Extramedullary Hematopoiesis-Related Pleural Effusion: The Case of β-Thalassemia

Athanassios Aessopos, MD, PhD, Stergios Tassiopoulos, MD, Dimitrios Farmakis, MD, PhD, Ioannis Moyssakis, MD, PhD, Maria Kati, MD, Katerina Polonifi, MD, and Maria Tsironi, MD, PhD First Department of Internal Medicine, School of Medicine, University of Athens, “Laiko” Hospital, Athens, Greece

Background. Thalassemia intermedia has a later clinical onset and a milder anemia than thalassemia major, characterized by high output state, left ventricle remodeling, and age-related pulmonary hypertension. Bone deformities, extramedullary hematopoiesis (EMH), and spleen and liver enlargement are the consequences of hypoxia and enhanced erythropoiesis. The EMH-related pleural effusion is rarely referred to in the literature of thalassemia. Methods. We reviewed the thalassemia patients’ medical records hospitalized for pleural effusion in our Department, within the last 6 years. Results. Eight (4 men) thalassemia intermedia patients admitted for symptomatic pleural effusion were identified. Common clinical findings on admission were dyspnea and apyrexia. Their mean hemoglobin level was 7.15 ⴞ 0.64 g/dL. Radiology revealed intrathoracic EMH and pleural effusion in all patients: exudative in seven patients and massive hemothorax in one. Cytologic fluid analysis was negative for malignancy. Fluid and serum

cultures, antibodies, and stains were negative for viral, bacterial, and fungal infection. The hemothorax case was successfully treated with repeated aspirations, transfusions, and hydroxyurea. Although repeated thoracentesis and radiation could not control the effusions in the rest of the cases, pleurodesis was successful in 5 patients, without serious adverse events. Treatment was further accomplished with hydroxyurea. No relapses were observed in the mean 30 month follow-up period. Conclusions. Afebrile, EMH-related pleuritis represents a potentially life-threatening complication in thalassemia. Therapy should be individualized and treatment is emerging. Pleurodesis seems to be an effective and safe therapeutic option for exudative effusions, while transfusion-chelation therapy combined with hydroxyurea may be helpful in suppressing increased erythropoiesis.

E

lung diseases, EMH is rarely included in the list of possible causes of pleural effusion. Herein, we report on eight ␤-thalassemia patients who presented with symptomatic pleural effusion associated with intrathoracic EMH. We describe this clinically significant complication and discuss the entity in aspects of potential pathogenesis, clinical picture, laboratory findings, and treatment options. In addition, we review similar literature-reported cases of EMH-related pleural effusion with a variety of underlying diseases. Accumulation of such cases reinforces the role of EMH as a potential pathogenetic mechanism for the development of pleural effusion.

xtramedullary hematopoiesis (EMH), the formation of apparently normal blood cells outside the confines of the bone marrow, is an unusual phenomenon in a variety of hematologic disorders. It usually occurs as a compensatory response to chronic hemolytic conditions or to bone marrow infiltration by neoplastic or fibrotic tissue [1, 2]. The EMH involves, predominantly, the spleen, liver, and lymph nodes and, less frequently, other sites such as the kidneys, adrenals, thymus, breast, heart, epididymis, retroperitoneal and retropleural space, pleura, and peritoneum. Intrathoracic EMH is re1atively common in thalassemia, major and intermedia, when erythropoiesis is not suppressed adequately by transfusions. It mainly consists of paravertebral masses in the posterior mediastinum, usually asymptomatic and on1y rarely complicated by spinal cord compression due to infiltration of the epidural space. There are only sporadic literature reports of thalassemia patients with EMHrelated pleural effusion while, in the classic handbooks of Accepted for publication Jan 4, 2006. Address correspondence to Dr Tsironi, First Department of Internal Medicine, “Laiko” General Hospital, 17 Aghiou Thoma St, Athens 115 27, Greece; e-mail: [email protected].

© 2006 by The Society of Thoracic Surgeons Published by Elsevier Inc

(Ann Thorac Surg 2006;81:2037– 43) © 2006 by The Society of Thoracic Surgeons

Patients and Methods We investigated the medical records of all ␤-thalassemia patients hospitalized in our department between 1999 and 2004. The Institutional Review Board approved the study (January 15, 2005). The diagnosis was suggested by x-ray, confirmed by lung-mediastinum computed tomographic (CT) scan, and investigated further by effusion aspiration. Information on the hematologic profile of the 0003-4975/06/$32.00 doi:10.1016/j.athoracsur.2006.01.026

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Extramedullary Hematopoiesis-Related Pleural Effusion: The Case of ␤-Thalassemia

Paravertebral mass Paravertebral mass Paravertebral mass Paraspinal mass Paravertebral mass Paravertebral mass Paravertebral mass CT ⫽ computed tomographic.

Paravertebral mass

7.5 8.1 6.6 6.8 6.5 7.9 6.5

7.3

9.0 1,500 10.3 4,500 8.4 580 8.5 2,500 8.0 3,500 9.5 1,500 8.5 1,200

10.0 650

18 11 36 3 20 6

M 53 Not known Occasionally

Sex Age (years) Genotype Age of transfusions’ onset (years) Age of splenectomy (years) Mean hemoglobin (g/dL) Mean serum ferritin (ng/ mL) Hemoglobin on admission (g/dL) Chest CT scan

28

F 33 IVS I:5/IVS I:6 29 F 43 IVS I:6/IVS I:110 Occasionally F 43 IVS I:6/IVS I:110 Occasionally M 29 IVS I:5/IVS I:6 15 F 47 IVS II:705/IVS I:6 Occasionally

3 2 1 Patient No.

Thirty percent of all TI patients hospitalized in our department during the study period (25 TI patients) presented with pleural effusion. In all these patients the primary complaint was dyspnea on effort, gradually developed during the former few weeks. On clinical examination, hepatomegaly was a common finding, but pedal edema and jugular vein distention were absent in all the patients. A systolic ejection murmur was audible over the left sternal border in all. Electrocardiogram showed low voltage in leads I II III, aVR, aVL, and aVF in all cases, atrial fibrillation in two, and nonspecific ST-T changes in three. An echocardiographic study was performed and revealed left ventricular (LV) dilatation with normal ejection fraction (0.58 to 0.70 in all patients). Moderate pulmonary hypertension, estimated by peak systolic tricuspid pressure gradient, was present in all cases (tricuspid gradient range, 36 to 52 mm Hg; mean, 47 mm Hg). Arterial blood gases values indicated moderate hypoxemia and hypercapnia (So2 ⬍ 85%, Po2 ⬍ 70 mm Hg, Pco2 ⬎ 45 mm Hg). Chest radiography was performed in all the patients and it detected widening of the ribs, diffuse lung fibrosis, large paravertebral and(or) paraspinal EMH masses, and pleural effusion. Diagnosis was confirmed by lung-mediastinum CT scan in all patients (Fig 1). Pleural effusion was unilateral in 6 patients and bilateral in 2 (Table 2). Pleural aspiration was performed in all patients. Pleural fluid was clear in gross appearance, not milky, turbid, or bloody, with the exception of one patient with hemothorax. Fluid laboratory analysis revealed massive hemothorax in one patient (pleural fluid hematocrit 15%) and exudative fluid in the remaining 7 patients, according to the criteria of Light and colleagues [3]. The ratio of pleural fluid to serum protein concentration was greater than 0.55 in all 7 patients. Even though

4

Results

M 39 IVSI:5/IVS I:6 30

5

6

7

8

patients was provided by the records of the thalassemia unit of our department. Among the 37 thalassemia patients hospitalized due to different reasons in our department during the above period, we have identified 8 ␤-thalassemia patients (4 men) aged 29 to 56 years, admitted for symptomatic pleural effusion (Table 1). All patients had been classified as thalassemia intermedia (TI) cases, had been transfused only occasionally, or had commenced blood transfusions after the age of 15 years. Their mean life-long hemoglobin level was 9.02 ⫾ 0.82 g/dL (range, 8.0 to 10.4 g/dL) and the total number of blood units that they had received prior to their admission ranged from 15 to 340 units (mean value 160). Their mean hemoglobin level on admission was 7.15 ⫾ 0.64 g/dL (range, 6.5 to 8.1 g/dL). Iron chelation therapy had not been applied, as a rule, and serum ferritin levels ranged between 580 ng/mL and 4,500 ng/mL (mean value 950). All had undergone a splenectomy and a cholocystectomy. The mean follow-up time after discharge was 30 months (range, 4 to 74 months) and patients’ consent was obtained for the follow-up information.

32

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M 56 IVS I:6/IVS I:110 Occasionally

AESSOPOS ET AL EMH-RELATED PLEURAL EFFUSION IN ␤-THALASSEMIA

Table 1. Patient Characteristics

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2039

All administrations were effective, without any side effects, with the exception of a 48-hour febrile reaction in patient No. 6 (pleurodesis with bleomycin). The patient who presented with hemothorax (No. 4) was successfully treated with repeated aspirations (with a total of 5 L of pleural fluid removed), transfusions (8 units of packed red blood cells in total), and hydroxyurea. The 6 patients who remained alive were discharged in fair condition and were advised to undergo a regular transfusion-chelation therapy with a pretransfusion hemoglobin level higher than 9.5 g/dL. Treatment was further accomplished with hydroxyurea administration (6 to 8 mg/kg/day). No relapses were observed, but arterial hypoxemia persisted in the follow-up period after discharge (Po2 ⬍ 80 mm Hg). Patient No. 6 died 4 months later due to pulmonary infection, but without pleural effusion. Fig 1. Chest x-ray depicting widening of the ribs, left pleural effusion, and extramedullary hematopoietic foci in a thalassemia intermedia patient (patient No. 8).

Comment

lactate dehydrogenase (LDH) levels of the pleural effusions were quite high, the ratio of pleural to serum LDH concentration was borderline for exudate (range, 0.45 to 0.75), which can be explained by the high serum LDH values due to the hemolytic process. Pleural fluid glucose level was more than 60 mg/dL in all cases (range, 78 to 108 mg/dL) and fluid pH tended to be rather alkaline. The pleural fluid leukocyte count was quite low (range, 480 to 3,200 ⫻ 103/mL), with a lymphocytic predominance (range, 53% to 70%). Cytologic fluid analysis was negative for malignancy. Mesothelial cells were present, while myeloid elements were absent. Fluid cultures and staining were negative for bacterial (including tuberculosis) or fungal infections, while serum and fluid antibodies for influenza A and B, parainfluenza, adeno-, corona-, and rhinoviruses, respiratory syncytial virus, and herpes simplex virus were negative (Table 2). Immunologic blood serum and pleural fluid tests were negative for rheumatoid factor and antinuclear antibodies. Although all patients were afebrile, a broad-spectrum antibiotic treatment was provided in all, along with oxygen supply. In patient No. 1, a low radiation dose (10 Gy in 7 sessions in 9 days) followed by nonsteroid and steroid treatment administration did not succeed in controlling the effusion. Repeated thoracentesis (8 liters totally aspirated) and transfusions were needed. This patient died of nosocomial pneumonia and cardiac failure several weeks later, during hospitalization. Patient No. 5 died during the procedure of CT-guided aspiration. Clinicians hesitated to aspirate under bedside conditions to avoid a potential puncture of a large-sized EMH mass. Thoracentesis could not control the effusions in the rest of the patients as fluid was reaccumulating rapidly and repeated thoracentesis, removing large amounts of fluid (approximately 4 to 8 L), was required for the patients’ relief. Two patients underwent pleurodesis with tetracycline, two with bleomycin, and one with talc. Patient No. 3 underwent sequential pleural sclerosis in both lungs.

In the present series it is of note that all patients hospitalized due to EMH-related pleural effusion had been classified as thalassemia intermedia, while regularly transfused and chelated thalassemia major patients were not met. Thalassemia intermedia is an extremely heterogeneous disease, both genetically and clinically. A wide variety of genotypes may underlay this condition. Our patients were not regularly transfused, as they were usually maintaining a relatively acceptable hemoglobin level (8 to 10.4 g/dL). Such patients are under a constant hypoxia due to the decreased central blood oxygen load and the defective peripheral hemoglobin desaturation, resulting from the inappropriate intraerythrocytic adaptation to anemia and the elevated fetal hemoglobin percentage [4]. Constant and long lasting hypoxia leads to enhanced rate of erythropoiesis and increased intestinal iron absorption. The former results in marked bone marrow hyperplasia, with subsequent skeletal deformities and development of extramedullary foci of hematopoiesis, as indicated in the chest roentgenograms and CT scans of all our patients [5]. Pleural effusion associated with EMH is a rather uncommon phenomenon, with sporadic reports in the literature [6 –19]. In the majority of the reported cases the underlying disease was myelofibrosis [15–19]. Some additional sporadic reports with hemolytic disorders, including thalassemia [6 –10], sickle cell disease, hereditary spherocytosis [12, 13], and dyserythropoietic anemia have also been presented (Table 3). However, as patients with hemoglobinopathies are presently under close and careful follow-up, their life expectancy has been prolonged; thus we face complications previously unknown or overlooked. In this study we report on eight TI patients who presented with EMH-related pleural effusion. The common finding in these patients and in those reported previously is that respiratory distress was the only symptom. Dyspnea is generally progressive and frequent aspirations are required, but usually no other symptoms are present on admission. Effusion is usually unilateral with similar left and right lung fre-

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Patient No. Lung involved Production rate Protein

Pleural/serum (g/dL) Lactate dehydrogenase Pleural/serum (U/L) pH Glucose (mg/dL) Pleural White blood cells (/␮L) Cytology

White blood cells Neuto/lympho (%) Fluid stains Viral antibodies (fluid and serum) Fluid cultures Treatment

Right Fast

2 Right Fast

3

0.60

0.55

Right & left Fast 0.55

0.72

0.65

0.68

7.45 80

7.35 78

7.50 85

2,500

3,000

Right Fast Hemothorax (Pleural fluid hematocrit: 15%)

480

Macrophages, mesothelial cells 30/65

Macrophages, Mesothelial cells mesothelial cells 25/70 35/53

Negative Negative

Negative Negative

Negative Radiotherapy Transfusions Aspirations

Negative Aspirations Pleurodesis (tetracycline) Transfusions Hydroxyurea

death

4

5 Right & left Fast 0.63

6 Left Fast

7 Right Fast

8 Left Fast

0.68

0.65

0.62

0.65

0.75

0.70

0.65

7.60 90

8.00 108

7.30 78

7.60 95

1,500

3,200

900

2,200

Mesothelial cells

Mesothelial cells, eosinophils

Mesothelial cells, eosinophils

Mesothelial cells, eosinophils

25/65

30/58

25/70

30/55

25/60

Negative Negative

Negative Negative

Negative Negative

Negative Negative

Negative Negative

Negative Negative

Negative Aspirations Pleurodesis (tetracycline) Transfusions Hydroxyurea

Negative Aspirations Transfusions Hydroxyurea

Negative Aspirations Transfusions

Negative Aspirations Pleurodesis (bleomycin) Transfusions Hydroxyurea fever

Negative Aspirations Pleurodesis (bleomycin) Transfusions Hydroxyurea

Negative Aspirations Pleurodesis (talc) Transfusions Hydroxyurea

death

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Complications

1

AESSOPOS ET AL EMH-RELATED PLEURAL EFFUSION IN ␤-THALASSEMIA

Table 2. Pleural Fluid Characteristics, Therapeutic Modalities Applied, and Disease Course

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Table 3. Review of the Presented and Literature Cases of Extramedullar Hematopoiesis-Related Pleural Effusion Presented cases 1

Underlying Disease Thalassemia intermedia

Sex Male

Age (Years) 53

Lung

Effusion Type

Right Exudative

Cytology Phagocytes Mesothelials Phagocytes, Mesothelials Mesothelials Mesothelials

2

Thalassemia intermedia

Male

39

Right

3

Thalassemia intermedia

Female

47

Right & left

4

Thalassemia intermedia

Male

29

Right

5 6

Thalassemia intermedia Thalassemia intermedia

Female Female

43 43

Right & left Left

Hemothorax Exudative Exudative

Mesothelials Mesothelials

7

Thalassemia intermedia

Female

33

Right

Exudative

Eosinophils Mesothelials

8

Thalassemia intermedia

Male

56

Left

Exudative

Eosinophils Mesothelials

Eosinophils

Hydroxyurea Negative for malignancy Negative for malignancy Negative for malignancy Negative for malignancy

Exudative

Exudative Negative for malignancy

Literature cases Smith 1988 [6]

Thalassemia intermedia

Female

46

Left

Hemothorax

Peng 1994 [7]

Thalassemia intermedia

Male

34

Right

Exudate

Chu 1999 [8]

a-thalassemia

Male

44

Left

Hemothorax

Ibabao 1999 [9]

Thalassemia major

Male

40

Right & left

Exudate

Treatment Aspirations Radiotherapy Pleurodesis (tetracycline) Hydroxyurea Pleurodesis (tetracycline) Hydroxyurea Aspirations Hydroxyurea Transfusions Pleurodesis (bleomycin) Hydroxyurea Pleurodesis (bleomycin) Hydroxyurea Pleurodesis (talc)

Surgery radiotherapy Pleurodesis (minocycline) Tube Thoracostomy Aspirations

Taher 2001 [10]

Thalassemia intermedia

Male

43

Right & left

Exudate

Chute 2004 [11]

Sickle thalassemia

Male

26

Right

Hemothorax

Negative for malignancy Not done

Muthuswamy 1989 [12] Bowen 2000 [14]

Hereditary spherocytosis Dyserythropoietic anemia Hereditary spherocytosis Myelofibrosis

Male

54

Right & left

Hemothorax

Not referred

Radiotherapy pleurodesis (talc) Pleurodesis (tetracycline) Tube thoracostomy Surgery

Female

84

Right

Exudate

Not referred

Aspirations

Male

64

Left

Hemothorax

Surgery

Female

73

Right

Hemothorax

Negative for malignancy LEB

Myelofibrosis Myelofibrosis Myelofibrosis Myelofibrosis

Female Male Female Male

61 60 33 71

Left Right & left Right Right & left

Hemothorax Exudate Exudate Exudate

LEB LEB LEB LEB

Xiros 2001 [13] Kupferschmid 1993 [15] Bartlett 1995 [16] Jowitt 1997 [17] Oren 1999 [18] Nadrous 2004 [19]

Pleurodesis (tetracycline) Radiotherapy Radiotherapy Pleurodesis Radiotherapy Radiotherapy

LEB ⫽ leukoerythroblastosis, erythroid and myeloid precursors, megacaryocytes.

quency, but bilateral effusions are not rare either. Pleural effusion is exudative in all cases, while myeloid elements are detected only in myelofibrosis ones. Hemothorax develops as a result of both EMH due to hemolytic anemias and myelofibrosis, rather fre-

quently occurring in the latter [6, 8, 11, 15, 16]. In hemoglobinopathies, EMH foci have a significant size and usually are apparent in chest x-rays, in contrast to myelofibrosis cases in which they are usually smaller and undetected by radiography.

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AESSOPOS ET AL EMH-RELATED PLEURAL EFFUSION IN ␤-THALASSEMIA

Pathogenetic Mechanisms In chronic hemolytic anemia the mean time between the appearance of extramedullary foci and the appearance of pleural effusion is quite long. It develops in middle-aged persons when the EMH foci have already acquired a respective size. The EMH masses are soft, deep red, and resemble splenic tissue on the cut surface. Histopathologically, they are formed of hematopoietic elements mixed with adipose tissue [20, 21]; vascularity is extremely dense while the surrounding background is poor and this structure renders the mass prompt to hemorrhage. Although the exact mechanism of the effusion is still unclear and probably multifactorial, mechanical lymphatic obstruction seems to contribute in a way. Moreover, local inflammatory reaction, triggered by the friction between the pleura and the implanted masses during respiration, may be present followed by liberation of inflammatory cytokines which increase the capillary permeability [9]. This can explain the exudative character of the effusion. Direct relation to bacterial, viral and/or fungal infection as well as immunologic mechanisms were not identified in this study as well as in previous ones. Hemothorax may occur as a result of intranodular hemorrhage and rupture of the thin nodular capsule into pleura [22]. To the contrary, in cases of myeloproliferative disease EMH is related to the main disease, occurring usually in the elderly. The vascularization and the invasive nature of the disease, in terms of diffuse infiltration by precursor blood cells, results in hemopoietic foci appearing in islets, therefore unrecognizable in the x-ray evaluation [23]. These foci consist of fibroid tissue in various proportions, penetrating to the interstitial lung tissue and lying on the pleura membranes, rarely forming nodules of variant size [24]. Because of these properties, the presence of myeloid cells in the pleural fluid and the development of hemothorax due to the rupture of small vessels is rather common in this category.

Therapeutic Considerations Decisions on the treatment of pleural effusion should be taken in a decisive way, as the fluid production is quite fast once it begins. Patient No. 5 in our series died soon after admission, before the CT-guided aspiration was applied. In the rest of our patients, significant and relapsing amounts of effusion were present, despite frequent aspirations. Pleural sclerosis with tetracycline, bleomycin, or talc had impressively good results in our series (patients Nos. 2, 3, 6, 7, and 8). Similar results concerning hemoglobinopathy cases, as well as a myelofibrosis one [17], have also been reported in the literature without further complications or adverse effects. Pleural fluid production was diminished dramatically after pleurodesis. This could probably be attributed to the nonmalignant nature of the underlying disease. Transfusions and hydroxyurea were applied in all these patients in our series. Transfusions, in addition to the relief of anemia symptoms, normalize the hemoglobin levels; hence eliminating the stimulus for the increased erythropoiesis.

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Hydroxyurea, apart from stimulating the synthesis of hemoglobin F [25] may help in inactivation and even shrinking of the ectopic hematopoietic tissue [26], minimizing their effect on fluid production. No relapses were referred during a mean period of 30 months. However, persisting hypoxemia was noted in all cases, suggesting that EMH-related pleural effusion occurs in patients with advanced lung disease. This emphasizes further the life-threatening character of this complication. Low-dose irradiation is strongly advocated in myeloproliferative cases with pleural effusion due to EMH [18, 19] as well as in thalassemia patients with spinal cord compression due to EMH [27]. However, in the first patient of our series radiotherapy had poor results and a rather negative answer to radiotherapy. The EMH-related hemothorax in patients with hemoglobinopathies could also be fatal, if underestimated or misdiagnosed, as in a previously reported sicklethalassemia case [11]. Therapy should be individualized. Depending on the fall of the hematocrit level, the rate of bleeding, and the possibility of fluid reproduction, surgical intervention is advocated as a first-line treatment. However, aspirations combined with transfusions may be an alternative approach in less aggressive hemorrhage cases, as in patient No. 4 of the current series. In myelofibrosis cases, hemothorax can be controlled by low-dose irradiation, which according to the literature [18, 19] has promising results. The variability of the underlying disorders seems to be an answer to the varying laboratory findings and the different efficacy of the therapeutic modalities, implying a cause-dependent pathogenetic mechanism. The infiltrative nature of EMH foci that form small, multiple islets of hematopoietic tissue could probably explain the efficacy of radiotherapy in such cases. In conclusion, EMH-related pleural effusion in hemoglobinopathies should be recognized as a potentially life-threatening entity in clinical practice. Treatment is emerging including the discussed alternative therapeutic procedures, which seem to have satisfactory results. In thalassemia intermedia patients in particular, the limitation of the transfusion-chelation therapy to an occasional or palliative basis to manage disease complications should be reconsidered as a treatment strategy. Under the light of the well-described benefits of regular therapy in thalassemia major [28 –30], earlier commencement of this treatment in TI would prevent the complications that result from the chronic and constantly increasing tissue hypoxia.

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