Spontaneous Bacterial Empyema in Cirrhotic Patients: A Prospective Study

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1 Spontaneous Bacterial Empyema in Cirrhotic Patients: A Prospective Study XAVIER XIOL, JOSEP M. CASTELLVÍ, JORDI GUARDIOLA, EVA SESÉ, JOSÉ CASTELLOTE, ANTONIA PERELLÓ, XAVIER CERVANTES, AND MARIA JESÚS IBORRA Spontaneous bacterial empyema (SBEM) is an infection Whereas spontaneous bacterial peritonitis (SBP) is of a preexisting hydrothorax in cirrhotic patients a well-known entity with a reported incidence between and has seldom been reported. To determine its inci- 15% and 20% in hospitalized cirrhotic patients with dence and primary characteristics, all cirrhotic patients ascites, 1-3 spontaneous bacterial empyema (SBEM) with pleural effusion underwent thoracentesis at our the infection of a preexisting hydrothorax has seldom hospital either on admission or when an infection was been reported. 4 Because 5% to 10% of cirrhotic patients suspected. Pleural fluid (PF) study included biochemiwith ascites have an associated hydrothorax, 5,6 SBEM cal analysis, polymorphonuclear (PMN) leukocyte count, and culture by two methods: conventional and modified could be expected to appear in 1% to 2% of hospitalized (inoculation of 10 ml of PF into a blood culture bottle at cirrhotic patients with ascites. Apart from case reports, the bedside). SBEM was defined according to previously only two retrospective series including a total of 15 reported criteria: PF culture positive or PMN count episodes have been published. 4,7 The aim of this study greater than 500 cells/ml, and exclusion of parapneumonic was to investigate incidence, bacteriology, and clinical effusions. Sixteen of the 120 (13%) cirrhotic characteristics of SBEM and to confirm the data ob- patients admitted with hydrothorax had 24 episodes of SBEM. In 10 of the 24 episodes (43%), SBEM was not tained in our previous retrospective study. 4 associated with spontaneous bacterial peritonitis (SBP). PF culture was positive by the conventional method in PATIENTS AND METHODS 8 episodes (33%) and by the modified method (blood cul- In a university-based reference hospital, from September ture inoculation) in 18 (75%) (P Å.004, McNemar). The 1988 to December 1992, a thoracentesis was performed on microorganisms identified in PF were Escherichia coli all cirrhotic patients with pleural effusion on admission (or in 8 episodes, Streptococcus species in 4, Enterococcus when the effusion was detected for the first time during hosspecies in 3, Klebsiella pneumoniae in 2, and Pseudomomission pitalization) or when an infection was suspected during ad- nas stutzeri in 1. All episodes were treated with antibiotencephalopathy, because of fever, abdominal or chest pain, hepatic ics without inserting a chest tube in any case. Mortality or shock. If ascites was present, a paracenteics during treatment was 20%. We conclude that SBEM is a sis also was performed at the same time. Pleural fluid (PF) common complication of cirrhotic patients with hydroclear study included bacteriologic study, cytology, polymorphonu- thorax. Almost half of the episodes were not associated (PMN) leukocyte count, and glucose, protein, amylase, with SBP; thus, thoracentesis should be performed in lactic dehydrogenase, and adenosine deaminase determina- patients with cirrhosis, pleural effusion, and suspected tions. ph also was performed if an infection was suspected. infection. Culture of PF should be performed by inocumethods: conventional and modified. 8 In the conventional The bacteriologic study was performed using two different lating 10 ml into a blood culture bottle at the bedside. (HEPATOLOGY 1996;23: ) method, a sample of PF was collected in an empty sterile container and sent to the Clinical Microbiology Laboratory. Ten milliliters was centrifuged at 3,000 rpm for 20 minutes. The sediment was cultured on enriched chocolate agar, blood agar, MacConkey s agar, and thioglycolate broth. The cul- Abbreviations: SBP, spontaneous bacterial peritonitis; SBEM, spontaneous tures were incubated at 35 C inaco 2 (10%-15%) incubator bacterial empyema; PF, pleural fluid; PMN, polymorphonuclear; AF, ascitic fluid; OLT, orthotopic liver transplantation. for 48 hours. Both plates and broth were examined at 24 and From the Gastroenterology Service, Hospital de Bellvitge, L Hospitaof PF was inoculated into a 70-mL Liquoid Blood Culture 48 hours for visible growth. In the modified method, 10 ml let de Llobregat, Barcelona, Spain. Received March 27, 1995; accepted October 21, TSB Roche (Hoffman-La Roche, Basel, Switzerland) at the Dr. Guardiola is now at the Hospital de Vilafranca, Sant Pere 4, Vilafranca, patient s bedside. It was incubated at 35 C for 24 hours. Then, Barcelona, Spain. the BCB Roche slide (Hoffman-La Roche) with three solid Dr. Castellote is now at the Hospital General de Manresa, Ctra de la Culla culture mediums (chocolate agar, MacConkey s agar, and s/n, Manresa, Barcelona, Spain. malt agar) was screwed to the culture bottle, and the agar Address reprint requests to: Xavier Xiol, M.D., Servicio Aparato Digestivo, surfaces of the culture mediums were flooded with the broth Pta 19, Hospital de Bellvitge, Feixa Llarga s/n, L Hospitalet de Lloof the culture bottle. The assembly was incubated at 35 C for bregat, Barcelona, Spain. Copyright 1996 by the American Association for the Study of Liver a further 24 hours. In both cases, the organism was identified Diseases. with routine laboratory methods if growth occurred. 9 Antibi /96/ $3.00/0 otic susceptibility was studied using standard agar dilution 719

2 720 XIOL ET AL. HEPATOLOGY April 1996 methods. 10 If there was no growth by 48 hours, the culture in 11 of 24 episodes, 4 of 10 patients (40%) without was considered negative. In patients with ascitic fluid (AF), SBP and in 7 of 14 patients with SBP being positive AF culture was performed only by the modified method. (50%) (not significant). The diagnosis of SBEM was established according to pre- PF culture was positive by the conventional method viously reported criteria 4 : in 8 episodes (33%), whereas it was positive by the 1. Positive PF culture and a PMN count greater than 250 cells/ml. Patients with negative culture, compatible clinical modified method in 18 cases (75%) (P Å.004) (Table course, and a PF PMN count ú500 cells/ml also were included 2). All cases with positive conventional culture also had as culture-negative SBEM; positive inoculated culture. The microorganisms identi- 2. Exclusion of parapneumonic infections 11 ; fied in PF were Escherichia coli in 8 episodes, Streptoa. no image of pneumonia on a chest radiograph or com- coccus species in 4, Enterococcus species in 3, Klebsiella puted tomography scan; pneumoniae in 2, and Pseudomonas stutzeri in 1. Deb. evidence of pleural effusion before the infectious epi- spite improving culture technique, 6 patients had a sode or PF transudate characteristics during infec- culture-negative SBEM. The etiologic diagnosis was tion 12 ; confirmed in 4 of 6 culture-negative SBEM, 2 by AF 3. Patients treated with esophageal variceal sclerotherapy culture, 1 by blood culture, and 1 by both ascitic and in the previous week or who tested seropositive for the human immunodeficiency virus were excluded from the study. blood cultures (Table 1). SBP was defined 13 as a positive AF culture plus an AF PF characteristics before, during, and after infection PMN count greater than 250 cells/ml. Culture-negative SBP appear in Table 3. PF LDH during infection (4.70 was diagnosed by an AF PMN count greater than 500 cells/ { 0.77 mkat/l) was significantly higher than LDH be- ml with neither bacterial growth in culture methods, nor fore infection (2.46 { 0.37 mkat/l) and after infection carcinomatosis, tuberculosis, or pancreatic ascites. The ab- (2.57 { 0.37 mkat/l). However, there were no changes sence of an intraabdominal source of infection was required in glucose and protein levels before, during, or after in both cases. infection. A chest tube was not placed in any case, be- When an infection was suspected, patients were treated cause no PF fulfilled the biochemical criteria required empirically with a third-generation cephalosporin (ceftriaxfor its insertion. In one patient, a pneumothorax apone 1 g/24 hr) after drawing blood cultures, PF, and AF. Once the results of cultures and antibiotic sensitivities were peared after a control thoracentesis, when the infection known, appropriate changes in treatment were made. In paand the patient was discharged a few days later. was already cured. A chest tube was inserted for 7 days, tients with confirmed SBEM, a control thoracentesis was performed after 7 to 10 days of antibiotic treatment. SBEM was The mortality rate during treatment was 20% (5 of considered to be healed when PF culture became negative 24). The cause of death was septic shock within 48 and the PF PMN count was less than 250 cells/ml. Criteria hours after starting treatment in 2 cases, esophageal used in our hospital for chest tube insertion are frank pus or variceal hemorrhage in 2, and hepatic insufficiency in ph õ7.1 plus glucose levels õ40 mg/100 ml In the remainder, the infection was cured after 7 to McNemar s test, Fisher s Exact Test, and ANOVA were 10 days of antibiotic treatment. Two other patients died used for statistical analysis when necessary. Results are exduring admission because of hepatic insufficiency, in pressed as mean { SEM and were considered significant at P õ.05. both cases several days after having finished antibiotic treatment. RESULTS Four of the 10 patients who were discharged died between 1 and 19 months after an SBEM episode. In During the study period, 120 cirrhotic patients with 5 patients, an orthotopic liver transplantation (OLT) hydrothorax were admitted to our unit; 95 (79%) had was performed between 2 and 24 months after SBEM detectable ascites in addition to pleural effusion. Sixteen (Fig. 1). All 5 patients who underwent transplantation of the 120 (13%) had 24 episodes of SBEM. One are presently alive (2-5 years after OLT). patient had five episodes, 1 had three episodes, 2 patients had two episodes, and 12 had one episode. Clinical DISCUSSION data of patients are presented in Table 1. All pa- This study confirms that SBEM is a frequent compli- tients had advanced cirrhosis and most had been cation of cirrhotic patients with hydrothorax; its 13% hospitalized on previous occasions with clinical signs incidence is similar to the reported SBP incidence in of progressive liver dysfunction. Abdominal pain, one cirrhotic patients with ascites. 1-3,13 We believe that of the most common symptoms, was caused by an asso- SBEM is rarely diagnosed, not only because patients ciated SBP in all cases. Ascites was absent in 6 of 24 with hydrothorax are unusual, but because thoracente- episodes of SBEM (25%). In 18 episodes, ascites was ses are not performed routinely in cirrhotic patients present; AF was infected in 14 and noninfected in 4. with hydrothorax. In fact, pleural effusion is not as In 2 of the 4 patients with noninfected ascites, a PMN obvious as ascites, and thoracentesis is difficult to perform count was not performed, because the paracentesis in comatose patients. We had few complications yielded a few drops of AF, which was only enough to related to the practice of diagnostic thoracentesis; thus, practice a culture that was negative (Table 1, episodes we think that this procedure may be as safe and effi- 1a and 1d). Therefore, in 10 of 24 episodes (43%), SBEM cient as paracentesis. 14 As shown in Table 1, there are was not associated with SBP (6 without ascites and 4 patients having a culture-positive SBEM associated with noninfected ascites). Blood cultures were positive with a culture-negative SBP, and vice versa, underlin-

3 HEPATOLOGY Vol. 23, No. 4, 1996 XIOL ET AL. 721 TABLE 1. Clinical Characteristics in the 24 Episodes of SBEM in 16 Patients PF AF Conventional Modified Patient T EH/IH Clinical Findings Pugh PVS Culture Culture PMN Culture PMN SBP Blood Cultures Antibiotic Outcome 1a 37.5 EH Chills 10 No Negative Negative 3,000 Negative ND No Negative Ceftriaxone Cured. Reinfected 5 mo later 1b 38.1 IH Abdominal pain 11 No Negative E. coli 3,895 Negative 1,575 Yes E. coli Ceftriaxone Cured. Reinfected 2 mo later 1c 37 IH Abdominal pain 10 No S. bovis S. bovis 8,500 S. bovis 34,265 Yes S. bovis Ceftriaxone Cured. Reinfected 1 mo later 1d 38 IH Thoracic pain, 11 No Negative K. pneumoniae 1,700 Negative 128 No K. pneumoniae Ceftriaxone Cured. Reinfected 2 mo later cough, 1e 38 IH Thoracic pain, 9 No S. bovis S. bovis 2,950 Negative ND No Negative Ceftriaxone Cured. OLT 1 mo later 2a 39 IH Abdominal pain, 10 Yes E. coli E. coli 7,905 E. coli 10,545 Yes E. coli Ceftriaxone Cured. Reinfected 7 mo later cough 2b 37.8 EH Abdominal pain, 11 Yes S. sanguis S. sanguis 3,404 S. sanguis 4,185 Yes S. sanguis Ceftriaxone Cured. Died of hepatic failure 1 cough, mo later (during admission) EH Abdominal pain, 10 No Negative E. coli 11,440 E. coli 21,712 Yes E. coli Ceftriaxone Died of bleeding esophageal thoracic pain, varices on day EH Encephalopathy 11 Yes E. coli E. coli 2,250 * * No E. coli Ceftriaxone Cured. Died of hepatic failure 3 mo later (during admission) EH Encephalopathy 13 Yes Negative E. coli 1,500 * * No E. coli Ceftriaxone Died of sepsis on day EH Abdominal pain, 12 No Negative Negative 530 E. coli 7,860 Yes E. coli Ceftriaxone Cured. Died of hepatic failure thoracic pain, 10 mo later 7 38 IH Abdominal pain 12 No Negative S. bovis 3,026 S. bovis 3,450 Yes Negative Ceftriaxone Died of bleeding esophageal varices on day IH Encephalopathy, 11 No Negative Negative 826 Citrobacter 2,760 Yes Negative Ceftriaxone Died of hepatic failure on day 8 freundii IH Abdominal pain 12 No Negative E. coli 560 E. coli 4,900 Yes Negative Ceftriaxone Cured. Died of hepatic failure 7 mo later EH Thoracic pain, 8 No Negative S. mitis 13,366 Negative 206 No Negative Ceftriaxone Cured. OLT 10 mo later cough 11a 38 EH Thoracic pain, 10 No E. coli E. coli 7,480 * * No Negative Ceftriaxone Cured. Reinfected 1.5 mo later 11b 39 EH Thoracic pain 10 No E. coli E. coli 6,674 * * No Negative Ceftriaxone Cured. Reinfected 2 mo later 11c 38 IH Dyspnea 11 No Negative P. stutzeri 1,600 * * No Negative Ciprofloxacin Cured. OLT 2 mo later IH Thoracic pain, 11 No Negative Negative 2,574 Negative 2,180 Yes Negative Ceftriaxone Cured. OLT 2 mo later EH Abdominal pain 12 No Negative Negative 1,600 Negative 1,850 Yes E. coli Ampicillin Cured. Died of hepatic failure 2 mo later 14a 37 IH Thoracic pain 9 No Negative Negative 3,404 E. faecalis 3,540 Yes Negative Ampicillin Cured. Reinfected 1.5 mo later 14b 39 IH 9 Yes Negative E. faecalis 4,680 E. faecalis 528 Yes Negative Ampicillin Cured. OLT 16 mo later IH Abdominal pain 12 No Negative K. pneumoniae 1,856 K. pneumoniae 1,240 Yes Negative Ceftriaxone Cured. Died of SBP 3 mo later IH Septic shock 11 No E. faecium E. faecium 2,890 * * No E. faecium Ceftriaxone Died of sepsis on day 1 Abbreviations: EH, extrahospitalary; IH, intrahospitalary; PVS, peritoneovenous shunt. * No AF present.

4 722 XIOL ET AL. HEPATOLOGY April 1996 TABLE 2. Comparison of Two PF Culture Methods in 24 not a prerequisite for SBEM, and supporting the hy- Episodes of SBEM pothesis that enteric microorganisms reach the PF No. of Isolates through a bacteremia, as has been reported in SBP. 13,15 Microorganisms Conventional Modified This is also suggested by the fact that blood cultures were positive in 4 of 10 cases without SBP. E. coli 4 8 The inoculation of 10 ml of PF into a TSB blood Streptococcus species 3 5 bottle at the patient s bedside had a significantly Enterococcus species 1 2 higher sensitivity for the diagnosis of SBEM than the K. pneumoniae 0 2 conventional method (77% vs. 33%, P Å.004). This is in P. stutzeri 0 1 accordance with previous SBP reports. 16,17 Analogous Negative* 16 6 results in AF have been described in our hospital 8 (77% Total vs. 57%, P Å.0001). The reason for improving sensitiv- * All microorganisms isolated by the conventional method were ity should be immediate inoculation, 18 since a TSB also isolated by the modified method. blood culture bottle contains an anticoagulant and opsonin inhibitor that protects bacteria from further complement- or phagocyte-mediate killing, 19 as well as proing the importance of performing a thoracentesis in tecting the cultured volume. 20 The modified method cirrhotic patients with pleural effusion and suspected allows the culture of a large volume of fluid, and SBEM infection. Because of our strategy of practicing thora- is probably an infection that involves a low concentracentesis in addition to paracentesis and blood cultures, tion of bacteria, as is SBP. 20 an etiologic diagnosis was obtained in 22 of the 24 infec- None of the patients in our series were treated with tions of the present series. a chest tube because PF did not meet the biochemical In contrast with our previous report, 4 40% of SBEM criteria required for its insertion (frank pus, or ph õ7.1 episodes were not associated with SBP, although the and glucose õ2.22 mmol/l [40 mg/l]). Because most of criteria used for SBEM diagnosis were the same. The our patients were cured without inserting a chest tube, difference could be because the previous study was ret- and because its insertion in cirrhotic patients with hyrospective. Six of 24 patients in the present series had drothorax can be harmful, 21 a chest tube should not hydrothorax without ascites, indicating that ascites is be used in the treatment of SBEM. The biochemical TABLE 3. PF Characteristics Before, During, and After SBEM Before SBEM During SBEM After SBEM Previous Effusion/ LDH Protein Glucose Patient Thoracentesis (mkat/l) (g/l) PMN LDH Protein (mmol/l) ph PMN LDH Protein PMN 1a Yes/Yes , b , c , d , e , a Yes/No , b , Yes/Yes ,440 * 4 Yes/Yes , Yes/No ,500 * 6 No/No Yes/No ,026 * 8 Yes/Yes Yes/No Yes/Yes , a Yes/No , b , c , Yes/Yes , No/No , a Yes/Yes , b , Yes/Yes , Yes/Yes ,890 * Abbreviation: LDH, lactic dehydrogenase. * Died before completing treatment. No PF available at the end of treatment.

5 HEPATOLOGY Vol. 23, No. 4, 1996 XIOL ET AL. 723 FIG. 1. Long-term evolution of the 16 patients who had an episode of SBEM. 2. Almdal TP, Skinhoj P. Spontaneous bacterial peritonitis in cirrhosis: incidence, diagnosis and prognosis. Scand J Gastroenterol 1987;22: Albillos A, Cuervas-Mons V, Millan I, Canton T, Montes J, Barrios C, Garrido A, et al. Ascitic fluid polymorphonuclear cell count and serum to ascites albumin gradient in the diagnosis of bacterial peritonitis. Gastroenterology 1990;98: Xiol X, Castellote J, Baliellas C, Ariza J, Gimenez A, Guardiola J, Casais L. Spontaneous bacterial empyema in cirrhotic patients: Analysis of eleven cases. HEPATOLOGY 1990;11: Esteve M, Xiol X, Fernandez F, Gonzalez-Huix F, Baliellas C, Casais L. Treatment and outcome of hepatic hydrothorax in liver cirrhosis. J Clin Nutr Gastroenterol 1986;1: Alberts WM, Salomon DA, Boyce G. Hepatic hydrothorax. Cause and management. Arch Intern Med 1991;151: Chesta J, Ponichik J, Brahm J, Gil R, Gil LC, Ruiz M, Latorre R, et al. Spontaneous bacterial pleuritis in patients with liver cirrhosis. Rev Med Chil 1991;119: Castellote J, Xiol X, Verdaguer J, Ribes J, Guardiola J, Gimenez A, Casais L. Comparison of two ascitic fluid culture methods in cirrhotic patients with spontaneous bacterial peritonitis. Am J Gastroenterol 1990;85: Martin WJ, Washington JA II. Enterobacteriaceae. In: Lenette EH, Ballows A, Hausler VJ, eds. Manual of clinical microbiology. 3rd ed. Washington, DC: American Society for Microbiology; characteristics of PF found in the present series were 1980: similar to those reported previously 4 and consist of an 10. Washington JA II, Sutter VL. Dilution susceptibility test: Agar increase in pleural LDH during infection. and macrobroth dilution procedures. In: Lenette EH, Ballows A, Hausler VJ, eds. Manual of clinical microbiology. 3rd ed. Wash- SBP is a recognized indication for OLT. 22 Because ington, DC: American Society for Microbiology; 1980: of SBP s similarities between and frequent association 11. Sahn SA. The pleura. Am Rev Respir Dis 1988;138: with SBP, we have indicated OLT in five patients with 12. Light RW, McGregor MI, Luchsinger PV, Ball WC. Pleural effu- SBEM. Three of these patients experienced SBP (in sions: the diagnostic separation of transudates and exudates. Ann Intern Med 1972;77: addition to SBEM), and two of them had suffered 13. Garcia Tsao G. Spontaneous bacterial peritonitis. Gastroenterol SBEM without SBP. In the other patients who survived Clin North Am 1992;21: the infection, this procedure was contraindicated be- 14. Runyon BA. Paracentesis of ascitic fluid. A safe procedure. Arch cause of age, active enolism, or portal thrombosis. Intern Med 1986;146: In conclusion, SBEM is a frequent complication in 15. Wyke RJ. Bacterial infections complicating liver disease. Baillieres Clin Gastroenterol 1989;3: cirrhotic patients with hydrothorax. Our study shows 16. Runyon BA, Umland ET, Merlin T. Inoculation of blood cultures that almost half of the cases of SBEM are not associ- with ascitic fluid. Improved detection of spontaneous bacterial ated with SBP, indicating the importance of performing peritonitis. Arch Intern Med 1987;147: thoracentesis in patients with cirrhosis, pleural effubacteriological diagnosis of spontaneous bacterial peritonitis. J 17. Bobadilla M, Sifuentes J, Garcia Tsao G. Improved method for sion, and signs or symptoms of infection, independently Clin Microbiol 1989;27: of their having ascites. PF culture should be performed 18. Runyon BA, Antillon MR, Akriviadis EA, McHutchison JG. Bedby inoculating 10 ml into a blood culture bottle at the side inoculation of blood culture bottles with ascitic fluid is superior bedside, because this method is more sensitive than to delayed inoculation in the detection of spontaneous bactebedside, the conventional method. A chest tube is not even nec- rial peritonitis. J Clin Microbiol 1990;28: Washington JA II. Cultures of normally sterile body fluids, tissue essary in patients with positive PF culture. SBEM wounds and abscesses. In: Washington JA II, Brewer NS, eds. should be considered an indication for liver trans- Laboratory procedures in clinical microbiology. New York: plantation, independently of SBP. Springer-Verlag; 1985: Acknowledgment: We thank Catalina Perelló for 20. Runyon BA, Canawati HN, Akriviadis EA. Optimization of ascitic fluid culture technique. Gastroenterology 1988;95:1351- useful linguistic correction and Dr. Josep Sol for statis tical assistance. 21. Runyon BA, Greenblatt M, Ming HC. Hepatic hydrothorax is a relative contraindication to chest tube insertion. Am J Gastroenterol 1986;81: REFERENCES 22. Tito L, Rimola A, Gines P, Llach J, Arroyo V, Rodes J. Recurrence 1. Conn HO, Fessel JM. Spontaneous bacterial peritonitis in cirrhosis: variations on a theme. Medicine 1971;50: predictive factors. HEPATOLOGY of spontaneous bacterial peritonitis in cirrhosis: Frequency and 1988;8:27-31.