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Cytokine activation in purulent pericarditis caused by Neisseria meningitidis serogroup C
International Journal of Cardiology 113 (2006) 419 – 421 www.elsevier.com/locate/ijcard
Letter to the Editor
Cytokine activation in purulent pericarditis caused by Neisseria meningitidis serogroup C Alexandre Leite de Souza a,*, Maristela Marques Salgado b, Carla C. Romano c, Maria das Grac¸as Adelino Alkmin d, Jaques Sztajnbok a, Jose´ E. Vidal e, Alberto J.S. Duarte f, Antonio Carlos Seguro g a
Intensive Care Unit, Emı´lio Ribas Institute of Infectology, Sa˜o Paulo, Brazil Department of Immunology, Immunology and Microbiology Service, Adolfo Lutz Institute, Sa˜o Paulo, Brazil c Department of Dermatology/LIM56, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil d Department of Immunology, Immunology and Microbiology Service, Adolfo Lutz Institute, Sa˜o Paulo, Brazil e Department of Infectious Diseases, Emı´lio Ribas Institute of Infectious Diseases, Sa˜o Paulo, Brazil f Department of Dermatology/LIM56, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil Intensive Care Unit, Emı´lio Ribas Institute of Infectology, Sa˜o Paulo, Brazil; Department of Nephrology, Laboratory of Basic Research, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil b
g
Received 20 September 2005; accepted 21 September 2005 Available online 1 December 2005
Abstract Herein, we report a case of purulent pericarditis caused by Neisseria meningitidis serogroup C in a previously healthy 5-year-old boy, which was detected in pericardial fluid by polymerase chain reaction. The concentrations of interleukin-6, interferon-gamma and interleukin10 in pericardial fluid were notably increased compared with serum. The role of polymerase chain reaction, counterimmunoelectrophoresis and latex agglutination test in the diagnosis, as well as the participation of cytokines in the pathogenesis of meningococcal pericarditis, are discussed. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Pericarditis; Neisseria meningitidis; Cytokines; Polymerase chain reaction; Counterimmunoelectrophoresis; Latex agglutination tests
1. Case report A previously healthy 5-year-old-boy presented with a 2day history of fever, nausea, repeated vomiting and abdominal pain. In the preceding 12 h, he had become drowsy and developed a stiff neck. Upon examination, there was no petechiae, temperature was 36.8 -C, heart rate was 80 bpm, respiratory rate was 20 breaths/min, and blood pressure was 120/70 mmHg. Heart sounds were normal without pericardial friction rub, and the precordial area was normal. The rest of the examination was unremarkable. The * Corresponding author. Rua da Consolac¸a˜o, 2270 Ap 304, CEP 01302001 Sa˜o Paulo, SP, Brasil. Tel.: +55 11 3066 7292; fax: +55 11 30882267. E-mail addresses: [email protected], [email protected] (A.L. de Souza). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.09.042
white blood cell (WBC) count was 14 103/mm3, with 80% polymorphonuclear neutrophils, 16% lymphocytes, and 4% monocytes. The blood chemistry was normal. The cerebrospinal fluid (CSF) was cloudy and had 2720/mm3 WBCs (98% polymorphonuclear neutrophils; 1% lymphocytes; 1% monocytes), 152 mg/dL protein and 2 mg/dL glucose. Gram stain of the CSF showed Gram-negative diplococci and Neisseria meningitidis serogroup C was detected by latex agglutination (LA) test. Blood and CSF samples were taken for culture. Ceftriaxone (100 mg/kg/day) and dexamethasone (0.6 mg/kg/day) were administered. The patient demonstrated marked clinical improvement over the first 24 h. On day 4, the patient complained of severe chest pain and developed a dry cough with fever (38.2 -C) but no rash. Physical examination showed a heart rate of 132 bpm
420
A.L. de Souza et al. / International Journal of Cardiology 113 (2006) 419 – 421 Table 1 Concentrations of cytokines by use of ELISA in serum and pericardial fluid in our patient with septic meningococcal pericarditis Serum (pg mL IL-4 IL-6 IL-10 IFN-g
15.2 321.4 86.0 274.7
1
)
Pericardial fluid (pg mL
1
)
32.5 631.4 486.0 937.7
IL-4=interleukin-4; IL-6=interleukin-6; IL-10=interleukin-10; IFN-g=interferon-gamma.
Fig. 1. A transthoracic echocardiogram showing the heart surrounded by moderate to a large pericardial effusion, seen as an echo-free space (arrow); DP=pericardial effusion, VD=right ventricle, VE=left ventricle.
and a respiratory rate of 34 breaths/min. The intensity of the heart sounds had decreased, and friction rub was detected. An electrocardiogram showed diffuse ST-segment elevation. A chest X-ray indicated an enlarged cardiac silhouette, and an echocardiogram revealed moderate to a large pericardial effusion (Fig. 1). Pericardiocentesis yielded 150 mL of cloudy fluid. This aspirated fluid presented 680 WBC/mm3, with 85% polymorphonuclear neutrophils, 10% lymphocytes, 5% monocytes, 4500 mg/ dL protein and 48 mg/dL glucose. Gram and Ziehl – Nielsen staining revealed no microorganisms. The cultures of pericardial fluid and blood were negative, but the CSF culture was positive for N. meningitidis phenotype C:23:P1.22,14-6. Immunological tests, including counterimmunoelectrophoresis (CIE), LA test and polymerase chain reaction (PCR—Fig. 2), of the pericardial fluid were positive for N. meningitidis serogroup C. Commercially available kits for enzyme-linked immunosorbent assays (ELISA) were used to measure cytokine levels in the pericardial fluid plus serum and their values are shown in Table 1.
1
2
3
4
5
6
7
8
600 bp 400 bp
Fig. 2. PCR amplification of the siaD gene in the N. meningitidis serogroups B and C. Lanes 1 and 8: 100 bp DNA ladder (0.8 Ag/well); lanes 2, 3 and 4, respectively: negative control, positive control (Nm573/03 strain) and pericardial fluid test for siaD B gene PCR; lanes 5, 6, and 7, respectively: negative control, positive control (Nm576/03 strain) and pericardial fluid test for siaD C gene PCR.
A diagnosis of meningococcal pericarditis was made, and ceftriaxone was continued for an additional 7 days. At 7 days after pericardiocentesis, the physical examination and echocardiography were normal, and the patient was discharged.
2. Discussion Pericarditis is rarely caused by N. meningitidis, which accounts for only 6% to 16% of purulent pericarditis, mostly in adults [1]. In addition, pericardial involvement in patients with meningococcal disease has been described in 3– 19% of cases [2]. Few cases of N. meningitidis pericarditis in children have been reported [1,2]. Our patient presented disseminated meningococcal disease with purulent pericarditis, confirmed by CIE [3], LA test [4] and PCR [4– 7], which were positive for N. meningitidis serogroup C in the pericardial fluid. The CIE, LA test and PCR are sensitive and specific assays with widening clinical applications for the diagnostic investigation of infected body fluids, mainly when cultures are negative [3– 7]. In our patient, cytokine concentrations were higher in pericardial fluid than in serum. This cytokine pattern suggests a compartmentalized inflammatory process in which these cytokines are released from inflammatory cells [8– 10] present in the pericardial fluid. In addition, the higher levels of cytokines such as interleukin-6, interferongamma and interleukin-10 in the pericardial fluid suggest their involvement in the pathogenesis of meningococcal pericarditis. We propose that, after invasion of the pericardium, N. meningitidis plays a role in the recruitment of inflammatory cells from the bloodstream to the pericardium. These inflammatory cells are in turn responsible for cytokine release and fluid buildup in the pericardial sac. In conclusion, immunological and molecular biology studies hold promise for diagnosis of meningococcal pericarditis and for clarifying the mechanisms involved. To our knowledge, this is the first case of N. meningitidisrelated purulent pericarditis diagnosed by CIE, LA test and PCR. This is also the first case in which cytokine activation in the pericardial fluid has been demonstrated in a patient with meningococcal disease.
A.L. de Souza et al. / International Journal of Cardiology 113 (2006) 419 – 421
Acknowledgments We are grateful to Gil Benard and Soraya Ogusuku of the Dermatology and Immunodeficiencies Laboratory of the University of Sa˜o Paulo School of Medicine University Hospital for their assistance in measuring cytokine levels, as well as to Anna Vera Custo´dio and Terezinha Pereira de Arau´ jo of the Adolfo Lutz Institute, Department of Immunology, for performing the counterimmunoelectrophoresis and latex agglutination tests. We would also like to thank the staff of the Adolfo Lutz Institute Department of Bacteriology for serotyping.
References [1] Finkelstein Y, Adler Y, Nussinovitch M, Varsano I, Amir V. A new classification for pericarditis associated with meningococcal infection. Eur J Pediatr 1997;156:585 – 8. [2] El Bashir H, Klaber R, Mukasa T, Booy R. Pericarditis after meningococcal infection: case report of a child with two distinct episodes. Pediatr Infect J Dis 2004;23(3):279 – 81.
421
[3] Simon HB, Tarr PI, Hutter Jr AM, Erdmann III AJ. Primary meningococcal pericarditis. Diagnosis by counter-current immunoelectrophoresis. JAMA 1976;235(3):278 – 80. [4] Ferna´ndez-Rodrı´guez A, Va´zquez JA, Sua´rez-Mier MP, et al. Latex agglutination for bacterial antigens and meningococcus PCR: two useful tools in legal sudden deaths. Forensic Sci Int 2005;13(1):13 – 20. [5] Taha M. Simultaneous approach for nonculture PCR-based identification and serogroup prediction of Neisseria meningitidis. J Clin Microbiol 2000;38(2):855 – 7. [6] Vienne P, Ducos-Galand M, Guiyoule A, et al. The role of particular strains of Neisseria meningitidis in meningococcal arthritis, pericarditis, and pneumonia. Clin Infect Dis 2003;37(12):1639 – 42. [7] Moumile K, Carbonnelle E, Dessemme P, et al. Culture-negative pericarditis caused by Neisseria meningitidis serogroup C. J Clin Microbiol 2004;42:923 – 4. [8] van Deuren M, Brandtzaeg P, van der Meer JW. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol Rev 2000;13(1):144 – 66. [9] Halstensen A, Ceska M, Brandtzaeg P, Redl H, Naess A, Waage A. Interleukin-8 in serum and cerebrospinal fluid from patients with meningococcal disease. J Infect Dis 1993;167:471 – 5. [10] van Deuren M, van der Ven-Jongekrijg J, Bartelink AK, van Dalen R, Sauerwein RW, van der Meer JW. Correlation between proinflammatory cytokines and antiinflammatory mediators and the severity of disease in meningococcal infections. J Infect Dis 1995;172:433 – 9.
Letter to the Editor
Cytokine activation in purulent pericarditis caused by Neisseria meningitidis serogroup C Alexandre Leite de Souza a,*, Maristela Marques Salgado b, Carla C. Romano c, Maria das Grac¸as Adelino Alkmin d, Jaques Sztajnbok a, Jose´ E. Vidal e, Alberto J.S. Duarte f, Antonio Carlos Seguro g a
Intensive Care Unit, Emı´lio Ribas Institute of Infectology, Sa˜o Paulo, Brazil Department of Immunology, Immunology and Microbiology Service, Adolfo Lutz Institute, Sa˜o Paulo, Brazil c Department of Dermatology/LIM56, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil d Department of Immunology, Immunology and Microbiology Service, Adolfo Lutz Institute, Sa˜o Paulo, Brazil e Department of Infectious Diseases, Emı´lio Ribas Institute of Infectious Diseases, Sa˜o Paulo, Brazil f Department of Dermatology/LIM56, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil Intensive Care Unit, Emı´lio Ribas Institute of Infectology, Sa˜o Paulo, Brazil; Department of Nephrology, Laboratory of Basic Research, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil b
g
Received 20 September 2005; accepted 21 September 2005 Available online 1 December 2005
Abstract Herein, we report a case of purulent pericarditis caused by Neisseria meningitidis serogroup C in a previously healthy 5-year-old boy, which was detected in pericardial fluid by polymerase chain reaction. The concentrations of interleukin-6, interferon-gamma and interleukin10 in pericardial fluid were notably increased compared with serum. The role of polymerase chain reaction, counterimmunoelectrophoresis and latex agglutination test in the diagnosis, as well as the participation of cytokines in the pathogenesis of meningococcal pericarditis, are discussed. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Pericarditis; Neisseria meningitidis; Cytokines; Polymerase chain reaction; Counterimmunoelectrophoresis; Latex agglutination tests
1. Case report A previously healthy 5-year-old-boy presented with a 2day history of fever, nausea, repeated vomiting and abdominal pain. In the preceding 12 h, he had become drowsy and developed a stiff neck. Upon examination, there was no petechiae, temperature was 36.8 -C, heart rate was 80 bpm, respiratory rate was 20 breaths/min, and blood pressure was 120/70 mmHg. Heart sounds were normal without pericardial friction rub, and the precordial area was normal. The rest of the examination was unremarkable. The * Corresponding author. Rua da Consolac¸a˜o, 2270 Ap 304, CEP 01302001 Sa˜o Paulo, SP, Brasil. Tel.: +55 11 3066 7292; fax: +55 11 30882267. E-mail addresses: [email protected], [email protected] (A.L. de Souza). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.09.042
white blood cell (WBC) count was 14 103/mm3, with 80% polymorphonuclear neutrophils, 16% lymphocytes, and 4% monocytes. The blood chemistry was normal. The cerebrospinal fluid (CSF) was cloudy and had 2720/mm3 WBCs (98% polymorphonuclear neutrophils; 1% lymphocytes; 1% monocytes), 152 mg/dL protein and 2 mg/dL glucose. Gram stain of the CSF showed Gram-negative diplococci and Neisseria meningitidis serogroup C was detected by latex agglutination (LA) test. Blood and CSF samples were taken for culture. Ceftriaxone (100 mg/kg/day) and dexamethasone (0.6 mg/kg/day) were administered. The patient demonstrated marked clinical improvement over the first 24 h. On day 4, the patient complained of severe chest pain and developed a dry cough with fever (38.2 -C) but no rash. Physical examination showed a heart rate of 132 bpm
420
A.L. de Souza et al. / International Journal of Cardiology 113 (2006) 419 – 421 Table 1 Concentrations of cytokines by use of ELISA in serum and pericardial fluid in our patient with septic meningococcal pericarditis Serum (pg mL IL-4 IL-6 IL-10 IFN-g
15.2 321.4 86.0 274.7
1
)
Pericardial fluid (pg mL
1
)
32.5 631.4 486.0 937.7
IL-4=interleukin-4; IL-6=interleukin-6; IL-10=interleukin-10; IFN-g=interferon-gamma.
Fig. 1. A transthoracic echocardiogram showing the heart surrounded by moderate to a large pericardial effusion, seen as an echo-free space (arrow); DP=pericardial effusion, VD=right ventricle, VE=left ventricle.
and a respiratory rate of 34 breaths/min. The intensity of the heart sounds had decreased, and friction rub was detected. An electrocardiogram showed diffuse ST-segment elevation. A chest X-ray indicated an enlarged cardiac silhouette, and an echocardiogram revealed moderate to a large pericardial effusion (Fig. 1). Pericardiocentesis yielded 150 mL of cloudy fluid. This aspirated fluid presented 680 WBC/mm3, with 85% polymorphonuclear neutrophils, 10% lymphocytes, 5% monocytes, 4500 mg/ dL protein and 48 mg/dL glucose. Gram and Ziehl – Nielsen staining revealed no microorganisms. The cultures of pericardial fluid and blood were negative, but the CSF culture was positive for N. meningitidis phenotype C:23:P1.22,14-6. Immunological tests, including counterimmunoelectrophoresis (CIE), LA test and polymerase chain reaction (PCR—Fig. 2), of the pericardial fluid were positive for N. meningitidis serogroup C. Commercially available kits for enzyme-linked immunosorbent assays (ELISA) were used to measure cytokine levels in the pericardial fluid plus serum and their values are shown in Table 1.
1
2
3
4
5
6
7
8
600 bp 400 bp
Fig. 2. PCR amplification of the siaD gene in the N. meningitidis serogroups B and C. Lanes 1 and 8: 100 bp DNA ladder (0.8 Ag/well); lanes 2, 3 and 4, respectively: negative control, positive control (Nm573/03 strain) and pericardial fluid test for siaD B gene PCR; lanes 5, 6, and 7, respectively: negative control, positive control (Nm576/03 strain) and pericardial fluid test for siaD C gene PCR.
A diagnosis of meningococcal pericarditis was made, and ceftriaxone was continued for an additional 7 days. At 7 days after pericardiocentesis, the physical examination and echocardiography were normal, and the patient was discharged.
2. Discussion Pericarditis is rarely caused by N. meningitidis, which accounts for only 6% to 16% of purulent pericarditis, mostly in adults [1]. In addition, pericardial involvement in patients with meningococcal disease has been described in 3– 19% of cases [2]. Few cases of N. meningitidis pericarditis in children have been reported [1,2]. Our patient presented disseminated meningococcal disease with purulent pericarditis, confirmed by CIE [3], LA test [4] and PCR [4– 7], which were positive for N. meningitidis serogroup C in the pericardial fluid. The CIE, LA test and PCR are sensitive and specific assays with widening clinical applications for the diagnostic investigation of infected body fluids, mainly when cultures are negative [3– 7]. In our patient, cytokine concentrations were higher in pericardial fluid than in serum. This cytokine pattern suggests a compartmentalized inflammatory process in which these cytokines are released from inflammatory cells [8– 10] present in the pericardial fluid. In addition, the higher levels of cytokines such as interleukin-6, interferongamma and interleukin-10 in the pericardial fluid suggest their involvement in the pathogenesis of meningococcal pericarditis. We propose that, after invasion of the pericardium, N. meningitidis plays a role in the recruitment of inflammatory cells from the bloodstream to the pericardium. These inflammatory cells are in turn responsible for cytokine release and fluid buildup in the pericardial sac. In conclusion, immunological and molecular biology studies hold promise for diagnosis of meningococcal pericarditis and for clarifying the mechanisms involved. To our knowledge, this is the first case of N. meningitidisrelated purulent pericarditis diagnosed by CIE, LA test and PCR. This is also the first case in which cytokine activation in the pericardial fluid has been demonstrated in a patient with meningococcal disease.
A.L. de Souza et al. / International Journal of Cardiology 113 (2006) 419 – 421
Acknowledgments We are grateful to Gil Benard and Soraya Ogusuku of the Dermatology and Immunodeficiencies Laboratory of the University of Sa˜o Paulo School of Medicine University Hospital for their assistance in measuring cytokine levels, as well as to Anna Vera Custo´dio and Terezinha Pereira de Arau´ jo of the Adolfo Lutz Institute, Department of Immunology, for performing the counterimmunoelectrophoresis and latex agglutination tests. We would also like to thank the staff of the Adolfo Lutz Institute Department of Bacteriology for serotyping.
References [1] Finkelstein Y, Adler Y, Nussinovitch M, Varsano I, Amir V. A new classification for pericarditis associated with meningococcal infection. Eur J Pediatr 1997;156:585 – 8. [2] El Bashir H, Klaber R, Mukasa T, Booy R. Pericarditis after meningococcal infection: case report of a child with two distinct episodes. Pediatr Infect J Dis 2004;23(3):279 – 81.
421
[3] Simon HB, Tarr PI, Hutter Jr AM, Erdmann III AJ. Primary meningococcal pericarditis. Diagnosis by counter-current immunoelectrophoresis. JAMA 1976;235(3):278 – 80. [4] Ferna´ndez-Rodrı´guez A, Va´zquez JA, Sua´rez-Mier MP, et al. Latex agglutination for bacterial antigens and meningococcus PCR: two useful tools in legal sudden deaths. Forensic Sci Int 2005;13(1):13 – 20. [5] Taha M. Simultaneous approach for nonculture PCR-based identification and serogroup prediction of Neisseria meningitidis. J Clin Microbiol 2000;38(2):855 – 7. [6] Vienne P, Ducos-Galand M, Guiyoule A, et al. The role of particular strains of Neisseria meningitidis in meningococcal arthritis, pericarditis, and pneumonia. Clin Infect Dis 2003;37(12):1639 – 42. [7] Moumile K, Carbonnelle E, Dessemme P, et al. Culture-negative pericarditis caused by Neisseria meningitidis serogroup C. J Clin Microbiol 2004;42:923 – 4. [8] van Deuren M, Brandtzaeg P, van der Meer JW. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol Rev 2000;13(1):144 – 66. [9] Halstensen A, Ceska M, Brandtzaeg P, Redl H, Naess A, Waage A. Interleukin-8 in serum and cerebrospinal fluid from patients with meningococcal disease. J Infect Dis 1993;167:471 – 5. [10] van Deuren M, van der Ven-Jongekrijg J, Bartelink AK, van Dalen R, Sauerwein RW, van der Meer JW. Correlation between proinflammatory cytokines and antiinflammatory mediators and the severity of disease in meningococcal infections. J Infect Dis 1995;172:433 – 9.