542
April 1976 TheJournalofPEDIATRICS
Prospective evaluation of treatment of Hemophilus influenzae meningitis Eifty children with Hemophilus influenzae meningitis have been enrolled in a prospective study. Patients were randomly assigned chloramphenicol or ampicillin treatment; there were no significant differences between groups in other respects. Countercurrent immunoeleetrophoresis proved to be a valuable tool for rapid diagnosis of the causative agent even in pretreated patients. Increasing quantities of capsular polyribosephosphate antigen detected in the initial cerebro~pincdfluid correlated significantly (r = 0.62419; p < O.01) with early and late sequelae of meningitis. None of the patients died. Severe and persistent neurologic or intellectual deficits were noted in four (8%) of the children, and an additional 14 (28%) had IQ scores between 70 and 90. The presence of bactericidal antibody in serum was not protective. Anti-PRP antibody generally was not present in acute serum specimens and irrespective of the quantity of antigenic stimulus provided by the disease was nondetectable in 21 of 24 children less than 17 months of age following recovery.
Ralph D. Feigin, M.D.,* Barbara W. Stechenberg, M.D., Margan J. Chang, M.D., Lisa M. Dunkle, M.D., Michael L. Wong, M.D., Helen Palkes, B.S., Phillip R. Dodge, M.D., and Hallowell Davis, M.D., St. Louis, Mo.
ALTHOUGH ANTIBIOTIC THERAPY has reduced the mortality rate, as many as 50% of the survivors of meningitis due to Hemophilus influenzae have some sequelae of their disease. 1-~ The studies from which these estimates of sequelae were derived have been retrospective; the patients who were evaluated had meningitis between 1951 and 1968.1-3 Although antibiotic treatment From the Edward Mallinckrodt Department of Pediatrics and the Department of Neurology, Washington University School of Medicine, and the Divisions of Infectious Diseases, Psychology and Neurology at St. Louis Children's Hospital. These studies were initiated with the aid of a grant from the Parke-Davis Company and recently have been supported by Grant No. 1RO1NSA112284 from the National Institutes of Neurological Diseases and Stroke. Dr. Feigin is the recipient of a Research Career Development A ward No. 1KO4A146206from the National Institutes of Allergy and Infectious Diseases. *Reprint address': Department of Pediatrics, St. Louis Children's Hospital, 500 S. Kingshighway, St, Louis, Mo. 63110.
Vol. 88, No. 4, part 1, pp. 542-548
of these individuals may have been relatively standardized during this period of time, ancillary methods employed in their care were not controlled. Eighteen months ago we instituted a prospective evaluation of children (one month to 15 years of age) with all types of bacterial meningitis. This report describes our initial findings in the first 50 children with H. influenzae meningitis who were enrolled in the study protocol.
See related articles, pp. 549 to 557 and 706. Abbreviations used PRP: polyribosephosphate CSF: cerebrospinal fluid CIE: counterimmunoelectrophoresis ADH: antidiuretic hormone MATERIALS
AND METHODS
Initial patient selection and evaluation. All patients with a history and physical examination suggestive of bacterial meningitis and in whom the initial CSF revealed findings
Volume 88 Number 4, part I
compatible with this diagnosis were enrolled in the study protocol The severity of the patient's illness was assessed utilizing the following criteria: (1) duration of illness as well as height and duration of fever prior to hospitalization; (2) level of consciousness; (3) presence or absence of seizure activity; (4) presence or absence of focal signs at the time of admission; (5) initial recordings of vital signs; and (6) results of chemical, morphologic, cultural, and immunologic evaluation of CSF obtained at the time of initial lumbar puncture. The following pertinent information also was sought and recorded: (1) antibiotic therapy including type, dose, and duration that was received during the week prior to admission; and (2) the status of the patient prior to development of meningitis including information relevant to developmental milestones, speech, hearing, vision, behavioral characteristics, and evidence of previous neurologic deficits. At the time of admission a complete physical and neurologic examination was performed and the precise duration of each sign and symptom of meningitis prior to admission was recorded. Head circumference was measured and transillumination of t h e head was performed. Initial laboratory evaluation. In addition to the usual morphologic and chemical determinations, CSF was cultured and CIE was performed. Blood was examined for white blood cell count and differential count, hemoglobin, hematocrit, and glucose, osmolality, sodium, potassium, chloride, carbon dioxide, and blood urea nitrogen concentrations. A blood culture was obtained and CIE for bacterial antigens was performed. Urine was obtained for determination of sodium, potassium, and osmolality. The nasopharynx and throat were cultured routinely. Treatment and subsequent evaluation in hospital. The choice of therapy was determined randomly from a sealed envelope in which the regimen to be employed was specified. Patients in group 1 received ampicillin at 300 mg/kg/24 hours in 6 divided doses intravenously for a period of 10 days, or longer if prolonged therapy was dictated by the course of the patient; those in group 2 received chloramphenicol at 100 mg/kg/24 hours in 4 divided doses intravenously for 10 days. Group 2 patients also received aequeous penicillin G at 10 million units/ mV24 hours in 6 divided doses. PeniciIlin was discontinued at the time H. influenzae was identified as the causative agent, usually within 12 hours. Generally, a multiple electrolyte solution was administered at a rate of 800-1,000 ml/m2/24 hours. Anticonvulsants were administered to those patients who had seizures prior to admittance or in hospital; they were not given to other children prophylactically. Vital signs were recorded every 15 minutes until stable;
Evaluation of H. influenzae treatment
54 3
and then hourly for another 72 hours, or longer if the status of the patient demanded it, and then every 4 hours until discharge. From this information, a fever index was computed according to the method of Fekety and McDaniel. 6 In an attempt to monitor the presence and severity of inappropriate secretion of antidiuretic hormone, body weight, serum electrolytes, and serum and urine osmolalities were determined at least daily. Urine was obtained sequentially, and careful measurements were made of volume, specific gravity, and electrolytes. Head circumference, transillumination, and a detailed neurologic evaluation were performed daily. The presence and quantity of H. influenzae antigen was also determined in blood and urine. In all patients CSF was evaluated as recorded above 48 hours after discontinuation of antibiotic treatment. Following discharge a detailed neurologic examination was performed at one, three, six, and 12 months utilizing a standardized form developed for the purposes of this study, Evoked response audiometry was performed at the Central Institute for the Deaf under the supervisior~ of one of us (H. D.). Detailed psychometric evaluation of each patient was made in our psychometric laboratory at the time of discharge and repeated after one year. Special laboratory methods. The presence and concentrations of H. influenzae type b capsular antigen was determined by CIE utilizing methods described previously.7-~ Bactericidal antibody to H. influenzae type b was determined according to the method of Fothergill and Wright 1~as previously modified? Assays were performed utilizing a standard strain of H. influenzae type b and the organism isolated from the patient, Anti-PRP H. influenzae antibody was determined (by Dr. Robert Baker, Indianapolis) using a double label modification" of the radioantigen binding technique of Farr? ~ Statistical analysis. Statistical analysis of the data was performed by Dr. Sung Choi of Washington University School of Medicine. When appropriate, techniques included analysis of variance on log-transformed data, multiple range tests, and correlation coefficients. RESULTS There were more males than females in our series (62% compared to 38%), but the difference was not significant by chi square. No significant differences were noted between the recipients of chloramphenicol or ampicillin in severity of disease as determined by comparisons of CSF data, days of illness, height and duration of fever prior to admission, levels of consciousness, focal neurologic signs or seizures, or the number who received antibiotic treatment prior to
544
Feigin et al.
The Journal of Pediatrics April 1976
Table I. Additional clinical and laboratory data
Number of patients Cerebrospinal fluid Positive culture-No. (%) Positive Gram stain-No. (%) *Positive CIE No. (%) Quantity of antigen present (ug/mI) Mean +_ I SD Median Range Subdural effusion-No. (%) tPositive transillumination Subdural fluid tapped Subdural fluid by tap or scan Seizure in hospital-No. (%) Fever (days) Mean + 1 SD Median Range Fever index (degree fever hr) Mean _+ 1 SD Median Range
I
Total group
.
Therapy with arnpicillin
50
28
22
46 (92) 42 (84) 37 (74)
26 (92s 21 (75) 22 (78.5)
20 (90.9) 16 (72.7) 20 (90.9)
1.60 _+ 2.65 0.32 0-10.24
1.76 +_ 2.90 0.32 0-10.24
1.41 _+ 2.37 0.32 0-10.24
16 (32) 4 (8) 6 (12) 11 (22)
9 (32.1) 3 (10.7) 5 (17.9) 5 (17.9)
7 (31.8) 1 (4.5) 1 (4.5) 6 (27.2)
3.04 +__2.6 2 0.2-9 18.88 _+ 20.4 15 0.8-94
3.06 + 2.9 2 0.25-8 21.28 _+ 12.34 12.4 1.4-94
I
Therapy with chloramphenicol
3.0 +_ 2.14 2 0.2-9 15.82 _+ 13.87 17.0 0.8-59.5
*CIE--antigenpresent by countercurrentimmunoelectrophoresis. tPositive transilluminationin patients with bacterial meningitishas been shown to correlate with subdural effusions?False positives can be obtained in the presence of tissue fluid in the scalp from an infiltratedintravenousinfusion; these were not used in our patients.
admission. Focal neurologic signs were noted in 10%, and seizures prior to admission in 24% of patients. Blood cultures were positive in 41 (82%), whereas antigen was detectable by CIE in the blood of 25 (50%) at the time of admission; in 37 (74%) patients, CSF and blood cultures were both positive. In five (10%) patients, the diagnosis of H. influenzae meningitis could have been made only by culture since CIE and Gram stains were negative. In three children diagnosis could be established only by CIE, since Gram stain and cultures of the CSF and blood were negative. Although 18 (36%) children had received some antibiotic treatment prior to admission, definitive diagnosis was possible in all patients by the performance of Gram stains, cultures of CSF and blood, and CIE of CSF and blood. No significant differences were noted between patients treated with ampicillin and chloramphenicol with regard to the percentage with positive CSF cultures or Gram stains or to the presence and quantity of CSF antigen (Table I). Pretreatment had no significant effect upon the nu tuber of white blood cells, the percentage of polymorphonuclear leukocytes, the concentration of glucose, or the quantity of antigen in the CSF. Although pretreated patients had negative cultures more frequently than untreated patients, the differences were not statistically significant. Throat and nasopharyn-
geal cultures were not of value in establishing the etiology of generalized sepsis or meningitis in patients with negative blood or CSF cultures. At the time of admission, serum concentrations of sodium were below 135 mEq/1 in 27 (54%) patients; the range was 117 to 140 mEq/1; the m e a n was 133 +_ 4.2 mEq/1 _ 1SD. On the fluid restricted regimen employed serum sodium concentrations generally reached levels of 135 mEq/1 or above during the first two days of hospitalization. There was no correlation of the depression in serum sodium concentration at the time of admission with the duration or severity of illness prior to admission. The initial (white blood cell count) generally was above normal. Depressions in the initial peripheral white blood cell count heralded more severe disease; depressed counts correlated significantly (p < 0.05) with prolonged fever in hospital and with the a m o u n t of antigen (p < 0.01) in the CSF. No significant differences between groups were noted in the incidence of subdural effusions or seizures in hospital or in the duration or height of fever (Table I). Prior to or subsequent to hospitalization, 29.8% of all children had"seizures, b u t none of them had seizures after the first 72 hours in hospital. Cerebrospinal fluid obtained 48 hours after therapy
Volume 88 Number 4, part 1
was discontinued showed no organisms on Gram stain or by culture, and no antigen by CIE in 49 of the 50 patients. Bacteriologic relapse occurred in one ampicillin-treated patient whose H. influenzae isolate was sensitive by tube dilution to < 0.1 ug/ml of this drug. Chloramphenicol treatment was initiated; the patient recovered but has a residual hearing deficit that is not of clinical importance. There were no differences between groups in the morphologic or chemical characteristics of the CSF obtained at the conclusion of therapy. The total white blood cell count and percentage of polymorphonuclear leukocytes were not normal, however, in the final CSF specimens; mean +_ 1 SD values of 61 + 14 and 6 + 12 respectively, were noted. Similarly, the CSF protein and glucose concentrations were not always normal; mean values were 46 +_ 49 mg/dl and 46 _+ 11 mg/dl, respectively. The CSF glucose was below 40 mg/dI at the time of discharge in t5 patients, but the CSF:blood glucose ratio was less than 40% in only two patients. At the time of discharge, neurologic or audiometric examinations were abnormal on 2t children (42%): 12 were recipients of ampicillin and nine of chloramphenicol. Subsequently, some neurologic or audiometric abnormality was noted in 17 of 45 children (37.8%) at one month, in nine of 35 children (25.7%) at three months, in four of 32 children (12.5%) at six months, and in one of 20 children (5%) at one year. These data reflect the tendency for minor and even some major neurologic deficits in patients following meningitis to disappear with time. The decreasing numbers of children seen at each follow-up visit does not reflect a failure of parents to return for the study. Only one of the initial 50 patients with H. influenzae meningitis did not return for repeated examinations. The early and late or permanent sequelae of meningitis which were detected in the 50 children included in this report are recorded in Table II. Overall, significant neurologic including intellectual deficits have persisted in four (8%) of the 50 children. There was a positive correlation (r = 0.62419; p < 0.01) of the quantity of antigen in the initial CSF with the development of early and permanent sequelae. In patients who had no sequelae (early or late), 0.82 _+ 1.88 ug/ml (mean _+ lSD) PRP was found in the initial CSF specimen. In contrast, 3.38 _+ 3.60 /~g/ml (mean + 1 SD) PRP antigen was present initially in the CSF of children who had early or late neurologic or intellectual deficits. These differences are highly significant (p < 0.01). Antigenemia was detected in most patients for two days and in several individuals for eight days. Antigenuria persisted in most patients for at least four days, and in one patient for 68 days. Prolonged
Evaluation of H. influenzae treatment
$45
Table II. Sequelae of Hemophilus influenzae meningitis
Total group Number of patients 50 Deaths 0 Ataxia Early 2 Persistent 1 Hemi- or quadriparesis Early 8 Persistent 2 Hearing deficit 3 Evoked response 3 Clinically 1* significant Blindness I* Subdural effusion Early 16 Longer than 3 0 months Intelligence quotient Mean 4-_ 1 SD 94 + 20 Range 30-150 Intelligence quotient Below 70 3t Below 80 7t IQ Below 90 17 Developmental 25 < chronological age
Therapy with ampiciltin
Therapy with ehloramphenicot
28 0
22 0
0 0
2 1
5 1 2 2 1
3 1 1 1 0
I
0
9 0
7 0
96 _+ 17 75-150
91 +- 23 30-129
2 3 9 15
1 4 8 10
*One patientwas blind,deaf, and had spasticquadriparesis. tThese includetwo of the same patientsrecorded under persistenthemior quadriparesis.
antigenemia and antigenuria correlated significantly (p < 0.01) with prolonged fever and with sequelae of meningitis, Bactericidal antibody could be detected at the time of admission (mean bactericidal antibody titer 3.58 x 10~) in 92.3% of the patients. In 80% of children who had bactericidal antibody present on admission, no increase in antibody titer was detected in a convalescent specimen obtained two to six weeks later. Anti-PRP antibody responses in 36 children are shown in Table III where they are compared to the ages of the patients and to the quantity of PRP antigen to which they were naturally exposed by their disease. It is apparent that with rare exception, children 17 months of age or less do not develop anti-PRP antibody during convalescence, irrespective of the quantity of the antigenic stimulus. A correlation matrix was prepared utilizing 88 variables representing clinical and laboratory data of the patients. Focal neurologic signs present at the time of admission
546
Feigin et al.
The Journal of Pediatrics April 1976
Table IlL Development of anti-PRP antibody in relation to age of patient Antigen (PRP) (t~g/ml) CSF No. of patients
Age range (mo)
25
1-19 Median 7.5 21-54 Median 28
11
N*
N~f
25
21
9
9
Mean + 1 SD (range)
1.38 + 2.20 (0-10.24) 2.37 + 4.46 (0-10.24)
Anti-PRP antibody (ng/ml)
Blood
N*
Nt
23
12
11
6
Convalescent
A cute
Mean +_ 1 S D (range)
0.11 _+ 0.19 (0-0.64) 0.01 + 0.01 (0-0.04)
N*
Nt
25
0
11
5
Mean +_ 1 SD (range)
0 _+ 0 (0) 449 _+ 628 (0-1585)
N*
N~(
24
3
11
8
Mean + 1SD (range)
12 +_ 45 (0-223) 654 _+ 829 (0-2575)
*Number of patients tested. tNumber of patients with detectableantigen or antibody.
correlated significantly and were strongly predictive of a neurologic abnormality at examination one, three, and six months following discharge (r = 0.69282, p < 0.01). Similarly, focal signs present at admission correlated significantly with low intellectual achievement following discharge (r = 0.55680; p < 0.001). Prolonged depression in serum sodium concentration as a reflection of inappropriate A D H secretion also correlated significantly with the presence of neurologic abnormalities at one month following discharge (r = 0.34524; p < 0.05). DISCUSSION In 1972 we reported the results of a retrospective comparison of ampieil!in and chloramphenicol therapy for H. influenzae meningitis. 1~ Bacteriologic relapse was noted in 4.4% of ampicillin recipients, whereas relapse was not observed in patients treated with chloramphenicol. No significant differences were observed in the prospective study reported here between treatment groups in respect to early or late sequelae of the disease ~,however, a longer follow-up period will be required to exclude differences in intellectual capability or in school performance; In contrast to the results of our retrospective study, 13 fever was not of greater magnitude or significantly prolonged in ampicillin recipients. One of 28 (3.6%) patients treated with ampicillin experienced a bacteriologic relapse, a rate similar to that reported on the basis of retrospective data. 13 Inappropriate secretion of antidiuretic hormone was suggested by the laboratory data obtained in 88% of the patients studied. In our experience, inappropriate secretion of A D H in children with acute bacterial meningitis is more the rule than the exception and is best avoided by careful monitoring of fluid administration. Possible adverse effects of this metabolic problem are highlighted by our findings that prolonged depression in serum
sodium correlated significantly with the presence of neurologic abnormality one month following discharge from the hospital. Swartz and Dodge, TM Dodge and Porter, 1~ and ShurtlefP 6 documented that subdural collections of fluid could be demonstrated by the technique of transillumination, and Dodge and Swartz 3 noted that transillumination was more consistently useful in their diagnosis than was fever, irritability, vomiting, seizures, fullness of the fontanelle, or enlarging head circumference (symptoms and signs generally used as indications for a subdural tap ). Observations in the present study support these earlier observations. We are unable to find a previous report in which subdural effusions were routinely sought by daily transillumination; however, the incidence of subdural effusions detected by this method in our patients (32%) is in accord with prior observations) Subdural paracentesis was used only to curtail vomiting or other symptoms of increased intracranial pressure. None of the patients required more than one subdural tap and most (92%) had none. Persistent subdural effusion (beyond three months) was not observed in any patient, thus confirming the suggestion ~ that repeated subdural taps are unnecessary and that the effusion will clear with time. Although seizures occurred in 29.8% of the children either prior to admission or during the first 72 hours of hospitalization, no children have been identified as having a permanent seizure disorder referable to their meningitis; three children remain on anticonvulsant therapy which was initiated during their hospitalization. These data support the concept that seizures which occur early in the course of disease generally are manifestations of an acute derangement in function of the cerebral cortex and have no prognostic significance unless they are persistent or difficult to control. Sell and associates1 in a retrospective study of H.
Volume 88 Number 4, part I
influenzae meningitis reported that 11 of 86 children died and that 29% of the survivors had severe or significant handicaps. Included in the group classified as severely handicapped were those whose IQ was 70 or less. Utilizing similar criteria, only 8% of our patients presently have significant or severe handicaps, and none o f our patients died. Sell and associates I also noted that 14% of survivors had possible residual abnormalities; included in this group were children who scored 70 to 80 o n intelligence tests. In addition, postmeningitic children functioned at significantly lower levels than did their age-matched peers? 7 We strongly suspect on the basis of our preliminary psychometric data and that of Sell's group" that minor residual deficits may be a major concomitant of H. influenzae meningitis. In 1969, on the basis of our observations, we suggested that it might be prudent to question the concept that bactericidal antibody was the only factor important for protection of the h u m a n host against H. influenzae infection in vivo? N o r d e n TM subsequently concurred that bactericidal activity may not be important in protection against H. influenzae infection in some cases. In the present study, most children had bactericidal antibody against H. influenzae type b at th e time of admission, and this activity did not prevent their disease. These data provide evidence in m a n which support the findings of Smith and associates 1~ who found no relation between bactericidal activity and the development of H. influenzae bacteremia and meningitis in the experimental animal. In contrast, anti-PRP antibody generally was nondetectable in the serum of our children at the time of admission. In five cases, anti-PRP antibody was found in the initial specimen but all of these children were 21 months of age or older. It has been shown that anti-PRP H. influenzae antibody can be induced by the use of crossreacting bacteria and that natural or artificially induced colonization of m a n by such bacteria may prime cells which will produce anti-PRP H. influenzae antibody when the host is exposed to H. influenzae. 2.... It is possible that the anti-PRP antibody detected shortly after admission in the serum of five of our children reflects an anamnestic response, as might be expected in older children whose antibody-producing cells have been primed by previous exposure to cross-reacting antigens. Only three of 24 children who were 17 months of age or younger developed anti-PRP antibody during convalescence, irrespective of the antigenic stimulus to which they were naturally exposed. It has been estimated that a serum level of anti-PRP H. influenzae type b antibody of at least 60 to 100 n g / m l would be required to prevent systemic infection in man. 21 Using these estimates, only one or two of the children under 19 months of age would
Evaluation of H. influenzae treatment
547
have been protected following their recovery from H. influenzae meningitis. These data are similar to reports concerning the development of anti-PRP antibody following immunization of children with 11. influenzae vaccine? 1,23 These antigen-antibody relationships described for naturally acquired infections serve to heighten our concern regarding the possibility of protecting children in the first year of life from H. influenzae infection by artificial immunization. The authors express their appreciation to the part-time clinical faculty who permitted us to enroll their patients in this study and to the housestaff without whose help the study could not have been performed. We thank Drs. Donald Anderson, Larry Pickering, and David Van Reken, former fellows in pediatric infectious diseases for their assistance. We also appreciate the assistance of our senior pediatric neurology colleagues and single out for special thanks Dr. Ed Dodson, Jay Pettegrew, Mary OlsonJohnson, John Manica, Robert Greenwood, William Farris, Elias Chalhub, ~indRoger Brumback who in their capacity as pediatric neurology fellows gave generously of their time. We also thank Mrs. Ira Hirsch who graciously performed and provided detailed evaluation of evoked response audiometry data. We thank Mrs. Judy Wilson and Mr. Joel Campbell for technical assistance and Ms. Judy Rodgers for help in the preparation of the manuscript. REFERENCES
1. Sell SHW, Merrill RE, Doyne EO, and Zinsky EP Jr: Longterm sequelae of Hemophilus influenzae meningitis, Pediatrics 49:206, 1972. 2. Sproles ET III, Azerrad J, Williamson C, and Merrill RE: Meningitis due to Hemophilus influenzae: Long term sequelae, J PEDIATR75:782, 1969. 3. Dodge PR, and Swartz MN: Bacterial meningitis. A review of selected aspects II. Special neurologic problems, postmeningitis complications and clinicopathological correlations, N Engl J Med 272:1003, 1965. 4. Turk DC, and May RJ: Hemophilus influenzae: Its clinical importance, London, 1965, University Press Ltd. p 27. 5. Feigin RD, Richmond D, Hosler MW, and Shackelford PG: Reassessment of the role of bactericidal antibody in Hemophilus influenzae infection, Am J Med Sci 262:338, 1971. 6. Fekety FR Jr, and McDaniel E: The fever index in evaluation of the course of infectious diseases; with special reference to pneumococcal pneumonia, Yale J Biol Med 41:282, 1968. 7. Shacketford PG, Campbell J, and Feigin RD: Countercurrent immunoetectrophoresis in the evaluation of childhood infections, J PEDIAXR85:478, 1974. 8. Ingram DL, Anderson P, and Smith DH: Countercurre~t immunoelectrophoresis in the diagnosis of systemic diseases caused by Hemophilus influenzae, type b, J P~DIATR 81:1156, 1972. 9. Coonrod JJ, and Rytel MW: Detection of type-s.pecific pneumococcal antigens by counterimmunoelectrophoresis. I. Methodology and immunologic properties of pneumococcal antigen, J Lab Clin Med 81:770, 1973. 10. Fothergill LD, and Wright J: Influenzal meningitis: the
54 8
11.
12.
13.
14.
15. 16. 17.
18.
Feigin et al,
relation of age incidence to the bactericidal power of blood against the causal organism, J Immunol 24:273, 1933. Gotschlich EC: A simple modification of the radioactive antigen-binding test by a double label technique, J Immunol 107:910, 1971. Farr RS: A quantitative immunochemical measure of the primary interaction between IBSA and antibody, J Infect Dis 103:239, 1958. Shackelford PG, Bobinski JE, Feigin RD, and Cherry JD: Therapy of Hemophilus influenzae reconsidered, N Engl J Med 287:634, 1972. Swartz MN, and Dodge PR: Bacterial meningitis--A review of selected aspects. I. General clinical features, special problems and unusual meningeal reactions mimicking bacterial meningitis, N Engt J Med 272:779, 1965. Dodge PR, and Porter P : Demonstration of intracranial pathology by transillumination, Arch Neurol 5:594, 1961. Shurtleff D: Transillumination of the skull of infants and children, Am J Dis Child 107:14, 1964. Sell SHW, Webb WW, Pate JE, and Doyne EO: Psychological sequelae to bacterial meningitis: Two controlled studies, Pediatrics 49:2t2, 1972. Norden CW: Prevalence of bactericidal antibodies to
The Journal of Pediatrics April 1976
19.
20.
21.
22.
23.
Haemophilus influenzae, type b, J Infect Dis 130:489, 1974. Smith AL, Smith DH, Averill DR Jr, Marino J, and Moxon ER: Production of Haemophilus influenzae b meningitis in infant rats by intraperitoneal inoculation, Infect Immun 8:278, 1973. Myerowitz RL, Handzel ZT, Schneerson R, and Robbins JB: Induction of Haemophilus influenzae type B capsular antibody in neonatal rabbits by gastrointestinal colonization with cross-reacting Escherichia coli, Infect Immun 7:137, 1973. Robbins JB, Parke JC Jr, Schneerson R, and Whisnant JK: Quantitative measurement of "natural" and immunizationinduced Haemophilus influenzae type b capsular polysaccharide antibodies, Pediatr Res 7:103, 1973. Schneerson R, and Robbins JB: Induction of serum Haemophilus influenzae type B capsular antibodies in adult volunteers fed cross-reacting Escherichia coli 075:K100:H5, N Engl J Med 292:1093, 1975. Smith DH, Peter G, Ingram DL, Harding AL, and Anderson P: Responses of children immunized with the capsular polysaccharide of Hemophilus influenzae, Pediatrics 52:637, 1973.
April 1976 TheJournalofPEDIATRICS
Prospective evaluation of treatment of Hemophilus influenzae meningitis Eifty children with Hemophilus influenzae meningitis have been enrolled in a prospective study. Patients were randomly assigned chloramphenicol or ampicillin treatment; there were no significant differences between groups in other respects. Countercurrent immunoeleetrophoresis proved to be a valuable tool for rapid diagnosis of the causative agent even in pretreated patients. Increasing quantities of capsular polyribosephosphate antigen detected in the initial cerebro~pincdfluid correlated significantly (r = 0.62419; p < O.01) with early and late sequelae of meningitis. None of the patients died. Severe and persistent neurologic or intellectual deficits were noted in four (8%) of the children, and an additional 14 (28%) had IQ scores between 70 and 90. The presence of bactericidal antibody in serum was not protective. Anti-PRP antibody generally was not present in acute serum specimens and irrespective of the quantity of antigenic stimulus provided by the disease was nondetectable in 21 of 24 children less than 17 months of age following recovery.
Ralph D. Feigin, M.D.,* Barbara W. Stechenberg, M.D., Margan J. Chang, M.D., Lisa M. Dunkle, M.D., Michael L. Wong, M.D., Helen Palkes, B.S., Phillip R. Dodge, M.D., and Hallowell Davis, M.D., St. Louis, Mo.
ALTHOUGH ANTIBIOTIC THERAPY has reduced the mortality rate, as many as 50% of the survivors of meningitis due to Hemophilus influenzae have some sequelae of their disease. 1-~ The studies from which these estimates of sequelae were derived have been retrospective; the patients who were evaluated had meningitis between 1951 and 1968.1-3 Although antibiotic treatment From the Edward Mallinckrodt Department of Pediatrics and the Department of Neurology, Washington University School of Medicine, and the Divisions of Infectious Diseases, Psychology and Neurology at St. Louis Children's Hospital. These studies were initiated with the aid of a grant from the Parke-Davis Company and recently have been supported by Grant No. 1RO1NSA112284 from the National Institutes of Neurological Diseases and Stroke. Dr. Feigin is the recipient of a Research Career Development A ward No. 1KO4A146206from the National Institutes of Allergy and Infectious Diseases. *Reprint address': Department of Pediatrics, St. Louis Children's Hospital, 500 S. Kingshighway, St, Louis, Mo. 63110.
Vol. 88, No. 4, part 1, pp. 542-548
of these individuals may have been relatively standardized during this period of time, ancillary methods employed in their care were not controlled. Eighteen months ago we instituted a prospective evaluation of children (one month to 15 years of age) with all types of bacterial meningitis. This report describes our initial findings in the first 50 children with H. influenzae meningitis who were enrolled in the study protocol.
See related articles, pp. 549 to 557 and 706. Abbreviations used PRP: polyribosephosphate CSF: cerebrospinal fluid CIE: counterimmunoelectrophoresis ADH: antidiuretic hormone MATERIALS
AND METHODS
Initial patient selection and evaluation. All patients with a history and physical examination suggestive of bacterial meningitis and in whom the initial CSF revealed findings
Volume 88 Number 4, part I
compatible with this diagnosis were enrolled in the study protocol The severity of the patient's illness was assessed utilizing the following criteria: (1) duration of illness as well as height and duration of fever prior to hospitalization; (2) level of consciousness; (3) presence or absence of seizure activity; (4) presence or absence of focal signs at the time of admission; (5) initial recordings of vital signs; and (6) results of chemical, morphologic, cultural, and immunologic evaluation of CSF obtained at the time of initial lumbar puncture. The following pertinent information also was sought and recorded: (1) antibiotic therapy including type, dose, and duration that was received during the week prior to admission; and (2) the status of the patient prior to development of meningitis including information relevant to developmental milestones, speech, hearing, vision, behavioral characteristics, and evidence of previous neurologic deficits. At the time of admission a complete physical and neurologic examination was performed and the precise duration of each sign and symptom of meningitis prior to admission was recorded. Head circumference was measured and transillumination of t h e head was performed. Initial laboratory evaluation. In addition to the usual morphologic and chemical determinations, CSF was cultured and CIE was performed. Blood was examined for white blood cell count and differential count, hemoglobin, hematocrit, and glucose, osmolality, sodium, potassium, chloride, carbon dioxide, and blood urea nitrogen concentrations. A blood culture was obtained and CIE for bacterial antigens was performed. Urine was obtained for determination of sodium, potassium, and osmolality. The nasopharynx and throat were cultured routinely. Treatment and subsequent evaluation in hospital. The choice of therapy was determined randomly from a sealed envelope in which the regimen to be employed was specified. Patients in group 1 received ampicillin at 300 mg/kg/24 hours in 6 divided doses intravenously for a period of 10 days, or longer if prolonged therapy was dictated by the course of the patient; those in group 2 received chloramphenicol at 100 mg/kg/24 hours in 4 divided doses intravenously for 10 days. Group 2 patients also received aequeous penicillin G at 10 million units/ mV24 hours in 6 divided doses. PeniciIlin was discontinued at the time H. influenzae was identified as the causative agent, usually within 12 hours. Generally, a multiple electrolyte solution was administered at a rate of 800-1,000 ml/m2/24 hours. Anticonvulsants were administered to those patients who had seizures prior to admittance or in hospital; they were not given to other children prophylactically. Vital signs were recorded every 15 minutes until stable;
Evaluation of H. influenzae treatment
54 3
and then hourly for another 72 hours, or longer if the status of the patient demanded it, and then every 4 hours until discharge. From this information, a fever index was computed according to the method of Fekety and McDaniel. 6 In an attempt to monitor the presence and severity of inappropriate secretion of antidiuretic hormone, body weight, serum electrolytes, and serum and urine osmolalities were determined at least daily. Urine was obtained sequentially, and careful measurements were made of volume, specific gravity, and electrolytes. Head circumference, transillumination, and a detailed neurologic evaluation were performed daily. The presence and quantity of H. influenzae antigen was also determined in blood and urine. In all patients CSF was evaluated as recorded above 48 hours after discontinuation of antibiotic treatment. Following discharge a detailed neurologic examination was performed at one, three, six, and 12 months utilizing a standardized form developed for the purposes of this study, Evoked response audiometry was performed at the Central Institute for the Deaf under the supervisior~ of one of us (H. D.). Detailed psychometric evaluation of each patient was made in our psychometric laboratory at the time of discharge and repeated after one year. Special laboratory methods. The presence and concentrations of H. influenzae type b capsular antigen was determined by CIE utilizing methods described previously.7-~ Bactericidal antibody to H. influenzae type b was determined according to the method of Fothergill and Wright 1~as previously modified? Assays were performed utilizing a standard strain of H. influenzae type b and the organism isolated from the patient, Anti-PRP H. influenzae antibody was determined (by Dr. Robert Baker, Indianapolis) using a double label modification" of the radioantigen binding technique of Farr? ~ Statistical analysis. Statistical analysis of the data was performed by Dr. Sung Choi of Washington University School of Medicine. When appropriate, techniques included analysis of variance on log-transformed data, multiple range tests, and correlation coefficients. RESULTS There were more males than females in our series (62% compared to 38%), but the difference was not significant by chi square. No significant differences were noted between the recipients of chloramphenicol or ampicillin in severity of disease as determined by comparisons of CSF data, days of illness, height and duration of fever prior to admission, levels of consciousness, focal neurologic signs or seizures, or the number who received antibiotic treatment prior to
544
Feigin et al.
The Journal of Pediatrics April 1976
Table I. Additional clinical and laboratory data
Number of patients Cerebrospinal fluid Positive culture-No. (%) Positive Gram stain-No. (%) *Positive CIE No. (%) Quantity of antigen present (ug/mI) Mean +_ I SD Median Range Subdural effusion-No. (%) tPositive transillumination Subdural fluid tapped Subdural fluid by tap or scan Seizure in hospital-No. (%) Fever (days) Mean + 1 SD Median Range Fever index (degree fever hr) Mean _+ 1 SD Median Range
I
Total group
.
Therapy with arnpicillin
50
28
22
46 (92) 42 (84) 37 (74)
26 (92s 21 (75) 22 (78.5)
20 (90.9) 16 (72.7) 20 (90.9)
1.60 _+ 2.65 0.32 0-10.24
1.76 +_ 2.90 0.32 0-10.24
1.41 _+ 2.37 0.32 0-10.24
16 (32) 4 (8) 6 (12) 11 (22)
9 (32.1) 3 (10.7) 5 (17.9) 5 (17.9)
7 (31.8) 1 (4.5) 1 (4.5) 6 (27.2)
3.04 +__2.6 2 0.2-9 18.88 _+ 20.4 15 0.8-94
3.06 + 2.9 2 0.25-8 21.28 _+ 12.34 12.4 1.4-94
I
Therapy with chloramphenicol
3.0 +_ 2.14 2 0.2-9 15.82 _+ 13.87 17.0 0.8-59.5
*CIE--antigenpresent by countercurrentimmunoelectrophoresis. tPositive transilluminationin patients with bacterial meningitishas been shown to correlate with subdural effusions?False positives can be obtained in the presence of tissue fluid in the scalp from an infiltratedintravenousinfusion; these were not used in our patients.
admission. Focal neurologic signs were noted in 10%, and seizures prior to admission in 24% of patients. Blood cultures were positive in 41 (82%), whereas antigen was detectable by CIE in the blood of 25 (50%) at the time of admission; in 37 (74%) patients, CSF and blood cultures were both positive. In five (10%) patients, the diagnosis of H. influenzae meningitis could have been made only by culture since CIE and Gram stains were negative. In three children diagnosis could be established only by CIE, since Gram stain and cultures of the CSF and blood were negative. Although 18 (36%) children had received some antibiotic treatment prior to admission, definitive diagnosis was possible in all patients by the performance of Gram stains, cultures of CSF and blood, and CIE of CSF and blood. No significant differences were noted between patients treated with ampicillin and chloramphenicol with regard to the percentage with positive CSF cultures or Gram stains or to the presence and quantity of CSF antigen (Table I). Pretreatment had no significant effect upon the nu tuber of white blood cells, the percentage of polymorphonuclear leukocytes, the concentration of glucose, or the quantity of antigen in the CSF. Although pretreated patients had negative cultures more frequently than untreated patients, the differences were not statistically significant. Throat and nasopharyn-
geal cultures were not of value in establishing the etiology of generalized sepsis or meningitis in patients with negative blood or CSF cultures. At the time of admission, serum concentrations of sodium were below 135 mEq/1 in 27 (54%) patients; the range was 117 to 140 mEq/1; the m e a n was 133 +_ 4.2 mEq/1 _ 1SD. On the fluid restricted regimen employed serum sodium concentrations generally reached levels of 135 mEq/1 or above during the first two days of hospitalization. There was no correlation of the depression in serum sodium concentration at the time of admission with the duration or severity of illness prior to admission. The initial (white blood cell count) generally was above normal. Depressions in the initial peripheral white blood cell count heralded more severe disease; depressed counts correlated significantly (p < 0.05) with prolonged fever in hospital and with the a m o u n t of antigen (p < 0.01) in the CSF. No significant differences between groups were noted in the incidence of subdural effusions or seizures in hospital or in the duration or height of fever (Table I). Prior to or subsequent to hospitalization, 29.8% of all children had"seizures, b u t none of them had seizures after the first 72 hours in hospital. Cerebrospinal fluid obtained 48 hours after therapy
Volume 88 Number 4, part 1
was discontinued showed no organisms on Gram stain or by culture, and no antigen by CIE in 49 of the 50 patients. Bacteriologic relapse occurred in one ampicillin-treated patient whose H. influenzae isolate was sensitive by tube dilution to < 0.1 ug/ml of this drug. Chloramphenicol treatment was initiated; the patient recovered but has a residual hearing deficit that is not of clinical importance. There were no differences between groups in the morphologic or chemical characteristics of the CSF obtained at the conclusion of therapy. The total white blood cell count and percentage of polymorphonuclear leukocytes were not normal, however, in the final CSF specimens; mean +_ 1 SD values of 61 + 14 and 6 + 12 respectively, were noted. Similarly, the CSF protein and glucose concentrations were not always normal; mean values were 46 +_ 49 mg/dl and 46 _+ 11 mg/dl, respectively. The CSF glucose was below 40 mg/dI at the time of discharge in t5 patients, but the CSF:blood glucose ratio was less than 40% in only two patients. At the time of discharge, neurologic or audiometric examinations were abnormal on 2t children (42%): 12 were recipients of ampicillin and nine of chloramphenicol. Subsequently, some neurologic or audiometric abnormality was noted in 17 of 45 children (37.8%) at one month, in nine of 35 children (25.7%) at three months, in four of 32 children (12.5%) at six months, and in one of 20 children (5%) at one year. These data reflect the tendency for minor and even some major neurologic deficits in patients following meningitis to disappear with time. The decreasing numbers of children seen at each follow-up visit does not reflect a failure of parents to return for the study. Only one of the initial 50 patients with H. influenzae meningitis did not return for repeated examinations. The early and late or permanent sequelae of meningitis which were detected in the 50 children included in this report are recorded in Table II. Overall, significant neurologic including intellectual deficits have persisted in four (8%) of the 50 children. There was a positive correlation (r = 0.62419; p < 0.01) of the quantity of antigen in the initial CSF with the development of early and permanent sequelae. In patients who had no sequelae (early or late), 0.82 _+ 1.88 ug/ml (mean _+ lSD) PRP was found in the initial CSF specimen. In contrast, 3.38 _+ 3.60 /~g/ml (mean + 1 SD) PRP antigen was present initially in the CSF of children who had early or late neurologic or intellectual deficits. These differences are highly significant (p < 0.01). Antigenemia was detected in most patients for two days and in several individuals for eight days. Antigenuria persisted in most patients for at least four days, and in one patient for 68 days. Prolonged
Evaluation of H. influenzae treatment
$45
Table II. Sequelae of Hemophilus influenzae meningitis
Total group Number of patients 50 Deaths 0 Ataxia Early 2 Persistent 1 Hemi- or quadriparesis Early 8 Persistent 2 Hearing deficit 3 Evoked response 3 Clinically 1* significant Blindness I* Subdural effusion Early 16 Longer than 3 0 months Intelligence quotient Mean 4-_ 1 SD 94 + 20 Range 30-150 Intelligence quotient Below 70 3t Below 80 7t IQ Below 90 17 Developmental 25 < chronological age
Therapy with ampiciltin
Therapy with ehloramphenicot
28 0
22 0
0 0
2 1
5 1 2 2 1
3 1 1 1 0
I
0
9 0
7 0
96 _+ 17 75-150
91 +- 23 30-129
2 3 9 15
1 4 8 10
*One patientwas blind,deaf, and had spasticquadriparesis. tThese includetwo of the same patientsrecorded under persistenthemior quadriparesis.
antigenemia and antigenuria correlated significantly (p < 0.01) with prolonged fever and with sequelae of meningitis, Bactericidal antibody could be detected at the time of admission (mean bactericidal antibody titer 3.58 x 10~) in 92.3% of the patients. In 80% of children who had bactericidal antibody present on admission, no increase in antibody titer was detected in a convalescent specimen obtained two to six weeks later. Anti-PRP antibody responses in 36 children are shown in Table III where they are compared to the ages of the patients and to the quantity of PRP antigen to which they were naturally exposed by their disease. It is apparent that with rare exception, children 17 months of age or less do not develop anti-PRP antibody during convalescence, irrespective of the quantity of the antigenic stimulus. A correlation matrix was prepared utilizing 88 variables representing clinical and laboratory data of the patients. Focal neurologic signs present at the time of admission
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Feigin et al.
The Journal of Pediatrics April 1976
Table IlL Development of anti-PRP antibody in relation to age of patient Antigen (PRP) (t~g/ml) CSF No. of patients
Age range (mo)
25
1-19 Median 7.5 21-54 Median 28
11
N*
N~f
25
21
9
9
Mean + 1 SD (range)
1.38 + 2.20 (0-10.24) 2.37 + 4.46 (0-10.24)
Anti-PRP antibody (ng/ml)
Blood
N*
Nt
23
12
11
6
Convalescent
A cute
Mean +_ 1 S D (range)
0.11 _+ 0.19 (0-0.64) 0.01 + 0.01 (0-0.04)
N*
Nt
25
0
11
5
Mean +_ 1 SD (range)
0 _+ 0 (0) 449 _+ 628 (0-1585)
N*
N~(
24
3
11
8
Mean + 1SD (range)
12 +_ 45 (0-223) 654 _+ 829 (0-2575)
*Number of patients tested. tNumber of patients with detectableantigen or antibody.
correlated significantly and were strongly predictive of a neurologic abnormality at examination one, three, and six months following discharge (r = 0.69282, p < 0.01). Similarly, focal signs present at admission correlated significantly with low intellectual achievement following discharge (r = 0.55680; p < 0.001). Prolonged depression in serum sodium concentration as a reflection of inappropriate A D H secretion also correlated significantly with the presence of neurologic abnormalities at one month following discharge (r = 0.34524; p < 0.05). DISCUSSION In 1972 we reported the results of a retrospective comparison of ampieil!in and chloramphenicol therapy for H. influenzae meningitis. 1~ Bacteriologic relapse was noted in 4.4% of ampicillin recipients, whereas relapse was not observed in patients treated with chloramphenicol. No significant differences were observed in the prospective study reported here between treatment groups in respect to early or late sequelae of the disease ~,however, a longer follow-up period will be required to exclude differences in intellectual capability or in school performance; In contrast to the results of our retrospective study, 13 fever was not of greater magnitude or significantly prolonged in ampicillin recipients. One of 28 (3.6%) patients treated with ampicillin experienced a bacteriologic relapse, a rate similar to that reported on the basis of retrospective data. 13 Inappropriate secretion of antidiuretic hormone was suggested by the laboratory data obtained in 88% of the patients studied. In our experience, inappropriate secretion of A D H in children with acute bacterial meningitis is more the rule than the exception and is best avoided by careful monitoring of fluid administration. Possible adverse effects of this metabolic problem are highlighted by our findings that prolonged depression in serum
sodium correlated significantly with the presence of neurologic abnormality one month following discharge from the hospital. Swartz and Dodge, TM Dodge and Porter, 1~ and ShurtlefP 6 documented that subdural collections of fluid could be demonstrated by the technique of transillumination, and Dodge and Swartz 3 noted that transillumination was more consistently useful in their diagnosis than was fever, irritability, vomiting, seizures, fullness of the fontanelle, or enlarging head circumference (symptoms and signs generally used as indications for a subdural tap ). Observations in the present study support these earlier observations. We are unable to find a previous report in which subdural effusions were routinely sought by daily transillumination; however, the incidence of subdural effusions detected by this method in our patients (32%) is in accord with prior observations) Subdural paracentesis was used only to curtail vomiting or other symptoms of increased intracranial pressure. None of the patients required more than one subdural tap and most (92%) had none. Persistent subdural effusion (beyond three months) was not observed in any patient, thus confirming the suggestion ~ that repeated subdural taps are unnecessary and that the effusion will clear with time. Although seizures occurred in 29.8% of the children either prior to admission or during the first 72 hours of hospitalization, no children have been identified as having a permanent seizure disorder referable to their meningitis; three children remain on anticonvulsant therapy which was initiated during their hospitalization. These data support the concept that seizures which occur early in the course of disease generally are manifestations of an acute derangement in function of the cerebral cortex and have no prognostic significance unless they are persistent or difficult to control. Sell and associates1 in a retrospective study of H.
Volume 88 Number 4, part I
influenzae meningitis reported that 11 of 86 children died and that 29% of the survivors had severe or significant handicaps. Included in the group classified as severely handicapped were those whose IQ was 70 or less. Utilizing similar criteria, only 8% of our patients presently have significant or severe handicaps, and none o f our patients died. Sell and associates I also noted that 14% of survivors had possible residual abnormalities; included in this group were children who scored 70 to 80 o n intelligence tests. In addition, postmeningitic children functioned at significantly lower levels than did their age-matched peers? 7 We strongly suspect on the basis of our preliminary psychometric data and that of Sell's group" that minor residual deficits may be a major concomitant of H. influenzae meningitis. In 1969, on the basis of our observations, we suggested that it might be prudent to question the concept that bactericidal antibody was the only factor important for protection of the h u m a n host against H. influenzae infection in vivo? N o r d e n TM subsequently concurred that bactericidal activity may not be important in protection against H. influenzae infection in some cases. In the present study, most children had bactericidal antibody against H. influenzae type b at th e time of admission, and this activity did not prevent their disease. These data provide evidence in m a n which support the findings of Smith and associates 1~ who found no relation between bactericidal activity and the development of H. influenzae bacteremia and meningitis in the experimental animal. In contrast, anti-PRP antibody generally was nondetectable in the serum of our children at the time of admission. In five cases, anti-PRP antibody was found in the initial specimen but all of these children were 21 months of age or older. It has been shown that anti-PRP H. influenzae antibody can be induced by the use of crossreacting bacteria and that natural or artificially induced colonization of m a n by such bacteria may prime cells which will produce anti-PRP H. influenzae antibody when the host is exposed to H. influenzae. 2.... It is possible that the anti-PRP antibody detected shortly after admission in the serum of five of our children reflects an anamnestic response, as might be expected in older children whose antibody-producing cells have been primed by previous exposure to cross-reacting antigens. Only three of 24 children who were 17 months of age or younger developed anti-PRP antibody during convalescence, irrespective of the antigenic stimulus to which they were naturally exposed. It has been estimated that a serum level of anti-PRP H. influenzae type b antibody of at least 60 to 100 n g / m l would be required to prevent systemic infection in man. 21 Using these estimates, only one or two of the children under 19 months of age would
Evaluation of H. influenzae treatment
547
have been protected following their recovery from H. influenzae meningitis. These data are similar to reports concerning the development of anti-PRP antibody following immunization of children with 11. influenzae vaccine? 1,23 These antigen-antibody relationships described for naturally acquired infections serve to heighten our concern regarding the possibility of protecting children in the first year of life from H. influenzae infection by artificial immunization. The authors express their appreciation to the part-time clinical faculty who permitted us to enroll their patients in this study and to the housestaff without whose help the study could not have been performed. We thank Drs. Donald Anderson, Larry Pickering, and David Van Reken, former fellows in pediatric infectious diseases for their assistance. We also appreciate the assistance of our senior pediatric neurology colleagues and single out for special thanks Dr. Ed Dodson, Jay Pettegrew, Mary OlsonJohnson, John Manica, Robert Greenwood, William Farris, Elias Chalhub, ~indRoger Brumback who in their capacity as pediatric neurology fellows gave generously of their time. We also thank Mrs. Ira Hirsch who graciously performed and provided detailed evaluation of evoked response audiometry data. We thank Mrs. Judy Wilson and Mr. Joel Campbell for technical assistance and Ms. Judy Rodgers for help in the preparation of the manuscript. REFERENCES
1. Sell SHW, Merrill RE, Doyne EO, and Zinsky EP Jr: Longterm sequelae of Hemophilus influenzae meningitis, Pediatrics 49:206, 1972. 2. Sproles ET III, Azerrad J, Williamson C, and Merrill RE: Meningitis due to Hemophilus influenzae: Long term sequelae, J PEDIATR75:782, 1969. 3. Dodge PR, and Swartz MN: Bacterial meningitis. A review of selected aspects II. Special neurologic problems, postmeningitis complications and clinicopathological correlations, N Engl J Med 272:1003, 1965. 4. Turk DC, and May RJ: Hemophilus influenzae: Its clinical importance, London, 1965, University Press Ltd. p 27. 5. Feigin RD, Richmond D, Hosler MW, and Shackelford PG: Reassessment of the role of bactericidal antibody in Hemophilus influenzae infection, Am J Med Sci 262:338, 1971. 6. Fekety FR Jr, and McDaniel E: The fever index in evaluation of the course of infectious diseases; with special reference to pneumococcal pneumonia, Yale J Biol Med 41:282, 1968. 7. Shacketford PG, Campbell J, and Feigin RD: Countercurrent immunoetectrophoresis in the evaluation of childhood infections, J PEDIAXR85:478, 1974. 8. Ingram DL, Anderson P, and Smith DH: Countercurre~t immunoelectrophoresis in the diagnosis of systemic diseases caused by Hemophilus influenzae, type b, J P~DIATR 81:1156, 1972. 9. Coonrod JJ, and Rytel MW: Detection of type-s.pecific pneumococcal antigens by counterimmunoelectrophoresis. I. Methodology and immunologic properties of pneumococcal antigen, J Lab Clin Med 81:770, 1973. 10. Fothergill LD, and Wright J: Influenzal meningitis: the
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relation of age incidence to the bactericidal power of blood against the causal organism, J Immunol 24:273, 1933. Gotschlich EC: A simple modification of the radioactive antigen-binding test by a double label technique, J Immunol 107:910, 1971. Farr RS: A quantitative immunochemical measure of the primary interaction between IBSA and antibody, J Infect Dis 103:239, 1958. Shackelford PG, Bobinski JE, Feigin RD, and Cherry JD: Therapy of Hemophilus influenzae reconsidered, N Engl J Med 287:634, 1972. Swartz MN, and Dodge PR: Bacterial meningitis--A review of selected aspects. I. General clinical features, special problems and unusual meningeal reactions mimicking bacterial meningitis, N Engt J Med 272:779, 1965. Dodge PR, and Porter P : Demonstration of intracranial pathology by transillumination, Arch Neurol 5:594, 1961. Shurtleff D: Transillumination of the skull of infants and children, Am J Dis Child 107:14, 1964. Sell SHW, Webb WW, Pate JE, and Doyne EO: Psychological sequelae to bacterial meningitis: Two controlled studies, Pediatrics 49:2t2, 1972. Norden CW: Prevalence of bactericidal antibodies to
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Haemophilus influenzae, type b, J Infect Dis 130:489, 1974. Smith AL, Smith DH, Averill DR Jr, Marino J, and Moxon ER: Production of Haemophilus influenzae b meningitis in infant rats by intraperitoneal inoculation, Infect Immun 8:278, 1973. Myerowitz RL, Handzel ZT, Schneerson R, and Robbins JB: Induction of Haemophilus influenzae type B capsular antibody in neonatal rabbits by gastrointestinal colonization with cross-reacting Escherichia coli, Infect Immun 7:137, 1973. Robbins JB, Parke JC Jr, Schneerson R, and Whisnant JK: Quantitative measurement of "natural" and immunizationinduced Haemophilus influenzae type b capsular polysaccharide antibodies, Pediatr Res 7:103, 1973. Schneerson R, and Robbins JB: Induction of serum Haemophilus influenzae type B capsular antibodies in adult volunteers fed cross-reacting Escherichia coli 075:K100:H5, N Engl J Med 292:1093, 1975. Smith DH, Peter G, Ingram DL, Harding AL, and Anderson P: Responses of children immunized with the capsular polysaccharide of Hemophilus influenzae, Pediatrics 52:637, 1973.
