Eosinophilic pleural effusion, peripheral eosinophilia, pleural thickening, and hepatosplenomegaly in sarcoidosis.

Abstract: In this atypical case of sarcoidosis with an unusual combination of clinical and laboratory findings, a 32-year-old male presented with a 3-month history of thoracic pain complicated with dyspnea. Laboratory tests, chest radiography, and CT scans of the chest and abdomen revealed eosinophilia of pleural effusion and blood, pleural thickening, hepatosplenomegaly, and bronchiolitis obliterans. In cases such as this, in which pleural fluid eosinophilia is accompanied by peripheral eosinophilia and splenohepatomegaly, underlying malignancies such as Hodgkin lymphoma should be ruled out. A biopsy of the mediastinal lymph nodes suggested noncaseating epithelioid granulomas, characteristic of sarcoidosis. The patient underwent prednisolone therapy for 1 year and is doing well 2 years after initial diagnosis.

Key Words: sarcoidosis, eosinophilia, pleura, blood, splenomegaly 

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Pleural involvement is uncommon in sarcoidosis, occurring in less than 3% of patients, (1) and includes pleural effusions, pleural thickening, and pneumothorax. Pleural eosinophilia is defined as the presence of 10% or more eosinophils among the leukocytes in the pleural fluid. (2) Eosinophilic pleural effusion associated with sarcoidosis has been regarded as exceptional in the literature, with only four cases previously described. (3-6)

To our knowledge, this is the first case report of sarcoidosis presenting as eosinophilic pleural effusion, peripheral eosinophilia, pleural thickening, splenomegaly, moderate hepatomegaly and bronchiolitis obliterans and the second case reporting the presence of eosinophilia in the pleural space and in the blood. (2)

Case Report

A 32-year-old white male presented to our institution with a 3-month history of diffuse thoracic pain complicated with dyspnea on exertion during the last week. He denied weight loss, night sweats, or fever. His medical history was unremarkable.

The chest radiograph at admission showed bilateral hilar and right paratracheal lymphadenopathy, diffuse fine reticulonodular opacities, and a right pleural effusion.

The patient's temperature was 37.1[degrees]C; pulse, 80 beats/min; respirations, 14 breaths/min; and blood pressure, 140/80 mm Hg. Examination of the chest revealed decreased breath sounds in the right base. Cardiac examination was normal. The abdomen was soft, nontender, and with mild splenomegaly. Physical examination showed no enlarged peripheral nodes or skin lesions. There was dullness to percussion and absent breath sounds in the lower one third of the right base. The tuberculin test proved negative. Eye examination was normal.

The laboratory findings revealed a white blood cell (WBC) count of 6,700 cells/[micro]L, with 73% neutrophils, 14% lymphocytes, 5% eosinophils, and 7% monocytes; platelet count was 249,000 cells/[micro]L, with hemoglobin of 15.7 g/dL and hematocrit of 47%. Blood chemistry results were normal for Na, K, creatinine, blood urea nitrogen, serum calcium, glucose, aspartate aminotransferase, alanine aminotransferase, and angiotensin-converting enzyme of 51 IU/L and lactate dehydrogenase of 192 U. Arterial blood gases on room air measured pH 7.42; PC[O.sub.2] was 37 mm Hg and P[O.sub.2] was 61 mm Hg. Erythrocyte sedimentation rate was 12 mm/h.

Pulmonary function tests showed a forced vital capacity of 4.76 (predicted, 5.31), an FE[V.sub.1] of 3.83 (predicted, 4.41), an inspiratory capacity of 2.58 (predicted 3.96), and an FE[F.sub.50] of 4.34 (predicted, 5.56). Total lung capacity (TLC) was 6.22 (predicted, 7.46), functional residual capacity was 2.93 (predicted, 3.46), residual volume was 1.48 (predicted, 1.86), residual volume/TLC was 23.79 (predicted, 26.44), and TLCOc was 3.08 (predicted, 3.98) (diffusion was performed with the rebreathing method). A 6-minute test walk revealed normal results.

Thoracocentesis on the right pleural cavity yielded 150 mL of serous fluid. Laboratory analysis demonstrated the fluid to be exudative: pH, 7.37; LDH, 380 IU/L; glucose, 86 mg/dL; and WBC count, 6,190/[micro]L. The differential of the WBC count measured 45% eosinophils, 25% neutrophils, 15% lymphocytes, and 15% monocytes. Pleural fluid Gram stain and culture findings were negative for Mycobacterium tuberculosis, bacteria, and fungi. Ziehl-Neelsen stains were negative. The cytologic examination of the fluid was negative for malignancy. Pleural biopsy was not performed because the patient lost consciousness twice during the procedure.

Fiberoptic bronchoscopy showed diffuse redness of the bronchial mucosa, and transbronchial biopsies were performed. Cultures of biopsy specimens did not grow M tuberculosis, bacteria, or fungi. Cytology and biopsies were negative for malignancy.

Chest computed tomography confirmed chest radiographic findings, depicting the presence of bilateral hilar node enlargement. A paratracheal mass, a right effusion, and subtle left pleural thickening were also demonstrated (Fig. 1). Abdominal CT confirmed splenomegaly and moderate hepatomegaly (Fig. 2).

The high-resolution CT findings included areas of moderate ground-glass appearance, micronodular intralobular hazy opacities, interlobular and intralobular septal thickening, bronchial dilation with wall thickening, mucous plugging, and pleural thickening (Fig. 3a). On expiration, areas indicative of bronchiolitis obliterans were depicted (Fig. 3b).

Because the patient's pleural fluid eosinophilia was accompanied by peripheral eosinophilia and splenohepatomegaly, an underlying malignancy, especially Hodgkin lymphoma, was suspected.

Thoracotomy was then performed, and histologic examination of mediastinal lymph nodes was obtained showing noncaseating noncalcified epithelioid granulomas with sharp margins characteristic of sarcoidosis (Fig. 4).

Whole-body gallium scanning confirmed the diagnosis of sarcoidosis in our patient with symmetrically increased uptake in the mediastinal and hilar nodes (lambda sign).

The patient was treated with prednisolone for 12 months, during which his symptoms, pulmonary function, radiographic, CT (Fig. 5) and gallium scanning findings showed marked improvement. Blood laboratory findings performed 1 year later revealed a WBC count of 6,280 cells/[micro]L and 1.9% neutrophils (within normal limits). Thus, previous eosinophilia was contributed to sarcoidosis activity.

Discussion

Schaumann first recognized pleural involvement of sarcoidosis in 1933 when it was described as a necropsy finding in a 45-year-old man. (7) Pleural sarcoidosis has been described as always associated with chronic sarcoidosis. Pleural lesions consist of the formation of granulomas bulging into the pleural cavity on either parietal or visceral surfaces, suggesting the access of some agent by lymphatic or hematogenous route. (8) These noncaseating granulomas may or may not be associated with pleural effusion. (4)

In the clinical setting of sarcoidosis, a pleural effusion should raise the possibility of pleural involvement. (8) One third of these effusions are bilateral. (3) The average age at which pleural sarcoidosis is diagnosed is 35 years. (3) Pleural involvement with sarcoidosis has been reported to account for 3% of cases (8) and usually occurs in conjunction with extensive pulmonary or extrapulmonary, multiorgan involvement, or both, (4,8,9) as in our case. Pleural effusion (either unilateral or bilateral) is the most common manifestation of pleural involvement in thoracic sarcoidosis according to Lum et al. (10)

[FIGURE 1 OMITTED]

A pleural effusion in a patient with histologically proven sarcoidosis is caused most probably by the primary disease. (5) However, a pleural effusion in a patient with known sarcoidosis may indicate superimposed tuberculosis or cardiac failure. (8) The diagnosis of pleural sarcoidosis depends initially on histologic demonstration of the disease in biopsies from conventional sites, such as the liver or lymph nodes, or by a Kveim test. (5) Definite evidence of pleural granulomata may sometimes be obtained by percutaneous biopsy, but this technique is not reliable in all cases. (5)

High-resolution CT, thoracoscopy, and biopsy can increase the detection of nodules and thickening of the pleura. (1)

In a patient with sarcoidosis and a pleural effusion, the pleural fluid should be studied by culture, cytology, cell count, protein, glucose, LDH, pH, specific gravity, and other studies. In patients with sarcoidosis demonstrating pleural involvement, the predominant cell is the erythrocyte, with the percentage ranging from 61 to 100% (8).

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Pleural eosinophilia is defined as the presence of 10% or more eosinophils among the leukocytes in the pleural fluid. (2)

An early study reported that eosinophilic effusions account for between 5 and 8% of exudative pleural effusions (11) but a more recent study identified eosinophilic effusions in 12.6% of patients with pleural fluid. (12) Eosinophilic effusions are significantly more often exudative than noneosinophilic effusions. (13)

Certain factors frequently produce pleural fluid eosinophilia, for example, malignancy, heart or renal failure, cirrhosis, serositis, pulmonary embolism, tuberculosis, rheumatoid arthritis, bloody effusion, pneumothorax, chest trauma, benign asbestos effusions, or a previous pleural puncture. (3,12-14) The introduction of air and blood at thoracentesis can produce eosinophilia detected on subsequent aspirations, with blood in the pleural space having been reported as the second most common cause of eosinophilic effusions. (15)

[FIGURE 4 OMITTED]

Eosinophilic pleural effusions of sarcoidosis have been reported in four previous cases. (3-6) Our patient had 40% eosinophils in a right pleural effusion. Durand et al (3) found 80% eosinophils in the initial pleural effusion and 40% eosinophils in the second pleural effusion; Berte et al (6) found 29% eosinophils, Beekman (4) found 15% eosinophils in a left pleural effusion and Nicholls et al (5) found eosinophils with the percentage not specified.

Peripheral blood eosinophilia occurs in 41% of sarcoidosis cases according to Renston et al. (16) Pleural fluid eosinophilia associated with peripheral eosinophilia has been also documented in other systemic diseases such as Hodgkin lymphoma, Loffler syndrome, polyarteritis, tropical eosinophilia, and hydatid disease. However, most eosinophilic pleural effusions are not associated with striking blood eosinophilia. (14) This is in accordance with our patient, who had 5% eosinophils on initial blood draw, and the patient reported by Durand et al, (3) who had 4% eosinophils.

Radiographically evident pleural thickening is extremely rare in sarcoidosis. Thickening of the pleural surface accounts for 9.2% of pulmonary sarcoidosis findings and indicates irreversible pulmonary change from sarcoidosis, (17,18) in contrast to our case. Most authors believe that microscopic involvement of the pleura with granulomas precedes the appearance of a pleural effusion.

Sarcoid pleural effusions may resolve spontaneously or require corticosteroids for resolution. Spontaneous resolution usually occurs within 4 to 12 weeks. Chronic pleural thickening has been observed after resolution of a pleural effusion. (8)

[FIGURE 5 OMITTED]

References

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14. Adelman M, Albelda SM, Gottlieb J, et al. Diagnostic utility of pleural fluid eosinophilia. Am J Med 1984;77:915-920.

15. Light RW. Pleural diseases. Baltimore, MD: Williams & Wilkins, 1995, pp 42.

16. Renston JP, Goldman ES, Hsu RM, et al. Peripheral blood eosinophilia in association with sarcoidosis. Mayo Clin Proc 2000;75:586-590.

17. Brauner MW, Grenier P, Mompoint D, et al. Pulmonary sarcoidosis: evaluation with high-resolution CT. Radiology 1989;172:467-471.

18. Saito W, Kobayashi H, Shinkai M, et al. [Pulmonary involvement in sarcoidosis: CT findings at diagnosis and their changes at follow-up in cases without corticosteroid treatment]. Nihon Kokyuki Gakkai Zasshi 2002;40:210-214.

Science without religion is lame, religion without science is blind.
--Albert Einstein

Evaggelos Vafiadis, MD, Maria S. Sidiropoulou, MD, Vasilios Voutsas, MD, Theodoros L. Giannopoulos, MD, Fotis Iordanidis, MD, Pandora Christaki, PHD, and Panagiotis Palladas, MD

From the Department of Computed Tomography and Ultrasonography, Second Clinic of Pneumonology, and Department of Pathology, General Regional Hospital "G. Papanikolaou," Thessaloniki 57010, Greece.

Reprint requests to Dr. Maria S. Sidiropoulou, 5 Patriarhou Ioakeim st, Thessaloniki 54622, Greece. Email: [e-mail]

Accepted August 26, 2005.

RELATED ARTICLE: Key Points

* A 32-year-old male had laboratory tests, chest radiograph, and CT scans that revealed eosinophilia of pleural effusion and had blood, pleural thickening, hepatosplenomegaly, and bronchiolitis obliterans.

* Differential diagnosis mainly included lymphoma and sarcoidosis.

* Biopsy of mediastinal lymph nodes was finally performed to determine a definite diagnosis and suggested noncaseating epithelioid granulomas characteristic of sarcoidosis.