- Email: [email protected]
A 34-Year-Old Man With Bilateral Paraspinal Masses and Shortness of Breath
[
Pulmonary, Critical Care, and Sleep Pearls
]
A 34-Year-Old Man With Bilateral Paraspinal Masses and Shortness of Breath Kyle White, MD; Charles Blay, MD; Ali Ataya, MD; Hassan Alnuaimat, MD; and Raju Reddy, MD
A 34-year-old man with history of b-thalassemia major and splenectomy presented with a 1-month history of progressively worsening dyspnea, orthopnea, localized chest discomfort, and lower extremity edema. He denied fevers, chills, nasal congestion, and night sweats. He denied tobacco, alcohol, and illicit substance abuse. Family history was remarkable for lung cancer in his mother. CHEST 2019; 156(5):e99-e102
CASE PRESENTATION:
Physical Examination On examination, he was afebrile, with a heart rate of 91 beats/min, BP 104/59 mm Hg, respiratory rate of 17 breaths/min, and oxygen saturation was 94% on a 2-L nasal cannula. He was ill-appearing and cachectic. He had jugular venous distension, enlarged facial bones, bibasilar lung crackles on auscultation, a systolic ejection
murmur along the left sternal border that was more prominent with inspiration, and bilateral lower extremity pitting edema.
Diagnostic Studies Laboratory values were significant for hemoglobin 10.3 g/dL, total bilirubin 4.7 mg/dL, direct bilirubin 1.4 mg/
Figure 1 – CT chest showing an enlarged pulmonary artery and bilateral paraspinal masses.
ABBREVIATIONS: EMH = extramedullary hematopoiesis; Hgb = hemoglobulin; NO = nitric oxide; PH = pulmonary hypertension; RHC = right heart catheterization; SPECT = single-photon emission computed tomography; Tc-99 SC = technetium-99m sulfur colloid; TM = b-thalassemia major AFFILIATIONS: From the Department of Internal Medicine (Drs White and Blay), University of Florida; Pulmonary, Critical Care and Sleep Medicine (Dr Ataya), UF Health Shands; Pulmonary, Critical Care and Sleep Medicine (Drs Alnuaimat and Reddy), University of Florida, Gainesville, FL.
chestjournal.org
CORRESPONDENCE TO: Raju Reddy, MD, Pulmonary, Critical Care and Sleep Medicine, University of Florida, 1600 SW Archer Rd, PO Box 100225, Gainesville, FL 32610; e-mail: [email protected]fl. edu Published by Elsevier Inc. under license from the American College of Chest Physicians. DOI: https://doi.org/10.1016/j.chest.2019.05.043
e99
Figure 2 – Technetium-99m sulfur colloid single-photon emission CT showed uptake in the paraspinal masses and liver.
dL, and brain natriuretic peptide 1,742 pg/mL (normal < 100 pg/mL). The remainder of the metabolic panel, complete blood count, and cardiac markers were normal. Chest radiograph showed pulmonary artery enlargement and cardiomegaly. CT scan of the chest showed soft-tissue masses in the anterior left hemithorax and bilateral posterior paraspinal region, cardiomegaly, and an enlarged main pulmonary artery at 4.8 cm (Fig 1). Echocardiogram revealed a severely dilated right ventricle with depressed systolic function and a right
e100 Pulmonary, Critical Care, and Sleep Pearls
ventricular systolic pressure of 80 mm Hg. Right heart catheterization (RHC) showed a mean pulmonary artery pressure of 35 mm Hg, pulmonary artery occlusion pressure of 10 mm Hg, cardiac output 6.4 L/ min, and pulmonary vascular resistance (PVR) of 3.9 Woods units. Technetium-99m sulfur colloid (Tc-99 SC) single-photon emission CT (SPECT-CT) showed tracer uptake in the thoracic masses (Fig 2).
What is the diagnosis?
[
156#5 CHEST NOVEMBER 2019
]
Diagnosis: Group 5 pulmonary hypertension resulting from b-thalassemia major with extramedullary hematopoiesis Discussion b-thalassemia is an inherited disorder caused by defective production of b-globulin, a component of hemoglobin A (Hgb A). There are two clinically significant variants of b-thalassemia: b-thalassemia intermedia and b-thalassemia major (TM). Although b-thalassemia intermedia patients generally follow a milder course with clinically significant anemia during times of illness only, TM patients are usually transfusion-dependent from infancy. Other clinical manifestations of TM include skeletal deformities; hepatosplenomegaly; various sites of extramedullary hematopoiesis (EMH) such as the ribs, vertebrae, and pelvic bones; hemolytic anemia; and pulmonary hypertension (PH). PH, defined as mean pulmonary artery pressure $ 20 mm Hg at rest, is a complex disorder with significant morbidity and mortality associated with several systemic disorders. PH associated with hematologic disorders is classified as group 5 in the 2018 6th World Symposium on PH. The prevalence of PH in TM ranges from 10% to 75% based on echocardiographic criteria; however, when assessed by RHC, the prevalence is significantly lower at 1.1%. Risk factors for developing PH in patients with TM include older age and history of splenectomy. The pathophysiology responsible for PH in b-thalassemia is multifactorial. First, chronic anemia from hemolysis increases PVR by hypoxia-induced vasoconstriction. Second, nitric oxide (NO) bioavailability is reduced in chronic hemolysis via multiple mechanisms. Released free Hgb reacts with NO to form nitrate and methemoglobin. The enzyme arginase, released during hemolysis, depletes L-arginine, the substrate for NO synthase. Third, excess iron deposition in the pulmonary vasculature resulting from a combination of abnormal iron homeostasis and chronic transfusion therapy results in increased endothelial dysfunction and arterial wall stiffening. Fourth, hypercoagulability in the pulmonary circulation resulting from endothelial dysfunction, increased oxidative stress, platelet activation, and abnormal circulating products of hemolysis increases vascular pressures. Last, splenectomy also contributes to the pathogenesis of PH in patients with TM. The spleen removes damaged erythrocytes. Loss of the spleen’s
chestjournal.org
filtration function promotes erythrocyte aggregation and microthrombi in the pulmonary and systemic vasculature. Although echocardiography tends to overestimate the prevalence of PH in TM patients, it remains the main screening tool. Echocardiogram findings that reveal peak tricuspid regurgitant jet velocity > 2.9 m/s or other echocardiographic signs of PH such as an enlarged right ventricle or reduced right ventricle systolic function, often warrant further investigation with an RHC. An RHC with mean pulmonary artery pressure $ 20 mm Hg at rest is consistent with PH; pulmonary artery occlusion pressure # 15 mm Hg and an elevated PVR > 3 Wood units confirms the presence of precapillary PH. Frequently, a high cardiac output state is present during RHC in thalassemia patients. The gold standard in diagnosing EMH is by biopsy, but procedure-related hemorrhage remains a concern. In such cases, Tc-99 SC SPECT-CT is an option. SPECTCT allows precise localization of sites of EMH and is a reliable noninvasive diagnostic method. Therapeutic options for the treatment of PH resulting from b-thalassemia mainly consist of treating the underlying disease process. PH-specific therapies are often used, but have little to no prospective, randomized control data to prove their efficacy. The main treatment strategy is selective transfusion and iron-chelation therapy, when necessary, to prevent secondary hemochromatosis. Hydroxyurea is used to increase Hgb F production, which has been shown to protect from development of PH. Stem cell transplant remains the only curative therapy for TM. Supportive care with supplemental oxygen to avoid hypoxia-induced pulmonary vasoconstriction, cardiopulmonary rehabilitation, and routine immunizations (including pneumococcal and annual influenza vaccination) should be standard of care. Diuretics, digoxin, and inotropic agents can be used when indicated to control volume status, arrhythmias, and cardiac dysfunction. Appropriate anticoagulation and evaluation for pulmonary endarterectomy should be considered for those with evidence of chronic thromboembolic disease. Among pulmonary vasodilator therapies, phosphodiesterase type 5 inhibitors are most commonly used. Endothelin receptor antagonists are also an option. Patients usually improve in their overall functional status and cardiopulmonary hemodynamics with PH specific therapy. Prostacyclin therapy is rarely necessary. L-carnitine administration is associated with
e101
improvement in hemodynamic measurements, but data are very limited.
SPECT-CT is a reliable tool to diagnose EMH. A biopsy may not be necessary.
The long-term impact on mortality in TM patients who develop PH remains unknown; however, the presence of PH in patients with TM is associated with significant morbidity. It is associated with reduction in 6-min walk distances and overall functional status. Cardiovascular complications resulting from iron overload cardiomyopathy or anemia-induced heart failure are the major causes of death in TM major patients and account for 71% of global deaths in this group. Because of recent advances in treatments such as safe transfusion practices and iron chelation therapy, long-term survival has improved.
4. In addition to hydroxyurea and RBC exchange transfusion to treat patients with TM, phosphodiesterase type 5 inhibitors are the most commonly used vasodilator in those with precapillary PH.
Clinical Course The patient was diuresed and started on tadalafil. A Tc99 SC SPECT-CT confirmed that the intrathoracic masses were indeed sites of EMH. He was started on hydroxyurea and underwent RBC exchange transfusion to improve oxygen-carrying capacity and correct his chronic hypoxic state. He was discharged on 2 L/min continuous oxygen by nasal cannula, tadalafil, hydroxyurea, and furosemide.
Clinical Pearls 1. Only 1.1% of patients with TM develop precapillary PH. 2. The pathophysiology responsible for PH in b-thalassemia is multifactorial and a consequence of chronic hemolysis, reduced NO bioavailability, iron overload, hypercoagulability, and splenectomy. 3. Common sites of EMH include the paravertebral area, medial surfaces of ribs, and pelvic bones. Tc-99 SC
e102 Pulmonary, Critical Care, and Sleep Pearls
Acknowlegments Financial/nonfinancial disclosures: None declared. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggest Readings El-Beshlawy A, Youssry I, El-Saidi S, et al. Pulmonary hypertension in beta-thalassemia major and the role of L-carnitine therapy. Pediatr Hematol Oncol. 2008;25(8):734-743. Karimi M, Borzouee M, Mehrabani A, Cohan N. Echocardiographic finding in beta-thalassemia intermedia and major: absence of pulmonary hypertension following hydroxyurea treatment in beta-thalassemia intermedia. Eur J Haematol. 2009;82(3):213-218. Derchi G, Galanello R, Bina P, et al. Prevalence and risk factors for pulmonary arterial hypertension in a large group of b-thalassemia patients using right heart catheterization: a Webthal study. Circulation. 2014;129(3):338-345. Bazan IS, Fares WH. Pulmonary hypertension: diagnostic and therapeutic challenges. Ther Clin Risk Manag. 2015;11:1221-1233. Lee S, Paudel O, Jiang Y, Yang XR, Sham JS. CD38 mediates angiotensin II-induced intracellular Ca(2þ) release in rat pulmonary arterial smooth muscle cells. Am J Respir Cell Mol Biol. 2015;52(3):332-341. Fraidenburg DR, Machado RF. Pulmonary hypertension associated with thalassemia syndromes. Ann N Y Acad Sci. 2016;1368(1):127-139. Kalantari S, Gomberg-Maitland M. Group 5 pulmonary hypertension: the orphan’s orphan disease. Cardiol Clin. 2016;34(3):443-449. Yang M, Roarke M. Diffuse pulmonary extramedullary hematopoiesis in myelofibrosis diagnosed with technetium-99m sulfur colloid bone marrow scintigraphy and single photon emission computerized tomography/CT. Am J Hematol. 2017;92(3):323-324. Yang M, Covington MF, Nguyen BD, Johnson GB, Mesa RA, Roarke MC. Tc-Sulfur colloid bone marrow scintigraphy in diagnosis of diffuse pulmonary extramedullary hematopoiesis secondary to myelofibrosis. J Nucl Med Technol. 2018;46(4):368-372. Frost A, Badesch D, Gibbs JSR, et al. Diagnosis of pulmonary hypertension. Eur Respir J. 2019;53(1):801904.
[
156#5 CHEST NOVEMBER 2019
]
Pulmonary, Critical Care, and Sleep Pearls
]
A 34-Year-Old Man With Bilateral Paraspinal Masses and Shortness of Breath Kyle White, MD; Charles Blay, MD; Ali Ataya, MD; Hassan Alnuaimat, MD; and Raju Reddy, MD
A 34-year-old man with history of b-thalassemia major and splenectomy presented with a 1-month history of progressively worsening dyspnea, orthopnea, localized chest discomfort, and lower extremity edema. He denied fevers, chills, nasal congestion, and night sweats. He denied tobacco, alcohol, and illicit substance abuse. Family history was remarkable for lung cancer in his mother. CHEST 2019; 156(5):e99-e102
CASE PRESENTATION:
Physical Examination On examination, he was afebrile, with a heart rate of 91 beats/min, BP 104/59 mm Hg, respiratory rate of 17 breaths/min, and oxygen saturation was 94% on a 2-L nasal cannula. He was ill-appearing and cachectic. He had jugular venous distension, enlarged facial bones, bibasilar lung crackles on auscultation, a systolic ejection
murmur along the left sternal border that was more prominent with inspiration, and bilateral lower extremity pitting edema.
Diagnostic Studies Laboratory values were significant for hemoglobin 10.3 g/dL, total bilirubin 4.7 mg/dL, direct bilirubin 1.4 mg/
Figure 1 – CT chest showing an enlarged pulmonary artery and bilateral paraspinal masses.
ABBREVIATIONS: EMH = extramedullary hematopoiesis; Hgb = hemoglobulin; NO = nitric oxide; PH = pulmonary hypertension; RHC = right heart catheterization; SPECT = single-photon emission computed tomography; Tc-99 SC = technetium-99m sulfur colloid; TM = b-thalassemia major AFFILIATIONS: From the Department of Internal Medicine (Drs White and Blay), University of Florida; Pulmonary, Critical Care and Sleep Medicine (Dr Ataya), UF Health Shands; Pulmonary, Critical Care and Sleep Medicine (Drs Alnuaimat and Reddy), University of Florida, Gainesville, FL.
chestjournal.org
CORRESPONDENCE TO: Raju Reddy, MD, Pulmonary, Critical Care and Sleep Medicine, University of Florida, 1600 SW Archer Rd, PO Box 100225, Gainesville, FL 32610; e-mail: [email protected]fl. edu Published by Elsevier Inc. under license from the American College of Chest Physicians. DOI: https://doi.org/10.1016/j.chest.2019.05.043
e99
Figure 2 – Technetium-99m sulfur colloid single-photon emission CT showed uptake in the paraspinal masses and liver.
dL, and brain natriuretic peptide 1,742 pg/mL (normal < 100 pg/mL). The remainder of the metabolic panel, complete blood count, and cardiac markers were normal. Chest radiograph showed pulmonary artery enlargement and cardiomegaly. CT scan of the chest showed soft-tissue masses in the anterior left hemithorax and bilateral posterior paraspinal region, cardiomegaly, and an enlarged main pulmonary artery at 4.8 cm (Fig 1). Echocardiogram revealed a severely dilated right ventricle with depressed systolic function and a right
e100 Pulmonary, Critical Care, and Sleep Pearls
ventricular systolic pressure of 80 mm Hg. Right heart catheterization (RHC) showed a mean pulmonary artery pressure of 35 mm Hg, pulmonary artery occlusion pressure of 10 mm Hg, cardiac output 6.4 L/ min, and pulmonary vascular resistance (PVR) of 3.9 Woods units. Technetium-99m sulfur colloid (Tc-99 SC) single-photon emission CT (SPECT-CT) showed tracer uptake in the thoracic masses (Fig 2).
What is the diagnosis?
[
156#5 CHEST NOVEMBER 2019
]
Diagnosis: Group 5 pulmonary hypertension resulting from b-thalassemia major with extramedullary hematopoiesis Discussion b-thalassemia is an inherited disorder caused by defective production of b-globulin, a component of hemoglobin A (Hgb A). There are two clinically significant variants of b-thalassemia: b-thalassemia intermedia and b-thalassemia major (TM). Although b-thalassemia intermedia patients generally follow a milder course with clinically significant anemia during times of illness only, TM patients are usually transfusion-dependent from infancy. Other clinical manifestations of TM include skeletal deformities; hepatosplenomegaly; various sites of extramedullary hematopoiesis (EMH) such as the ribs, vertebrae, and pelvic bones; hemolytic anemia; and pulmonary hypertension (PH). PH, defined as mean pulmonary artery pressure $ 20 mm Hg at rest, is a complex disorder with significant morbidity and mortality associated with several systemic disorders. PH associated with hematologic disorders is classified as group 5 in the 2018 6th World Symposium on PH. The prevalence of PH in TM ranges from 10% to 75% based on echocardiographic criteria; however, when assessed by RHC, the prevalence is significantly lower at 1.1%. Risk factors for developing PH in patients with TM include older age and history of splenectomy. The pathophysiology responsible for PH in b-thalassemia is multifactorial. First, chronic anemia from hemolysis increases PVR by hypoxia-induced vasoconstriction. Second, nitric oxide (NO) bioavailability is reduced in chronic hemolysis via multiple mechanisms. Released free Hgb reacts with NO to form nitrate and methemoglobin. The enzyme arginase, released during hemolysis, depletes L-arginine, the substrate for NO synthase. Third, excess iron deposition in the pulmonary vasculature resulting from a combination of abnormal iron homeostasis and chronic transfusion therapy results in increased endothelial dysfunction and arterial wall stiffening. Fourth, hypercoagulability in the pulmonary circulation resulting from endothelial dysfunction, increased oxidative stress, platelet activation, and abnormal circulating products of hemolysis increases vascular pressures. Last, splenectomy also contributes to the pathogenesis of PH in patients with TM. The spleen removes damaged erythrocytes. Loss of the spleen’s
chestjournal.org
filtration function promotes erythrocyte aggregation and microthrombi in the pulmonary and systemic vasculature. Although echocardiography tends to overestimate the prevalence of PH in TM patients, it remains the main screening tool. Echocardiogram findings that reveal peak tricuspid regurgitant jet velocity > 2.9 m/s or other echocardiographic signs of PH such as an enlarged right ventricle or reduced right ventricle systolic function, often warrant further investigation with an RHC. An RHC with mean pulmonary artery pressure $ 20 mm Hg at rest is consistent with PH; pulmonary artery occlusion pressure # 15 mm Hg and an elevated PVR > 3 Wood units confirms the presence of precapillary PH. Frequently, a high cardiac output state is present during RHC in thalassemia patients. The gold standard in diagnosing EMH is by biopsy, but procedure-related hemorrhage remains a concern. In such cases, Tc-99 SC SPECT-CT is an option. SPECTCT allows precise localization of sites of EMH and is a reliable noninvasive diagnostic method. Therapeutic options for the treatment of PH resulting from b-thalassemia mainly consist of treating the underlying disease process. PH-specific therapies are often used, but have little to no prospective, randomized control data to prove their efficacy. The main treatment strategy is selective transfusion and iron-chelation therapy, when necessary, to prevent secondary hemochromatosis. Hydroxyurea is used to increase Hgb F production, which has been shown to protect from development of PH. Stem cell transplant remains the only curative therapy for TM. Supportive care with supplemental oxygen to avoid hypoxia-induced pulmonary vasoconstriction, cardiopulmonary rehabilitation, and routine immunizations (including pneumococcal and annual influenza vaccination) should be standard of care. Diuretics, digoxin, and inotropic agents can be used when indicated to control volume status, arrhythmias, and cardiac dysfunction. Appropriate anticoagulation and evaluation for pulmonary endarterectomy should be considered for those with evidence of chronic thromboembolic disease. Among pulmonary vasodilator therapies, phosphodiesterase type 5 inhibitors are most commonly used. Endothelin receptor antagonists are also an option. Patients usually improve in their overall functional status and cardiopulmonary hemodynamics with PH specific therapy. Prostacyclin therapy is rarely necessary. L-carnitine administration is associated with
e101
improvement in hemodynamic measurements, but data are very limited.
SPECT-CT is a reliable tool to diagnose EMH. A biopsy may not be necessary.
The long-term impact on mortality in TM patients who develop PH remains unknown; however, the presence of PH in patients with TM is associated with significant morbidity. It is associated with reduction in 6-min walk distances and overall functional status. Cardiovascular complications resulting from iron overload cardiomyopathy or anemia-induced heart failure are the major causes of death in TM major patients and account for 71% of global deaths in this group. Because of recent advances in treatments such as safe transfusion practices and iron chelation therapy, long-term survival has improved.
4. In addition to hydroxyurea and RBC exchange transfusion to treat patients with TM, phosphodiesterase type 5 inhibitors are the most commonly used vasodilator in those with precapillary PH.
Clinical Course The patient was diuresed and started on tadalafil. A Tc99 SC SPECT-CT confirmed that the intrathoracic masses were indeed sites of EMH. He was started on hydroxyurea and underwent RBC exchange transfusion to improve oxygen-carrying capacity and correct his chronic hypoxic state. He was discharged on 2 L/min continuous oxygen by nasal cannula, tadalafil, hydroxyurea, and furosemide.
Clinical Pearls 1. Only 1.1% of patients with TM develop precapillary PH. 2. The pathophysiology responsible for PH in b-thalassemia is multifactorial and a consequence of chronic hemolysis, reduced NO bioavailability, iron overload, hypercoagulability, and splenectomy. 3. Common sites of EMH include the paravertebral area, medial surfaces of ribs, and pelvic bones. Tc-99 SC
e102 Pulmonary, Critical Care, and Sleep Pearls
Acknowlegments Financial/nonfinancial disclosures: None declared. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggest Readings El-Beshlawy A, Youssry I, El-Saidi S, et al. Pulmonary hypertension in beta-thalassemia major and the role of L-carnitine therapy. Pediatr Hematol Oncol. 2008;25(8):734-743. Karimi M, Borzouee M, Mehrabani A, Cohan N. Echocardiographic finding in beta-thalassemia intermedia and major: absence of pulmonary hypertension following hydroxyurea treatment in beta-thalassemia intermedia. Eur J Haematol. 2009;82(3):213-218. Derchi G, Galanello R, Bina P, et al. Prevalence and risk factors for pulmonary arterial hypertension in a large group of b-thalassemia patients using right heart catheterization: a Webthal study. Circulation. 2014;129(3):338-345. Bazan IS, Fares WH. Pulmonary hypertension: diagnostic and therapeutic challenges. Ther Clin Risk Manag. 2015;11:1221-1233. Lee S, Paudel O, Jiang Y, Yang XR, Sham JS. CD38 mediates angiotensin II-induced intracellular Ca(2þ) release in rat pulmonary arterial smooth muscle cells. Am J Respir Cell Mol Biol. 2015;52(3):332-341. Fraidenburg DR, Machado RF. Pulmonary hypertension associated with thalassemia syndromes. Ann N Y Acad Sci. 2016;1368(1):127-139. Kalantari S, Gomberg-Maitland M. Group 5 pulmonary hypertension: the orphan’s orphan disease. Cardiol Clin. 2016;34(3):443-449. Yang M, Roarke M. Diffuse pulmonary extramedullary hematopoiesis in myelofibrosis diagnosed with technetium-99m sulfur colloid bone marrow scintigraphy and single photon emission computerized tomography/CT. Am J Hematol. 2017;92(3):323-324. Yang M, Covington MF, Nguyen BD, Johnson GB, Mesa RA, Roarke MC. Tc-Sulfur colloid bone marrow scintigraphy in diagnosis of diffuse pulmonary extramedullary hematopoiesis secondary to myelofibrosis. J Nucl Med Technol. 2018;46(4):368-372. Frost A, Badesch D, Gibbs JSR, et al. Diagnosis of pulmonary hypertension. Eur Respir J. 2019;53(1):801904.
[
156#5 CHEST NOVEMBER 2019
]