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VOLUME 79 . MARCH 1987 . NUMBER 3

PEDIATRICS Vol. 79 No. 3 March 1 987 321

1cs

b-CAPSA

I Haemophilus

influenzae,

Type

b,

Capsular

Polysaccharide

Vaccine

Safety

Steven

B. Black,

MD,

Henry

R. Shinefield,

MD, and the Northern

California

Permanente

Medical

Care

Program

Departments

of

Pediatrics

Vaccine

Study

Group*

From the Departments of Pediatrics, Kaiser Permanente Medical Care Program, Northern California Region

ABSTRACT. The b-CAPSA I capsular polysaccharide vaccine for Haemophilus influenzae type b was given to 87,541 children 2 through 5 years of age in the Kaiser Permanente Medical Care Program, and the children

were then followed using a multiple modality surveil-lance. Phase 1 consisted of 24-hour recall of immediate

side effects which were recorded on questionnaires given to families of 13,500 children. Local side effects were found to be uncommon: 2.3% had a temperature of 38.3#{176}C(1O1#{176}F); 4.8% had local erythema, 2.9% local swelling, and 12.6% local tenderness; two children had wheezing shortly after immunization. In Phase 2, 30 days

after immunization, questionnaires were mailed to

par-ents of all 87,541 children, who were asked to respond to questions about illnesses and health care. Phase 3 con-sisted of active surveillance of patient health care use by

physicians and nurses during the 30 days after immuni-zation. During the 30-day reporting periods, there were

40 hospitalizations, including one for wheezing and one

for febrile seizure. Of the 40 hospitalizations, only the

Received for publication Sept 22, 1986; accepted Oct 29, 1986. Presented, in part, at the annual meeting of the American Pediatric Society, Washington, DC, May 5-7, 1986, and

pub-lished in abstract form in the proceedings.

*Vaccine Study Group physicians: Marts Beekley, Evelyn R.

Callas, Cecil Chang, Yan C. Chow, Bennett N. Coplan, Aubert C. Dykes, Russell J. Erickson, Brien L. Hensley, Arthur E. Lande, Spencer A. Larsen, Allan Lavetter, Chinh T. L#{233},Thomas E. Liston, Patrick D. Mullin, Jeffrey Miller, Pius A. Morozumi, Hallie Morrow, Richard G. Pastcan, Ronald M. Shapera, Mark

P. Sloan.

Reprint requests to (S.B.B.) Department of Pediatrics, Kaiser

Permanente Medical Center, 280 W MacArthur Blvd, Oakland,

CA 94611.

PEDIATRICS (ISSN 0031 4005). Copyright © 1987 by the American Academy of Pediatrics.

one for wheezing was believed by the admitting physician to be probably associated with vaccine administration.

Three children had seizures within 30 days of

immuni-zation. None of the seizures was believed by the reporting

physician to be associated with immunization. Adverse effects of the vaccine were mild, limited to local reactions

and occasional temperature elevation; bronchospasm after immunization occurred rarely. Pediatrics 1987;79:321-325; Haemophilus influenzae, type b,

immu-nization, capsular polysaccharide vaccine.

Haemophilu influenzae type b is the most

com-mon cause of meningitis in preschool children and

is a common cause of epiglottitis, septic arthritis, cellulitis, and pneumonia.’ Although studies

dem-onstrating the safety and efficacy of an H influenzae type b polysaccharide vaccine were performed in

Finland in 1974,2 no large-scale studies have dem-onstrated its safety and efficacy in this country.

The b-CAPSA I H influenzae type b polysaccharide

vaccine (Praxis Biologics, Rochester, NY) was

li-censed by the US Food and Drug Administration

in April 1985. Using this vaccine, we have immu-nized and followed 87,541 children between the ages of 2 and 5 years using a multiple modality surveil-lance system. We report here our findings

concern-ing medical events associated with administration

of the vaccine. Studies of vaccine efficacy are on-going.

MATERIALS AND METHODS

A total of 87,541 children 2 through 5 years of

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age were immunized with b-CAPSA I vaccine at

the 22 medical centers of the Northern California

Kaiser Permanente Medical Care Program from

June 1, 1985, to June 30, 1986. At each facility, one pediatrician was responsible for local coordination

of the study project. Surveillance of these children was undertaken using a multiple modality

ap-proach. Phase 1 consisted of 24-hour recall of

im-mediate side effects. Phase 2 consisted of a simu-lated, passive survey for possible delayed effects that occurred within 30 days of immunization. Phase 3 consisted of active surveillance for health

plan use within 30 days of immunization.

In phase 1, the survey for immediate side effects, the parents of 13,500 children at three of the

med-ical centers were given a postcard questionnaire at the time of immunization to record quantitatively and qualitatively any reactions occurring within 24 hours of immunization. On the questionnaire, local

erythema, swelling, and tenderness at the injection site were each graded as none, <2.54 cm (<1 in) in

diameter, or 2.54 cm (1 in) in diameter. Parents mailed this postage prepaid postcard back to the vaccine study office. Data analysis in this phase of the study was based on 4,557 of the 13,500 ques-tionnaires (33.8%) that were returned. To evaluate the extent that the returned questionnaires might represent a biased sample compared with the entire

vaccinated cohort, a telephone interview of a

sub-sample ofthe families, consisting of 500 consecutive vaccine recipients, was conducted about 2 weeks after immunization to ask about immediate postim-munization side effects.

In phase 2, the 30-day, stimulated, passive

sur-vey, the parents of all children receiving H

influ-enzae type b immunization were asked to self-ad-dress an envelope at the time of immunization. The envelopes were put in batches by date and used to

send a postage prepaid questionnaire to the families

of all 87,541 immunized children 30 days after immunization. The questionnaire asked for the child’s age, sex, and medical record number, as well

as any illnesses or hospitalizations during the 30

days. Space was provided to allow the parents to comment. Data analyses were based upon 18,122 of the 87,541 questionnaires (20.7%) that were re-turned. Again, to evaluate the extent that the re-turned 30-day questionnaires might be a biased sample compared with the entire vaccinated cohort, a telephone interview of the families of a second subsample of 500 vaccine recipients was conducted about 40 days after immunization to ask about medical events since b-CAPSA I immunization.

In phase 3, the active surveillance of health plan

use, the physician monitor at each facility was

responsible for monitoring and coordinating the

surveillance program. Physicians and nurses were asked to fill out a utilization-reporting form for each emergency department visit, hospitalization,

pediatric clinic visit, or telephone call requesting advice during the 30 days after b-CAPSA I immu-nization of the 87,541 children. Utilizations were

classified by the health care provider as “probably

related,” “possibly related,” or “probably not re-lated” to b-CAPSA I administration. Although an

ill child would normally be hospitalized at one of the Kaiser Foundation hospitals, a child who

be-came ill outside the area of the health plan and was hospitalized at a non-health plan hospital would have to submit a request for reimbursement to our

health plan. These records were reviewed also for hospital utilization. For children seen with the di-agnosis of otitis, upper respiratory tract infection, gastroenteritis, or routine well-child care no

utili-zation forms were generated unless they were

hos-pitalized. This was done to minimize the burden of

paperwork for the practicing pediatricians. In

ad-dition, to validate the utilization information, a utilization profile during 1 month was developed at our Oakland medical center by reviewing and tab-ulating all clinic visit records and the emergency department registration log for all children 2

through 5 years of age. This profile was compared

with the reporting of utilization in the clinic and emergency room for children who had received

b-CAPSA I immunization within 30 days.

The accuracy ofthe hospitalization recording was verified at each facility by the physician monitor. Hospital admissions to the pediatric service were

checked to identify children immunized within the 30 days before admission. This served to confirm the initial reporting process by the physician.

Hos-pitalizations reported in phase 3 were also

cross-checked with hospitalizations reported by parents

in the phase 2 questionnaire.

Demographic data for the 18,122 children whose parents returned the 30-day survey questionnaires were generated. To validate these demographic data, records were pulled and age and sex infor-mation was recorded for a third subset sampling of

500 consecutive recipients of the vaccine at three medical centers.

Throughout the study, to compare study data and validation samples, statistical analysis was done by

calculating

x2

values and determining P values.

Confidence intervals were also calculated.

RESULTS

Age and sex were about evenly distributed among

the 118,040 children 2 through 5 years of age in the

Northern California Kaiser Permanente Medical

(3)

dis-TABLE 2. Twenty-Four-Hour Surveillance for Local Side Effects

With 500 Children in Validation Survey

in 4,577 Immunized Study Children Compared

Side No. (%) of Immunized

Effect Study Children

No. (%) of Children

in Validation Survey

None <2.54 Cm 2.54 Cm Any

Reaction

None Any

Reaction

4,338 (95.2) 205 (4.5) 14 (0.3)

4,425 (95.1) 123 (2.7) 10 (0.2) 3,981 (87.4) 503 (11.0) 73 (1.6)

219 (4.8)*

133 (2.9)t 576 (12.6)

482 (95.5) 18 (4#{149}5)* 488 (97.6) 12 (2.4)t

442 (88.4) 58 (11.6)

ARTICLES 323

tribution of the 18,122 immunized children whose parents responded to the 30-day survey

question-naire (phase 2) is shown in Table 1. Within each age group, the male-female distribution was about equal. The age and sex distribution ofthe validation sample did not vary significantly from these

ques-tionnaire respondents (P = .996). The highest

per-centage of immunized children were those who were

2 years old.

Information about local reactions during the 24 hours after immunization (phase 1) is given in

Table 2. The most commonly experienced local reaction was tenderness at the injection site. Again, the data in the validation survey did not

signifi-cantly differ from the 24-hour (phase 1) question-naire respondents for erythema, local swelling, or local tenderness, although there was an apparent

slight overreporting bias for the questionnaire

re-spondents compared with the validation sample.

The response rates for fever within 24 hours of immunization are shown in Table 3 and included a temperature of<38.3#{176}C (<101#{176}F)for 97.7% of

chil-dren. Temperature elevations to 39.4#{176}C (103#{176}F)

were uncommon, occurring in less than 0.1% of children. Of children in the validation sample, 2.8% had a temperature of 38.3#{176}C (101#{176}F) (Table 3),

which did not significantly differ from that in the

2.3% of immunized children responding to the

ques-tionnaire (P = .57).

Other associations reported by questionnaire re-spondents during the 24-hour reporting period were

TABLE 1. Ag

Whose Parents

e Distribution of Immunized Children

Returned 30-Day Questionnaires

Age (yr) No. (%) of Children

in 30-Day

Questionnaire Group

No. (%) of Children

in Validation

Subset

2 6,008 (33.2) 164 (32.8)*

3 5,873 (32.4) 162 (32.4)* 4 4,447 (24.5) 125 (25.0)* 5 1,794 (9.9) 49 (9.8)*

*x2= .06,P= .996.

Erythema Swelling Tenderness

* P = .25 (95% confidence limit = 4.2% to 5.5%).

1P = .59 (95% confidence limit = 2.5% to 3.5%).

:1:

P = .64 (95% confidence limit = 11.7% to 13.6%).

abnormal sleep pattern in 8.9% of recipients, wheezing in 0.7%, vomiting in 0.9%, and diarrhea in 2.2%.

Of the 18,122 (20.7%) questionnaires returned at 30 days (phase 2), 13,972 (77.1%) listed upper

res-piratory tract infection, otitis, or no illness (Table 4). The illness rates reported in the validation study did not differ significantly from the rates reported by the questionnaire respondents. The parents of three children reported seizures occurring within 30 days of immunization; all three were brought to medical attention and are reported in the health plan use data below. Parents listed 39

hospitaliza-tions, of which 14 were for elective surgical proce-dures.

From the phase 3 physician-monitored survey of health plan use, 1,346 events were recorded during the study period. Of the reported utilizations, 113 occurred in emergency departments, 1,005 in a pe-diatric clinic or pediatrician’s office, 201 were tele-phone calls for advice, and 27 were hospitalizations.

Of 27 hospitalizations reported in the phase 3

uti-lization survey, 26 (96.2%) were reported by parents on the phase 2 30-day questionnaire. In 13 cases of elective surgery in services other than pediatrics, no utilization reporting occurred. In addition, the

family of one child with meningitis due to H

influ-enzae type b 1 week after b-CAPSA I immunization did not return a 30-day questionnaire.

Only one hospitalization was causally associated with immunization by the reporting

physician-TABLE 3. Twenty-Four-Hour Surveillance for Peak

Temperatures in 4,577 Immunized Study Children Corn-pared With 500 Children in Validation Survey

Peak Temperature (C) No. (%) of Immunized Study Children

<38.3#{176} 4,452 (97.7)

38.3#{176}-38.8#{176} 78 (1.7)

38.9#{176}-39.38#{176} 23 (0.5) 39.4#{176} 4 (0.09)

Total 38.3#{176} 105 (2.3)*

* = .57 (95% confidence limit = 1.9% to 2.8%), corn-pared with 14/500 (2.8%) with temperature 38.3#{176}C in validation survey.

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TABLE 4. Illnesses Reported by Parents of 18,122 Immunized Children Compared

With 500 Children in Validation Survey

Illness No. (%) of Eve nts Reported

Immunized

Children

Validation Survey

Cold, otitis, or none Wheezing within 30 d

Vomiting and/or diarrhea within 30 d Seizures

13,972 (77.1)* 424 (2.3)t

3,963 (21.9) 3

396 (79.2)* 16 (3.2)t

98 (19.6) 0

* = .60 (95% confidence limit 76.5% to 77.7%).

t P = .25 (95% confidence limit 2.1% to 2.5%).

:1:

P = .31 (95% confidence limit 21.3% to 22.5%).

that of a 31-month-old child with wheezing one

hour after immunization. This child’s twin also experienced wheezing after immunization but did

not require hospitalization. Both of these children

had a prior history of asthma. Three children had

seizures within 1 month of immunization, one re-quiring hospitalization. The same three children were reported in both the 30-day parental question-naire and the utilization survey, and all had seizures in association with fever. Two of these, in whom the febrile seizure occurred 3 and 4 weeks,

respec-tively, after immunization, had a history of prior episodes of febrile seizure; the child with no prior history had the seizure 2 weeks after immunization associated with a temperature of 39.4#{176}C(103#{176}F).

All three episodes of seizures during the reporting period were classified by the physicians caring for the children as “probably not” associated with vac-cine administration. All three children were neu-rologically normal when last evaluated at follow-up ranging between 2 and 11 months.

When the results of the validation survey of medical utilization during a 4-week period at the Oakland facility were cross-checked with the results of the concurrent phase 3 study, one case had not

been reported appropriately. Of 26 children who

had diagnoses for which reports should have been generated, one child who had sought medical atten-tion for an insect bite had not been reported in the concurrent phase 3 surveillance.The one reportable hospitalization during the 1-month validation study

was reported appropriately.

During the reporting period, six children were hospitalized with diseases due to H influenzae type b after immunization (Table 5). Two had invasive disease during the fourth week after immunization

with b-CAPSA I. One child had a blood culture positive for epiglottitis, and one had meningitis.

Both children were 3 years of age and were consid-ered previously healthy, normal children. In four children, disease due to H influenzae type b devel-oped requiring hospitalization of the children within 1 week of receiving the vaccine. Three of

these children had positive blood cultures (one

par-TABLE 5. Cases of Disease Due to Haemophilus

influenzae Type b After b-CAPSA I Administration Case Category No. of Days After

Cases Immunization

Nonimmune (<14 d after

b-CAPSA I administration)

Epiglottitis 1 2

Meningitis 1 7

Parapharyngeal cellulitis 1 4

Periorbital cellulitis 1 2

Vaccine failure (4 wk after

b-CAPSA I administration)

Epiglottitis 1 28

Meningitis 1 30

apharyngeal cellulitis, one epiglottitis, one

menin-gitis), and one child had periorbital cellulitis with negative blood culture results but a leading edge culture positive for H influenzae

type

b.

DISCUSSION

We have intensively followed a cohort of 87,541 children ages 2 through 5 years who have received

the b-CAPSA I Haemophilus type b vaccine to

identify possible immediate and long-term side ef-fects of its use. We have found local side effects to be uncommon and mild, with local tenderness at

the injection site the most common. Fever was the

most common systemic effect: less than 1 % of

chil-dren had a temperature of 38.9#{176}C (102#{176}F). Only

one hospitalization was related by the admitting

physician to immunization-that of an asthmatic child in whom wheezing developed after immuni-zation. Many asthmatic children were immunized,

however, and only this child and his identical twin

had wheezing within 1 hour of immunization.

Wheezing occurred in less than 0.7% of all children

within 24 hours of immunization. Wheezing soon after immunization may rarely occur. The febrile

seizures reported in three children within 30 days of immunization were not thought by the physicians caring for these children to be causally related to the administration of vaccine, and we believe these

episodes were sporadic events unrelated to the

(5)

ARTICLES 325

Epiglottitis developed in a 3-year-old child 4 weeks after receiving b-CAPSA I vaccine. In a second 3-year-old child, meningitis developed 4 weeks after immunization. These two cases were

considered to represent cases of vaccine failure. In addition, as part of the utilization surveillance, we noted four children who were hospitalized for disease due to H influenzae type b within 1 week of

immunization, three of whom had bacteremic

dis-ease. Although the significance of these four cases is not certain, it is possible that the administration

of H influenzae type b polysaccharide vaccine

briefly places the vaccine recipient at increased risk of disease. A similar phenomenon has been

ob-served experimentally after the administration of

typhoid vaccine.3 We plan to evaluate the

signifi-cance, if any, of the cases of H influenzae type b

disease occurring soon after immunization as part of an efficacy study of the b-CAPSA I vaccine currently in progress.

Our study was based upon a multiple modality surveillance system which allows monitoring of im-mediate and delayed medical events after

immuni-zation. We used extensive validation surveys and compared the findings in the different phases of the surveillance to assure the reliability of the data

obtained and to document the temporal association of events with immunization. Because our health

plan has a closed membership and is self-sufficient, we were able to reliably contact and maintain con-tact with our patients and to monitor utilization. Pediatricians working within the health plan are a cohesive group and frequently work together on

projects such as this study. Parents readily coop-erated with the study as has been our experience with numerous past projects. These factors greatly

facilitated the performanceiif this study.

Some patterns emerged in the data reporting.

The parents of children who became sick during the 30-day surveillance period after immunization were more likely to return the study questionnaires than those whose children were not ill, as demon-strated by the slight overreporting bias found in phases 1 and 2 compared with their respective validation surveys. This was most dramatic in the return rates for questionnaires of families whose

children were hospitalized (96.2%) and for families

whose children had seizures (100%).

In conclusion, the administration of the b-CAPSA I H influenzae type b vaccine is safe and not associated with any serious long-term sequelae, and side effects of immunization are limited to mild

local reactions and rare episodes of bronchospasm.

ACKNOWLEDGMENTS

This research was supported and the vaccine provided by Praxis Biologics, Rochester, NY.

Isela Esquer and Leisa Ling assisted with medical record review and data entry. Bruce H. Fireman, MA, assisted in statistical analysis.

REFERENCES

1. Cochi SL, Broome, CV, Hightower AW: Immunization of US children with Haemophilus influenzae type b polysac-charide vaccine: A cost-effectiveness model of strategy as-sessment. JAMA 1985;253:521-529

2. Peltola H, K#{228}yhtyH, Sivonen A, et al: Haemophilus

influ-enzae type b capsular polysaccharide vaccine in children: A double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics 1977;60:730-737

3. Raettig H: Provocation of an infection by vaccination: IV. Provocation during experimental S typhi murium epidemic after preceding immunization. Zentralbi Bakteriol 1959;

175:618-631

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1987;79;321

Pediatrics

Steven B. Black and Henry R. Shinefield

b-CAPSA I Haemophilus influenzae, Type b, Capsular Polysaccharide Vaccine Safety

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1987;79;321

Pediatrics

Steven B. Black and Henry R. Shinefield

b-CAPSA I Haemophilus influenzae, Type b, Capsular Polysaccharide Vaccine Safety

http://pediatrics.aappublications.org/content/79/3/321

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American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1987 by the

been published continuously since 1948. Pediatrics is owned, published, and trademarked by the

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