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Persistent pleocytosis in bacterial meningitis
March 1976
424
The Journal o f P E D I A T R I C S
Persistent pleocytosis in bacterial meningitis Persistent pleocytosis of greater than 60 white blood cells/mm ~ was commonly seen in children adequately treated for bacterial meningitis. It occurred in 13 of 21 (62%) children with Hemophilus influenzae meningitis and in 2 of 9 (22%) with pneumococcal meningitis. Pleocytosis alone cannot be used as an indication of prolonging therapy," signifieanee of persistent pleocytosis is not known.
S. A. C h a r t r a n d , M . D . , and C. T. Cho, M . D . , Ph.D.,* K a n s a s City, Kan.
THE CEREBROSPINAL FLUID findings in acute bacte-
rial meningitis have often been used in assessing therapeutic responses and in determining duration of antibiotic treatment. 1-~ Wehrle and colleagues 1 ~ formulated rather stringent criteria for discontinuing therapy for bacterial meningitis: the body temperature should have been normal for five days, and clinical signs of meningitis should have disappeared; the CSF should contain fewer than 30 cells/ram 3, have a normal glucose concentration, and have a protein concentration of less than 60 mg/dl. The criteria of Smith and associates~ varied only in that these authors accepted up to 50 cells/mm 3 and a concentration of protein of less than 50 mg/dl. Information concerning the sequential CSF responses in patients with acute bacterial meningitis under appropriate therapy is incomplete. Review of the literature failed to provide adequate CSF data to support the above suggestions. Experiences with several patients who after therapy for 14 days or longer had CSF cell counts of greater than 50/ mm 3 prompted us to re-evaluate the CSF responses in Hemophilus influenzae meningitis. MATERIALS
AND METHODS
Records of all patients between 1 month and 15 years of age with acute bacterial meningitis due to Hemophilus influenzae type B or Streptococcus pneumoniae admitted to the University of Kansas Medical Center from Septem-
ber, 1970, to December, 1974, were reviewed retrospectively. Criteria for acceptance into the study were a clinical diagnosis of meningitis and isolation of the organism from the CSF. Children with previous neurosurgical procedures, malignancies, or altered immune states were excluded from the study. Patients who had not had follow-up examinations of spinal fluid were also excluded. A total of 30 patients were included in the study. An average of 3.8 lumbar punctures had been performed on each patient. Children with persistent pleocytosis received more lumbar punctures than those without persistent pleocytosis. A small number of patients with persistent pleocytosis had spinal taps during their follow-up visits as outpatients. All children with H. influenzae meningitis received ampicillin (200 to 400 m g / k g / d a y ) or chloramphenicol (100 mg/kg/day) intravenously for at least 10 days; patients with pneumococcal meningitis were treated with aqueous penicillin (250,000 to 600,000 units/kg/day) intravenously for a minimum of ten days. The clinical and laboratory findings on each patient were evaluated; these included age, sex, race, duration of illness and treatment prior to admission, signs and symptoms, CSF findings, antibiotic therapy, hospital course, and sequelae. A patient was considered afebrile when the rectal temperature was less than 38 ~ C for more than 48 hours. RESULTS
From the Departments of Pediatries and Microbiology, University of Kansas Medical Center, College of Health Sciences and Hospital. *Reprint address: Department of Pediatrics, University of Kansas Medical Center, 39th & Rainbow Blvd., Kansas City, Kan. 661039
Vol. 88, No. 3, pp. 424-426
Clinical and laboratory characteristics. Twenty-eight of the 30 patients (93%) were afebrile for a minimum of five days prior to the final CSF examination. Two patients (7%) were febrile at the time of the last CSF examination and continued to be febrile for several days afterward;
Volume 88 Number 3 nevertheless, administration of the antibiotic was discontinued- Each patient eventually became afebrile and did well. Among the 30 patients, 21 had H. influenzae meningitis and 9 had pneumonococcal meningitis. These patients were divided into three groups based on the WBC count in the CSF after completion of ten days or more o f therapy. Group 1 consisted of 13 patients With H. influenzae meningitis whose WBC count was greater than 60/ram ~ (persistent pleocytosis); in Group 2 were 8 patients with H. influenzae whose WBC was less than 60/ mm 3 (without pleocytosis), and Group 3 consisted of 9 patients with pneumococcal meningitis. The clinical and laboratory findings of these three groups of patients are summarized in Table I. Thirteen of the 21 children (62%) with H. influenzae meningitis and two of the nine (22%) with pneumococcal meningitis had persistent pleocytosis. There were no significant differences in numbers of sequelae among these three groups of patients. One patient was readmitted for septic arthritis due to H. influenzae. Five days prior to this admission the patient had completed a 10-day course of therapy with ampicillin, 400 mg/kg/day intravenously, for H. influenzae meningitis. No patient in any of the three groups had a relapse of meningitis. None of the patients died. Sequential CSF changes. The sequential changes of the cell counts and of the sugar and protein concentrations in the CSF are listed in Table II. The CSF leukocyte counts in patients with H. influenzae and pneumococca! meningitis were similar except on Day 1 when the pleocytosis in patients with pneumococcal meningitis was almost double that in patients with H. influenzae meningitis. Patients in each group had a large number of leukocytes on Day 1, followed by a sharp fall by Day 3. After 8 to 10 days, however, the cell counts differed distinctly. Whereas the leukocyte counts in children with pneumococcat meningitis continued to fall steadily; the pleocytosis in H. influenzae meningitis was more varied (Table I). The final examination of the CSF of the 13 children with persistent pleocytosis associated with H. influenzae meningitis were performed 11 to 35 (average 20) days after the initiation of appropriate therapy. The leukocyte counts in the CSF ranged from 72 to 506/ram ~ (average 128); in two patients more than 50% of the cells were polymorphonuclear leukocytes. There was a predominance of males with persistent pleocytosis: 11 male and 2 female children. Additionally, the average febrile course was 7.8 days for patients with persistent pleocytosis versus 5.3 days for those without. The prolonged fever and the persistent pleocytosis were not attributable to the antibiotic therapy (ampicillin or chloramphenicol). Further-
Pleoeytosis in meningitis
42S
Table I. Comparative features of bacterial meningitis H. influenzae meningitis
Characteristics
With persistent pleoeytosis (13 patients)
18.0 mo* Mean age 11:2 Sex (M:F) 3,1 Days of illness prior to diagnosis (average) 7.8 Duration of fever]" 1~ Sequelae 0 Deaths: 2,902 Initial CSF (WBe/mm:9 3/12 (25%) Glucose ( < 20 mg/dl) 1/8 (12%) Protein ( > 200 rng/dl) Persistent pleo13 cytosis (final CSF > 60 cells/mm3)
PneumoI Without | persistent coccal | pleocytosis meningitis 1(8 patients) (9 patients) 13.1 mo 3:5 4.2
5 yr 10 mo 4:5 3.7
5.3 1w 0 3,645
3.6 2 0 3,494
4/7 (57%)
5/9 (56%)
1/7 (14%)
7/8 (88%)
0
2
*A 14-year-oldboy with H. influenzaemeningitiswas not included in this computation. ]'Temperature of greater than 38~ average day of fever after the initiationof antibiotictherapy. ~Hydrocephalusand developmentaldelay. w delay. 82 patient with spastic hemiplegia, the other with severe mental retardation,neitherchild had persistentpleocytosis.
more, persistent pleocytosis was not related to the patient's age, duration of illness, and treatments prior to admission, glucose and protein concentrations in the CSF, or sequelae. The concentrations o f CSF glucose returned to values within the normal range after 24 hours of antibiotic therapy in most patients. The initial mean protein concentrations of the CSF in patients with H. influenzae meningitis and pneumococcal meningitis were 126 m g / d l and 261 mg/dl, respectively. The CSF protein concentrations of more than 200 mg/dl occurred in 12 to 14% of children with H. influenzae meningitis versus 88% of children with pneumococcal meningitis. After 8 to 10 days of treatment the protein concentrations returned to normal values in the majority of patients. DISCUSSION Our data indicate that persistent pleocytosis of more than 60 cells/mm 3 is not uncommon after what is considered a reasonable period of antibiotic therapy for bacte-
426
Chartrand and Cho
The Journal of Pediatrics March 1976
Table 1I. Sequential spinal fluid changes in bacterial m e n i n g i t i s H. inftuenzae (21 patients)
Day of therapy
Cells (turn~)
Glucose (mg/dO
I Protein I (mg/dl)
0
3,162 _+ 905* (0-15, 250) 3,925 • 1,477 (135-9,300) 1,948 + 732 (162-6,100) 544 • 252 (51-1,368) 305 • 164 (48-1,617) 44• 8 (11-77) 76 • 10 (3-160) 94 • 20 (4-176)
36 • 7 (0-104) 52 • 8 (27-76) 45 • 6 (16-58) 50 • 7 (23-61) 42 + 4 (22-64) 47• 3 (32-55) 51 • 7 (32-63) 48• 3 (38-61)
126 • 22 (20-330) 88 • 29 (40-260) 97 • 16 (70-140) 108 • 37 (34-218) 107 _+ 22 (42-240) 38 • 3 (,29-54) 51 • 7 (23-122) 40 • 3 (22-54)
1 2 3 4-7 8-10 11-15 15
S. pneumoniae (9 patients)
No. of patients
Cells (mm~)
21
3,496 • 934 (7-7,535) 6,940 • 6,629 (330-13,500) 2,006 _+ 715 (495-3,580)
346 • 208 (65-1,172) 42 • 6 (5-98) 17 • 5 (3-24) 6 + 1 (5-7)
8 9 5 11 11 18
11
I
Glucose [ (rng/dl)
Protein (mg/dl)
No. of patients
28 +- 10 (0-100) 56 • 16 (40-71) 52 • 6 (42-70) -
261 • 57 (13-530) -
9
142 ___44 (56-196) -
3
58 • 3 (55-63) 61 • 2 (56-65) 44 • 3 (38-50) 57 • 3 (54-60)
79 • 12 (56-110) 42• 6 (23-56) 49 + 10 (20-66) 10 • 5 (5-15)
5
2
5 4 3
Numbers in parentheses represent the range. *Mean +_ standard error. -- = Data insufficient.
rial meningitis. S u b s e q u e n t observations suggest t h a t the infection in the central nervous system h a d b e e n controlled in each o f these patients. Such a p h e n o m e n o n o f pleocytosis after antibiotic therapy can also be i n f e r r e d from o t h e r reports. 4-7 Significance of persistent pleocytosis, however, is n o t clear. It is more often seen in c h i l d r e n with prolonged fever d u r i n g therapy for H. influenzae meningitis. Pleocytosis is not associated with d u r a t i o n o f illness, prior therapy, a particular antibiotic, complications, or relapse. Neurologic e x a m i n a t i o n s were performed two to six m o n t h s after recovery from the acute infection; we f o u n d no significant difference in i n c i d e n c e o f sequelae a m o n g patients with or without persistent pleocytosis. It should be e m p h a s i z e d t h a t the r e l a t i o n s h i p between persistent pleocytosis a n d sequelae s h o u l d b e further studied by a m o r e detailed e v a l u a t i o n o n a larger n u m b e r o f patients. It is important, however, to recognize that pleocytosis alone is not a n indication o f for p r o l o n g ing t r e a t m e n t o f bacterial meningitis.
REFERENCES
1. Wehrle PF, Mathies AW, and Leedom JM: The critically ill child: management of acute bacterial meningitis, Pediatrics 44:991, 1969. 2. Wehrle PF: Meningitis, in Top FH, and Wehrle PF, editors: Communicable and infectious diseases, Saint Louis, 1972, The CV Mosby Company, p 415. 3. Smith DH, Ingrain DL, Smith AL, Gilles F, and Bresnan MJ: Bacterial meningitis: a symposium, Pediatrics 52:586, 1973. 4. Schulkind ML, Altemeier WA, and Ayoub EM: A comparison of ampicillin and chloramphenicol therapy in Hemophilus influenzae meningitis, Pediatrics 4 8 : 4 1 1 , 1971. 5. Shackleford PG, Bobinski JE, Feigin RD, and Cherry JD: Therapy of Haemophilus influenzae meningitis reconsidered, N Engl J Med 287:634, 1972. 6. Bachman DS: Hemophilus meningitis: comparison of H. influenzae and parainfluenzae, Pediatrics 55:526, 1975. 7. Wilson HD, and Haltalin KC: Ampicillin in Haemophilus influenzae meningitis, Am J Dis Child 129:208, 1975.
424
The Journal o f P E D I A T R I C S
Persistent pleocytosis in bacterial meningitis Persistent pleocytosis of greater than 60 white blood cells/mm ~ was commonly seen in children adequately treated for bacterial meningitis. It occurred in 13 of 21 (62%) children with Hemophilus influenzae meningitis and in 2 of 9 (22%) with pneumococcal meningitis. Pleocytosis alone cannot be used as an indication of prolonging therapy," signifieanee of persistent pleocytosis is not known.
S. A. C h a r t r a n d , M . D . , and C. T. Cho, M . D . , Ph.D.,* K a n s a s City, Kan.
THE CEREBROSPINAL FLUID findings in acute bacte-
rial meningitis have often been used in assessing therapeutic responses and in determining duration of antibiotic treatment. 1-~ Wehrle and colleagues 1 ~ formulated rather stringent criteria for discontinuing therapy for bacterial meningitis: the body temperature should have been normal for five days, and clinical signs of meningitis should have disappeared; the CSF should contain fewer than 30 cells/ram 3, have a normal glucose concentration, and have a protein concentration of less than 60 mg/dl. The criteria of Smith and associates~ varied only in that these authors accepted up to 50 cells/mm 3 and a concentration of protein of less than 50 mg/dl. Information concerning the sequential CSF responses in patients with acute bacterial meningitis under appropriate therapy is incomplete. Review of the literature failed to provide adequate CSF data to support the above suggestions. Experiences with several patients who after therapy for 14 days or longer had CSF cell counts of greater than 50/ mm 3 prompted us to re-evaluate the CSF responses in Hemophilus influenzae meningitis. MATERIALS
AND METHODS
Records of all patients between 1 month and 15 years of age with acute bacterial meningitis due to Hemophilus influenzae type B or Streptococcus pneumoniae admitted to the University of Kansas Medical Center from Septem-
ber, 1970, to December, 1974, were reviewed retrospectively. Criteria for acceptance into the study were a clinical diagnosis of meningitis and isolation of the organism from the CSF. Children with previous neurosurgical procedures, malignancies, or altered immune states were excluded from the study. Patients who had not had follow-up examinations of spinal fluid were also excluded. A total of 30 patients were included in the study. An average of 3.8 lumbar punctures had been performed on each patient. Children with persistent pleocytosis received more lumbar punctures than those without persistent pleocytosis. A small number of patients with persistent pleocytosis had spinal taps during their follow-up visits as outpatients. All children with H. influenzae meningitis received ampicillin (200 to 400 m g / k g / d a y ) or chloramphenicol (100 mg/kg/day) intravenously for at least 10 days; patients with pneumococcal meningitis were treated with aqueous penicillin (250,000 to 600,000 units/kg/day) intravenously for a minimum of ten days. The clinical and laboratory findings on each patient were evaluated; these included age, sex, race, duration of illness and treatment prior to admission, signs and symptoms, CSF findings, antibiotic therapy, hospital course, and sequelae. A patient was considered afebrile when the rectal temperature was less than 38 ~ C for more than 48 hours. RESULTS
From the Departments of Pediatries and Microbiology, University of Kansas Medical Center, College of Health Sciences and Hospital. *Reprint address: Department of Pediatrics, University of Kansas Medical Center, 39th & Rainbow Blvd., Kansas City, Kan. 661039
Vol. 88, No. 3, pp. 424-426
Clinical and laboratory characteristics. Twenty-eight of the 30 patients (93%) were afebrile for a minimum of five days prior to the final CSF examination. Two patients (7%) were febrile at the time of the last CSF examination and continued to be febrile for several days afterward;
Volume 88 Number 3 nevertheless, administration of the antibiotic was discontinued- Each patient eventually became afebrile and did well. Among the 30 patients, 21 had H. influenzae meningitis and 9 had pneumonococcal meningitis. These patients were divided into three groups based on the WBC count in the CSF after completion of ten days or more o f therapy. Group 1 consisted of 13 patients With H. influenzae meningitis whose WBC count was greater than 60/ram ~ (persistent pleocytosis); in Group 2 were 8 patients with H. influenzae whose WBC was less than 60/ mm 3 (without pleocytosis), and Group 3 consisted of 9 patients with pneumococcal meningitis. The clinical and laboratory findings of these three groups of patients are summarized in Table I. Thirteen of the 21 children (62%) with H. influenzae meningitis and two of the nine (22%) with pneumococcal meningitis had persistent pleocytosis. There were no significant differences in numbers of sequelae among these three groups of patients. One patient was readmitted for septic arthritis due to H. influenzae. Five days prior to this admission the patient had completed a 10-day course of therapy with ampicillin, 400 mg/kg/day intravenously, for H. influenzae meningitis. No patient in any of the three groups had a relapse of meningitis. None of the patients died. Sequential CSF changes. The sequential changes of the cell counts and of the sugar and protein concentrations in the CSF are listed in Table II. The CSF leukocyte counts in patients with H. influenzae and pneumococca! meningitis were similar except on Day 1 when the pleocytosis in patients with pneumococcal meningitis was almost double that in patients with H. influenzae meningitis. Patients in each group had a large number of leukocytes on Day 1, followed by a sharp fall by Day 3. After 8 to 10 days, however, the cell counts differed distinctly. Whereas the leukocyte counts in children with pneumococcat meningitis continued to fall steadily; the pleocytosis in H. influenzae meningitis was more varied (Table I). The final examination of the CSF of the 13 children with persistent pleocytosis associated with H. influenzae meningitis were performed 11 to 35 (average 20) days after the initiation of appropriate therapy. The leukocyte counts in the CSF ranged from 72 to 506/ram ~ (average 128); in two patients more than 50% of the cells were polymorphonuclear leukocytes. There was a predominance of males with persistent pleocytosis: 11 male and 2 female children. Additionally, the average febrile course was 7.8 days for patients with persistent pleocytosis versus 5.3 days for those without. The prolonged fever and the persistent pleocytosis were not attributable to the antibiotic therapy (ampicillin or chloramphenicol). Further-
Pleoeytosis in meningitis
42S
Table I. Comparative features of bacterial meningitis H. influenzae meningitis
Characteristics
With persistent pleoeytosis (13 patients)
18.0 mo* Mean age 11:2 Sex (M:F) 3,1 Days of illness prior to diagnosis (average) 7.8 Duration of fever]" 1~ Sequelae 0 Deaths: 2,902 Initial CSF (WBe/mm:9 3/12 (25%) Glucose ( < 20 mg/dl) 1/8 (12%) Protein ( > 200 rng/dl) Persistent pleo13 cytosis (final CSF > 60 cells/mm3)
PneumoI Without | persistent coccal | pleocytosis meningitis 1(8 patients) (9 patients) 13.1 mo 3:5 4.2
5 yr 10 mo 4:5 3.7
5.3 1w 0 3,645
3.6 2 0 3,494
4/7 (57%)
5/9 (56%)
1/7 (14%)
7/8 (88%)
0
2
*A 14-year-oldboy with H. influenzaemeningitiswas not included in this computation. ]'Temperature of greater than 38~ average day of fever after the initiationof antibiotictherapy. ~Hydrocephalusand developmentaldelay. w delay. 82 patient with spastic hemiplegia, the other with severe mental retardation,neitherchild had persistentpleocytosis.
more, persistent pleocytosis was not related to the patient's age, duration of illness, and treatments prior to admission, glucose and protein concentrations in the CSF, or sequelae. The concentrations o f CSF glucose returned to values within the normal range after 24 hours of antibiotic therapy in most patients. The initial mean protein concentrations of the CSF in patients with H. influenzae meningitis and pneumococcal meningitis were 126 m g / d l and 261 mg/dl, respectively. The CSF protein concentrations of more than 200 mg/dl occurred in 12 to 14% of children with H. influenzae meningitis versus 88% of children with pneumococcal meningitis. After 8 to 10 days of treatment the protein concentrations returned to normal values in the majority of patients. DISCUSSION Our data indicate that persistent pleocytosis of more than 60 cells/mm 3 is not uncommon after what is considered a reasonable period of antibiotic therapy for bacte-
426
Chartrand and Cho
The Journal of Pediatrics March 1976
Table 1I. Sequential spinal fluid changes in bacterial m e n i n g i t i s H. inftuenzae (21 patients)
Day of therapy
Cells (turn~)
Glucose (mg/dO
I Protein I (mg/dl)
0
3,162 _+ 905* (0-15, 250) 3,925 • 1,477 (135-9,300) 1,948 + 732 (162-6,100) 544 • 252 (51-1,368) 305 • 164 (48-1,617) 44• 8 (11-77) 76 • 10 (3-160) 94 • 20 (4-176)
36 • 7 (0-104) 52 • 8 (27-76) 45 • 6 (16-58) 50 • 7 (23-61) 42 + 4 (22-64) 47• 3 (32-55) 51 • 7 (32-63) 48• 3 (38-61)
126 • 22 (20-330) 88 • 29 (40-260) 97 • 16 (70-140) 108 • 37 (34-218) 107 _+ 22 (42-240) 38 • 3 (,29-54) 51 • 7 (23-122) 40 • 3 (22-54)
1 2 3 4-7 8-10 11-15 15
S. pneumoniae (9 patients)
No. of patients
Cells (mm~)
21
3,496 • 934 (7-7,535) 6,940 • 6,629 (330-13,500) 2,006 _+ 715 (495-3,580)
346 • 208 (65-1,172) 42 • 6 (5-98) 17 • 5 (3-24) 6 + 1 (5-7)
8 9 5 11 11 18
11
I
Glucose [ (rng/dl)
Protein (mg/dl)
No. of patients
28 +- 10 (0-100) 56 • 16 (40-71) 52 • 6 (42-70) -
261 • 57 (13-530) -
9
142 ___44 (56-196) -
3
58 • 3 (55-63) 61 • 2 (56-65) 44 • 3 (38-50) 57 • 3 (54-60)
79 • 12 (56-110) 42• 6 (23-56) 49 + 10 (20-66) 10 • 5 (5-15)
5
2
5 4 3
Numbers in parentheses represent the range. *Mean +_ standard error. -- = Data insufficient.
rial meningitis. S u b s e q u e n t observations suggest t h a t the infection in the central nervous system h a d b e e n controlled in each o f these patients. Such a p h e n o m e n o n o f pleocytosis after antibiotic therapy can also be i n f e r r e d from o t h e r reports. 4-7 Significance of persistent pleocytosis, however, is n o t clear. It is more often seen in c h i l d r e n with prolonged fever d u r i n g therapy for H. influenzae meningitis. Pleocytosis is not associated with d u r a t i o n o f illness, prior therapy, a particular antibiotic, complications, or relapse. Neurologic e x a m i n a t i o n s were performed two to six m o n t h s after recovery from the acute infection; we f o u n d no significant difference in i n c i d e n c e o f sequelae a m o n g patients with or without persistent pleocytosis. It should be e m p h a s i z e d t h a t the r e l a t i o n s h i p between persistent pleocytosis a n d sequelae s h o u l d b e further studied by a m o r e detailed e v a l u a t i o n o n a larger n u m b e r o f patients. It is important, however, to recognize that pleocytosis alone is not a n indication o f for p r o l o n g ing t r e a t m e n t o f bacterial meningitis.
REFERENCES
1. Wehrle PF, Mathies AW, and Leedom JM: The critically ill child: management of acute bacterial meningitis, Pediatrics 44:991, 1969. 2. Wehrle PF: Meningitis, in Top FH, and Wehrle PF, editors: Communicable and infectious diseases, Saint Louis, 1972, The CV Mosby Company, p 415. 3. Smith DH, Ingrain DL, Smith AL, Gilles F, and Bresnan MJ: Bacterial meningitis: a symposium, Pediatrics 52:586, 1973. 4. Schulkind ML, Altemeier WA, and Ayoub EM: A comparison of ampicillin and chloramphenicol therapy in Hemophilus influenzae meningitis, Pediatrics 4 8 : 4 1 1 , 1971. 5. Shackleford PG, Bobinski JE, Feigin RD, and Cherry JD: Therapy of Haemophilus influenzae meningitis reconsidered, N Engl J Med 287:634, 1972. 6. Bachman DS: Hemophilus meningitis: comparison of H. influenzae and parainfluenzae, Pediatrics 55:526, 1975. 7. Wilson HD, and Haltalin KC: Ampicillin in Haemophilus influenzae meningitis, Am J Dis Child 129:208, 1975.