ORIGINAL CONTRIBUTION
meningitis, bacterial, pediatric
Pdiatric Bacterial Meningitis" Is Prior Antibiotic Therapy Associated With an Altered Clinical Presentation? Steven G Rothrock, MD*
Study hypothesis: The clinical features of children treated with oral
Medicine, Loma Linda University
Steven M Green, MD ~
Medical Center, Loma Linda,
Joseph Wren §
antibiotics before the diagnosis of bacterial meningitis differ from those who receive no antibiotics.
California,* and Riverside General
Debbie Letai, MD, PhD IP
From the Departments of Emergency
Hospital, Riverside, California;t Loma Linda University School of
Lynda Daniel-Underwood, MS §
Design: Retrospective case series.
Edward Pillar, O0 JI
Setting: University medical center.
Medicine;§ the Emergency Medicine Residency, Loma Linda University Medical Center, Loma Linda, California; kland California Emergency Physicians' Medical Group, Oakland, California.; Receivedfor publication March 1I, 1991. Revision received June 26, 1991. Acceptedfor publication August 13, 1991. Presented at the Societyfor Academic Emergency _Medicine Annual Meeting in Minneapolis, Minnesota, May 1990.
Participants: TWO hundred fifty-eight children 24 months old or younger with bacterial meningitis hospitalized during a 12-year period. Eighty-three children were treated with oral antibiotics before the diagnosis of meningitis, and 175 children were not. Interventions: None. Methods: The emergency department chart and hospital records were reviewed for presenting demographic, historical, physical examination, and laboratory features. Clinical features of pretreated and untreated patients were compared. Results: Pretreated children demonstrated less frequent temperature
of 38.3 C or higher, altered mental status and a longer duration of symptoms before diagnosis, with more frequent vomiting; ear, nose, and throat infections; and physician visits in the week before detection of meningitis (P< .05 for all comparisons). There was no difference in incidence of upper respiratory symptoms, seizures, nuchal rigidity, Kernig's and Brudzinski's signs, focal neurolegic signs, mortality, and length of hospitalization between groups. Conclusion: Clinical features of children who have taken antibiotics before the detection of meningitis differ significantly from those who have not undergone antibiotic therapy. Physicians should be aware of these differences when evaluating young children on antibiotics for the possibility of meningitis.[Rothrock SG, Green SM, Wren J, Letai D, Daniel-Underwood L, Pillar E: Pediatric bacterial meningitis: Is prior antibiotic therapy associated with an altered clinical presentation? Ann Emerg Med February 1992;21:146-152.]
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INTRODUCTION Initiation of antibiotic therapy before the detection of meningitis occurs in 30% to 55% of pediatric eases. 1-1s It is believed that this treatment befme hospital admission masks the diagnosis of meningitis. 16-1a Studies comparing cerebrospinal fluid (CSF) findings in children with partially treated and untreated bacterial meningitis are often cited as supporting evidence, l'2,s'a,9Al'13d9 Only three studies have compared clinical features between children with partially treated and untreated bacterial meningitis and found that signs and symptoms differ only minimally between groups on presentation. 6"14'15 However, these studies were limited by inadequate numbers of patients, absence of statistical analysis, and geographically isolated study populations. Our study was performed to address the deficiencies of prior studies and compare clinical features in children who have with those who have not received antibiotic treatment before the diagnosis of bacterial meningitis.
MATERIALS AND METHODS Computer files were used to identify- all children aged 24 months or younger hospitalized at a university medical center with a diagnosis of bacterial meningitis from January 1, 1979, to July 1, 1990. Patients were considered to have bacterial meningitis if they met any one of the following criteria: positive CSF culture; positive CSF Gram stain; positive CSF counterimmune electrophoresis, latex agglutination, or other bacterial antigen study; or a positive blood culture with CSF WBCs of more than 30 if 1 month old or younger and more than 5 if more than 1 month old (with at least one neutrophil per high-power field). Patients were excluded if they had a prior neurosurgieal procedure, underlying immunoeompromised state (eg, sickle cell dis~ ease, leukemia), or proven viral tubercular or parasitic meningitis. Also excluded were neonates diagnosed with meningitis before their initial discharge from the hospital. The records of the ED or clinic where the diagnosis of meningitis was made were reviewed for presenting demographic, historical, physical, and laboratory features. When initial records were unavailable or incomplete, the admission history and physical examination were reviewed for this information. For patients transferred from a separate facility, the presenting signs and symptoms of the treating physician who made the diagnosis of meningitis were recorded. Inpatient records were reviewed for extrameningeal infections, mortality rates, and duration of hospitalization.
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Historical and physical features were defined to assist with uniform data collection before chart review. Symptom duration was defined as the duration of the most prominent symptom or chief complaint that resulted in the patient presenting to the physician. Respiratory symptoms were defined as cough, sore throat, and earache. History of fever was defined as an historical record that the child had any temperature above normal, even if no temperature was ever recorded. On physical examination, only the initial temperature taken was recorded and used for analysis. An altered mental status was defined as any evidence of lethargy, inconsolability, obtundation, or coma. Patients were defined as having evidence of ear, nose, and throat (ENT) infections if any of the following were recorded: bulging, erythema, loss of light reflex, or obscuration of tympanic membrane landmarks; pharyngeal erythema, tonsillar or pharyngeal exudates; or purulent nasal discharge in addition to a diagnosis of ENT infection by the examining physician. Patients were divided into partially treated and untreated groups based on whether they had received antibiotic's in the 24 hours before detection of meningitis. Rates of specific clinical characteristics were calculated for each group. Nondocumented clinical features were categorized as absent. Rates of documentation of each clinical feature also were calculated. With Z2 and Student's t-test analyses (two-tailed), the incidence of clinical features was compared between partially treated and untreated groups. Significance was set at P < .05. The decision to make each comparison was made before data analysis; therefore, no statistical corrections for multiple comparisons were made. Before data analysis, sample size calculations were performed 2° using rates of historical and physical examination features reported in untreated children from prior studies: temperature of 38.3 C and higher (38% to 75%), upper respiratory infection (44%), altered mental status (22% to 53%), meningeal signs (29% to 31%), seizures (25% to 47%), and mortality (19% to 36%). 6,14d5 To detect a 25% difference in rates of each clinical feature from these reported rates with a power of 80% ((x of .05), at least 64 patients each were needed in the pretreated and untreated groups.
RESULTS Three hundred thirty-two patients aged 24 months or younger with meningitis were identified during the study period. No eases of meningitis involving tuberculosis or immunocompromised patients were identified. Seventeen patients with neonatal I~
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meningitis and 24 patients with prior neurosurgical procedures were excluded. Of the remaining cases, 33 were excluded based on negative CSF eultures, Gram stains, and bacterial antigen studies, leaving 258 patients for analysis. The diagnosis of bacterial meningitis was based on the CSF culture in 129 untreated patients (74%) and 49 patients receiving prior treatment (59%). The method of diagnosis in euhurenegative patients is listed. (Table 1).
Table 1,
Method of diagnosis of meningitis Pretreated (19 No. 49 24 8 2
Method of Diagnosis CSF culture CSF antigen Gram stain* Blood culture*
Patients 83) % 59 29 10 2
Untreated Patients (N 175) No. % 129 74 33 19 9 15 4 2
"Positive Gram stain in presenceof negative CSF culture and antigen study• rpositive blood culture in the presenceof negativeCSFculture, Gramstain, and antigen studywith CSFWBCs of more than 30 per high-powerfield in infants less than 1 mnnth old and morethan 5 in children more than 1 month old (with 1 or mere neutrephil per high-powerfield)•
Table 2.
Comparison of clinical features Clinical Feature Historical Age (years +- SD) Sex (male) Symptom duration (days +_ SD) Fever Lethargy or irritable Vomiting Upper respiratory symptoms Seizure before admission No. of physician visits in week before diagnosis (_+ SD) Physical Temperature ~ 38.3 C Altered mental status ENT infections Nuchal rigidity Brudzinski's sign Koenig's sign Focal neurologic abnormality Outcome Length of hospitalization (days +- SD) Mortality
Pretreated Children (N = 83) No. % 0.78 +- 0.47 100" 49 (59%) 100 4.6 82 72 59
Untreated Children (N = 175) No. % 0.70 -+ 0.48 100" 99 (57%) 100
~ 4.0 (99%) (87%) (71%)
96 100 98 93
2.9 +- 2.8 167 (95%) 166 (95%) 95 (54%)
97 97 95 94
< .85 NS NS < .05
46 (55%) 18 (22%)
88 83
81 (46%) 40 123%)
77 75
NS NS
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Table 3.
Antibiotics given before detection of meningitis 1.33 _+ 0.69
.28 (.62)
< 05
49 (59%) 44 {53%) 35 (42%) 49 (59%) 11 (13%) 9 (11%)
95 98 90 93 16 18
135 (77%) 136 {78%) 39 (22%) 95 (54%) 18 (10%) 16 (9%)
96 98 98 91 21 19
< .005 < .005 < .005 NS NS NS
4 (5%)
98
11 (6%)
92
NS
13.7 _+ 7.5 8 (10%)
100 100
15.7 -+ 9.5 15 (9%)
100 180
NS NS
*Rate of documentationof clinical feature as percentage.
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P NS NS
Mean patient age was 8.6 months, with a range of from 1 week to 24 months. Eighty-three children (32%) were designated as pretreated based on a history of antibiotic therapy in the 24 hours before the detection of meningitis. In this group, mean _+ SD age was 9.5 + 6 months, with a range of from 1 to 24 months. Mean age of untreated patients was 8.3 _+6 months, with a range of from 1 week to 24 months. Fifty-nine percent of pretreated patients and 57% of untreated patients were male. Sex and mean age did not differ between groups (Table 2). The most common historical features in both groups were fever, irritability, and lethargy. Vomiting was more common in the pretreated than in the untreated group of patients (71% vs 54%, respectively; P < .05). Mean duration of symptoms and number of physician visits in the week before the detection of meningitis was greater in the pretreated group than in the untreated group (P < .05). The rate of all other historical features did not differ significantly between groups (Table 2). Antibiotics given to children before the detection of meningitis are listed (Table 3) as are the diagnoses of children seen in the week before the detection of meningitis (Table 4). Mean duration of antibiotic therapy before the deteetion of meningitis was 2.4 days (range, 0.5 to ten days). Pretreated patients more often had physical findings of ENT infections (including otitis media, pharyngitis, tonsillitis, and sinusitis), whereas untreated patients more often had an altered mental status and temperature of 38.3 C or above (P < .05 for all comparisons). The rates of all other physical features did not differ significantly between groups. Length of hospitalization and mortality rates also did not differ between groups. Positive CSF Gram stains and cultures were more common in untreated patients (P < .05). Mean serum WBC count, CSF cell count, CSF glucose, and CSF protein did not differ signifi- I~
ANNALS OF EMERGENCY MEDICINE
Antibiotic Ampicillin* Amoxacillin t Penicillin Sulfisoxazole/erythromycin Cefaclor Erythromycin Unspecified Amoxacillin/clavulanate Trimethoprim/sulfamethoxazole Total
No. of Patients 26 21 13 9 8 6 5 4 2 94*
% 28 22 14 10 9 6 5 4 2
*Includes two patients who also received IN penicdlin one to two days before finaJ presentation. qncludes one patient who received IM ceftriaxoneone day before final presentation• *Total adds up to more than 83 becauseseveral patients had taken multiple antibiotics in the preceding seven days•
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cantly between groups (Table 5). The most common organisms responsible for meningitis in each group were Haemophilus influenzae and Streptococcuspneumoniae. Other responsible organisms are listed (Table 6). Extrameningeal infections (excluding otitis media and pharyngitis) were noted during hospitalization in 48 children with untreated meningitis (28%) and 24 children with pretreated meningitis (29%). Pneumonia was the most common extrameningeal infection noted in both groups. Other extrameningeal infections are listed (Table 7).
Table 4.
Diagnoses in children seen by physician in week before detection of meningitis Pretreated Children Diagnosis Otitis media Unspecified* Pharyngitis Upper respiratory infection* Pneumonia Gastroenteritis
Untreated Children*
DISCUSSION The diagnosis of meningitis in young children can be difficult. As many as 55% of children are seen by a physician and started on antibiotics before meningitis is detected. 1-1s Retrospectively, it is not possible to determine whether patients who reeeived preliminary treatment were initially misdiagnosed or suffered from infections (eg, otitis media or occult baeteremia) that later progressed to meningitis. It is probable that both scenarios occur. With a large proportion of children given antibiotics before diagnosis, an understanding of the effect of this treatment on the clinical characteristics of the disease is important. Prior studies have attempted to address the effect of prior therapy on presenting features and have yielded conflicting results. 6'14,15 Reports of prior oral antibiotic therapy affecting children with bacterial meningitis have concentrated primarily on CSF parameters. 1"2,5'a'9,ll'13A9 Conflicting studies indicate that pretreat-
No. 45 13 10 9 8 4
% 46 13 11 9 8 4
No. 4 23 1 4 1 5
% 8 46 2 8 2 10
Febrile seizu@
3
3
2
4
Table 6.
Viral syndrome
2
2
2
4
Organisms responsiblefor meningitis
Cervical adenitis
1
1
0
Fever uncertain etiology
1
I
3
Facial cellulitis
1
1
O
Anemia
g
Pretreated Children (N - 83)
6
1
2
Nephrosis
0
1
2
Well baby
0
1
2
Congenital heart disease
0
1
2
O 97"
1 50
2
Otitis extema Total
ment either has no effect or is associated with a minimal decrease in CSF WBC counts in young children. 2'4-6"8'13'21 •
*None received antibiotics or took antibiotics if they were prescribed. tNo specified diagnosis noted in records or records unavailable. *Excluding otitis media and pharyngitis.
Organism H influenzae S pneumoniae Neisseria meningitides Group B Streptococcus Escherichia call Streptococcus fecaelis Pseudomonas aeruginosa Salmonella eeteridites
No. 70 11 0
% 84 13
Untreated Children (N = 175) No. 130 23 2
%
P
74
NS
13
NS
1
1
1
10
6
1 0
1
5 3
3 2
1 1
1 1
O O
{None of these patients had a lumbar puncture as part of the initial work-up. ~Total adds up to more than 83 because several patients were given mere then one diagnosis during their initial presentation and others were seen by more than one physician.
Table 7.
Extrameningeal infections* noted during hospitalization Table 5.
Pretreated Children (N = 83)
Comparison of laboratory features Laboratory Feature Serum WBCs (1,000 cells/mm 3 ± SD) CSF WBCs (1,000 cells/mm 3 ~ SD) Positive CSF Gram stain CSF glucose (g/dL ± SB) CSt: protein (mg/dL ± SD) Positive CSF culture
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Pretreated Children (N - 83)
Untreated Children (N = 175)
P
15.4 ± 9.2
13.3 ± 8.4
NS
4.5 _+ 9.0
6.1 ± 5.1
NS
26/64 {41%) 28.1 _+ 25 155 _+ 132 49/76 (65%)
92/134 (69%) 31.3 ± 31.7 182 -+ 140 129/148 (87%)
< .005 NS NS < .005
Infection Pneumonia Sinusitis Mastoiditis Intracranial abscess Urinary tract infection Cellulitis
No. 13 7 O 1 2 1
% 16 8 1 2 1
Untreated Children (N = 175) No, 17 13 7 4 1 2
% 10' 7 4 2 1 1 1
Bacterial infectious diarrhea
0
2
Septic arthritis
0
1
1
Pulmonary abscess
0
1
1
24
48
Total
"P
*Excluding otitis media and pharyngitis. *Percentage based on ratio ef patients with particular infection divided by the total number of patients with meningitis in each group.
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There is stronger evidence that preliminary oral antibiotics decrease the rate of positive CSF cultures and Gram stains in children with bacterial meningitis, s,8-n,la'14,19,22 This alteration of CSF parameters suggests that the differentiation of bacterial from viral meningitis may be more difficult in partially treated patients. However, studies detailing the laboratory diagnosis of meningitis are of little value when faced with the decision of whether to perform a lumbar puncture in a child after initiation of oral antibiotic therapy for an apparent minor illness. Our results suggest that children with partially treated meningitis have a more subtle presentation than untreated children. Although the duration of symptoms before diagnosis was longer in pretreated children, they exhibited significantly decreased rates of altered mental status and temperature of 38.3 C and above. Several explanations for a more subtle clinical presentation in pretreated children exist. The most obvious is that preliminary therapy has some effect on the infection. This argument is supported by studies that show decreased CSF WBC counts, culture rates, and Gram stains and increased CSF glucose and protein levels in pretreated patients, s'a-n'13J4'19,22 Certain oral antibiotics (eg, erythromycin) have poor CSF penetration, whereas others (eg, penicillin) have a poor effect against common infecting organisms (H influenzae).23-25 Doses of oral antibiotics that penetrate the blood-brain barrier usually result in CSF antibiotic concentrations that are below the minimal inhibitory concentration of most bacteria that cause meningitis. .9 There is another explanation for the altered or more subtle clinical presentation in pretreated patients. Patients with pretreated meningitis may have a less virulent strain of organism and thus are more often misdiagnosed and subsequently placed on antibiotics.3,26,27 All pretreated patients had at least one of the common signs and symptoms associated with meningitis: altered mental status, nuchal rigidity, fever, vomiting, focal neurologic abnormality, or Kernig's or Brudzinski's sign. It is possible that an important factor in the ultimate correct diagnosis of meningitis may have been the fact that these children had been seen recently by a physician and were not improving with the antibiotics that had been initiated. The less frequent temperature of 38.3 C and above in pretreated children might be related to the higher incidence of recent physician visits. It is possible that parents who had been given antibiotics for their child also were counseled on the methods of fever reduction, including appropriate antipyretic dosing.
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Unfortunately, ED charts and hospital records in almost all cases were not detailed in documenting the use of antipyretics and other fever-reducing measures by parents. ENT infections (ie, otitis media, pharyngitis, tonsillitis, and sinusitis) and vomiting were more common in pretreated than in untreated children. One possible explanation is that physicians who initially saw these patients were dissuaded from considering the diagnosis of meningitis when confronted with a likely somce (eg, otitis media and pharyngitis) of their symptoms. Methods used by clinicians to diagnosis ENT infections are not specific. Several studies have shown that otoscopic findings in patients diagnosed with otitis media (eg, tympanic membrane erythema, loss of light reflex, and retraction) are unreliable. 28-3° In our study-, no patient diagnosed with otitis media had documentation of pneumotoscopy, a test found to be much more reliable than direct otoscopy.3°'31 Because physicians used nonspecific criteria for diagnosis, it is not possible to verify that children actually had otitis media. Documentation of the presence of pharyngeal infections was also difficult because of reliance on the subjective impression of this finding. Even if the diagnosis of an ENT infection was correct in the majority of instances, physicians should be aware that such infections can occur concunently in children with meningitis. Upper and lower respiratory infections were the most common diagnoses in children seen in the week before detection of meningitis and in hospitalized patients. The most common bacteria that cause respiratory infections (H influeraae and S pneumoniae) are also the most frequent causes of bacterial meningitis. Our results differ from those of prior pediatric studies that have examined clinical features in patients with partially treated meningitis (Table 8). Winklestein examined the effect of preliminary antibiotic treatment on children with bacterial meningitis and concluded that only the duration of symptoms differed between pretreated and untreated patients. 15 However, his study was limited by an inadequate sample size (only 37 patients) and had a less than 50% power to detect a 25% difference between rates of clinical features in pretreated and untreated groups. In addition to being geographically isolated (Eskimos), his patient population may have included several patients with viral meningitis because all cases with CSF WBC counts of more than 100 mm 3 and with more than 50% neutrophils were enrolled. Two other studies that examined clinical features primarily in children also had several limitations.6"14 The numbers of patients were small, and the criteria used to define bacterial menin- 11~
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BACTERIAL M E N I N G I T I S Rothrock et al
gitis as well as patient ages were not included in either study. Statistical analyses were not performed in either study, although our interpretation of Singh et al's data revealed no significant difference in clinical features between pretreated and untreated patients. 14 Our interpretation of Harter's data revealed that untreated patients were more likely to be obtunded than were pretreated patients (41% vs 9%, P < .05 by Fisher's exact test). 6 Two prior adult studies with mean patient ages of more than 20 years found that symptom duration was longer in pretreated patients and that other signs and symptoms did not differ between groups, a2'a3 It is doubtful that data obtained from adult studies are applicable to our population. Our population, unlike that in other pediatric studies, ineluded no children more than 24 months old. Eighteen to 24 months is often cited as the age range below which meningeal signs become less reliable and nonspeeifie signs and symptoms (eg, inconsola-
TABLE 8.
Comparison with prior pediatric studies Current Study (1991)
Hatter 6 (1963)
Singh el aP 4 (1980)
Winklestein TM (1970)
258
70
104
37
Mean age
0.75
ND*
ND*
0.63*
(range) (yr)
(g - 2)
ND*
32
49
A, B, C, or Og
ND*
Study Feature Total no. of patients
Receiving
(0
12)
ND
53
57
"Turbid CSF plus
A, B, or E~
antibiotics (%) Criteria for diagnosis
PMN leukocytosis"
of bacterial meningitis NS1t
NS2*
Pretreated
Clinical features
Pretreated
that differed
group had
group had longer
between treated
longer symptom
symptom duration
and untreated
duration, more
groups
vomiting, lower temperatures, and more ENT infections
More than 80%
Yes
No
No
No
University
Military
Medical
Indian health
medical center,
hospital,
college,
service,
California
Texas
India
Alaska
power to detect
25% difference between groups Population
*ND, not documented in article although studies included "children" only; reported as median, not as a mean. *NSt, no statistical comparisons made by authors; however, on our examination of their data, patients who had received no antecedent therapy were more obtunded than were pretreated patients (14 of 3B vs three of 34, P < .05 by Fisher's exact test). *NS2, no statistical comparisons made; however, on our analysis of their results, no statistically significant difference was found between groups. ~A, culture; B, Gram stain; C, CSF antigenic test; D, positive blood culture with CSF pleecytesis; E, CSF WBC of more than 100/mL plus more than 50% neutrophils or CSh glucose of less than 40.
5 6 / 1 51
bility, feeding, and eye contact) become more important in making the diagnosis of meningitis, t8'34'35 Thus, knowledge of any factor, such as preliminary antibiotic therapy, that can alter these nonspecific signs and symptoms can be important. Because signs and symptoms of meningitis differ between age groups, any study that groups children less than and more than 24 months old into the same category might also yield conflicting or inaccurate data. Criteria used to identify eases of bacterial meningitis in our study were also more strict than those used in prior studies. We included only patients with proven bacterial meningitis by culture, antigen study, or Gram stain. We purposely kept diagnostic •criteria strict to avoid including cases of viral meningitis that might have had different presenting clinical features than cases of bacterial meningitis. There are several limitations to our study. Because data collection was retrospective, not all signs and symptoms were documented uniformly. For significant features, however, rates of documentation of the presence or absence of each feature were all 91% or higher. The retrospective nature of our study made it impossible to assess whether nondoeumented features were present. We believe that absent features were less likely to be recorded. This assumption potentially underestimates the incidence of all features. However, in our opinion, the alternative method of calculating the incidence of clinical features by dividing the number with documented present features by the number doeumented as present or absent overestimates the incidence. This method also assumes that nondoeumented features occur at a similar incidence to documented features. Another problem with retrospective data collection was the necessity of relying on potentially inexact historical and physical features. An example was the historical presence of fever in study patients. The authors attempted to document whether the earegiver felt that the child had an elevated temperature before presentation. In almost all eases, however, the exact level and site (rectal vs axillary vs oral) of elevated temperatures were not documented. Thus, this factor was potentially inaccurate because it was based on both the subjective impression of fever by the caregiver and the documentation of the history taker. A final factor to be considered in analyzing our results is the patient population. The study hospital is a tertiary referral center for children and has a pediatric ICU and all pediatric subspeciahies. Thus, the number of more difficult or advanced eases of baeterial meningitis might be higher than in other settings. It is uneertain what effeet this factor might have on study results.
•
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CONCLUSION A retrospective study was performed to compare clinical features in children 24 months old or younger who were treated with antibiotics before the detection of meningitis with features of children who received no prior antibiotic therapy. Children pretreated with antibiotics had a longer duration of symptoms before diagnosis and were less likely to have a temperature of 38.3 C and above and an altered mental status. Pretreated children also had more frequent vomiting and ENT infections than untreated patients. Because of the retrospective nature of this study, we cannot state that preliminary antibiotics are the cause of this difference in signs and symptoms. However, these results indicate that prior antibiotic therapy is associated with an altered clinical presentation of meningitis in children 24 months old or younger. Physicians should be aware of this altered clinical presentation and maintain a high index of suspicion in evaluating children who have already been started on antibiotic therapy for seemingly minor illnesses.
•
REFERENCES 1. Converse GM, Gwaltney JM, Strassburg DA, et al: Alteration of cerebrospinal fluid findings by partial treatment of bacterial meningitis. J Pediatr 1973;83:220-225. 2. Dalton HP, Allison M J: Modification of laboratory results by partial treatment of bacterial meningitis. Am J Clin Pathoi 1968;49:410-413. 3. Davis SD, Hill HR, Feigi P, et ah Partial antibiotic therapy in Haemophflus influenzae meningitis. Am J Dis Child 1975;129:802-807. 4. Feigin RD, Dodge PR: Bacterial meningitis: Newer concepts of pathophysiology and neuro[ogic sequelae. Pediatr Clin North Am 1976;23:541-556. 5. Geiseler PJ, Nelson KE, Levin S: Community acquired puru[ent meningitis; A review of 1,316 cases during the antibiotic era, 1954--1976. Rev Infect Dis 1980;2:725-745. 6. Harter DH: Preliminary antibiotic therapy in bacterial meningitis. Arch Neural 1963;9:31-35. 7. I4odges GR, Perkins RL: Acute bacterial meningitis: An analysis of factors influencing prognosis. Am J Med Sci 1975;27g:427-440. 8. Jarvis CW, Saxena KM: Does prior antibiotic treatment hamper the diagnosis of acute bacteria[ meningitis? An analysis of a series of 135 childhood cases. Clin Pediatr1972;11:201204. 9. Kaptan SL, Smith EO, Wills C: Association between preadmissian oral antibiotic therapy and cerebrospinal fluid findings and sequelae caused by Haemophgusinfluenzaetype B meningitis. Pediatr Infect Dis 1986;8:626-632. 10. Mandal BK: The dilemma of partially treated meningitis. ScandJ Infect Dis 1976;8:185-188. 11. Pickens S, Sangster G, Gray JA: The effects of preadmission antibiotics on the bacteriological diagnosis of pyogenic meningitis. SpendJ Infect Dis 1978;10:183-185. 12. Quaade F, Kristensen KP: Purulent meningitis: A review of 658 cases• Acta Mad[ca Scand 1962;I 71:543-550.
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13. Shahet I, Shahar E, Meyerovich J, et aL Diagnosis of bacterial meningitis in previously treated children. South MealJ 1985;78:299-301. 14. Singh M, Singh S, Gill P: Effect of partial treatment on purulent meningitis. TropGeogrMed 1980;32:16q 8. 15. Winklestein JA: The influence of partial treatment with penicillin on the diagnosis of bacterial meningitis. J Pediatr 1970;77:619-624. 16. Behrman RE, Vaughan VC, Nelson WE: Nelson Textbaokof Pediatrics, ed 13. Philadelphia, WB Saunders, 1987, p 589-573. 17. Barkin RM, Rosen P: EmergencyPediatrics:A Guide to Ambulatory Care,ed 3. St Louis, CV Mosby, 1990, p 591-598. 18. Ehrlich FE, Heldrich FJ, Tepas J J: Pediatric EmergencyMedicine, ed 1. Rocky[fie, Maryland, Aspen Pub@hers, Inc, 1987, p 152-157. 19. Fe[dman WE: Effect of prior antibiotic therapy on concentrations of bacteria in CSF. Am J Dis Child 1978;132:672-674. 20. Zar JH: BiostafisticalAnalysis. Engbweod Cliffs, New Jersey, Prentice Hall, 1984, p 387-403. 21. Blazer S, Berant M, Alon U: Bacterial meningitis: Effect of antibiotic treatment on cerebrospinal fluid. Am J Clio Pathe11983;80:386-387. 22. Short Reports: Acute bacterial meningitis in childhood: Aspects of prehospital care in 687 eases. Arch Dis Child1977;52:501-509. 23. Hieber JP, Nelson JD: A pharmacologic evaluation of penicillin in children with purulent meningitis. N Engl J Mad 1977;297:410-413. 24. Grigsby ME, Johnson JB, Simmons GW: Some laboratory and clinical experiences with erythromycin. Ant[bier Chemother1953;3:1029-1034. 25. Dougherty JM, Overturf GD: Blunting the continuing menace of acute bacterial meningitis. Emerg Med Reports 1987;8:137-144. 26, Hahn SM: Current concepts in bacterial meningitis. West J Med 1989;151:180-188. 27. KapJan SL, Feigin RD: Clinical presentatiens, prognostic factors and diagnosis of bacterial meningitis, in Sande MA, Smith AL, Root RK (eds): Bacteria/Meningitis. New York, Churchill Livingstone, 1985, p 83-94. 28. Cantanken El, Bluestone CB, Fria TJ, et ah Identification of otitis media with effusion in children. Ann Otol Rhine/Larynge11980;89:190-227. 29. Bluestone CB, Cantekin El: Design factors in the characterization and identification of otitis media and certain related conditions. Ann Oto/Rhl#ol Laryngo/1979;88(suppl 60):13~27. 30. Karma P}4: Otoscopic diagnosis of middle ear effusion in acute and nonacute otitis media-The value of different etoscopic f;ndings. Int J Pediatr Otorhino/aryngo11989;17:37. 31. Schwartz DM, Schwartz RH: Acoustic immittance findings in acute otitis media. Ann Otol Rhine/Laryngol 1980;suppl 88:211-213. 32. Bohr V, Rasmussen N, Hansen B, et ah 875 cases ef bacterial meningitis: Diagnostic procedures and the impact of preadmission antibiotic therapy. J infect 1983;7:193-202. 33. Romer FK: Difficulties in the diagnosis of bacterial meningitis--Evaluation of antibiotic pretreatment and causes of admission to hospital. Lancet 1977;1:345-347. 34. Callaham M: Fulminant bacterial meningitis without meningeal signs. Ann EmergMad 1989;18:90-93. 35. Fleischer G, Ludwig S (eds): Textbookof Pediatric EmergencyMedicine. Baltimore, Williams & Wilkins, 1988, p 419-428.
Address for reprints: Steven G Rothrock, MD, Department of Emergency Medicine, Loma Linda University Medical Center, 11234 Andersen Street, Loma Linda, California 92350.
15 2
5 7
meningitis, bacterial, pediatric
Pdiatric Bacterial Meningitis" Is Prior Antibiotic Therapy Associated With an Altered Clinical Presentation? Steven G Rothrock, MD*
Study hypothesis: The clinical features of children treated with oral
Medicine, Loma Linda University
Steven M Green, MD ~
Medical Center, Loma Linda,
Joseph Wren §
antibiotics before the diagnosis of bacterial meningitis differ from those who receive no antibiotics.
California,* and Riverside General
Debbie Letai, MD, PhD IP
From the Departments of Emergency
Hospital, Riverside, California;t Loma Linda University School of
Lynda Daniel-Underwood, MS §
Design: Retrospective case series.
Edward Pillar, O0 JI
Setting: University medical center.
Medicine;§ the Emergency Medicine Residency, Loma Linda University Medical Center, Loma Linda, California; kland California Emergency Physicians' Medical Group, Oakland, California.; Receivedfor publication March 1I, 1991. Revision received June 26, 1991. Acceptedfor publication August 13, 1991. Presented at the Societyfor Academic Emergency _Medicine Annual Meeting in Minneapolis, Minnesota, May 1990.
Participants: TWO hundred fifty-eight children 24 months old or younger with bacterial meningitis hospitalized during a 12-year period. Eighty-three children were treated with oral antibiotics before the diagnosis of meningitis, and 175 children were not. Interventions: None. Methods: The emergency department chart and hospital records were reviewed for presenting demographic, historical, physical examination, and laboratory features. Clinical features of pretreated and untreated patients were compared. Results: Pretreated children demonstrated less frequent temperature
of 38.3 C or higher, altered mental status and a longer duration of symptoms before diagnosis, with more frequent vomiting; ear, nose, and throat infections; and physician visits in the week before detection of meningitis (P< .05 for all comparisons). There was no difference in incidence of upper respiratory symptoms, seizures, nuchal rigidity, Kernig's and Brudzinski's signs, focal neurolegic signs, mortality, and length of hospitalization between groups. Conclusion: Clinical features of children who have taken antibiotics before the detection of meningitis differ significantly from those who have not undergone antibiotic therapy. Physicians should be aware of these differences when evaluating young children on antibiotics for the possibility of meningitis.[Rothrock SG, Green SM, Wren J, Letai D, Daniel-Underwood L, Pillar E: Pediatric bacterial meningitis: Is prior antibiotic therapy associated with an altered clinical presentation? Ann Emerg Med February 1992;21:146-152.]
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INTRODUCTION Initiation of antibiotic therapy before the detection of meningitis occurs in 30% to 55% of pediatric eases. 1-1s It is believed that this treatment befme hospital admission masks the diagnosis of meningitis. 16-1a Studies comparing cerebrospinal fluid (CSF) findings in children with partially treated and untreated bacterial meningitis are often cited as supporting evidence, l'2,s'a,9Al'13d9 Only three studies have compared clinical features between children with partially treated and untreated bacterial meningitis and found that signs and symptoms differ only minimally between groups on presentation. 6"14'15 However, these studies were limited by inadequate numbers of patients, absence of statistical analysis, and geographically isolated study populations. Our study was performed to address the deficiencies of prior studies and compare clinical features in children who have with those who have not received antibiotic treatment before the diagnosis of bacterial meningitis.
MATERIALS AND METHODS Computer files were used to identify- all children aged 24 months or younger hospitalized at a university medical center with a diagnosis of bacterial meningitis from January 1, 1979, to July 1, 1990. Patients were considered to have bacterial meningitis if they met any one of the following criteria: positive CSF culture; positive CSF Gram stain; positive CSF counterimmune electrophoresis, latex agglutination, or other bacterial antigen study; or a positive blood culture with CSF WBCs of more than 30 if 1 month old or younger and more than 5 if more than 1 month old (with at least one neutrophil per high-power field). Patients were excluded if they had a prior neurosurgieal procedure, underlying immunoeompromised state (eg, sickle cell dis~ ease, leukemia), or proven viral tubercular or parasitic meningitis. Also excluded were neonates diagnosed with meningitis before their initial discharge from the hospital. The records of the ED or clinic where the diagnosis of meningitis was made were reviewed for presenting demographic, historical, physical, and laboratory features. When initial records were unavailable or incomplete, the admission history and physical examination were reviewed for this information. For patients transferred from a separate facility, the presenting signs and symptoms of the treating physician who made the diagnosis of meningitis were recorded. Inpatient records were reviewed for extrameningeal infections, mortality rates, and duration of hospitalization.
52/147
Historical and physical features were defined to assist with uniform data collection before chart review. Symptom duration was defined as the duration of the most prominent symptom or chief complaint that resulted in the patient presenting to the physician. Respiratory symptoms were defined as cough, sore throat, and earache. History of fever was defined as an historical record that the child had any temperature above normal, even if no temperature was ever recorded. On physical examination, only the initial temperature taken was recorded and used for analysis. An altered mental status was defined as any evidence of lethargy, inconsolability, obtundation, or coma. Patients were defined as having evidence of ear, nose, and throat (ENT) infections if any of the following were recorded: bulging, erythema, loss of light reflex, or obscuration of tympanic membrane landmarks; pharyngeal erythema, tonsillar or pharyngeal exudates; or purulent nasal discharge in addition to a diagnosis of ENT infection by the examining physician. Patients were divided into partially treated and untreated groups based on whether they had received antibiotic's in the 24 hours before detection of meningitis. Rates of specific clinical characteristics were calculated for each group. Nondocumented clinical features were categorized as absent. Rates of documentation of each clinical feature also were calculated. With Z2 and Student's t-test analyses (two-tailed), the incidence of clinical features was compared between partially treated and untreated groups. Significance was set at P < .05. The decision to make each comparison was made before data analysis; therefore, no statistical corrections for multiple comparisons were made. Before data analysis, sample size calculations were performed 2° using rates of historical and physical examination features reported in untreated children from prior studies: temperature of 38.3 C and higher (38% to 75%), upper respiratory infection (44%), altered mental status (22% to 53%), meningeal signs (29% to 31%), seizures (25% to 47%), and mortality (19% to 36%). 6,14d5 To detect a 25% difference in rates of each clinical feature from these reported rates with a power of 80% ((x of .05), at least 64 patients each were needed in the pretreated and untreated groups.
RESULTS Three hundred thirty-two patients aged 24 months or younger with meningitis were identified during the study period. No eases of meningitis involving tuberculosis or immunocompromised patients were identified. Seventeen patients with neonatal I~
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Rothrock et al
meningitis and 24 patients with prior neurosurgical procedures were excluded. Of the remaining cases, 33 were excluded based on negative CSF eultures, Gram stains, and bacterial antigen studies, leaving 258 patients for analysis. The diagnosis of bacterial meningitis was based on the CSF culture in 129 untreated patients (74%) and 49 patients receiving prior treatment (59%). The method of diagnosis in euhurenegative patients is listed. (Table 1).
Table 1,
Method of diagnosis of meningitis Pretreated (19 No. 49 24 8 2
Method of Diagnosis CSF culture CSF antigen Gram stain* Blood culture*
Patients 83) % 59 29 10 2
Untreated Patients (N 175) No. % 129 74 33 19 9 15 4 2
"Positive Gram stain in presenceof negative CSF culture and antigen study• rpositive blood culture in the presenceof negativeCSFculture, Gramstain, and antigen studywith CSFWBCs of more than 30 per high-powerfield in infants less than 1 mnnth old and morethan 5 in children more than 1 month old (with 1 or mere neutrephil per high-powerfield)•
Table 2.
Comparison of clinical features Clinical Feature Historical Age (years +- SD) Sex (male) Symptom duration (days +_ SD) Fever Lethargy or irritable Vomiting Upper respiratory symptoms Seizure before admission No. of physician visits in week before diagnosis (_+ SD) Physical Temperature ~ 38.3 C Altered mental status ENT infections Nuchal rigidity Brudzinski's sign Koenig's sign Focal neurologic abnormality Outcome Length of hospitalization (days +- SD) Mortality
Pretreated Children (N = 83) No. % 0.78 +- 0.47 100" 49 (59%) 100 4.6 82 72 59
Untreated Children (N = 175) No. % 0.70 -+ 0.48 100" 99 (57%) 100
~ 4.0 (99%) (87%) (71%)
96 100 98 93
2.9 +- 2.8 167 (95%) 166 (95%) 95 (54%)
97 97 95 94
< .85 NS NS < .05
46 (55%) 18 (22%)
88 83
81 (46%) 40 123%)
77 75
NS NS
21:2
Table 3.
Antibiotics given before detection of meningitis 1.33 _+ 0.69
.28 (.62)
< 05
49 (59%) 44 {53%) 35 (42%) 49 (59%) 11 (13%) 9 (11%)
95 98 90 93 16 18
135 (77%) 136 {78%) 39 (22%) 95 (54%) 18 (10%) 16 (9%)
96 98 98 91 21 19
< .005 < .005 < .005 NS NS NS
4 (5%)
98
11 (6%)
92
NS
13.7 _+ 7.5 8 (10%)
100 100
15.7 -+ 9.5 15 (9%)
100 180
NS NS
*Rate of documentationof clinical feature as percentage.
FEBRUARY 1992
P NS NS
Mean patient age was 8.6 months, with a range of from 1 week to 24 months. Eighty-three children (32%) were designated as pretreated based on a history of antibiotic therapy in the 24 hours before the detection of meningitis. In this group, mean _+ SD age was 9.5 + 6 months, with a range of from 1 to 24 months. Mean age of untreated patients was 8.3 _+6 months, with a range of from 1 week to 24 months. Fifty-nine percent of pretreated patients and 57% of untreated patients were male. Sex and mean age did not differ between groups (Table 2). The most common historical features in both groups were fever, irritability, and lethargy. Vomiting was more common in the pretreated than in the untreated group of patients (71% vs 54%, respectively; P < .05). Mean duration of symptoms and number of physician visits in the week before the detection of meningitis was greater in the pretreated group than in the untreated group (P < .05). The rate of all other historical features did not differ significantly between groups (Table 2). Antibiotics given to children before the detection of meningitis are listed (Table 3) as are the diagnoses of children seen in the week before the detection of meningitis (Table 4). Mean duration of antibiotic therapy before the deteetion of meningitis was 2.4 days (range, 0.5 to ten days). Pretreated patients more often had physical findings of ENT infections (including otitis media, pharyngitis, tonsillitis, and sinusitis), whereas untreated patients more often had an altered mental status and temperature of 38.3 C or above (P < .05 for all comparisons). The rates of all other physical features did not differ significantly between groups. Length of hospitalization and mortality rates also did not differ between groups. Positive CSF Gram stains and cultures were more common in untreated patients (P < .05). Mean serum WBC count, CSF cell count, CSF glucose, and CSF protein did not differ signifi- I~
ANNALS OF EMERGENCY MEDICINE
Antibiotic Ampicillin* Amoxacillin t Penicillin Sulfisoxazole/erythromycin Cefaclor Erythromycin Unspecified Amoxacillin/clavulanate Trimethoprim/sulfamethoxazole Total
No. of Patients 26 21 13 9 8 6 5 4 2 94*
% 28 22 14 10 9 6 5 4 2
*Includes two patients who also received IN penicdlin one to two days before finaJ presentation. qncludes one patient who received IM ceftriaxoneone day before final presentation• *Total adds up to more than 83 becauseseveral patients had taken multiple antibiotics in the preceding seven days•
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cantly between groups (Table 5). The most common organisms responsible for meningitis in each group were Haemophilus influenzae and Streptococcuspneumoniae. Other responsible organisms are listed (Table 6). Extrameningeal infections (excluding otitis media and pharyngitis) were noted during hospitalization in 48 children with untreated meningitis (28%) and 24 children with pretreated meningitis (29%). Pneumonia was the most common extrameningeal infection noted in both groups. Other extrameningeal infections are listed (Table 7).
Table 4.
Diagnoses in children seen by physician in week before detection of meningitis Pretreated Children Diagnosis Otitis media Unspecified* Pharyngitis Upper respiratory infection* Pneumonia Gastroenteritis
Untreated Children*
DISCUSSION The diagnosis of meningitis in young children can be difficult. As many as 55% of children are seen by a physician and started on antibiotics before meningitis is detected. 1-1s Retrospectively, it is not possible to determine whether patients who reeeived preliminary treatment were initially misdiagnosed or suffered from infections (eg, otitis media or occult baeteremia) that later progressed to meningitis. It is probable that both scenarios occur. With a large proportion of children given antibiotics before diagnosis, an understanding of the effect of this treatment on the clinical characteristics of the disease is important. Prior studies have attempted to address the effect of prior therapy on presenting features and have yielded conflicting results. 6'14,15 Reports of prior oral antibiotic therapy affecting children with bacterial meningitis have concentrated primarily on CSF parameters. 1"2,5'a'9,ll'13A9 Conflicting studies indicate that pretreat-
No. 45 13 10 9 8 4
% 46 13 11 9 8 4
No. 4 23 1 4 1 5
% 8 46 2 8 2 10
Febrile seizu@
3
3
2
4
Table 6.
Viral syndrome
2
2
2
4
Organisms responsiblefor meningitis
Cervical adenitis
1
1
0
Fever uncertain etiology
1
I
3
Facial cellulitis
1
1
O
Anemia
g
Pretreated Children (N - 83)
6
1
2
Nephrosis
0
1
2
Well baby
0
1
2
Congenital heart disease
0
1
2
O 97"
1 50
2
Otitis extema Total
ment either has no effect or is associated with a minimal decrease in CSF WBC counts in young children. 2'4-6"8'13'21 •
*None received antibiotics or took antibiotics if they were prescribed. tNo specified diagnosis noted in records or records unavailable. *Excluding otitis media and pharyngitis.
Organism H influenzae S pneumoniae Neisseria meningitides Group B Streptococcus Escherichia call Streptococcus fecaelis Pseudomonas aeruginosa Salmonella eeteridites
No. 70 11 0
% 84 13
Untreated Children (N = 175) No. 130 23 2
%
P
74
NS
13
NS
1
1
1
10
6
1 0
1
5 3
3 2
1 1
1 1
O O
{None of these patients had a lumbar puncture as part of the initial work-up. ~Total adds up to more than 83 because several patients were given mere then one diagnosis during their initial presentation and others were seen by more than one physician.
Table 7.
Extrameningeal infections* noted during hospitalization Table 5.
Pretreated Children (N = 83)
Comparison of laboratory features Laboratory Feature Serum WBCs (1,000 cells/mm 3 ± SD) CSF WBCs (1,000 cells/mm 3 ~ SD) Positive CSF Gram stain CSF glucose (g/dL ± SB) CSt: protein (mg/dL ± SD) Positive CSF culture
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Pretreated Children (N - 83)
Untreated Children (N = 175)
P
15.4 ± 9.2
13.3 ± 8.4
NS
4.5 _+ 9.0
6.1 ± 5.1
NS
26/64 {41%) 28.1 _+ 25 155 _+ 132 49/76 (65%)
92/134 (69%) 31.3 ± 31.7 182 -+ 140 129/148 (87%)
< .005 NS NS < .005
Infection Pneumonia Sinusitis Mastoiditis Intracranial abscess Urinary tract infection Cellulitis
No. 13 7 O 1 2 1
% 16 8 1 2 1
Untreated Children (N = 175) No, 17 13 7 4 1 2
% 10' 7 4 2 1 1 1
Bacterial infectious diarrhea
0
2
Septic arthritis
0
1
1
Pulmonary abscess
0
1
1
24
48
Total
"P
*Excluding otitis media and pharyngitis. *Percentage based on ratio ef patients with particular infection divided by the total number of patients with meningitis in each group.
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There is stronger evidence that preliminary oral antibiotics decrease the rate of positive CSF cultures and Gram stains in children with bacterial meningitis, s,8-n,la'14,19,22 This alteration of CSF parameters suggests that the differentiation of bacterial from viral meningitis may be more difficult in partially treated patients. However, studies detailing the laboratory diagnosis of meningitis are of little value when faced with the decision of whether to perform a lumbar puncture in a child after initiation of oral antibiotic therapy for an apparent minor illness. Our results suggest that children with partially treated meningitis have a more subtle presentation than untreated children. Although the duration of symptoms before diagnosis was longer in pretreated children, they exhibited significantly decreased rates of altered mental status and temperature of 38.3 C and above. Several explanations for a more subtle clinical presentation in pretreated children exist. The most obvious is that preliminary therapy has some effect on the infection. This argument is supported by studies that show decreased CSF WBC counts, culture rates, and Gram stains and increased CSF glucose and protein levels in pretreated patients, s'a-n'13J4'19,22 Certain oral antibiotics (eg, erythromycin) have poor CSF penetration, whereas others (eg, penicillin) have a poor effect against common infecting organisms (H influenzae).23-25 Doses of oral antibiotics that penetrate the blood-brain barrier usually result in CSF antibiotic concentrations that are below the minimal inhibitory concentration of most bacteria that cause meningitis. .9 There is another explanation for the altered or more subtle clinical presentation in pretreated patients. Patients with pretreated meningitis may have a less virulent strain of organism and thus are more often misdiagnosed and subsequently placed on antibiotics.3,26,27 All pretreated patients had at least one of the common signs and symptoms associated with meningitis: altered mental status, nuchal rigidity, fever, vomiting, focal neurologic abnormality, or Kernig's or Brudzinski's sign. It is possible that an important factor in the ultimate correct diagnosis of meningitis may have been the fact that these children had been seen recently by a physician and were not improving with the antibiotics that had been initiated. The less frequent temperature of 38.3 C and above in pretreated children might be related to the higher incidence of recent physician visits. It is possible that parents who had been given antibiotics for their child also were counseled on the methods of fever reduction, including appropriate antipyretic dosing.
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Unfortunately, ED charts and hospital records in almost all cases were not detailed in documenting the use of antipyretics and other fever-reducing measures by parents. ENT infections (ie, otitis media, pharyngitis, tonsillitis, and sinusitis) and vomiting were more common in pretreated than in untreated children. One possible explanation is that physicians who initially saw these patients were dissuaded from considering the diagnosis of meningitis when confronted with a likely somce (eg, otitis media and pharyngitis) of their symptoms. Methods used by clinicians to diagnosis ENT infections are not specific. Several studies have shown that otoscopic findings in patients diagnosed with otitis media (eg, tympanic membrane erythema, loss of light reflex, and retraction) are unreliable. 28-3° In our study-, no patient diagnosed with otitis media had documentation of pneumotoscopy, a test found to be much more reliable than direct otoscopy.3°'31 Because physicians used nonspecific criteria for diagnosis, it is not possible to verify that children actually had otitis media. Documentation of the presence of pharyngeal infections was also difficult because of reliance on the subjective impression of this finding. Even if the diagnosis of an ENT infection was correct in the majority of instances, physicians should be aware that such infections can occur concunently in children with meningitis. Upper and lower respiratory infections were the most common diagnoses in children seen in the week before detection of meningitis and in hospitalized patients. The most common bacteria that cause respiratory infections (H influeraae and S pneumoniae) are also the most frequent causes of bacterial meningitis. Our results differ from those of prior pediatric studies that have examined clinical features in patients with partially treated meningitis (Table 8). Winklestein examined the effect of preliminary antibiotic treatment on children with bacterial meningitis and concluded that only the duration of symptoms differed between pretreated and untreated patients. 15 However, his study was limited by an inadequate sample size (only 37 patients) and had a less than 50% power to detect a 25% difference between rates of clinical features in pretreated and untreated groups. In addition to being geographically isolated (Eskimos), his patient population may have included several patients with viral meningitis because all cases with CSF WBC counts of more than 100 mm 3 and with more than 50% neutrophils were enrolled. Two other studies that examined clinical features primarily in children also had several limitations.6"14 The numbers of patients were small, and the criteria used to define bacterial menin- 11~
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BACTERIAL M E N I N G I T I S Rothrock et al
gitis as well as patient ages were not included in either study. Statistical analyses were not performed in either study, although our interpretation of Singh et al's data revealed no significant difference in clinical features between pretreated and untreated patients. 14 Our interpretation of Harter's data revealed that untreated patients were more likely to be obtunded than were pretreated patients (41% vs 9%, P < .05 by Fisher's exact test). 6 Two prior adult studies with mean patient ages of more than 20 years found that symptom duration was longer in pretreated patients and that other signs and symptoms did not differ between groups, a2'a3 It is doubtful that data obtained from adult studies are applicable to our population. Our population, unlike that in other pediatric studies, ineluded no children more than 24 months old. Eighteen to 24 months is often cited as the age range below which meningeal signs become less reliable and nonspeeifie signs and symptoms (eg, inconsola-
TABLE 8.
Comparison with prior pediatric studies Current Study (1991)
Hatter 6 (1963)
Singh el aP 4 (1980)
Winklestein TM (1970)
258
70
104
37
Mean age
0.75
ND*
ND*
0.63*
(range) (yr)
(g - 2)
ND*
32
49
A, B, C, or Og
ND*
Study Feature Total no. of patients
Receiving
(0
12)
ND
53
57
"Turbid CSF plus
A, B, or E~
antibiotics (%) Criteria for diagnosis
PMN leukocytosis"
of bacterial meningitis NS1t
NS2*
Pretreated
Clinical features
Pretreated
that differed
group had
group had longer
between treated
longer symptom
symptom duration
and untreated
duration, more
groups
vomiting, lower temperatures, and more ENT infections
More than 80%
Yes
No
No
No
University
Military
Medical
Indian health
medical center,
hospital,
college,
service,
California
Texas
India
Alaska
power to detect
25% difference between groups Population
*ND, not documented in article although studies included "children" only; reported as median, not as a mean. *NSt, no statistical comparisons made by authors; however, on our examination of their data, patients who had received no antecedent therapy were more obtunded than were pretreated patients (14 of 3B vs three of 34, P < .05 by Fisher's exact test). *NS2, no statistical comparisons made; however, on our analysis of their results, no statistically significant difference was found between groups. ~A, culture; B, Gram stain; C, CSF antigenic test; D, positive blood culture with CSF pleecytesis; E, CSF WBC of more than 100/mL plus more than 50% neutrophils or CSh glucose of less than 40.
5 6 / 1 51
bility, feeding, and eye contact) become more important in making the diagnosis of meningitis, t8'34'35 Thus, knowledge of any factor, such as preliminary antibiotic therapy, that can alter these nonspecific signs and symptoms can be important. Because signs and symptoms of meningitis differ between age groups, any study that groups children less than and more than 24 months old into the same category might also yield conflicting or inaccurate data. Criteria used to identify eases of bacterial meningitis in our study were also more strict than those used in prior studies. We included only patients with proven bacterial meningitis by culture, antigen study, or Gram stain. We purposely kept diagnostic •criteria strict to avoid including cases of viral meningitis that might have had different presenting clinical features than cases of bacterial meningitis. There are several limitations to our study. Because data collection was retrospective, not all signs and symptoms were documented uniformly. For significant features, however, rates of documentation of the presence or absence of each feature were all 91% or higher. The retrospective nature of our study made it impossible to assess whether nondoeumented features were present. We believe that absent features were less likely to be recorded. This assumption potentially underestimates the incidence of all features. However, in our opinion, the alternative method of calculating the incidence of clinical features by dividing the number with documented present features by the number doeumented as present or absent overestimates the incidence. This method also assumes that nondoeumented features occur at a similar incidence to documented features. Another problem with retrospective data collection was the necessity of relying on potentially inexact historical and physical features. An example was the historical presence of fever in study patients. The authors attempted to document whether the earegiver felt that the child had an elevated temperature before presentation. In almost all eases, however, the exact level and site (rectal vs axillary vs oral) of elevated temperatures were not documented. Thus, this factor was potentially inaccurate because it was based on both the subjective impression of fever by the caregiver and the documentation of the history taker. A final factor to be considered in analyzing our results is the patient population. The study hospital is a tertiary referral center for children and has a pediatric ICU and all pediatric subspeciahies. Thus, the number of more difficult or advanced eases of baeterial meningitis might be higher than in other settings. It is uneertain what effeet this factor might have on study results.
•
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Rothrock et al
CONCLUSION A retrospective study was performed to compare clinical features in children 24 months old or younger who were treated with antibiotics before the detection of meningitis with features of children who received no prior antibiotic therapy. Children pretreated with antibiotics had a longer duration of symptoms before diagnosis and were less likely to have a temperature of 38.3 C and above and an altered mental status. Pretreated children also had more frequent vomiting and ENT infections than untreated patients. Because of the retrospective nature of this study, we cannot state that preliminary antibiotics are the cause of this difference in signs and symptoms. However, these results indicate that prior antibiotic therapy is associated with an altered clinical presentation of meningitis in children 24 months old or younger. Physicians should be aware of this altered clinical presentation and maintain a high index of suspicion in evaluating children who have already been started on antibiotic therapy for seemingly minor illnesses.
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Address for reprints: Steven G Rothrock, MD, Department of Emergency Medicine, Loma Linda University Medical Center, 11234 Andersen Street, Loma Linda, California 92350.
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