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Similar Pleural Fluid Findings in Pleuropulmonary Tularemia and Tuberculous Pleurisy
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syndrome as a complication of percutaneous left ventricular puncture. Am J Cardiol 1966; 17:86-90 Kaye D, Frankl W, Arditi LI. Probable postcardiotomy syndrome following implantation of a transvenous pacemaker: a report of the first case. Am Heart J 1975; 90:627-30 Stelzner TJ, King TE Jr, Antony VB, et al. The pleuropulmonary manifestations of the postcardiac injury syndrome. Chest 1983; 84:383-87 Twomey SL, Bernett GE. Immunofluorescence method for detecting anti-myocardial antibodies, and its use in diagnosing heart disease. Clin Chern 1975; 21:1903-06 Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders: II. Relation of the concentration of the proteins in serum and cerebrospinal fluid. Scand J Clin Lab Invest 1977; 37:391-96 Khan AH. The postcardiac injury syndromes. Clin Cardiol1992; 15:67-72 De Scheerder I, Vandekerckhove J, Robbrecht J, et al. Post-cardiac injury syndrome and an increased humoral immune response against the major contractile proteins (actin and myosin). Am J Cardiol1985; 56:631-33 De Scheerder I, De Buyzere M, Robbrecht J, et al. Postoperative immunological response against contractile proteins after coronary bypass surgery. Br Heart J 1986; 56:440-44 Engle MA, McCabe JC, Ebert PA, et al. The postpericardiotomy syndrome and antiheart antibodies. Circulation 1974; 49:401-06 Engle MA, Zabriskie JB, Senterfit LB, eta!. Immunologic an virologic studies in the postpericardiotomy syndrome. J Pediatr 1975; 87:1103-08 Engle MA, Gay WA, McCabe J, et al. Postpericardiotomy syndrome in adults: incidence, autoimmunity and virology. Circulation 1981; 64(suppl 11):58-60 Maisch B, Berg PA, Kochsiek K. Clinical significance of immunopathological findings in patients with post-pericardiotomy syndrome: I. Relevance of antibody pattern. Clin Exp Immunol 1979; 38:189-97 Liem KL, Ten Veen JH, Lie KI, et al. Incidence and significance of heartmuscle antibodies in patients with acute myocardial infarction and unstable angina. Acta Med Scand 1979; 206:473-75 Vander Geld H. Anti-heart antibodies in the postpericardiotomy and the postmyocardial-infarction syndromes. Lancet 1964; 2:617-21 Webber SA, Wilson NJ, Fung MY, et al. Autoantibody production after cardiopulmonary bypass with special reference to postpericardiotomy syndrome. J Pediatr 1992; 121:744-47 Kim YK, Mohsenifar Z, Koerner SK. Lymphocytic pleural effusion in postpericardiotomy syndrome. Am Heart J 1988; 115:1077-79 Pettersson T, Klockars M, Hellstrom PE. Chemical and immunological features of pleural effusions: a comparison between rheumatoid arthritis and other diseases. Thorax 1982; 37:354-61
Similar Pleural Fluid Findings in Pleuropulmonary Tularemia and Tuberculous Pleurisy* Tom Pettersson, MD; Peter Nyberg, MD; Dan Nordstrom, MD; and Henrik Riska, MD, FCCP
Biochemical and cellular characteristics of pleural fluid from two patients with pleuropulmonary tulare, *From the Mjolbolsta Hospital, Mjolbolsta, Finland, and the Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
572
mia and 39 patients with tuberculous pleurisy were compared. High pleural fluid concentrations of adenosine deaminase, lysozyme, and ~ 2 -microglobulin occurred in both diseases. As is the case with tuberculous pleural effusions, pleural fluid in tularemia showed an abundance of lymphocytes, predominantly CD4-positive T lymphocytes. The similar pleural fluid findings suggest analogous local pathogenetic mechanisms in tularemia and tuberculosis. In the diagnostic evaluation of a lymphocyte-rich exudative pleural effusion with a high adenosine deaminase concentration, a possible cause to consider is tularemia.
(CHEST 1996; 109:572-75)
ACE=angiotensin-converting enzyme; ADA=adenosine deaEninase; ~M=lysozyme
Key words: adenosine deaminase; pleural effusion; T lymphocytes; tuberculosis; tularemia ,llthough tularemia is regarded as a rare cause of pleural
f t effusion, tularemic pneumonia often is complicated by
pleural involvement and effusion.l· 2 Pleurisy and pleural effusion without pneumonia is another, more uncommon presentation of tularemia. 3 Pleuropulmonary tularemia often causes differential diagnostic difficulties and may, in particular, be confused with tuberculous pleurisy. 4•5 The pleural effusion in pleuropulmonary tularemia has been described as a turbid or serosanguineous exudate with a predominance of either lymphocytes or neutrophils. 4•6•7 The effusion is not a low-glucose one, and there is no pleural fluid acidosis. 8 The biochemical composition of pleural fluid in tularemia, however, has not been described in detail. We analyzed lymphocyte subpopulations and several biochemical variables in the pleural fluid of two patients with tularemia and compared the results with those obtained in patients with tuberculous pleurisy. CASE REPORTS CASE
1
A 66-year-old previously healthy gardener was admitted to the hospital because of a 2-month history of breathlessness on exertion, mild right-sided chest pain, upper abdominal discomfort, and lowgrade fever. Physical examination revealed dullness with decreased breath sounds at the right lung base. He had no cutaneous symptoms and no lymphadenopathy or splenomegaly, but the liver appeared slightly enlarged. A chest x-ray film revealed a right-sided pleural effusion but no pulmonary parenchymal infiltrates or hilar adenopathy. He had a moderate leukocytosis with 65% lymphocytes and among them reactive forms. A tuberculin skin test (2 tuberculin unit [TU]) was positive. The pleural effusion was a sanguinolent exudate with a lymphocytic predominance (Table 1). A diagnosis of tuberculous pleurisy was considered likely, but an incidental serologic investigation revealed a diagnostic agglutination titer against Francisella tularensis of 1:160. He was treated with streptomycin, 1 ggiven IM each day for 2 weeks. Symptoms of pleurisy gradually disappeared. A chest x-ray film 2 months afterdiscontinuation of the medication showed clearing of the effusion, but pleural adhesions remained. AsubseSelected Reports
sis and/or clinical findings and a positive response to specific antituberculous therapy.
quent serum specimen yielded a F tularensis titer of 1:640. The route of infection with F tularensis remained unclarified. Cultures to show Mycobacterium tuberculosis remained negative. CASE
METHODS
2
The following biochemical analyses were performed on pleural fluid (stored at -20°C until assayed): adenosine deaminase (ADA) was determined according to the colorimetric method of Gitlsti.9 Lysozyme (lZM ) was measured with a turbidimetric method (Testomar Lysozyme; Behring Institute; Mannheim, Germany) and angiotensin-converting enzyme (ACE) was assayed spectrophotometrically.10 I32-Microglobulin was determined with a radioimmunoassay (Pharmacia AB; Uppsala, Sweden) and soluble interleukin-2 receptor with an immunoenzymometric assay (Immunotech SA; Marseilles, France). Complement C3 and C4 concentrations were determined with radial immunodiffusion. Reference values in normal humau s erum lor the variables investigated are shown in Table l. In patient 1, acid a-naphthyl acetate esterase staining of cytocentrifuged preparations of mononuclear cells was used to identifY T lymphocytes. 11 .12 A lymphocyte was scored as positive if its cytoplasm contained a single dot or a few dots of the reddish-brown reaction product. In patient 2, the proportions of CD4- and CD8positive lymphocytes among mononuclear cells were studied using the avidin-biotin-peroxidase complex method in combination with monoclonal antibodies. 13 Positivity was indicated by brown staining of the cytoplasm. In each preparation, 100 cells in total were counted.
A 52-year-old retired farmer, who 20 years earlier had been treated for tuberculosis, was investigated because of fever and dyspnea. Achest x-ray film showed an infiltrate in the lower lobe of the right lung. While receiving antimicrobial drug treatment, he made a good clinical recovery, but a right-sided pleural effusion developed. At thoracentesis, serosanguineous, lymphocyte-rich pleural exudate was removed (Table 1, pleural fluid sample A). A chest xray film 2 months later revealed only pleural adhesions. Four months later, the patient was readmitted to the hospital because of fever, breathlessness, and right-sided chest pain on inspiration. Inspiratory rales were audible over the base of the right lung. There were no cutaneous symptoms, lymphadenopathy, or hepatosplenomegaly. Achest x-ray Hlm showed a diffuse infiltrate in the lower lobe of the right lung and a right-sided pleural effusion. Serum C-reactive protein concentration was 238 mgtL. A tuberculin skin test (2 TU ) was positive. Straw-colored, turbid lymphocyterich exudate was removed on two separate occasions (Table 1, samples Band C). A pleural biopsy obtained with Abrams' needle showed nonspecific inflammatory changes. Tuberculosis was considered the most likely cause of the pleural effusion, but serologic investigations showed a diagnostic agglutination titer against F tularensis of 1:160. In a serum specimen drawn 2 weeks later, the titer had risen to 1:640. The diagnosis of tularemia was further verified by demonstration ofF tularensis in pleural fluid culture. The patient was successfully treated with streptomycin, 1.2 g given IM each day for 2 weeks, followed b yoral ciprofloxacin hydrochloride, 1 g daily for another month. The source of infection remained unknown. Cultures to demonstrate M tuberculosis remained negative . For comparison, 39 consecutive patients (8 women and 31 men; median age, 62 years; range, 21 to 90 years) with tuberculous pleurisy treated at the same hospital were included . The diagnosis was established by a positive staining or culture of M tuberculosis in sputum or in pleural fluid, or, in the absence of bacteriologic verification, by pleural biopsy findin~s compatible with tubercula-
RESULTS
Results of cellular arid biochemical analyses of pleural fluid in the two tularemia patients arid in the patients with tuberculous pleurisy are shown in Table l. Both types of infection were associated with lymphocyte-rich exudates. Similar pleural fluid glucose arid lactate dehydrogenase concentrations were measured in tularemia as in tuberculosis, and pleural fluid concentrations of ADA, l.ZM, arid 132microglobulin were high in both diseases. In tularemia, the pleural fluid concentration of soluble interleukin-2 receptor
Table !-Pleural Fluid Data on Two Patients With Pleuropulmonary Tularemia* Tularemia Patient 2 Variable 1 Protein, giL Glucose, mmoi!L Lactate dehydrogenase, U/L ADA, U/L LZM, mg!L ACE, U/mL l32-microglobulin, mg!L Soluble interleukin-2 receptor, picomoi!L C3, giL C4, giL Leukocytes, xlWIL Lymphocytes, %
Patient 1
A
B
c
Tuberculosis, Median (Range)
50 4.9 573 ND 8.8 24.6 4.8 ND
47 5.1 584 ND ND 25.0 5.2 ND
41 3.4 2,501 214 ND ND ND ND
3.2 1,630 94 13.0 28.1 5.5 120
51 (32-58) 4.2 (0.2-9.9) 1000 (263-18100) 78 (7-182) 18.0 (3.5-167.0) 25.7 (1.7-100.8) 5.2 (3.7-33.0) 419 (300-512)
0.37 0.12 952 90.5
0.40 0.08 3,320 71.0
0.47 0.06 1,850 74.0
ND ND 2,000 72.5
0.59 (0.14-1.45) 0.22 (0.07-0.44) 1658 (9-6080) 82.0 (31.5-100)
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*In patient 2, thoracentesis was performed on three separate occasions (A, B, and C). Data on 39 patients with tuberculous pleurisy are shown for comparison. ND=not determined. 1Reference intervals for normal human serum: protein, 60 to 78 giL; lactate dehydrogenase, 0 to 450 U/L; ADA, 4 to 30 UIL; LZM, 0 to 7.2 mg!L; ~2-microglobulin , 0 to 2.4 mg!L; ACE, 16.5 to 47.5 U/mL; soluble interleukin-2 receptor, 15 to 128 picomoi!L; C3, 0.55 to 1.20 giL; C4, 0.20 to 0.50 giL. CHEST /109/ 2/ FEBRUARY, 1996
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was lower than in tuberculosis but it was close to the upper normal serum level. In both diseases, the pleural fluid concentration of ACE was rather low. No patient with tularemia or tuberculosis had particularly low pleural fluid C3 or C4 concentrations. In patient 1, acid a-naphthyl acetate esterase-positive lymphocytes constituted 90% of all mononuclear cells in pleural fluid and 74% of all mononuclear cells in peripheral blood. In patient 2, 64% of the mononuclear cells in pleural fluid sample Bwere CD4-positive and 17%, COS-positive; in peripheral blood, there were 36% CD4-positive cells and 37% CD8-positive cells. DISCUSSION
We observed quite similar pleural fluid findings in pleuropulmonary tularemia and in tuberculous pleurisy. In fact, in the two patients with tularemia, tuberculosis had initially been considered the most likely cause of the pleural effusion. In neither of them was the diagnosis of tularemia suggested by medical history or by physical findings, such as an ulcerative cutaneous lesion or lymphadenopathy? The diagnosis of tularemia usually is based on serologic methods. Antibodies first appear about the 2nd week of infection. An agglutination titer of 1:160 is presumed to be diagnostic. It is desirable to show a fourfold or greater rise in titer in a serum sample obtained 10 days to 2 weeks later. Culture of F tularensis requires special media and should only be attempted in an appropriate laboratory because of the hazard to the personnel. F tularensis rarely has been cultured from pleural fluid.3 In our patients, the high agglutination titers against F tularensis were more or less incidentally discovered during a systematic diagnostic workup. A fourfold rise in titer was demonstrated in both patients. In patient 2, the diagnosis was further confirmed by the demonstration of the organism by culture of pleural fluid. This patient had the pneumonic form of tularemia with pleural involvement, whereas patient 1 represented the more uncommon type of intrathoracic tularemia presenting as an isolated pleural effusion. Several studies have shown that a high concentration of ADA in pleural fluid serves as a useful adjunct in the diagnosis of tuberculous pleurisy.l 4-16 However, high pleural fluid ADA values also have been recorded in other infections, such as Q fever, 6 and psittacosis,l7 and in rheumatoid arthritis.18J 9 Based on our present results, we agree with Syrjala et al5 that tularemia should be added to the list of diseases that may cause a high pleural fluid ADA concentration. High pleural fluid concentrations of LZM and 132-microglobulin have been reported to occur in tuberculous pleurisy and in rheumatoid arthritis.20·21 In the present study, pleural fluid concentrations of LZM and l32-microglobulin in patients with tularemia were as high as in patients with tuberculous pleurisy. There are only a few reports on the. occurrence of ACE in pleural fluid, but it seems that high pleural fluid ACE concentrations may occur in patients with rheumatoid pleurisy. 22 We observed rather low pleural fluid ACE concentrations in both tularemia and tuberculosis. In tularemia, there was an abundance of T lymphocytes in pleural fluid. Again, a parallel may be drawn to the situ574
ation in tuberculous pleural effusions, where a predominance ofT lymphocytes is a consistent finding.23 In concordance with previous reports 13·24 on tuberculous pleural effusions, we observed that the majority of the pleural fluid T lymphocytes in tularemia are CD4-positive. These observations suggest similar local immunopathogenetic events in pleuropulmonary tularemia as in tuberculous pleurisy. Pleural biopsy in tularemia has been reported most often to show infiltration with lymphocytes but may reveal a granulomatous inflammation. 4 Presence ofT helper/inducer lymphocytes in pleural fluid may be necessary for macrophage activation and granuloma formation and maintenance, which play an essential role in the defense against intracellular pathogens such as M tuberculosis and F tularensis. The high pleural fluid concentrations of ADA and 132-microglobulin probably reflect such local T lymphocyte-mediated immune reactions. The absence of particularly low C3 and C4 concentrations in pleural fluid suggests that local immune complex formation in pleural fluid is not a feature of tuberculosis or tularemia. In conclusion, pleural effusions in tuberculosis and tularemia cannot be differentiated by cytologic or biochemical analysis of pleural fluid. When a patient presents with a T lymphocyte-rich exudative pleural effusion with high ADA, LZM or l32-microglobulin concentrations, tularemia needs to be considered among the possible causes.
REFERENCES
1 Dennis JM, Boudreau RP. Pleuropulmonary tularemia: its roentgen manifestations. Radiology 1957; 68:25-30 2 Rubin SA. Radiographic spectrum ofpleuropulmonary tularemia. AJR 1978; 131:277-81 3 Funk LM, Simpson SO, Mertz G, et al. Tularemia presenting as an isolated pleural effusion. West J Med 1992; 156:415-17 4 Schmid GP, Catino D, Suffin SC, et al. Granulomatous pleuritis caused by Fmncisella tularensis: possible confusion with tuberculous pleuritis. Am Rev Respir Dis 1983; 128:314-16 5 Syrjalii H, Koskela P, Kujala P, et al. Guillain-Barre syndrome and tularemia pleuritis with high adenosine deaminase activity in pleural fluid. Infection 1989; 17:152-53 6 Blackford SD, CaseyCJ. Pleuropulmonary tularemia. Arch Intern Med 1941; 67:43-71 7 Sahn S. Pleural effusion in the atypical pneumonias. Semin Respir Infect 1988; 3:322-34 8 Harrell R, Bates JH. Clinical recognition and treatment of tularemia. Internal Med 1987; 8:115-23 9 Giusti G. Adenosine deaminase. In: Bergmayer HU, ed. Methods of enzymatic analysis. vol 2. 2nd ed. New York: Academic Press, 1974; 1092-99 10 Cushman DW, Cheung HS. Spectrophotomebic assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem Pharmacol1971; 20:1637-48 l l Mueller J, Brun del ReG, Buerki H, et al. Nonspecific acid esterase activity: a criterion for the differentiation ofT and B lymphocytes in mouse lymph nodes. Eur J Immunol1975; 5:270-74 12 Pettersson T. Acid alpha-naphthyl acetate esterase staining of lymphocytes in pleural effusions. Acta Cytol1982; 26:109-14 13 Bergroth V, Konttinen YT, Nordstrom D, et al. Lymphocyte subpopulations, activation phenotypes, and spontaneous proliferation in tuberculous pleurisy. Chest 1988; 91:338-41 14 Piras MA, Gakis C, Budroni M, et al. Adenosine deaminase activity in pleural effusions: an aid to differential diagnosis. BMJ 1978; 2:1751-52 Selected Reports
15 Ocana I, Martfnez-Vazguez JM, Segura R, et al. Adenosine deaminase in pleural fluids: test for diagnosis of tuberculous pleural effusion. Chest 1983; 84:51-3 16 Esteban C, Oribe M, Fernandez A, et al. Increased adenosine deaminase activity in Q fever pneumonia with pleural effusion. Chest 1994; 105:648 17 Orriols R,Muiioz X, Drobnic Z, et al. High adenosine deaminase activity in pleural effusion due to psittacosis. Chest 1992; 101:881-82 18 Pettersson T, Ojala K, Weber TH. Adenosine deaminase in the diagnosis of pleural effusions. Acta Med Scand 1984; 215:299-304 19 Ocaiia I, Ribera E , Martinez-Vazquez JM, et al. Adenosine deaminase activity in rheumatoid pleural effusion. Ann Rheum Dis 1988; 47:394-97 20 Klockars M, Pettersson T, Riska H, et al. Pleural fluid lysozyme in human disease. Arch Intern Med 1979; 139:73-7 21 Riska H , Pettersson T, Froseth B, et al. Beta2-microglobulin in pleural effusions. Acta Med Scand 1982; 211:45-50 22 Romer FK, Geday H . Activity of angiotensin-converting enzyme in pleural fluid and serum in non-sarcoid, nontuberculous pleural effusion. Eur J Respir Dis 1982; 63:102-06 23 Pettersson T, Klockars M, Hellstrom PE, et al. T and B yl mphocytes in pleural effusions. Chest 1978; 73:49-51 24 Barnes PF, Mistry SD, Cooper CL, et al. Compartmentalization of a CD4+ T yl mphocyte subpopulation in tuberculous pleuritis. J Immunol1989; 142:1114-19
sis for patients who d evelop right-sided heart failure. (CHEST 1996; 109:575-77)
PA=pulmonary artery; RV=right ventricle; RVOT=right ventricular outflow tract; RVOTO=right ventricular outflow tract obstruction; VSD=ventricular septal defect
Key words: lung transplantation; outflow tract obstruction; right ventricle
Right ventricular outflow tract obstruction (RVOTO) is an uncommon complication of lung transplantation for pulmonary hypertension. RVOTO typically presents in the early postoperative period1-3 and often is associated with the use of inotropic agents.4
Delayed Right Heart Failure Following Lung Transplantation* Paul M. Kirshbom, MD; Victor F. Tapson, MD, FCCP; Kevin Harrison, MD; R. Duane Davis, MD; and William Gaynor, MD
J. J.
Dynamic right ventricular outflow tract obstruction (RVOTO) has been reported following lung transplantation for pulmonary hypertension, usually in association with the use of inotropic agents. This report describes delayed severe right-sided heart failure associated with right ventricular outflow tract obstruction following sequential bilateral lung transplantation and closure of a ventricular septal defect. The patient had no evidence of outflow tract obstruction in the early posttransplant period but developed progressive right heart failure more than 2 months later. Catheterization revealed dynamic RVOTO and an elevated right ventricular end-diastolic pressure. The patient was treated with metoprolol tartrate and diltiazem hydrochloride with resolution of the outflow tract obstruction and heart failure. This case demonstrates that RVOTO can occur in the late posttransplant period and must be included in the differential diagno*From the Divisions of General and Thoracic Surgery (Drs. K.irshbom,. Davis, and Gaynor), Pulmonary Medicine (Dr. Tar.son), and Cardiology (Dr. Harrison), Duke University Medica! Center, Durham:Nc. R!7Jrint requests: Dr. Gaynor, Pediatric Cardiothoracic Surgery, Third Floor, Children's Hospital of Philadelphia, 34th Street and Civic Center Blvd, Philadelphia, PA 19104
FIGURE 1. Representative frames from the right ventriculogram demonstrating end-diastolic dimension of RVOT (top) and marked infundibular narrowing at end-systole (bottom). Peak instantaneous RVOT gradient was 39 mm Hg with a mean gradient of 24 mm Hg. CHEST /109/2/ FEBRUARY, 1996
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syndrome as a complication of percutaneous left ventricular puncture. Am J Cardiol 1966; 17:86-90 Kaye D, Frankl W, Arditi LI. Probable postcardiotomy syndrome following implantation of a transvenous pacemaker: a report of the first case. Am Heart J 1975; 90:627-30 Stelzner TJ, King TE Jr, Antony VB, et al. The pleuropulmonary manifestations of the postcardiac injury syndrome. Chest 1983; 84:383-87 Twomey SL, Bernett GE. Immunofluorescence method for detecting anti-myocardial antibodies, and its use in diagnosing heart disease. Clin Chern 1975; 21:1903-06 Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders: II. Relation of the concentration of the proteins in serum and cerebrospinal fluid. Scand J Clin Lab Invest 1977; 37:391-96 Khan AH. The postcardiac injury syndromes. Clin Cardiol1992; 15:67-72 De Scheerder I, Vandekerckhove J, Robbrecht J, et al. Post-cardiac injury syndrome and an increased humoral immune response against the major contractile proteins (actin and myosin). Am J Cardiol1985; 56:631-33 De Scheerder I, De Buyzere M, Robbrecht J, et al. Postoperative immunological response against contractile proteins after coronary bypass surgery. Br Heart J 1986; 56:440-44 Engle MA, McCabe JC, Ebert PA, et al. The postpericardiotomy syndrome and antiheart antibodies. Circulation 1974; 49:401-06 Engle MA, Zabriskie JB, Senterfit LB, eta!. Immunologic an virologic studies in the postpericardiotomy syndrome. J Pediatr 1975; 87:1103-08 Engle MA, Gay WA, McCabe J, et al. Postpericardiotomy syndrome in adults: incidence, autoimmunity and virology. Circulation 1981; 64(suppl 11):58-60 Maisch B, Berg PA, Kochsiek K. Clinical significance of immunopathological findings in patients with post-pericardiotomy syndrome: I. Relevance of antibody pattern. Clin Exp Immunol 1979; 38:189-97 Liem KL, Ten Veen JH, Lie KI, et al. Incidence and significance of heartmuscle antibodies in patients with acute myocardial infarction and unstable angina. Acta Med Scand 1979; 206:473-75 Vander Geld H. Anti-heart antibodies in the postpericardiotomy and the postmyocardial-infarction syndromes. Lancet 1964; 2:617-21 Webber SA, Wilson NJ, Fung MY, et al. Autoantibody production after cardiopulmonary bypass with special reference to postpericardiotomy syndrome. J Pediatr 1992; 121:744-47 Kim YK, Mohsenifar Z, Koerner SK. Lymphocytic pleural effusion in postpericardiotomy syndrome. Am Heart J 1988; 115:1077-79 Pettersson T, Klockars M, Hellstrom PE. Chemical and immunological features of pleural effusions: a comparison between rheumatoid arthritis and other diseases. Thorax 1982; 37:354-61
Similar Pleural Fluid Findings in Pleuropulmonary Tularemia and Tuberculous Pleurisy* Tom Pettersson, MD; Peter Nyberg, MD; Dan Nordstrom, MD; and Henrik Riska, MD, FCCP
Biochemical and cellular characteristics of pleural fluid from two patients with pleuropulmonary tulare, *From the Mjolbolsta Hospital, Mjolbolsta, Finland, and the Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
572
mia and 39 patients with tuberculous pleurisy were compared. High pleural fluid concentrations of adenosine deaminase, lysozyme, and ~ 2 -microglobulin occurred in both diseases. As is the case with tuberculous pleural effusions, pleural fluid in tularemia showed an abundance of lymphocytes, predominantly CD4-positive T lymphocytes. The similar pleural fluid findings suggest analogous local pathogenetic mechanisms in tularemia and tuberculosis. In the diagnostic evaluation of a lymphocyte-rich exudative pleural effusion with a high adenosine deaminase concentration, a possible cause to consider is tularemia.
(CHEST 1996; 109:572-75)
ACE=angiotensin-converting enzyme; ADA=adenosine deaEninase; ~M=lysozyme
Key words: adenosine deaminase; pleural effusion; T lymphocytes; tuberculosis; tularemia ,llthough tularemia is regarded as a rare cause of pleural
f t effusion, tularemic pneumonia often is complicated by
pleural involvement and effusion.l· 2 Pleurisy and pleural effusion without pneumonia is another, more uncommon presentation of tularemia. 3 Pleuropulmonary tularemia often causes differential diagnostic difficulties and may, in particular, be confused with tuberculous pleurisy. 4•5 The pleural effusion in pleuropulmonary tularemia has been described as a turbid or serosanguineous exudate with a predominance of either lymphocytes or neutrophils. 4•6•7 The effusion is not a low-glucose one, and there is no pleural fluid acidosis. 8 The biochemical composition of pleural fluid in tularemia, however, has not been described in detail. We analyzed lymphocyte subpopulations and several biochemical variables in the pleural fluid of two patients with tularemia and compared the results with those obtained in patients with tuberculous pleurisy. CASE REPORTS CASE
1
A 66-year-old previously healthy gardener was admitted to the hospital because of a 2-month history of breathlessness on exertion, mild right-sided chest pain, upper abdominal discomfort, and lowgrade fever. Physical examination revealed dullness with decreased breath sounds at the right lung base. He had no cutaneous symptoms and no lymphadenopathy or splenomegaly, but the liver appeared slightly enlarged. A chest x-ray film revealed a right-sided pleural effusion but no pulmonary parenchymal infiltrates or hilar adenopathy. He had a moderate leukocytosis with 65% lymphocytes and among them reactive forms. A tuberculin skin test (2 tuberculin unit [TU]) was positive. The pleural effusion was a sanguinolent exudate with a lymphocytic predominance (Table 1). A diagnosis of tuberculous pleurisy was considered likely, but an incidental serologic investigation revealed a diagnostic agglutination titer against Francisella tularensis of 1:160. He was treated with streptomycin, 1 ggiven IM each day for 2 weeks. Symptoms of pleurisy gradually disappeared. A chest x-ray film 2 months afterdiscontinuation of the medication showed clearing of the effusion, but pleural adhesions remained. AsubseSelected Reports
sis and/or clinical findings and a positive response to specific antituberculous therapy.
quent serum specimen yielded a F tularensis titer of 1:640. The route of infection with F tularensis remained unclarified. Cultures to show Mycobacterium tuberculosis remained negative. CASE
METHODS
2
The following biochemical analyses were performed on pleural fluid (stored at -20°C until assayed): adenosine deaminase (ADA) was determined according to the colorimetric method of Gitlsti.9 Lysozyme (lZM ) was measured with a turbidimetric method (Testomar Lysozyme; Behring Institute; Mannheim, Germany) and angiotensin-converting enzyme (ACE) was assayed spectrophotometrically.10 I32-Microglobulin was determined with a radioimmunoassay (Pharmacia AB; Uppsala, Sweden) and soluble interleukin-2 receptor with an immunoenzymometric assay (Immunotech SA; Marseilles, France). Complement C3 and C4 concentrations were determined with radial immunodiffusion. Reference values in normal humau s erum lor the variables investigated are shown in Table l. In patient 1, acid a-naphthyl acetate esterase staining of cytocentrifuged preparations of mononuclear cells was used to identifY T lymphocytes. 11 .12 A lymphocyte was scored as positive if its cytoplasm contained a single dot or a few dots of the reddish-brown reaction product. In patient 2, the proportions of CD4- and CD8positive lymphocytes among mononuclear cells were studied using the avidin-biotin-peroxidase complex method in combination with monoclonal antibodies. 13 Positivity was indicated by brown staining of the cytoplasm. In each preparation, 100 cells in total were counted.
A 52-year-old retired farmer, who 20 years earlier had been treated for tuberculosis, was investigated because of fever and dyspnea. Achest x-ray film showed an infiltrate in the lower lobe of the right lung. While receiving antimicrobial drug treatment, he made a good clinical recovery, but a right-sided pleural effusion developed. At thoracentesis, serosanguineous, lymphocyte-rich pleural exudate was removed (Table 1, pleural fluid sample A). A chest xray film 2 months later revealed only pleural adhesions. Four months later, the patient was readmitted to the hospital because of fever, breathlessness, and right-sided chest pain on inspiration. Inspiratory rales were audible over the base of the right lung. There were no cutaneous symptoms, lymphadenopathy, or hepatosplenomegaly. Achest x-ray Hlm showed a diffuse infiltrate in the lower lobe of the right lung and a right-sided pleural effusion. Serum C-reactive protein concentration was 238 mgtL. A tuberculin skin test (2 TU ) was positive. Straw-colored, turbid lymphocyterich exudate was removed on two separate occasions (Table 1, samples Band C). A pleural biopsy obtained with Abrams' needle showed nonspecific inflammatory changes. Tuberculosis was considered the most likely cause of the pleural effusion, but serologic investigations showed a diagnostic agglutination titer against F tularensis of 1:160. In a serum specimen drawn 2 weeks later, the titer had risen to 1:640. The diagnosis of tularemia was further verified by demonstration ofF tularensis in pleural fluid culture. The patient was successfully treated with streptomycin, 1.2 g given IM each day for 2 weeks, followed b yoral ciprofloxacin hydrochloride, 1 g daily for another month. The source of infection remained unknown. Cultures to demonstrate M tuberculosis remained negative . For comparison, 39 consecutive patients (8 women and 31 men; median age, 62 years; range, 21 to 90 years) with tuberculous pleurisy treated at the same hospital were included . The diagnosis was established by a positive staining or culture of M tuberculosis in sputum or in pleural fluid, or, in the absence of bacteriologic verification, by pleural biopsy findin~s compatible with tubercula-
RESULTS
Results of cellular arid biochemical analyses of pleural fluid in the two tularemia patients arid in the patients with tuberculous pleurisy are shown in Table l. Both types of infection were associated with lymphocyte-rich exudates. Similar pleural fluid glucose arid lactate dehydrogenase concentrations were measured in tularemia as in tuberculosis, and pleural fluid concentrations of ADA, l.ZM, arid 132microglobulin were high in both diseases. In tularemia, the pleural fluid concentration of soluble interleukin-2 receptor
Table !-Pleural Fluid Data on Two Patients With Pleuropulmonary Tularemia* Tularemia Patient 2 Variable 1 Protein, giL Glucose, mmoi!L Lactate dehydrogenase, U/L ADA, U/L LZM, mg!L ACE, U/mL l32-microglobulin, mg!L Soluble interleukin-2 receptor, picomoi!L C3, giL C4, giL Leukocytes, xlWIL Lymphocytes, %
Patient 1
A
B
c
Tuberculosis, Median (Range)
50 4.9 573 ND 8.8 24.6 4.8 ND
47 5.1 584 ND ND 25.0 5.2 ND
41 3.4 2,501 214 ND ND ND ND
3.2 1,630 94 13.0 28.1 5.5 120
51 (32-58) 4.2 (0.2-9.9) 1000 (263-18100) 78 (7-182) 18.0 (3.5-167.0) 25.7 (1.7-100.8) 5.2 (3.7-33.0) 419 (300-512)
0.37 0.12 952 90.5
0.40 0.08 3,320 71.0
0.47 0.06 1,850 74.0
ND ND 2,000 72.5
0.59 (0.14-1.45) 0.22 (0.07-0.44) 1658 (9-6080) 82.0 (31.5-100)
42
*In patient 2, thoracentesis was performed on three separate occasions (A, B, and C). Data on 39 patients with tuberculous pleurisy are shown for comparison. ND=not determined. 1Reference intervals for normal human serum: protein, 60 to 78 giL; lactate dehydrogenase, 0 to 450 U/L; ADA, 4 to 30 UIL; LZM, 0 to 7.2 mg!L; ~2-microglobulin , 0 to 2.4 mg!L; ACE, 16.5 to 47.5 U/mL; soluble interleukin-2 receptor, 15 to 128 picomoi!L; C3, 0.55 to 1.20 giL; C4, 0.20 to 0.50 giL. CHEST /109/ 2/ FEBRUARY, 1996
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was lower than in tuberculosis but it was close to the upper normal serum level. In both diseases, the pleural fluid concentration of ACE was rather low. No patient with tularemia or tuberculosis had particularly low pleural fluid C3 or C4 concentrations. In patient 1, acid a-naphthyl acetate esterase-positive lymphocytes constituted 90% of all mononuclear cells in pleural fluid and 74% of all mononuclear cells in peripheral blood. In patient 2, 64% of the mononuclear cells in pleural fluid sample Bwere CD4-positive and 17%, COS-positive; in peripheral blood, there were 36% CD4-positive cells and 37% CD8-positive cells. DISCUSSION
We observed quite similar pleural fluid findings in pleuropulmonary tularemia and in tuberculous pleurisy. In fact, in the two patients with tularemia, tuberculosis had initially been considered the most likely cause of the pleural effusion. In neither of them was the diagnosis of tularemia suggested by medical history or by physical findings, such as an ulcerative cutaneous lesion or lymphadenopathy? The diagnosis of tularemia usually is based on serologic methods. Antibodies first appear about the 2nd week of infection. An agglutination titer of 1:160 is presumed to be diagnostic. It is desirable to show a fourfold or greater rise in titer in a serum sample obtained 10 days to 2 weeks later. Culture of F tularensis requires special media and should only be attempted in an appropriate laboratory because of the hazard to the personnel. F tularensis rarely has been cultured from pleural fluid.3 In our patients, the high agglutination titers against F tularensis were more or less incidentally discovered during a systematic diagnostic workup. A fourfold rise in titer was demonstrated in both patients. In patient 2, the diagnosis was further confirmed by the demonstration of the organism by culture of pleural fluid. This patient had the pneumonic form of tularemia with pleural involvement, whereas patient 1 represented the more uncommon type of intrathoracic tularemia presenting as an isolated pleural effusion. Several studies have shown that a high concentration of ADA in pleural fluid serves as a useful adjunct in the diagnosis of tuberculous pleurisy.l 4-16 However, high pleural fluid ADA values also have been recorded in other infections, such as Q fever, 6 and psittacosis,l7 and in rheumatoid arthritis.18J 9 Based on our present results, we agree with Syrjala et al5 that tularemia should be added to the list of diseases that may cause a high pleural fluid ADA concentration. High pleural fluid concentrations of LZM and 132-microglobulin have been reported to occur in tuberculous pleurisy and in rheumatoid arthritis.20·21 In the present study, pleural fluid concentrations of LZM and l32-microglobulin in patients with tularemia were as high as in patients with tuberculous pleurisy. There are only a few reports on the. occurrence of ACE in pleural fluid, but it seems that high pleural fluid ACE concentrations may occur in patients with rheumatoid pleurisy. 22 We observed rather low pleural fluid ACE concentrations in both tularemia and tuberculosis. In tularemia, there was an abundance of T lymphocytes in pleural fluid. Again, a parallel may be drawn to the situ574
ation in tuberculous pleural effusions, where a predominance ofT lymphocytes is a consistent finding.23 In concordance with previous reports 13·24 on tuberculous pleural effusions, we observed that the majority of the pleural fluid T lymphocytes in tularemia are CD4-positive. These observations suggest similar local immunopathogenetic events in pleuropulmonary tularemia as in tuberculous pleurisy. Pleural biopsy in tularemia has been reported most often to show infiltration with lymphocytes but may reveal a granulomatous inflammation. 4 Presence ofT helper/inducer lymphocytes in pleural fluid may be necessary for macrophage activation and granuloma formation and maintenance, which play an essential role in the defense against intracellular pathogens such as M tuberculosis and F tularensis. The high pleural fluid concentrations of ADA and 132-microglobulin probably reflect such local T lymphocyte-mediated immune reactions. The absence of particularly low C3 and C4 concentrations in pleural fluid suggests that local immune complex formation in pleural fluid is not a feature of tuberculosis or tularemia. In conclusion, pleural effusions in tuberculosis and tularemia cannot be differentiated by cytologic or biochemical analysis of pleural fluid. When a patient presents with a T lymphocyte-rich exudative pleural effusion with high ADA, LZM or l32-microglobulin concentrations, tularemia needs to be considered among the possible causes.
REFERENCES
1 Dennis JM, Boudreau RP. Pleuropulmonary tularemia: its roentgen manifestations. Radiology 1957; 68:25-30 2 Rubin SA. Radiographic spectrum ofpleuropulmonary tularemia. AJR 1978; 131:277-81 3 Funk LM, Simpson SO, Mertz G, et al. Tularemia presenting as an isolated pleural effusion. West J Med 1992; 156:415-17 4 Schmid GP, Catino D, Suffin SC, et al. Granulomatous pleuritis caused by Fmncisella tularensis: possible confusion with tuberculous pleuritis. Am Rev Respir Dis 1983; 128:314-16 5 Syrjalii H, Koskela P, Kujala P, et al. Guillain-Barre syndrome and tularemia pleuritis with high adenosine deaminase activity in pleural fluid. Infection 1989; 17:152-53 6 Blackford SD, CaseyCJ. Pleuropulmonary tularemia. Arch Intern Med 1941; 67:43-71 7 Sahn S. Pleural effusion in the atypical pneumonias. Semin Respir Infect 1988; 3:322-34 8 Harrell R, Bates JH. Clinical recognition and treatment of tularemia. Internal Med 1987; 8:115-23 9 Giusti G. Adenosine deaminase. In: Bergmayer HU, ed. Methods of enzymatic analysis. vol 2. 2nd ed. New York: Academic Press, 1974; 1092-99 10 Cushman DW, Cheung HS. Spectrophotomebic assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem Pharmacol1971; 20:1637-48 l l Mueller J, Brun del ReG, Buerki H, et al. Nonspecific acid esterase activity: a criterion for the differentiation ofT and B lymphocytes in mouse lymph nodes. Eur J Immunol1975; 5:270-74 12 Pettersson T. Acid alpha-naphthyl acetate esterase staining of lymphocytes in pleural effusions. Acta Cytol1982; 26:109-14 13 Bergroth V, Konttinen YT, Nordstrom D, et al. Lymphocyte subpopulations, activation phenotypes, and spontaneous proliferation in tuberculous pleurisy. Chest 1988; 91:338-41 14 Piras MA, Gakis C, Budroni M, et al. Adenosine deaminase activity in pleural effusions: an aid to differential diagnosis. BMJ 1978; 2:1751-52 Selected Reports
15 Ocana I, Martfnez-Vazguez JM, Segura R, et al. Adenosine deaminase in pleural fluids: test for diagnosis of tuberculous pleural effusion. Chest 1983; 84:51-3 16 Esteban C, Oribe M, Fernandez A, et al. Increased adenosine deaminase activity in Q fever pneumonia with pleural effusion. Chest 1994; 105:648 17 Orriols R,Muiioz X, Drobnic Z, et al. High adenosine deaminase activity in pleural effusion due to psittacosis. Chest 1992; 101:881-82 18 Pettersson T, Ojala K, Weber TH. Adenosine deaminase in the diagnosis of pleural effusions. Acta Med Scand 1984; 215:299-304 19 Ocaiia I, Ribera E , Martinez-Vazquez JM, et al. Adenosine deaminase activity in rheumatoid pleural effusion. Ann Rheum Dis 1988; 47:394-97 20 Klockars M, Pettersson T, Riska H, et al. Pleural fluid lysozyme in human disease. Arch Intern Med 1979; 139:73-7 21 Riska H , Pettersson T, Froseth B, et al. Beta2-microglobulin in pleural effusions. Acta Med Scand 1982; 211:45-50 22 Romer FK, Geday H . Activity of angiotensin-converting enzyme in pleural fluid and serum in non-sarcoid, nontuberculous pleural effusion. Eur J Respir Dis 1982; 63:102-06 23 Pettersson T, Klockars M, Hellstrom PE, et al. T and B yl mphocytes in pleural effusions. Chest 1978; 73:49-51 24 Barnes PF, Mistry SD, Cooper CL, et al. Compartmentalization of a CD4+ T yl mphocyte subpopulation in tuberculous pleuritis. J Immunol1989; 142:1114-19
sis for patients who d evelop right-sided heart failure. (CHEST 1996; 109:575-77)
PA=pulmonary artery; RV=right ventricle; RVOT=right ventricular outflow tract; RVOTO=right ventricular outflow tract obstruction; VSD=ventricular septal defect
Key words: lung transplantation; outflow tract obstruction; right ventricle
Right ventricular outflow tract obstruction (RVOTO) is an uncommon complication of lung transplantation for pulmonary hypertension. RVOTO typically presents in the early postoperative period1-3 and often is associated with the use of inotropic agents.4
Delayed Right Heart Failure Following Lung Transplantation* Paul M. Kirshbom, MD; Victor F. Tapson, MD, FCCP; Kevin Harrison, MD; R. Duane Davis, MD; and William Gaynor, MD
J. J.
Dynamic right ventricular outflow tract obstruction (RVOTO) has been reported following lung transplantation for pulmonary hypertension, usually in association with the use of inotropic agents. This report describes delayed severe right-sided heart failure associated with right ventricular outflow tract obstruction following sequential bilateral lung transplantation and closure of a ventricular septal defect. The patient had no evidence of outflow tract obstruction in the early posttransplant period but developed progressive right heart failure more than 2 months later. Catheterization revealed dynamic RVOTO and an elevated right ventricular end-diastolic pressure. The patient was treated with metoprolol tartrate and diltiazem hydrochloride with resolution of the outflow tract obstruction and heart failure. This case demonstrates that RVOTO can occur in the late posttransplant period and must be included in the differential diagno*From the Divisions of General and Thoracic Surgery (Drs. K.irshbom,. Davis, and Gaynor), Pulmonary Medicine (Dr. Tar.son), and Cardiology (Dr. Harrison), Duke University Medica! Center, Durham:Nc. R!7Jrint requests: Dr. Gaynor, Pediatric Cardiothoracic Surgery, Third Floor, Children's Hospital of Philadelphia, 34th Street and Civic Center Blvd, Philadelphia, PA 19104
FIGURE 1. Representative frames from the right ventriculogram demonstrating end-diastolic dimension of RVOT (top) and marked infundibular narrowing at end-systole (bottom). Peak instantaneous RVOT gradient was 39 mm Hg with a mean gradient of 24 mm Hg. CHEST /109/2/ FEBRUARY, 1996
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