) were started. Her general condition improved soon after initiation of treatment. After one month of treatment, 6MWD had markedly improved to 395 m with 1 L/min nasal O2 , BNP had decreased to 12.9 pg/mL, and UA had also decreased to 4.8 mg/dL. UCG examination revealed normal contraction of the heart, and the abnormal contour of the inter-ventricular septum and her tricuspid valve regurgitation had disappeared (Fig. 2B). Her general condition was stable in New York Heart Association (NYHA) Class II, and she was discharged on August 31, 2008 with 1.5 mg/day warfarin (prothrombin-international normalized ratio: 2.35) and beraprost sodium without oxygen therapy. Her BNP and UA were maintained at low levels (BNP 17.2 pg/mL and UA 4.7 mg/dL) during a year of observation in the out-patient clinic without any signs of heart failure (NYHA Class I).
Discussion In the updated Dana Point classification, BMT is not characterized as associated with PH. However, drugs- and toxins-induced PAH are included in the category of PAH [4]. In addition, chemotherapeutic agents are classified as ‘possible’ risk factors in the updated lists for PAH [10]. Although PVOD has been reported in association with BMT [5—9], attributed in part to direct injury by chemotherapeutic agents and radiation therapy [11,12], PAH as a complication of BMT has only rarely been reported. In the present case, (1) PH occurred after BMT, (2) enhanced chest CT scan and ventilation-perfusion scintigraphy did not reveal pulmonary embolism, and (3) her clinical course did not deteriorate and was instead improved with medical treatment. We therefore diagnosed her PH as PAH related to BMT. However, because we did not perform lung biopsy, we could not exclude the possibility of PVOD, the most common form of PH associated with BMT. Vaksmann et al. described the onset of PAH 5 months post-BMT in an 8-year-old girl conditioned with busulphan, cyclophosphamide, and cytarabine [13]. They found no signs of pulmonary vein involvement that would have suggested veno-occlusive disease. Open-lung biopsy revealed lesions located exclusively in small pulmonary arteries and arterioles with medial hypertrophy and intimal fibrosis associated with plexiform lesions, and the pulmonary veins and venules were normal. Prostacyclin and diltiazem infusion reduced pulmonary vascular resistance without significant modification of systemic vascular resistance or cardiac output, and the patient was discharged from hospital on oral diltiazem
H. Nakaoka et al. and an anticoagulant in NYHA Class II. Our patient was also treated with busulphan and cyclophosphamide, and subsequently with BMT, and her pulmonary hypertension markedly improved with oral prostacyclin and an anticoagulant. PH has been reported as a complication of BMT in several disease groups. Although we excluded PTE in this case, there are reports of PTE in association with BMT [14]. Whether epithelial-alveolar injury induced by chemotherapeutic agents or radiation results in the development of PTE or whether other factors play a role in the pathogenesis of PTE is unknown. PAH of late onset after BMT has been reported in association with GVHD [15]. Bronchiolitis obliterans, interstitial pneumonia, and pulmonary fibrosis are well-recognized complications of BMT. These disorders are strongly associated with GVHD, suggesting that the small airways and lung parenchyma are tissues targeted by immune processes in the post-transplant period. However, serum KL6 level after BMT was maintained as normal and chest CT scan in our patient yielded no evidence of pulmonary complications and no signs of GVHD. Another possible cause of PAH is infection with a vasculotrophic virus, such as HHV8 or HIV [16], which has been postulated to play a role in PAH. A reactivation of the viruses during post-transplant period has been reported. However, there was no evidence of HHV8 or HIV infection in our patient. Holcomb et al. suggested that PH associated with hematologic malignancies has received considerable attention as a potential cause of PVOD [17]. In general, the clinical course of PVOD is progressive, and, though there may be a few patients who respond to medical therapy, long-term survival is poor and remission has never been reported. The cause of PVOD remains unclear, although association of it with multiple conditions has been reported, and most cases of it have been diagnosed at autopsy. The actual incidence of PVOD after BMT is unknown, and it may be more prevalent than commonly believed, given the difficulty in diagnosing it. It is possible that less severe cases of it are diagnosed as other illnesses [9]. We therefore cannot exclude the possibility of chemotherapy-induced injury to the pulmonary vascular endothelium in this patient, various possibilities remain, such as PAH associated with drugs and toxins, a less severe case of PVOD, or other illness. The issue of interest in this case is the underlying pathological cause of the vascular injury. Although we were unable to clearly determine the cause of her PH, early appropriate treatment resulted in improvement of her PH. While the possibility of coincidental overlap with toxicity after BMT cannot be excluded, the clinical context suggests that injury to pulmonary vessels may occur after BMT, and not only in the context of GVHD. There has been no previous report of reversible PAH in association with BMT in an adult. In the early stage of human PAH, the disease has two components: pulmonary vasoconstriction and vascular remodeling. As the disease progresses, the capacity of the pulmonary vascular bed to dilate and recruit unused vasculature is lost. Considering the effectiveness of the medical treatment, the vasoconstriction of small arteries may be the pivotal mechanism for the pathogenesis of PAH in this case. Whatever its pathogenesis, this case indicates that PH should be considered in post-BMT patients with dyspnea
PH associated with BMT without evidence of pulmonary parenchymal disease or bronchiolitis. We have presented here for the first time an adult case of PAH after BMT with marked improvement with medical treatment. This case indicates that attention must be paid to the clinical symptoms and physical findings of PH as a possible complication of BMT.
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