CASE RECORDS OF TH E MASSACH USET TS GENER A L H OSPITA L

Case Records of the Massachusetts General Hospital

Weekly Clinicopathological Exercises

FOUNDED BY RICHARD C. CABOT

N A N C Y L E E H A R R I S , M. D. , Editor W I L L I A M F. M C N E E L Y , M. D. , Associate Editor J O - A N N E O. S H E P A R D , M. D. , Associate Editor S A L L Y H . E B E L I N G , Assistant Editor S T A C E Y M. E L L E N D E R , Assistant Editor C H R I S T I N E C . P E T E R S , Assistant Editor Case 8-2002

PRESENTATION OF CASE

A 56-year-old woman was admitted to the hospital because of a persistent left-sided pleural effusion. The patient had a history of rheumatoid arthritis, which had become disabling about two years before the current admission. She had otherwise been well until six months before admission, when she entered another hospital because of pleuritic left-sided chest pain. Analysis of a specimen of arterial blood obtained while the patient was breathing ambient air revealed that the partial pressure of oxygen was 66 mm Hg, the partial pressure of carbon dioxide 24 mm Hg, and the pH 7.46. The urine was normal, and cultures of urine and blood were sterile. The hematocrit was 35.1 percent; the white-cell count was 9900 per cubic millimeter, with 65 percent neutrophils, 17 percent lymphocytes, 15 percent monocytes, 2 percent eosinophils, and 1 percent basophils; the platelet count was 261,000 per cubic millimeter; and the mean corpuscular volume was 100.1 m3. The prothrombin time, partial-thromboplastin time, and D-dimer value were normal. The glucose level was 115 mg per deciliter (6.4 mmol per liter), and the albumin level was 3.3 g per deciliter. The levels of electrolytes, aspartate aminotransferase, and alanine aminotransferase were normal. The level of thyrotropin was slightly low, at 0.28 mU per milliliter, but the free thyroxine and triiodothyronine levels were normal, as were the levels of urea nitrogen, creatinine, conjugated and total bilirubin, and alkaline phosphatase. Chest radiographs obtained at this time showed a left-sided pleural effusion and a patchy opacity in the left lower lobe; the size of the heart was normal (Fig. 1). A ventilationperfusion scan revealed a low prob-

ability of pulmonary embolism. Thoracentesis yielded cloudy fluid that contained 120,000 red cells and 97,400 white cells per cubic millimeter; of the white cells, 78 percent were neutrophils, 7 percent lymphocytes, 9 percent monocytes, and 6 percent eosinophils. The specific gravity of the specimen was 1.030; the glucose level was 47 mg per deciliter (2.6 mmol per liter), the cholesterol level was 143 mg per deciliter (3.7 mmol per liter), the albumin level was 2.3 g per deciliter, the total protein level was 4.6 g per deciliter, the amylase level was 31 U per liter, and the lactate dehydrogenase level was 1565 U per liter. Microscopical examination of the fluid showed no acid-fast bacilli, fungi, or other microorganisms; anaerobic, fungal, and mycobacterial cultures were sterile. A chest radiograph obtained after the thoracentesis disclosed a substantial decrease in the size of the left-sided pleural effusion; an area of increased density at the base of the left lung; and a nodule, 8 mm in diameter, in the left upper lobe that had not been clearly identified on the previous examination. Antibiotic therapy was begun. A computed tomographic (CT) scan of the thorax (Fig. 2), obtained

Figure 1. Posteroanterior Chest Radiograph Showing a Left-Sided Pleural Effusion and a Patchy Opacity in the Left Lower Lobe.

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

without the administration of contrast material, showed the left-sided pleural effusion as well as airspace disease in the lingula and left lower lobe, suspected to be atelectasis; centrilobular emphysema and bullous disease were also present and were worse in the upper lobes than in the lower lobes. No definite endobronchial lesion or lymphadenopathy was identified, and the heart appeared normal. On the eighth hospital day, repeated chest radiographs revealed increased aeration at the base of the left lung and again showed the opacity in the left lower lobe; the pleural effusion had decreased further in size. The next day, the patient was discharged. Sixteen weeks before the current admission, the patient returned to the same hospital because of chest pain. Repeated radiographs of the chest disclosed increased density at the left lung base; the effusion had increased in size, and there was underlying atelectasis, pneumonia, or both. The right lung and heart remained normal. Antibiotics were administered. Four weeks later, the patient returned to the same hospital because of fever and cough. The findings on chest radiographs were unchanged. Twelve days later, CT scanning showed the small, left-sided pleural effusion and subsegmental atelectasis or scarring in the lingula but no other abnormalities. Eighteen days later, chest radiographs again showed the effusion, as well as decreased parenchymal density at the left lung base, and again showed scarring or subsegmental atelectasis in the lingula. Two weeks later, findings on additional radiographs of the chest were unchanged. Sixteen days before the current admission, the patient consulted a pulmonologist because of the persistent left-sided pleural effusion. Physical examination revealed decreased breath sounds and a few rhonchi at the left lung base but no other abnormalities. The findings on a thoracic CT scan were unchanged, ex-

cept for the appearance of bilateral axillary lymph nodes; a few of the nodes on the right side were minimally enlarged, but they contained fat and were not considered abnormal. An abdominal and pelvic CT scan obtained on the same day was unremarkable. The patient was referred to this hospital. She had a 30-pack-year history of cigarette smoking but had stopped smoking three months earlier. She had no known exposure to asbestos or other industrial dusts and no recent history of chills, sweats, sputum production, hemoptysis, headache, bone pain, or weight loss. Her only current medication was prednisone (10 or 20 mg daily). She had taken methotrexate but had discontinued it six months before admission because she believed that it worsened her breathing. She had also reportedly taken etanercept, an inhibitor of tumor necrosis factor, but the timing and dosage were uncertain. The temperature was 36.9C, the pulse was 108, and the respirations were 18. The blood pressure was 135/75 mm Hg. On physical examination, the patient appeared comfortable at rest. There were prominent rheumatoid deformities that involved the hands, ankles, and knees, and the gait was very slow. No rash or cervical lymphadenopathy was found. Soft, bilateral axillary lymph nodes were palpated; the nodes on the right side were slightly enlarged. The lungs were clear except for evidence of the left-sided pleural effusion. The heart and abdomen were normal. There was peripheral edema (++) bilaterally, without signs of deep venous thrombosis. The hematocrit was 40.4 percent; the white-cell count was 11,000 per cubic millimeter, with 71 percent neutrophils, 22 percent lymphocytes, 5 percent monocytes, 1 percent eosinophils, and 1 percent basophils; the platelet count was 348,000 per cubic millimeter. The prothrombin time was normal, and the partial-thromboplastin time was in the low-to-normal range, at 22.7 seconds. The glucose level was 122 mg per deciliter (6.8 mmol per liter). The levels of urea nitrogen, creatinine, and electrolytes were normal. An electrocardiogram revealed sinus tachycardia at a rate of 105 beats per minute, with left atrial enlargement and minor, nonspecific ST-segment and T-wave abnormalities. A diagnostic procedure was performed.
DIFFERENTIAL DIAGNOSIS

DR. DEBORAH A. QUINN*: May we review the radiographs? DR. THERESA C. MCLOUD (Cardiothoracic Radiology): A series of radiographs was obtained over
Figure 2. CT Scan of the Thorax Showing a Left-Sided Pleural Effusion (Arrows).
*Assistant physician, Pulmonary and Critical Care Unit, Massachusetts General Hospital; instructor in medicine, Harvard Medical School.

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CASE RECORDS OF TH E MAS SACH USET TS GENER A L H OSPITA L

about a six-month period. On the initial radiograph (Fig. 1), there is evidence of a left-sided pleural effusion, and there is a patchy opacity in the left lower lobe that suggests the presence of atelectasis underlying the effusion. The chest radiograph obtained after thoracentesis shows a decrease in the size of the effusion, but there is a persistent opacity, probably atelectasis, in the left lower lobe; there is also a small nodule, 8 mm in diameter, in the left upper lobe. On a subsequent CT scan (Fig. 2), no nodule is seen, but the scan confirms the presence of the left-sided pleural effusion. In addition, other scans reveal patchy air-space disease involving the anterior portion of the left lower lobe and the lingula, as well as some atelectasis in the left lower lobe. In summary, over a period of about six months a left-sided pleural effusion and a few nonspecific opacities at the base of the left lung were noted on multiple imaging studies. DR. QUINN: The first step in developing a differential diagnosis of a pleural effusion is to establish whether the effusion is a transudate or an exudate by analysis of fluid obtained at thoracentesis. Transudative effusions are caused by imbalances in the plasma osmotic or hydrostatic pressures and occur in congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome. Exudative effusions are caused by impairment of the lymphatic drainage of the pleural space or by pleural inflammation and are found in a wide range of illnesses.1 The features of exudative effusions may be used as criteria to distinguish them from transudative effusions (Table 1). In this case, the lactate dehydrogenase level of 1565 U per liter and the cholesterol level of 143 mg

per deciliter meet the criteria for an exudative effusion. On the basis of the patients history, the possible causes of an exudative effusion in this case include hypothyroidism, pulmonary embolism, asbestosis, drugs, cancer, infections (including fungal infections, nocardial infections, actinomycosis, and tuberculosis), and rheumatoid pleuritis. Findings in the pleural fluid can help one differentiate among these possible diagnoses. This patients pleural fluid was cloudy, with high counts of red and white cells, a predominance of neutrophils, and a low glucose level. The pH of the pleural fluid was not recorded, but this information would have been helpful. The physicians caring for this patient considered the possibility of hypothyroidism. Hypothyroidism has obvious symptoms, and it sometimes causes a pleural effusion.2 However, in that circumstance the pleuralfluid glucose level is not low, as it was in this case. Furthermore, this patients free thyroxine and triiodothyronine levels were normal, making hypothyroidism an unlikely cause of the effusion. Pulmonary embolism is also a consideration. Pleural effusions in cases of pulmonary embolism are usually small and unilateral3 and are often bloody, with more than 10,000 red cells per cubic millimeter. The number of white cells is variable, with a predominance of either neutrophils or lymphocytes.3 In this case, a ventilationperfusion lung scan showed a low probability of pulmonary embolism; in addition, the result of a D-dimer test was normal, although the technique for measuring the D-dimer is not reported. This patient had no known risk factors for pulmonary embolism, so other diagnoses seem more likely.

TABLE 1. INDICATORS

OF

EXUDATIVE PLEURAL EFFUSIONS.*

SENSITIVITY EXUDATE SPECIFICITY EXUDATE

INDICATOR

FOR

FOR

REFERENCE

percent

Light criteria PF protein:serum protein >0.5 PF LDH >200 U/liter PF LDH:serum LDH >0.6 Modified Light criteria PF protein:serum protein >0.5 PF LDH >45% upper limit of normal PF LDH:serum LDH >0.6 Cholesterol and LDH PF cholesterol >45 mg/dl PF LDH >200 U/liter Albumin Serum albumin PF albumin <1.2 g/dl

98

7282

Gottehrer et al.,2 Bynum and Wilson,3 Epler et al.4 Bynum and Wilson3

Increased

Increased

99

98

Epler et al.4

95

100

Hillerdal5

*PF denotes pleural fluid, and LDH lactate dehydrogenase. To convert the value for cholesterol to millimoles per liter, multiply by 0.02586. The modified Light criteria had higher sensitivity and specificity for identifying an exudate in the same study population.3

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

A benign pleural effusion is the most common manifestation of asbestosis in the first 20 years after exposure to asbestos.4 The effusion may be serosanguineous or just bloody, usually with a red-cell count of less than 6000 per cubic millimeter and occasionally with a predominance of eosinophils. The glucose level in the pleural fluid in persons with this type of effusion equals the serum glucose level,1 and the effusion can persist for several months.5 Considering this patients low glucose level, her high cell counts, the absence of eosinophilia, and the absence of known exposure to asbestos, a diagnosis of benign asbestosrelated pleural effusion seems unlikely. Several medications have been shown to cause druginduced pleural effusions, including procainamide (associated with a lupus-like reaction), nitrofurantoin, dantrolene, methysergide, procarbazine, methotrexate, bromocriptine, practolol, amiodarone, mitomycin, bleomycin, and minoxidil.1 This patient had been treated with methotrexate for her rheumatoid arthritis, but she had discontinued it six months before the current admission because of shortness of breath. In a series of 45 patients treated for rheumatoid arthritis with methotrexate for three years, there were no reports of pleural effusions.6 Most reported cases of pleural effusion during methotrexate therapy involve patients being treated for a malignant tumor.7,8 The effusion in this case persisted, even though the patient had not been treated with methotrexate for six months, and therefore methotrexate appears to be an unlikely cause. This patient had also been treated with etanercept, an inhibitor of tumor necrosis factor that has not been associated with the development of pleural effusions.9 Because this patient had a 30-pack-year history of smoking, it is possible that the effusion was due to cancer. A pleural effusion may be the first sign of cancer, in which case the most common sites of the primary tumor are the lung and the breast. The effusions tend to range from moderate to massive, with 90 percent larger than 500 ml and 59 percent larger than 1000 ml. They can be unilateral or bilateral.10 The characteristics of the pleural fluid in these cases are nonspecific, although a low pH and a low glucose level have been associated with shorter survival.10,11 This patient had had a small, persistent effusion for six months, and at the time of admission she had no symptoms such as hemoptysis, chest pain, dyspnea, cough, bone pain, or weight loss that would suggest the presence of a malignant tumor. The patient had been taking prednisone daily for an unknown length of time and had previously taken methotrexate. Infections due to immunosuppression and pleural effusion, such as actinomycosis, nocardial infection, aspergillosis, cryptococcosis, and histoplasmosis, are therefore diagnostic possibilities.6,12-15 Parasitic infections, bacterial infections with parapneu-

monic effusions, and atypical forms of pneumonia (including those caused by viruses, mycoplasma, Q fever, and legionella) have been associated with pleural effusions1 but are unlikely diagnoses in this case because of the indolent course and the absence of acute symptoms at the time of admission. At presentation, actinomycosis and nocardial infection have similar radiologic features, including homogeneous, dense air-space disease. Abscess formation, pleural thickening, and chest-wall involvement are common. Chronic pneumonia with cough and fever is often present.12,16,17 In fungal diseases such as aspergillosis and histoplasmosis, the pleural-fluid glucose levels equal the serum glucose levels.1 Aspergillosis often causes nodular pleural thickening and is associated with tuberculosis or postoperative lung infection.18 In the current case, the absence of pleural changes, the negative cultures for fungus, the indolent course, the low glucose level in the pleural fluid, and the absence of a history of travel to areas where histoplasmosis is endemic make fungal disease an unlikely diagnosis. Tuberculous effusions are estimated to occur in 4 percent of newly diagnosed cases of tuberculosis.1 The effusions are usually small to moderate in size, but they can be massive. They occur more often on the right side than on the left but may be bilateral.19 The white-cell count has been reported to range from 2000 to 8000 cells per cubic millimeter,19,20 with approximately 44 percent of these effusions containing more than 50 percent lymphocytes.19 A predominance of neutrophils has also been reported19-21 and has been found to occur early in the disease.1 Mycobacterium tuberculosis is cultured from the pleural fluid in 35 to 64 percent of cases of tuberculous effusions; staining for acid-fast bacilli is positive in less than 10 percent.1,19-21 If more than 5 percent of the cells in the pleural fluid are mesothelial, the presence of a tuberculous effusion can be ruled out,22 but mesothelial cells either were not present in this patients specimen or were not measured. Any inflammatory process can cause a paucity of mesothelial cells. CT scanning can be helpful in distinguishing tuberculous effusions from other types of pleural effusions, and it can reveal small areas of cavitation not seen on chest films.23 In a series of 24 patients with tuberculous pleurisy,23 only 2 patients had no evidence of enlarged hilar or mediastinal nodes, cavitary lung disease, or fibronodular parenchymal changes. Both of these patients had rib enlargement, and one had a subcapsular tissue mass. In a series of 66 patients with tuberculous pleurisy,24 all but 1 had pleural thickening of more than 1 cm. The patient under discussion had no pleural thickening. She did have an 8-mm nodule in the left upper lobe, a finding that may be consistent with an old tuberculous infection. However, because of the absence of other findings consistent with

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CASE RECORDS OF TH E MASSACH USET TS GENER A L H OSPITA L

tuberculosis on CT scanning, tuberculous pleurisy is not likely in this case. This patient had rheumatoid arthritis, which had become disabling two years before admission. On physical examination, she had prominent rheumatoid deformities involving the hands, ankles, and knees. Several extraarticular features of rheumatoid arthritis may involve the lung; they include pulmonary fibrosis, upper-lobe fibrobullous disease, necrobiotic nodules, pulmonary hypertension, Caplans syndrome, bronchiolitis obliterans, follicular bronchiolitis, and pleural effusion.12 Pulmonary manifestations may precede or follow the diagnosis of rheumatoid arthritis.25 Pleural effusion, which may recur more than 10 years after the diagnosis,25 has been found to be one of the most frequent manifestations of rheumatoid arthritis in the lung; the incidence varies from 2 to 52 percent.25 Pleural effusion in cases of rheumatoid arthritis has a striking male predominance, in contrast to pleural effusion in articular rheumatoid arthritis, which has a female predominance.25 Seventy-one to 95 percent of rheumatoid effusions occur in men.25-27 The average age of patients with rheumatoid effusions is 51 to 57 years,25,26,28,29 and more than 50 percent of patients are over the age of 50.26 This type of effusion is usually unilateral 26,27 but has been reported to occur bilaterally,27 and the pleural fluid is usually yellow-green but may be turbid, opaque, clear, straw-colored, or bloody.26,27,30 Rheumatoid effusions can resolve in three to four weeks, but characteristically they persist for several months or years.25,27 Several laboratory findings are characteristic of pleural fluid in patients with rheumatoid effusions. Pleuralfluid glucose levels are less than 30 mg per deciliter (1.7 mmol per liter) in 66 percent of rheumatoid effusions and less than 50 mg per deciliter (2.8 mmol per liter) in 80 percent.26 When the effusion is persistent, the glucose level decreases over time.31 The pH of the pleural fluid is generally 7.00 to 7.13.28,31 A low pleural-fluid glucose level and a low pleuralfluid pH are not specific to rheumatoid arthritis; they are also found in cases of empyema, tuberculosis, and malignant tumors.10,28,32 The low glucose levels appear to be caused by blockage of the transfer of glucose from the blood to the pleura,1,27 and the low pH results from the metabolism of glucose and the accumulation of lactate and carbon dioxide.32 The white-cell counts in rheumatoid effusions are variable: during the acute phase there is a predominance of neutrophils, but in the chronic phase there is a predominance of lymphocytes.31 The rheumatoid factor in the pleural fluid is characteristically greater than 1:320,29 but high levels of rheumatoid factor in the pleural fluid are also found in cases of bacterial pneumonia, tuberculosis, and carcinoma.1 The combination of a low pH, a low glucose level, and a low C4 level in the pleural fluid

is a good indicator of the presence of rheumatoid effusion.28 Rheumatoid factor and complement levels were not measured in this case. For a variety of reasons the persistence of the pleural effusion; the low pleural-fluid glucose level; the high levels of lactate dehydrogenase and cholesterol; the absence of evidence of pleural thickening, hilar or mediastinal lymphadenopathy, or other important parenchymal changes on the CT scans; and the absence of fever, cough, chest pain, weight loss, bone pain, and dyspnea at the time of diagnosis I believe that the probable cause of the pleural effusion is rheumatoid arthritis.
CLINICAL DIAGNOSIS

Pleural effusion with a parapneumonic, malignant, or rheumatoid cause.

DR. DEBORAH A. QUINNS DIAGNOSIS

Pleural effusion caused by rheumatoid arthritis.

PATHOLOGICAL DISCUSSION

DR. EUGENE J. MARK: The diagnostic procedure was video-assisted thoracoscopy and drainage of the

Figure 3. Lymphocytic Infiltrate (Arrows) in the Adipose Tissue of the Chest Wall beneath the Parietal Pleura (P), Consisting of Edematous Connective Tissue with Proliferating Capillaries (Hematoxylin and Eosin, 150).

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

pleural effusion. The surgeon removed 150 ml of thick, yellow, cloudy fluid and saw a white, fibrinous, exudative membrane on top of a thickened and inflamed pleura. He dbrided the membrane and took a biopsy specimen of the parietal pleura and the underlying chest wall. Histopathological examination of the pleural specimen showed a progression of changes rarely found in a single specimen, including fibrin layered on the surface, neutrophilic debris in areas without fibrin, and a lymphocytic infiltrate in the adipose tissue beneath the parietal pleura (Fig. 3). These changes are commonly observed in patients who have benign pleural effusions from various causes. In this case, however, more specific changes were found. There were palisading histiocytes and fibroblasts, which were oriented perpendicularly to the serosal surface (Fig. 4), as well as hyperplastic mesothelial cells and multinucleated cells with vacuolated cytoplasm (Fig. 5). Such multinucleated cells are infrequently found in cases of rheumatoid pleuritis; when seen in cases of pleu-

M M

Figure 5. Hyperplastic Mesothelial Cells and Multinucleated Cells (M), Some with Vacuolated Cytoplasm (Arrow), along the Surface of the Serosa (Hematoxylin and Eosin, 500).

Figure 6. Rheumatoid Nodule with Central Necrosis (N), Bounded in Part by Palisading Histiocytes (Arrow), in the Parietal Pleura (Hematoxylin and Eosin, 150). The serosal surface is covered by fibrin. Figure 4. Palisading, Elongated Histiocytes and Fibroblasts (between Arrows) That Are Perpendicular to the Serosal Surface of the Parietal Pleura (Hematoxylin and Eosin, 250).

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CASE RECORDS OF TH E MAS SACH USET TS GENER A L H OSPITA L

ral effusion, they strongly suggest the presence of a rheumatoid effusion.33 Finally, a microscopical rheumatoid nodule with central necrosis was present in the thickened pleura and was bounded in part by palisading histiocytes (Fig. 6). The histopathological changes in rheumatoid pleuritis34-37 are listed in sequence in Table 2. Although pleural effusions and fibrinous pleuritis are relatively common in patients with systemic rheumatoid disease, rheumatoid nodules in the pleura are less common

TABLE 2. SEQUENCE OF HISTOPATHOLOGICAL CHANGES IN RHEUMATOID PLEURITIS.

Fibrin Neutrophilic exudate Lymphocytic inflammation Mesothelial hyperplasia Multinucleated mesothelial cells Palisading histiocytes Rheumatoid nodule Fibrosis

than rheumatoid disease in the lung parenchyma.38,39 At autopsy, active or chronic rheumatoid disease is found in the lung or pleura in up to 50 percent of patients with systemic rheumatoid disease40; a smaller proportion of such patients have clinical or radiographic manifestations of rheumatoid disease in the pleura or lung during life. DR. JOSEPH F. ARENA (Neurosurgery): What is the ultimate prognosis for patients with rheumatoid pleuritis? DR. QUINN: Patients generally do well. If the effusions persist, patients may eventually have pleural thickening. DR. MARK: This patient has been well since the thoracoscopy, with no additional signs or symptoms of disease in the chest. The progression of rheumatoid disease is better assessed by arthritis than by pleuritis.
ANATOMICAL DIAGNOSIS

Rheumatoid pleuritis.
REFERENCES
1. Sahn SA. The pleura. Am Rev Respir Dis 1988;138:184-234. 2. Gottehrer A, Roa J, Stanford GG, Chernow B, Sahn SA. Hypothyroidism and pleural effusions. Chest 1990;98:1130-2. 3. Bynum LJ, Wilson JE III. Characteristics of pleural effusions associated with pulmonary embolism. Arch Intern Med 1976;136:159-62.

4. Epler GR , McLoud TC, Gaensler EA. Prevalence and incidence of benign asbestos pleural effusion in a working population. JAMA 1982;247: 617-22. 5. Hillerdal G. Non-malignant asbestos pleural disease. Thorax 1981;36: 669-75. 6. Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, Kohler JA. Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis. J Rheumatol 1990; 17:1628-35. 7. Walden PAM, Mitchell-Weggs PF, Coppin C, Dent J, Bagshawe KD. Pleurisy and methotrexate treatment. Br Med J 1977;2:867. 8. Everts CS, Westcott JL, Bragg DG. Methotrexate therapy and pulmonary disease. Radiology 1973;107:539-43. 9. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, control trial. Ann Intern Med 1999; 130:478-86. 10. Chernow B, Sahn SA. Carcinomatous involvement of the pleura: an analysis of 96 patients. Am J Med 1977;63:695-702. 11. Sahn SA, Good JT. Pleural fluid pH in malignant effusions: diagnostic, prognostic, and therapeutic implications. Ann Intern Med 1988;108:3459. 12. Diseases of altered immunologic activity. In: Fraser RG, Par JA. Diagnosis of diseases of the chest. 2nd ed. Vol. 2. Philadelphia: W.B. Saunders, 1978:881-980. 13. Young EJ, Hirsh DD, Fainstein V, Williams TW. Pleural effusions due to Cryptococcus neoformans: a review of the literature and report of two cases with cryptococcal antigen determinations. Am Rev Respir Dis 1980; 121:743-7. 14. Schnader J, Pina EM, Baughman RP, Glassroth J, Adebonojo S. Clinical conference on management dilemmas: progressive pneumonia in a patient receiving long-term steroid therapy. Chest 1999;115:260-6. 15. Gruberg L, Thaler M, Rozenman J, Bank I, Pras M. Nocardia asteroides infection complicating rheumatoid arthritis. J Rheumatol 1991;18: 459-61. 16. Bates M, Cruickshank G. Thoracic actinomycosis. Thorax 1957;12:99124. 17. Feigin DS. Nocardiosis of the lung: chest radiographic findings in 21 cases. Radiology 1986;159:9-14. 18. Krakowka P, Rowinska E, Halweg H. Infection of the pleura by Aspergillus fumigatus. Thorax 1970;25:245-53. 19. Epstein DM, Kline LR, Albelda SM, Miller WT. Tuberculous pleural effusions. Chest 1987;91:106-9. 20. Seibert AF, Haynes J Jr, Middleton R , Bass JB Jr. Tuberculous pleural effusion: twenty-year experience. Chest 1991;99:883-6. 21. Pettersson T, Riska H. Diagnostic value of total and differential leukocyte counts in pleural effusions. Acta Med Scand 1981;210:12935. 22. Hurwitz S, Leiman G, Shapiro C. Mesothelial cells in pleural fluid: TB or not TB? S Afr Med J 1980;57:937-9. 23. Hulnick DH, Naidich DP, McCauley DI. Pleural tuberculosis evaluated by computed tomography. Radiology 1983;149:759-65. 24. Yilmaz MU, Kumcuoglu Z, Utkaner G, Yalniz O, Erkmen G. Computed tomography findings in tuberculous pleurisy. Int J Tuberc Lung Dis 1998;2:164-7. 25. Walker WC, Wright V. Pulmonary lesions and rheumatoid arthritis. Medicine (Baltimore) 1968;47:501-20. 26. Lillington GA, Carr DT, Mayne JG. Rheumatoid pleurisy with effusion. Arch Intern Med 1971;128:764-8. 27. Carr DT, Mayne JG. Pleurisy with effusion in rheumatoid arthritis, with reference to the low concentration of glucose in pleural fluid. Am Rev Respir Dis 1962;85:345-50. 28. Pettersson T, Klockars M, Hellstrom P-E. Chemical and immunological features of pleural effusions: comparison between rheumatoid arthritis and other diseases. Thorax 1982;37:354-61. 29. Halla JT, Schrohenloher RE, Volanakis JE. Immune complexes and other laboratory features of pleural effusions: a comparison of rheumatoid arthritis, systemic lupus erythematosus, and other diseases. Ann Intern Med 1980;92:748-52. 30. Berger HW, Seckler SG. Pleural and pericardial effusions in rheumatoid disease. Ann Intern Med 1966;64:1291-7. 31. Sahn SA, Kaplan RL, Maulitz RM, Good JT Jr. Rheumatoid pleurisy: observations on the development of low pleural fluid pH and glucose level. Am J Respir Crit Care Med 1980;140:1237-8. 32. Potts DE, Willcox MA, Good JT Jr, Taryle DA, Sahn SA. The acidosis of low-glucose pleural effusions. Am Rev Respir Dis 1978;117:66571. 33. Keagle M, Marcks KA, Kaiser JS. Cytologic manifestation of rheuma-

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toid arthritis in pleural effusion: a case report. Acta Cytol 1981;25:339. 34. Baggenstoss AH, Rosenberg EF. Visceral lesions associated with chronic infectious (rheumatoid) arthritis. Arch Pathol 1943;35:50316. 35. Lee SS, Trimble RB. Rheumatoid arthritis with bloody and cholesterol pleural effusion. Arch Pathol Lab Med 1985;109:769-71. 36. Case Records of the Massachusetts General Hospital (Case 27-1982). N Engl J Med 1982;307:104-12. 37. Case Records of the Massachusetts General Hospital (Case 37-1992). N Engl J Med 1992;327:873-80.

38. Portner MM, Gracie WA Jr. Rheumatoid lung disease with cavitary nodules, pneumothorax and eosinophilia. N Engl J Med 1966;275:697700. 39. Tserkezoglou A, Metakidis S, Papastamatiou-Tsimara H, Zoitopoulos M. Solitary rheumatoid nodule of the pleura and rheumatoid pleural effusion. Thorax 1978;33:769-72. 40. Hunninghake GW, Fauci AS. Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis 1979;119:471-503. Copyright 2002 Massachusetts Medical Society.

35-MILLIMETER SLIDES FOR THE CASE RECORDS Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a medical teaching exercise or reference material is eligible to receive 35-mm slides, with identifying legends, of the pertinent x-ray films, electrocardiograms, gross specimens, and photomicrographs of each case. The slides are 2 in. by 2 in., for use with a standard 35-mm projector. These slides, which illustrate the current cases in the Journal, are mailed from the Department of Pathology to correspond to the week of publication and may be retained by the subscriber. Each year approximately 250 slides from 40 cases are sent to each subscriber. The cost of the subscription is $450 per year. Application forms for the current subscription year, which began in January, may be obtained from Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone [617] 726-2974). Slides from individual cases may be obtained at a cost of $35 per case.

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