Report of Two Cases of Aseptic Meningitis with Persistence of Pneumoco
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《微生物临床杂志》
Service de Pediatrie Generale de l'Hpital Robert Debre, Paris, France
Laboratoire de Microbiologie de l'Hpital Robert Debre, Paris, France
ABSTRACT
We describe two cases of aseptic meningitis occurring some time after pneumococcal meningitis. Both cases may have resulted from an inflammatory response to persistent pneumococcal cell membrane components, as the cerebrospinal fluid samples were positive by the Binax NOW Streptococcus pneumoniae antigen test. Potential mechanisms and diagnostic impact are discussed.
CASE REPORTS
Case 1. A previously healthy 5-month-old girl was admitted on January 2004 to the pediatric department of Robert Debre Hospital (Paris, France) for fever (40°C) and vomiting. She had received an injection of diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b combined vaccine and two injections of heptavalent pneumococcal conjugated vaccine when she was 2 and 3 months old. On admission, the white blood cell (WBC) count was 30,600 x 106/liter, the platelet count was 631 x 109/liter, and the C-reactive protein (CRP) level was 90 mg/liter. The cerebrospinal fluid (CSF) samples contained 651 x 106 WBC/liter (with 97% granulocytes), 2.24 g of protein/liter, and 0.3 mmol of glucose/liter (the plasma glucose concentration was 5.9 mmol/liter). Gram staining of CSF samples revealed numerous gram-positive diplococci. The test for Streptococcus pneumoniae antigen using the NOW antigen kit (Binax, Portland, ME) gave positive results on both CSF and urine samples. On the basis of these initial results and given the possibility of decreased susceptibility to penicillin of the presumed microorganism, empirical therapy, consisting of intravenous cefotaxime (300 mg/kg of body weight/day) and vancomycin (60 mg/kg/day), was started.
Bacterial count of S. pneumoniae in CSF samples was performed by culture on a chocolate agar plate after 24 h of incubation at 37°C in 5% CO2. The MICs of penicillin G, amoxicillin, and cefotaxime were determined by using the Etest method (AB Biodisk) on Mueller-Hinton medium with 10% sheep blood (bioMerieux) after 24 h of incubation at 37°C in 5% CO2. The serogroup was identified by latex particle agglutination (Serum Staten Institute, Copenhagen, Denmark). CSF culture yielded 107 CFU/ml of S. pneumoniae serotype 6B susceptible to penicillin G (MIC < 0.1 mg/liter) (1). A second lumbar puncture was performed 48 h later, and CSF analysis revealed 3,210 x 106 WBC/liter (with 56% granulocytes), 1.57 g protein/liter, and 0.5 mmol glucose/liter. Gram staining of CSF revealed very few gram-positive diplococci. The CSF culture was negative. The Binax NOW S. pneumoniae antigen test was not performed. Cefotaxime was given for a total of 15 days, and vancomycin was given for a total of 3 days. The presence of a brain abscess was ruled out by magnetic resonance imaging of the brain performed on day 7. Apyrexia was obtained at day 14. Blood tests shortly before hospital discharge showed a CRP level of <10 mg/liter and a platelet count of 1,192 x 109/liter. The child was treated with salicylic acid (50 mg/day) for 6 weeks before a new blood test was performed. It showed a WBC count at 13,300 x 106/liter, a platelet count at 462 x 109/liter, and a CRP level of <10 mg/liter.
Nine weeks after the initial admission, the child was admitted for fever (39.6°C) without neck stiffness. The WBC count was 21,200 x 106/liter, the platelet count was 631 x 109/liter, and the C-reactive protein level was 90 mg/liter. The CSF sample contained 1,650 x 106 WBC/liter (93% granulocytes) and normal protein and glucose levels. CSF Gram staining and culture were negative. Enteroviral PCR, herpesviral PCR, and interferon gave negative results for CSF samples. The Binax NOW S. pneumoniae antigen test gave positive results for CSF and urine samples, and treatment combining cefotaxime (300 mg/kg/day) and vancomycin (60 mg/kg/day) was initiated. Apyrexia was obtained on day 2. No other source of fever, such as a urinary or respiratory tract infection or otitis media, was identified. Because the CSF cultures remained negative, antibiotics were withdrawn on day 6. Because of this inflammatory syndrome, the girl was treated with salicylic acid (100 mg/day) for 12 weeks.
An evaluation of the immunologic status of the patient was performed when she was 7 months old. The levels of immunoglobulins (immunoglobulins G, A, and M), complement fractions, and lymphocyte subpopulations were normal. Antibody titers to tetanus, Haemophilus influenzae type b, diphtheria, poliovirus, and pertussis vaccine antigens were normal. The lymphoblastic transformation tests were positive for mitogens and antigens (tetanus toxoid). Fever or signs of meningeal irritation did not recur during 18 months of follow-up.
Case 2. A previously healthy 11-month-old girl was admitted in December 2003 to the pediatric department of Robert Debre Hospital (Paris, France) for fever (40°C), vomiting, nuchal rigidity, and anisocoria. She had received the full course of diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b vaccination but had not received heptavalent pneumococcal conjugated vaccine.
On admission, the WBC count was 6,300 x 106/liter, the platelet count was 327 x 109/liter, and the C-reactive protein level was 297 mg/liter. The CSF sample contained 319 x 106 WBC/liter (88% granulocytes), 3.02 g protein/liter, and 0 mmol glucose/liter (the plasma glucose concentration was 5.1 mmol/liter). Gram staining of CSF samples revealed numerous gram-positive diplococci. On the basis of these initial results and given the possibility of decreased susceptibility to penicillin of the presumed microorganism, empirical therapy, consisting of intravenous cefotaxime (300 mg/kg of body weight/day) and vancomycin (60 mg/kg/day), was started. CSF culture yielded 109 CFU/liter of S. pneumoniae serotype 19 susceptible to penicillin G (MIC < 0.1 mg/liter). A second lumbar puncture performed 48 h later was traumatic, and both CSF gram staining and culture were negative. The Binax NOW S. pneumoniae antigen test was not performed. Magnetic resonance imaging of the brain on day 5 showed subdural effusion along the left frontal lobes. These findings and the persistence of fever led us to add rifampin (20 mg/kg/day) on day 6. Vancomycin was withdrawn on day 10, and cefotaxime and rifampin were withdrawn on day 20. Apyrexia was obtained on day 17, and the C-reactive protein level returned to normal levels on day 22.
Five weeks after the initial admission, the child was readmitted with fever (40°C). The WBC count was 21,500 x 106/liter, the platelet count was 335 x 109/liter, and the C-reactive protein level was 108 mg/liter. The CSF sample contained 250 x 106 WBC/liter (84% granulocytes) and normal protein and glucose levels. CSF gram staining and culture were negative. Enteroviral PCR, herpesviral PCR, and interferon were negative on CSF samples. Neisseria meningitidis PCR based on amplification of the crgA gene and S. pneumoniae PCR based on amplification of the lytA gene on the CSF samples gave negative results. The Binax NOW S. pneumoniae antigen test was positive on both CSF and urine samples. Accordingly, treatment was started with cefotaxime (300 mg/kg/day) and vancomycin (60 mg/kg/day). The patient's temperature returned to normal on day 3, and the C-reactive protein level fell below 10 mg/liter on day 10. No other source of fever, such as a urinary or respiratory tract infection or otitis media, was identified. Because culture of all bacteriological samples remained negative, antibiotics were withdrawn on day 4. Because of this inflammatory syndrome, the girl was treated with prednisolone (2 mg/kg/day) for four weeks.
Eight weeks after the initial diagnosis, the child had a new episode of fever. The WBC count was 24,700 x 106/liter, and the C-reactive protein level was 185 mg/liter. The CSF sample contained 157 x 106 WBC/liter (95% granulocytes) and normal protein and glucose levels. CSF gram staining and culture were negative. The Binax NOW S. pneumoniae antigen test gave a positive result on the CSF sample. On the basis of experience with the previous episodes, this episode was treated only with prednisolone (0.5 mg/kg/day). Apyrexia was achieved on day 2. Prednisolone was withdrawn after 6 weeks. An evaluation of the immunologic status of the patient was performed when she was 3 years old. The levels of immunoglobulins (immunoglobulins G, A, and M), complement fractions, and lymphocyte subpopulations were normal. Fever or sign of meningeal irritation did not recur during 18 months of follow-up.
Discussion. The Binax NOW S. pneumoniae antigen test targets the C polysaccharide cell wall antigen common to all S. pneumoniae serotypes. Streptococcus mitis is also known to harbor pneumococcal C-polysaccharide-like antigens (4), but S. mitis is an uncommon cause of bacterial meningitis (8). On CSF samples, this test provides a rapid and very reliable diagnosis of S. pneumoniae meningitis with a sensitivity of 95.4% and a specificity of nearly 100%. Thus, the Binax NOW S. pneumoniae test on CSF samples allows initiation of a prompt and adequate treatment, particularly if CSF gram staining and culture are not conclusive.
However, the duration of detection of a positive result by the Binax NOW S. pneumoniae antigen test on CSF samples after pneumococcal meningitis has not been evaluated,and the maximum duration reported is 20 days (9). For the first time, we report the prolonged persistence of a positive test result by Binax NOW S. pneumoniae antigen test in CSF samples for at least 90 days after a first episode of pneumococcal meningitis. These results strongly suggest a prolonged persistence of pneumococcal cell wall components in the CSF after pneumococcal meningitis. Thus, according to our observations, the cell wall components detected by the Binax NOW S. pneumoniae antigen test in CSF samples a long time after pneumococcal meningitis could be involved in the occurrence of aseptic meningitis. Several questions are addressed by the long-term persistence of a positive Binax NOW S. pneumoniae antigen test result in CSF samples after an episode of pneumococcal meningitis: first, the impact of such a test in the management of prolonged or recurrent fever following pneumococcal meningitis but also the mechanism of occurrence of secondary fever after pneumococcal meningitis.
Prolonged and secondary fever that persists or occurs after successful treatment of severe bacterial infections can challenge the initial diagnosis and initiate further investigations (2, 3, 6, 7). A secondary fever associated with an inflammatory syndrome has previously been reported after pneumococcal meningitis, but all these cases occurred between 4 and 15 days after the initial defervescence (2, 3). Secondary fevers have often been attributed to urinary and respiratory tract infections (3, 6, 7). Recurrent bacterial meningitis is involved in some cases of secondary fever. Recurrent bacterial meningitis may be due to disorders of the immune system, such as complement deficiency, or to dural defects (10).
For both our patients, the Binax NOW S. pneumoniae antigen test gave positive results for CSF samples during the episode of pneumococcal meningitis and also during the subsequent episode of aseptic meningitis. Thus, the diagnosis of aseptic meningitis could be challenged by recurrent pneumococcal meningitis. Herpes- and enteroviral infection have been ruled out by negative PCR and negative interferon dosage in CSF samples during the subsequent infection.
However, the negative CSF culture for both patient and S. pneumoniae PCR in the CSF samples for one patient suggested that a sterile meningeal reaction associated with fever and inflammatory syndrome had occurred more than 15 days after sterilization of the CSF.
In such a situation, the diagnostic impact of the Binax NOW S. pneumoniae antigen test is limited, as it could be positive in both a second episode of pneumococcal meningitis and a sterile meningeal reaction after pneumococcal meningitis. Therefore, the Binax NOW S. pneumoniae antigen test in the CSF samples a few weeks after a recent pneumococcal meningitis is unable to differentiate a second pneumococcal meningitis from a sterile meningeal reaction.
The mechanisms of aseptic meningitis remain unclear. Host inflammatory responses to pneumococci can be triggered by direct interaction of subcapsular cell wall components, such as peptidoglycans and lipoteichoid acids with host Toll-like receptors, initiating the production of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin 1, and interleukin 6 (5). Microbial toxins, such as pneumolysins and bacterial DNA, may also trigger host immune responses (5). It can be hypothesized that such mechanisms could be involved in the occurrence of these aseptic meningitis, but this has not been investigated in our study.
Finally, the Binax NOW S. pneumoniae antigen test can continue to give positive results on CSF samples for a prolonged period independently of an infectious recurrence. The precise mechanisms underlying these aseptic meningitis after pneumococcal meningitis are unclear, and further studies are needed to confirm the possible role of persistent bacterial cell wall components.
ACKNOWLEDGMENTS
We thank Denis Angoulvant (INSERM E0226-Universite Claude Bernard Lyon I) for his assistance in translation.
All authors had no conflict of interest.
FOOTNOTES
Corresponding author. Mailing address: Service de Pediatrie Generale, Hpital Robert Debre, 48 Boulevard Serurier, 75019 Paris, France. Phone: 33 1 40 03 20 48. Fax: 33 1 40 03 20 43. E-mail: francois.angoulvant@rdb.aphp.fr.
Published ahead of print on 27 September 2006.
REFERENCES
Angoulvant, F., P. Bidet, C. Doit, G. Aubertin, V. Soussan, E. Bingen, A. Bourrillon, and A. Faye. 2005. Serotype 6B pneumococcal meningitis in an immunocompetent infant immunized with heptavalent pneumococcal conjugated vaccine. Clin. Infect. Dis. 40:494-495.
Balagtas, R. C., S. Levin, K. E. Nelson, and S. P. Gotoff. 1970. Secondary and prolonged fevers in bacterial meningitis. J. Pediatr. 77:957-964.
Daoud, A. S., M. Zaki, and Q. A. al-Saleh. 1989. Prolonged and secondary fever in childhood bacterial meningitis. Eur. J. Pediatr. 149:114-116.
Gillespie, S. H., P. H. McWhinney, S. Patel, J. G. Raynes, K. P. McAdam, R. A. Whiley, and J. M. Hardie. 1993. Species of alpha-hemolytic streptococci possessing a C-polysaccharide phosphorylcholine-containing antigen. Infect. Immun. 61:3076-3077.
Koedel, U., W. M. Scheld, and H. W. Pfister. 2002. Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Infect. Dis. 2:721-736.
La Via, W. V., and M. I. Marks. 1992. Prolonged and secondary fevers in childhood bacterial meningitis. Antibiot. Chemother. 45:201-208.
Lin, T. Y., J. D. Nelson, and G. H. McCracken, Jr. 1984. Fever during treatment for bacterial meningitis. Pediatr. Infect. Dis. 3:319-322.
Moller, K., E. H. Frederiksen, J. H. Wandall, and P. Skinhoj. 1999. Meningitis caused by streptococci other than Streptococcus pneumoniae: a retrospective clinical study. Scand. J. Infect. Dis. 31:375-381.
Saha, S. K., G. L. Darmstadt, N. Yamanaka, D. S. Billal, T. Nasreen, M. Islam, and D. H. Hamer. 2005. Rapid diagnosis of pneumococcal meningitis: implications for treatment and measuring disease burden. Pediatr. Infect. Dis. J. 24:1093-1098.
Wang, H. S., M. F. Kuo, and S. C. Huang. 2005. Diagnostic approach to recurrent bacterial meningitis in children. Chang Gung Med. J. 28:441-452.(Franois Angoulvant, Julie Lachenaud, Pat)
Laboratoire de Microbiologie de l'Hpital Robert Debre, Paris, France
ABSTRACT
We describe two cases of aseptic meningitis occurring some time after pneumococcal meningitis. Both cases may have resulted from an inflammatory response to persistent pneumococcal cell membrane components, as the cerebrospinal fluid samples were positive by the Binax NOW Streptococcus pneumoniae antigen test. Potential mechanisms and diagnostic impact are discussed.
CASE REPORTS
Case 1. A previously healthy 5-month-old girl was admitted on January 2004 to the pediatric department of Robert Debre Hospital (Paris, France) for fever (40°C) and vomiting. She had received an injection of diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b combined vaccine and two injections of heptavalent pneumococcal conjugated vaccine when she was 2 and 3 months old. On admission, the white blood cell (WBC) count was 30,600 x 106/liter, the platelet count was 631 x 109/liter, and the C-reactive protein (CRP) level was 90 mg/liter. The cerebrospinal fluid (CSF) samples contained 651 x 106 WBC/liter (with 97% granulocytes), 2.24 g of protein/liter, and 0.3 mmol of glucose/liter (the plasma glucose concentration was 5.9 mmol/liter). Gram staining of CSF samples revealed numerous gram-positive diplococci. The test for Streptococcus pneumoniae antigen using the NOW antigen kit (Binax, Portland, ME) gave positive results on both CSF and urine samples. On the basis of these initial results and given the possibility of decreased susceptibility to penicillin of the presumed microorganism, empirical therapy, consisting of intravenous cefotaxime (300 mg/kg of body weight/day) and vancomycin (60 mg/kg/day), was started.
Bacterial count of S. pneumoniae in CSF samples was performed by culture on a chocolate agar plate after 24 h of incubation at 37°C in 5% CO2. The MICs of penicillin G, amoxicillin, and cefotaxime were determined by using the Etest method (AB Biodisk) on Mueller-Hinton medium with 10% sheep blood (bioMerieux) after 24 h of incubation at 37°C in 5% CO2. The serogroup was identified by latex particle agglutination (Serum Staten Institute, Copenhagen, Denmark). CSF culture yielded 107 CFU/ml of S. pneumoniae serotype 6B susceptible to penicillin G (MIC < 0.1 mg/liter) (1). A second lumbar puncture was performed 48 h later, and CSF analysis revealed 3,210 x 106 WBC/liter (with 56% granulocytes), 1.57 g protein/liter, and 0.5 mmol glucose/liter. Gram staining of CSF revealed very few gram-positive diplococci. The CSF culture was negative. The Binax NOW S. pneumoniae antigen test was not performed. Cefotaxime was given for a total of 15 days, and vancomycin was given for a total of 3 days. The presence of a brain abscess was ruled out by magnetic resonance imaging of the brain performed on day 7. Apyrexia was obtained at day 14. Blood tests shortly before hospital discharge showed a CRP level of <10 mg/liter and a platelet count of 1,192 x 109/liter. The child was treated with salicylic acid (50 mg/day) for 6 weeks before a new blood test was performed. It showed a WBC count at 13,300 x 106/liter, a platelet count at 462 x 109/liter, and a CRP level of <10 mg/liter.
Nine weeks after the initial admission, the child was admitted for fever (39.6°C) without neck stiffness. The WBC count was 21,200 x 106/liter, the platelet count was 631 x 109/liter, and the C-reactive protein level was 90 mg/liter. The CSF sample contained 1,650 x 106 WBC/liter (93% granulocytes) and normal protein and glucose levels. CSF Gram staining and culture were negative. Enteroviral PCR, herpesviral PCR, and interferon gave negative results for CSF samples. The Binax NOW S. pneumoniae antigen test gave positive results for CSF and urine samples, and treatment combining cefotaxime (300 mg/kg/day) and vancomycin (60 mg/kg/day) was initiated. Apyrexia was obtained on day 2. No other source of fever, such as a urinary or respiratory tract infection or otitis media, was identified. Because the CSF cultures remained negative, antibiotics were withdrawn on day 6. Because of this inflammatory syndrome, the girl was treated with salicylic acid (100 mg/day) for 12 weeks.
An evaluation of the immunologic status of the patient was performed when she was 7 months old. The levels of immunoglobulins (immunoglobulins G, A, and M), complement fractions, and lymphocyte subpopulations were normal. Antibody titers to tetanus, Haemophilus influenzae type b, diphtheria, poliovirus, and pertussis vaccine antigens were normal. The lymphoblastic transformation tests were positive for mitogens and antigens (tetanus toxoid). Fever or signs of meningeal irritation did not recur during 18 months of follow-up.
Case 2. A previously healthy 11-month-old girl was admitted in December 2003 to the pediatric department of Robert Debre Hospital (Paris, France) for fever (40°C), vomiting, nuchal rigidity, and anisocoria. She had received the full course of diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b vaccination but had not received heptavalent pneumococcal conjugated vaccine.
On admission, the WBC count was 6,300 x 106/liter, the platelet count was 327 x 109/liter, and the C-reactive protein level was 297 mg/liter. The CSF sample contained 319 x 106 WBC/liter (88% granulocytes), 3.02 g protein/liter, and 0 mmol glucose/liter (the plasma glucose concentration was 5.1 mmol/liter). Gram staining of CSF samples revealed numerous gram-positive diplococci. On the basis of these initial results and given the possibility of decreased susceptibility to penicillin of the presumed microorganism, empirical therapy, consisting of intravenous cefotaxime (300 mg/kg of body weight/day) and vancomycin (60 mg/kg/day), was started. CSF culture yielded 109 CFU/liter of S. pneumoniae serotype 19 susceptible to penicillin G (MIC < 0.1 mg/liter). A second lumbar puncture performed 48 h later was traumatic, and both CSF gram staining and culture were negative. The Binax NOW S. pneumoniae antigen test was not performed. Magnetic resonance imaging of the brain on day 5 showed subdural effusion along the left frontal lobes. These findings and the persistence of fever led us to add rifampin (20 mg/kg/day) on day 6. Vancomycin was withdrawn on day 10, and cefotaxime and rifampin were withdrawn on day 20. Apyrexia was obtained on day 17, and the C-reactive protein level returned to normal levels on day 22.
Five weeks after the initial admission, the child was readmitted with fever (40°C). The WBC count was 21,500 x 106/liter, the platelet count was 335 x 109/liter, and the C-reactive protein level was 108 mg/liter. The CSF sample contained 250 x 106 WBC/liter (84% granulocytes) and normal protein and glucose levels. CSF gram staining and culture were negative. Enteroviral PCR, herpesviral PCR, and interferon were negative on CSF samples. Neisseria meningitidis PCR based on amplification of the crgA gene and S. pneumoniae PCR based on amplification of the lytA gene on the CSF samples gave negative results. The Binax NOW S. pneumoniae antigen test was positive on both CSF and urine samples. Accordingly, treatment was started with cefotaxime (300 mg/kg/day) and vancomycin (60 mg/kg/day). The patient's temperature returned to normal on day 3, and the C-reactive protein level fell below 10 mg/liter on day 10. No other source of fever, such as a urinary or respiratory tract infection or otitis media, was identified. Because culture of all bacteriological samples remained negative, antibiotics were withdrawn on day 4. Because of this inflammatory syndrome, the girl was treated with prednisolone (2 mg/kg/day) for four weeks.
Eight weeks after the initial diagnosis, the child had a new episode of fever. The WBC count was 24,700 x 106/liter, and the C-reactive protein level was 185 mg/liter. The CSF sample contained 157 x 106 WBC/liter (95% granulocytes) and normal protein and glucose levels. CSF gram staining and culture were negative. The Binax NOW S. pneumoniae antigen test gave a positive result on the CSF sample. On the basis of experience with the previous episodes, this episode was treated only with prednisolone (0.5 mg/kg/day). Apyrexia was achieved on day 2. Prednisolone was withdrawn after 6 weeks. An evaluation of the immunologic status of the patient was performed when she was 3 years old. The levels of immunoglobulins (immunoglobulins G, A, and M), complement fractions, and lymphocyte subpopulations were normal. Fever or sign of meningeal irritation did not recur during 18 months of follow-up.
Discussion. The Binax NOW S. pneumoniae antigen test targets the C polysaccharide cell wall antigen common to all S. pneumoniae serotypes. Streptococcus mitis is also known to harbor pneumococcal C-polysaccharide-like antigens (4), but S. mitis is an uncommon cause of bacterial meningitis (8). On CSF samples, this test provides a rapid and very reliable diagnosis of S. pneumoniae meningitis with a sensitivity of 95.4% and a specificity of nearly 100%. Thus, the Binax NOW S. pneumoniae test on CSF samples allows initiation of a prompt and adequate treatment, particularly if CSF gram staining and culture are not conclusive.
However, the duration of detection of a positive result by the Binax NOW S. pneumoniae antigen test on CSF samples after pneumococcal meningitis has not been evaluated,and the maximum duration reported is 20 days (9). For the first time, we report the prolonged persistence of a positive test result by Binax NOW S. pneumoniae antigen test in CSF samples for at least 90 days after a first episode of pneumococcal meningitis. These results strongly suggest a prolonged persistence of pneumococcal cell wall components in the CSF after pneumococcal meningitis. Thus, according to our observations, the cell wall components detected by the Binax NOW S. pneumoniae antigen test in CSF samples a long time after pneumococcal meningitis could be involved in the occurrence of aseptic meningitis. Several questions are addressed by the long-term persistence of a positive Binax NOW S. pneumoniae antigen test result in CSF samples after an episode of pneumococcal meningitis: first, the impact of such a test in the management of prolonged or recurrent fever following pneumococcal meningitis but also the mechanism of occurrence of secondary fever after pneumococcal meningitis.
Prolonged and secondary fever that persists or occurs after successful treatment of severe bacterial infections can challenge the initial diagnosis and initiate further investigations (2, 3, 6, 7). A secondary fever associated with an inflammatory syndrome has previously been reported after pneumococcal meningitis, but all these cases occurred between 4 and 15 days after the initial defervescence (2, 3). Secondary fevers have often been attributed to urinary and respiratory tract infections (3, 6, 7). Recurrent bacterial meningitis is involved in some cases of secondary fever. Recurrent bacterial meningitis may be due to disorders of the immune system, such as complement deficiency, or to dural defects (10).
For both our patients, the Binax NOW S. pneumoniae antigen test gave positive results for CSF samples during the episode of pneumococcal meningitis and also during the subsequent episode of aseptic meningitis. Thus, the diagnosis of aseptic meningitis could be challenged by recurrent pneumococcal meningitis. Herpes- and enteroviral infection have been ruled out by negative PCR and negative interferon dosage in CSF samples during the subsequent infection.
However, the negative CSF culture for both patient and S. pneumoniae PCR in the CSF samples for one patient suggested that a sterile meningeal reaction associated with fever and inflammatory syndrome had occurred more than 15 days after sterilization of the CSF.
In such a situation, the diagnostic impact of the Binax NOW S. pneumoniae antigen test is limited, as it could be positive in both a second episode of pneumococcal meningitis and a sterile meningeal reaction after pneumococcal meningitis. Therefore, the Binax NOW S. pneumoniae antigen test in the CSF samples a few weeks after a recent pneumococcal meningitis is unable to differentiate a second pneumococcal meningitis from a sterile meningeal reaction.
The mechanisms of aseptic meningitis remain unclear. Host inflammatory responses to pneumococci can be triggered by direct interaction of subcapsular cell wall components, such as peptidoglycans and lipoteichoid acids with host Toll-like receptors, initiating the production of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin 1, and interleukin 6 (5). Microbial toxins, such as pneumolysins and bacterial DNA, may also trigger host immune responses (5). It can be hypothesized that such mechanisms could be involved in the occurrence of these aseptic meningitis, but this has not been investigated in our study.
Finally, the Binax NOW S. pneumoniae antigen test can continue to give positive results on CSF samples for a prolonged period independently of an infectious recurrence. The precise mechanisms underlying these aseptic meningitis after pneumococcal meningitis are unclear, and further studies are needed to confirm the possible role of persistent bacterial cell wall components.
ACKNOWLEDGMENTS
We thank Denis Angoulvant (INSERM E0226-Universite Claude Bernard Lyon I) for his assistance in translation.
All authors had no conflict of interest.
FOOTNOTES
Corresponding author. Mailing address: Service de Pediatrie Generale, Hpital Robert Debre, 48 Boulevard Serurier, 75019 Paris, France. Phone: 33 1 40 03 20 48. Fax: 33 1 40 03 20 43. E-mail: francois.angoulvant@rdb.aphp.fr.
Published ahead of print on 27 September 2006.
REFERENCES
Angoulvant, F., P. Bidet, C. Doit, G. Aubertin, V. Soussan, E. Bingen, A. Bourrillon, and A. Faye. 2005. Serotype 6B pneumococcal meningitis in an immunocompetent infant immunized with heptavalent pneumococcal conjugated vaccine. Clin. Infect. Dis. 40:494-495.
Balagtas, R. C., S. Levin, K. E. Nelson, and S. P. Gotoff. 1970. Secondary and prolonged fevers in bacterial meningitis. J. Pediatr. 77:957-964.
Daoud, A. S., M. Zaki, and Q. A. al-Saleh. 1989. Prolonged and secondary fever in childhood bacterial meningitis. Eur. J. Pediatr. 149:114-116.
Gillespie, S. H., P. H. McWhinney, S. Patel, J. G. Raynes, K. P. McAdam, R. A. Whiley, and J. M. Hardie. 1993. Species of alpha-hemolytic streptococci possessing a C-polysaccharide phosphorylcholine-containing antigen. Infect. Immun. 61:3076-3077.
Koedel, U., W. M. Scheld, and H. W. Pfister. 2002. Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Infect. Dis. 2:721-736.
La Via, W. V., and M. I. Marks. 1992. Prolonged and secondary fevers in childhood bacterial meningitis. Antibiot. Chemother. 45:201-208.
Lin, T. Y., J. D. Nelson, and G. H. McCracken, Jr. 1984. Fever during treatment for bacterial meningitis. Pediatr. Infect. Dis. 3:319-322.
Moller, K., E. H. Frederiksen, J. H. Wandall, and P. Skinhoj. 1999. Meningitis caused by streptococci other than Streptococcus pneumoniae: a retrospective clinical study. Scand. J. Infect. Dis. 31:375-381.
Saha, S. K., G. L. Darmstadt, N. Yamanaka, D. S. Billal, T. Nasreen, M. Islam, and D. H. Hamer. 2005. Rapid diagnosis of pneumococcal meningitis: implications for treatment and measuring disease burden. Pediatr. Infect. Dis. J. 24:1093-1098.
Wang, H. S., M. F. Kuo, and S. C. Huang. 2005. Diagnostic approach to recurrent bacterial meningitis in children. Chang Gung Med. J. 28:441-452.(Franois Angoulvant, Julie Lachenaud, Pat)