Amencan Journal of Eptderruotogy Copyright © 1992 by The Johns Hopkins University School of Hygiene and Pubfc Health AH nghts reserved
Vol. 136, No 2 Printed in U.S.A.
Risk Factors for Invasive Haemophilus influenzae Type b in Los Angeles County Children 18-60 Months of Age
C. M. Vadheim,1 D. P. Greenberg,1 N. Bordenave,1 L. Ziontz,1 P. Christenson,1 S. H. Waterman,2 and J. I. Ward1
Potential factors that confer risk or protection for invasive Haemophilus influenzae type b disease were evaluated in Los Angeles County children 18-60 months of age by case-control methods. In this age group, 79 H. influenzae type b cases were identified by overlapping surveillance methods, and 221 random controls were selected by random digit dialing. Cases and controls were similar in sex, prior health, proportion attending day care, parental educational level, history of breast feeding, and proportion vaccinated with measles/mumps/rubella vaccine. The effect of H. influenzae type b vaccination was controlled in all analyses, and results of vaccine efficacy have been reported elsewhere. Cases were more likely to have a significant underlying medical condition, reside in a home with more than six residents, have a lower yearly household Income, have two or more smokers in the home, and to be black. Using conditional logistic regression models, the following were significant independent risk factors after adjusting for age, month of diagnosis, H. influenzae type b vaccine status, and the other factors: 1) more than two smokers in the house (odds ratio (OR) = 6.00; 95% confidence interval (Cl) 1.49-24.06); 2) household size of more than six persons (OR for more than six vs. less than three persons = 3.71; 95% Cl 1.10-12.60); and 3) black maternal race (OR for black vs. Hispanic = 3.47; 95% Cl 1.41-8.53). We conclude that exposure to smoking in the home, living in households with more than six members, and the black race are each independently associated with an increased risk for H. influenzae type b disease in Los Angeles County children and, when combined, constitute a major reason for H. influenzae type b disease occurrence. Am J Epidemiol 1992;136:221-35. ethnic groups; Haemophilus influenzae; immunization; population; risk factors; smoking
Haemophilus influenzae type b remains an important cause of mortality and serious morbidity in children under 5 years of age, despite improved modes of therapy (1-5) and the recent availability of vaccines. How-
ever, the routine use in infants of new H. influenzae type b conjugate vaccines is expected to reduce the incidence of disease significantly, and the identification of special risk groups may facilitate vaccination of
Received for publication June 3, 1991, and in final form February 10, 1992. Abbreviations: Cl, confidence interval; Hboc, Haemophilus mlluenzae type b digosacchande conjugate vaccine; ICD-9, International Classification of Diseases, Ninth Revision; PRP, H. influenzae type b pctysacchande vaccine; PRP-O, H. influenzae type b polysacchande-diptTtherium toxoid conjugate vaccine; OR, odds ratio. 1 UCLA Center for Vaccine Research, Harbor-UCU\ Medical Center, UCLA School of Medicine, Torrance, CA. 2 Acute Communicable Disease Division, Los Angeles County Department of Health Services, Los Angeles, CA. Reprint requests to Dr. C. M. Vadheim, UCLA Center
for Vaccine Research, Harbor-UCLA Medical Center, Bldg. E-6, 1124 W. Carson St, Torrance, CA 90502. This research was supported by a grant from Connaught Laboratories, Inc., Swrftwater, PA. The authors thank Sophia Castro, Christopher Reyes, Debra Turner, and Liberty Teodoro, who spent countless hours ascertaining demographic and clinical information and documenting vaccination histories from hospital personnel, physicians, and parents of H. influenzae type b cases and controls. They also thank Nancie Bendana and Robert Gordon of the Los Angeles County Department of Health Services for their cooperation and help with this project.
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those groups at greatest risk. Previous studies have shown that several factors influence a child's risk for developing invasive H. injluenzae type b disease. These factors include young age (highest risk for children between 6 and 18 months of age) (1, 2, 4, 6-11), presence of underlying immunodeficiency (1, 12, 13), day-care attendance (3, 9, 10, 14), low socioeconomic status (10, 14), living in crowded conditions (9, 10, 14, 15), parental smoking (10), and ethnicity ( 1 , 3 6, 10, 16). Factors shown to be protective include breast feeding (of young infants) (10, 15) and vaccination with H. injluenzae type b vaccines (17, 18). Los Angeles County, California, provides a unique setting in which to conduct population-based studies of invasive H. injluenzae type b disease. It is among the largest and most diverse populations in the United States, and invasive H. injluenzae type b disease has been reportable since 1982. The purpose of this study was to examine in detail the effects of several risk and protective factors for invasive H. injluenzae type b disease in children 18 months of age and older, using a case-control study design and controlling for the effects of H. injluenzae type b vaccination. MATERIALS AND METHODS Study population
The study was conducted between July 1, 1988, and July 31, 1989, for all of Los Angeles County (total population, 8.7 million; 750,000 persons under the age of 5 years). The population is ethnically diverse; in the age group less than 5 years of age, 47 percent of the population is Hispanic, 29 percent is Caucasian (non-Hispanic), 15 percent is black, and the remainder (9 percent) is composed of many other ethnic groups (Los Angeles County statistics (19)). Only children 18-59 months of age were included in this study. Surveillance methods and case ascertainment
The county is served by 151 acute-care hospitals and six independent microbiology
laboratories, which were the basis of H. injluenzae type b case ascertainment. H. injluenzae type b cases were ascertained using multiple overlapping case-finding methods. Invasive H. injluenzae type b has been reportable in Los Angeles County since 1982 and in the state of California since 1989. On the basis of past surveillance (1988-1990), we estimate that 75-80 percent of invasive H. injluenzae type b cases are reported to the Health Department as required (passive surveillance). To ensure more complete surveillance, several methods of active case finding were initiated in 1988. A letter about the H. injluenzae type b surveillance program was sent to all hospital, laboratory, and medical records directors of each hospital/laboratory serving Los Angeles County residents, and meetings were held with all infection control practitioners to solicit their participation in the project. Active surveillance involved telephoning these practitioners in each hospital once or twice each month to ascertain suspected cases of invasive H. injluenzae type b disease. In addition, all hospital and independent laboratories with the capability of processing blood and cerebrospinal fluid cultures, serotyping, and/or performing latex agglutination tests for H. injluenzae type b were contacted by telephone at least once each month. Finally, laboratory logs from a random sample of approximately 50 percent of laboratories were searched for any specimen from a sterile body site that was positive for H. injluenzae type b, and in-patient hospital medical records were searched to ascertain additional cases. Reviews of medical records were performed by examining all charts with any of the following discharge diagnoses: H. injluenzae type b meningitis {International Classification of Diseases, Ninth Revision (ICD9), code 320.0), H. injluenzae type b bacteremia (ICD-9 code 038.41), H. injluenzae type b pneumonia (ICD-9 code 482.2), other H. injluenzae disease (ICD-9 code 041.5), acute epiglottitis (ICD-9 code 464.3), septic arthritis (ICD-9 code 711.0), facial cellulitis (ICD-9 code 682.0), and abscess of eyelid (ICD-9 code 373.13). Medical records were reviewed at all large hospitals on a quarterly
Risk Factors for Invasive Haemophilus influenzae 223
basis; and medium-size hospitals (five to ten H. influenzae type b cases per year) were reviewed on a biannual basis. Medical records from a 20 percent sample of the small hospitals were reviewed after the first 6 months of the study, and no unreported cases were found. Therefore, chart reviews at the small hospitals were conducted only once, at the end of the study. From the analysis of all surveillance data (1988 to present), we estimate that only 3 percent of all H. influenzae type b cases (including suspect cases) are found by medical records review. For each case, the following demographic, clinical, and laboratory information was obtained, primarily from hospital medical and laboratory records and from health department records: name, city of residence, telephone number, race, sex, date of birth, dates of hospitalization, date of onset of symptoms, details on laboratory results (date, site of specimen, test results), H. influenzae type b diagnoses, disease outcome, and any concurrent medical conditions. A total of 380 cases were identified in all age groups. However, only cases meeting the following criteria were eligible for inclusion in the case-control study: 1) met the case definitions of "definite" or "probable" invasive H. influenzae type b disease (see below); 2) resident of Los Angeles County for at least 1 month prior to onset of H. influenzae type b disease; 3) age between 18 and 59 months at onset of H. influenzae type b disease; and 4) accessible by home telephone (95 percent). A total of 88 cases met these criteria. For each case, the primary physician was interviewed by telephone to obtain additional information on clinical illness, concurrent medical conditions, and vaccination status and to obtain permission to contact the case's parent. Cases were classified as "definite," "probable," or "suspected" invasive H. influenzae type b disease using the following case definitions: 1) definite case: clinical findings consistent with invasive H. influenzae type b infection plus cultures positive for H. influenzae type b from a normally sterile body site, or clinical signs and symptoms consis-
tent with epiglottitis plus a positive culture from the pharynx, epiglottis, or blood; 2) probable case: clinical findings consistent with invasive H. influenzae type b infection plus H. influenzae type b antigen (by latex particle agglutination test) positive in cerebrospinal fluid, blood, joint fluid, or fluid from other normally sterile body site; 3) suspected case: other clinically suspected cases. Only definite and probable cases were included in this study. All H. influenzae type b strains were shown to be serotype b by slide agglutination, counterimmunoelectrophoresis, and/or type b capsular gene probe analysis (courtesy of E. Richard Moxon, Oxford, England). Selection of controls
Controls were obtained by random digit dialing of telephone numbers throughout Los Angeles County. A series of random telephone numbers was generated by computer, using randomly selected Los Angeles County prefixes and randomly generated suffixes. Each number was called systematically to identify households containing at least one child between 18 and 60 months of age. Each number was called until it was either resolved or until at least 12 calls were made, over a span of 6 weeks and covering days, nights, and weekends. Since vaccination practices changed over the course of the study, controls were indexed by month of illness of the case, with the goal of obtaining approximately 2-3 age-appropriate controls for each case stratified for time of illness. In families with more than one eligible control child, the youngest was used as the control. Case and control survey
After obtaining verbal consent, we interviewed parents of cases and controls using a standardized telephone questionnaire (in English or Spanish) to obtain further details of the child's H. influenzae type b illness (cases only), names and addresses of all physicians/clinics caring for the child, and information about possible risk factors for H. influenzae type b disease. Specifically, information was obtained on sex and date of
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birth of the child, breast-feeding history, general health, concurrent medical conditions, day-care attendance (size, number of hours attended per week), parental ethnicity, parental education and occupation, total yearly household income, household composition, number of persons sleeping in the same room as the case/control, number of smokers in the household, and the source and method of payment for the child's usual medical care. For cases and controls, all questions were based on conditions during the 2-week period prior to onset of//, influenzae type b disease or the 2 weeks prior to the first of the month for which they served as a control (index period). For purposes of the study, day-care attendance was defined as any child care arrangement involving at least two nonrelated children and lasting at least 4 hours per week in the 2 weeks prior to diagnosis (beginning of index month for controls). Day care was further categorized as day-care home, small day-care center (less than five children), and large day-care center. Maternal and paternal occupations and socioeconomic status were categorized using the method of Green (20), which was developed for scoring socioeconomic status for health behavior research. To determine vaccination history, we interviewed all physicians/clinics caring for cases and controls by telephone to obtain the date, manufacturer, and lot number (when possible) of any H. influenzae type b vaccination (//. influenzae type b polysaccharide vaccine (PRP), PRP-diphtheria toxoid conjugate vaccine (PRP-D; Prohibit; Connaught Laboratories, Inc., Swiftwater, Pennsylvania), Haemophilus b oligosaccharide conjugate vaccine (Hboc; Hib TITER; Lederle/Praxis, Rochester, New York)) and measles/mumps/rubella vaccination. A case child was defined as being vaccinated if he/ she had received a vaccine prior to the date of onset of disease. A control child was defined as vaccinated if he/she had received a vaccine prior to the first day of the month for which he/she served as a control. Information on measles/mumps/rubella vaccination was obtained to provide an independent assessment of potential differences in
vaccination practices between cases and controls. Analytical methods
Cases and controls were initially compared for the presence of several known or suspected risk factors for H. influenzae type b disease by univariate analysis. These variables included sex, history of being breastfed, day-care attendance during the 2 weeks before disease onset/index period, number of persons sleeping in the same room as the case/control child, total household size, number of children less than 5 or 10 years of age. residing in the household, number of persons who smoke in the home, general health prior to disease/index date, concurrent chronic disease or genetic defect, type of facility providing usual medical care for the child, usual method of payment for health care, maternal and paternal ethnicity, maternal and paternal educational level, annual household income, PRP vaccination, PRP-D vaccination (children vaccinated with both PRP-D and PRP removed from analysis), and measles/mumps/rubella vaccination. Each potential risk factor was individually examined with Mantel-Haenszel x2 tests, adjusting (by stratification) for age group (18-23 months, 24-35 months, 3659 months) and index month. Unadjusted comparisons were also made with Fisher's exact test. We verified adjusted univariate results in simple logistic regression models before embarking on the modeling of interactions and confounding of risk factors, which have mathematics assumptions and no parallel in stratification methods. Statistically significant differences between cases and controls were observed for several variables in the univariate analyses. As some of these variables were highly interrelated, we then fit a logistic regression model with two variables at a time to gain a better understanding of the pairwise interaction of these factors and risk for H. influenzae type b disease. For the final analysis of risk factors and for calculation of adjusted odds ratio estimates (OR), a conditional logistic regression
Risk Factors for Invasive Haemophilus influenzae
model was utilized (21). All regression analyses were corrected for age in months (1823 months, 24-35 months, 36-60 months) and month of illness/index month, both known to be significantly related to H. influenzae type b disease risk and probability of vaccination. Of other potential variables, only those found to provide significant independent risk for H. influenzae type b disease in the previous analytical step (pairwise analyses) were used in the model, in order to avoid unstable estimates due to correlated risk factors and multicollinearity. Odds ratio estimates (OR), adjusted for age group, month of disease, vaccination status, and the other independent risk factors, were thus computed for maternal ethnicity, exposure to smoking in the home, and household size. Finally, to confirm that no substantial confounding was overlooked, each factor not in the model was temporarily added to the model on an individual basis to examine the resulting changes in the odds ratio estimates.
RESULTS H. influenzae type b cases and disease incidence
Between July 1, 1988, and July 31, 1989, a total of 380 cases of definite or probable H. influenzae type b occurred in Los Angeles County residents. Of these, 88 were eligible for the study based on study criteria (see Materials and Methods). The annual incidence of invasive H. influenzae type b disease in Los Angeles County for 1988-1989 was 29.9/100,000 children aged 18-23 months, 14.8/100,000 children aged 24-35 months, and 7.8/100,000 children aged 3660 months. Of the 88 eligible cases, 47 (59 percent) had meningitis, 14 (18 percent) had pneumonia, six (8 percent) had epiglottitis, four (5 percent) had facial cellulitis, three (4 percent) had bacteremia alone, two (3 percent) had septic arthritis, and three (4 percent) had multiple sites of H. influenzae type b infection. There was a 4/88 case/fatality ratio (4.5 percent).
225
For 80 (91 percent) of the 88 potentially eligible case children, parents were interviewed by telephone, and for 79 (90 percent), vaccination status was verified by independent physician/clinic interview. Of the remaining eight potentially eligible cases, four could not be contacted even by the visiting public health nurse (one was found not to have a telephone), and an additional four could not be interviewed despite numerous telephone attempts and letters sent to the home. Of the eight noninterviewed cases, more were Hispanic (66 percent of those of known ethnicity vs. 27 percent of interviewed cases), female (75 percent vs. 54 percent of interviewed cases), and hospitalized in a county hospital (88 percent vs. 37 percent of interviewed cases). Controls
A total of 15,299 random telephone numbers were used to obtain controls. Of these, only 34 percent (5,224 numbers) were residential numbers. Of the residential numbers, 92 percent (4,806 numbers) belonged to residences with no children 18-60 months of age, and 1 percent (54 numbers) belonged to families who spoke neither English nor Spanish. Two percent of all households refused the interview. The remainder resulted in 237 control interviews, 223 with sufficient data for inclusion in the current study. Univariate analyses of risk factors
Several basic univariate comparisons of cases and controls are shown in table 1. For the overall study population, cases and controls were similar in sex ratio, proportion attending day care, general health, level of maternal education, prior history of breast feeding, and proportions vaccinated with measles/mumps/rubella and H. influenzae type b PRP vaccine (22). In contrast, cases differed from controls on several other factors, including presence of underlying medical conditions, maternal ethnicity, number of persons or children residing in the home, use of Medicare, smoking in the home, and vaccination with PRP-D vaccine (22).
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TABLE 1. Selected risk and protedve factors for Haemophlhjs Influenzae type b (Hib) disease: univariate comparisons of cases and controls among Los Angeles County, California, children, 1988-1989 Cases*
Controls*
%
Adjusted p value*
0/211
0
2
36/69 23/69 10/69
52 33 14
143/211 63/211 5/211
68 30 2
Breast-fed (history) Vaccinated with PRP§ Vaccinated with PRP-D§ Vaccinated with MMR§
32/69 16/76 3/76 52/71
46 21 4 73
114/209 49/201 48/209 159/201
55 24 23 79
Factor
Nat
%
No.
9/76
12
Attend day care
25/70
Maternal ethnicity Caucasian Black Hispanic Other Total household size 1-3 persons 4-6 persons >6 persons
Concurrent disease^
Children
Vol. 136, No 2 Printed in U.S.A.
Risk Factors for Invasive Haemophilus influenzae Type b in Los Angeles County Children 18-60 Months of Age
C. M. Vadheim,1 D. P. Greenberg,1 N. Bordenave,1 L. Ziontz,1 P. Christenson,1 S. H. Waterman,2 and J. I. Ward1
Potential factors that confer risk or protection for invasive Haemophilus influenzae type b disease were evaluated in Los Angeles County children 18-60 months of age by case-control methods. In this age group, 79 H. influenzae type b cases were identified by overlapping surveillance methods, and 221 random controls were selected by random digit dialing. Cases and controls were similar in sex, prior health, proportion attending day care, parental educational level, history of breast feeding, and proportion vaccinated with measles/mumps/rubella vaccine. The effect of H. influenzae type b vaccination was controlled in all analyses, and results of vaccine efficacy have been reported elsewhere. Cases were more likely to have a significant underlying medical condition, reside in a home with more than six residents, have a lower yearly household Income, have two or more smokers in the home, and to be black. Using conditional logistic regression models, the following were significant independent risk factors after adjusting for age, month of diagnosis, H. influenzae type b vaccine status, and the other factors: 1) more than two smokers in the house (odds ratio (OR) = 6.00; 95% confidence interval (Cl) 1.49-24.06); 2) household size of more than six persons (OR for more than six vs. less than three persons = 3.71; 95% Cl 1.10-12.60); and 3) black maternal race (OR for black vs. Hispanic = 3.47; 95% Cl 1.41-8.53). We conclude that exposure to smoking in the home, living in households with more than six members, and the black race are each independently associated with an increased risk for H. influenzae type b disease in Los Angeles County children and, when combined, constitute a major reason for H. influenzae type b disease occurrence. Am J Epidemiol 1992;136:221-35. ethnic groups; Haemophilus influenzae; immunization; population; risk factors; smoking
Haemophilus influenzae type b remains an important cause of mortality and serious morbidity in children under 5 years of age, despite improved modes of therapy (1-5) and the recent availability of vaccines. How-
ever, the routine use in infants of new H. influenzae type b conjugate vaccines is expected to reduce the incidence of disease significantly, and the identification of special risk groups may facilitate vaccination of
Received for publication June 3, 1991, and in final form February 10, 1992. Abbreviations: Cl, confidence interval; Hboc, Haemophilus mlluenzae type b digosacchande conjugate vaccine; ICD-9, International Classification of Diseases, Ninth Revision; PRP, H. influenzae type b pctysacchande vaccine; PRP-O, H. influenzae type b polysacchande-diptTtherium toxoid conjugate vaccine; OR, odds ratio. 1 UCLA Center for Vaccine Research, Harbor-UCU\ Medical Center, UCLA School of Medicine, Torrance, CA. 2 Acute Communicable Disease Division, Los Angeles County Department of Health Services, Los Angeles, CA. Reprint requests to Dr. C. M. Vadheim, UCLA Center
for Vaccine Research, Harbor-UCLA Medical Center, Bldg. E-6, 1124 W. Carson St, Torrance, CA 90502. This research was supported by a grant from Connaught Laboratories, Inc., Swrftwater, PA. The authors thank Sophia Castro, Christopher Reyes, Debra Turner, and Liberty Teodoro, who spent countless hours ascertaining demographic and clinical information and documenting vaccination histories from hospital personnel, physicians, and parents of H. influenzae type b cases and controls. They also thank Nancie Bendana and Robert Gordon of the Los Angeles County Department of Health Services for their cooperation and help with this project.
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those groups at greatest risk. Previous studies have shown that several factors influence a child's risk for developing invasive H. injluenzae type b disease. These factors include young age (highest risk for children between 6 and 18 months of age) (1, 2, 4, 6-11), presence of underlying immunodeficiency (1, 12, 13), day-care attendance (3, 9, 10, 14), low socioeconomic status (10, 14), living in crowded conditions (9, 10, 14, 15), parental smoking (10), and ethnicity ( 1 , 3 6, 10, 16). Factors shown to be protective include breast feeding (of young infants) (10, 15) and vaccination with H. injluenzae type b vaccines (17, 18). Los Angeles County, California, provides a unique setting in which to conduct population-based studies of invasive H. injluenzae type b disease. It is among the largest and most diverse populations in the United States, and invasive H. injluenzae type b disease has been reportable since 1982. The purpose of this study was to examine in detail the effects of several risk and protective factors for invasive H. injluenzae type b disease in children 18 months of age and older, using a case-control study design and controlling for the effects of H. injluenzae type b vaccination. MATERIALS AND METHODS Study population
The study was conducted between July 1, 1988, and July 31, 1989, for all of Los Angeles County (total population, 8.7 million; 750,000 persons under the age of 5 years). The population is ethnically diverse; in the age group less than 5 years of age, 47 percent of the population is Hispanic, 29 percent is Caucasian (non-Hispanic), 15 percent is black, and the remainder (9 percent) is composed of many other ethnic groups (Los Angeles County statistics (19)). Only children 18-59 months of age were included in this study. Surveillance methods and case ascertainment
The county is served by 151 acute-care hospitals and six independent microbiology
laboratories, which were the basis of H. injluenzae type b case ascertainment. H. injluenzae type b cases were ascertained using multiple overlapping case-finding methods. Invasive H. injluenzae type b has been reportable in Los Angeles County since 1982 and in the state of California since 1989. On the basis of past surveillance (1988-1990), we estimate that 75-80 percent of invasive H. injluenzae type b cases are reported to the Health Department as required (passive surveillance). To ensure more complete surveillance, several methods of active case finding were initiated in 1988. A letter about the H. injluenzae type b surveillance program was sent to all hospital, laboratory, and medical records directors of each hospital/laboratory serving Los Angeles County residents, and meetings were held with all infection control practitioners to solicit their participation in the project. Active surveillance involved telephoning these practitioners in each hospital once or twice each month to ascertain suspected cases of invasive H. injluenzae type b disease. In addition, all hospital and independent laboratories with the capability of processing blood and cerebrospinal fluid cultures, serotyping, and/or performing latex agglutination tests for H. injluenzae type b were contacted by telephone at least once each month. Finally, laboratory logs from a random sample of approximately 50 percent of laboratories were searched for any specimen from a sterile body site that was positive for H. injluenzae type b, and in-patient hospital medical records were searched to ascertain additional cases. Reviews of medical records were performed by examining all charts with any of the following discharge diagnoses: H. injluenzae type b meningitis {International Classification of Diseases, Ninth Revision (ICD9), code 320.0), H. injluenzae type b bacteremia (ICD-9 code 038.41), H. injluenzae type b pneumonia (ICD-9 code 482.2), other H. injluenzae disease (ICD-9 code 041.5), acute epiglottitis (ICD-9 code 464.3), septic arthritis (ICD-9 code 711.0), facial cellulitis (ICD-9 code 682.0), and abscess of eyelid (ICD-9 code 373.13). Medical records were reviewed at all large hospitals on a quarterly
Risk Factors for Invasive Haemophilus influenzae 223
basis; and medium-size hospitals (five to ten H. influenzae type b cases per year) were reviewed on a biannual basis. Medical records from a 20 percent sample of the small hospitals were reviewed after the first 6 months of the study, and no unreported cases were found. Therefore, chart reviews at the small hospitals were conducted only once, at the end of the study. From the analysis of all surveillance data (1988 to present), we estimate that only 3 percent of all H. influenzae type b cases (including suspect cases) are found by medical records review. For each case, the following demographic, clinical, and laboratory information was obtained, primarily from hospital medical and laboratory records and from health department records: name, city of residence, telephone number, race, sex, date of birth, dates of hospitalization, date of onset of symptoms, details on laboratory results (date, site of specimen, test results), H. influenzae type b diagnoses, disease outcome, and any concurrent medical conditions. A total of 380 cases were identified in all age groups. However, only cases meeting the following criteria were eligible for inclusion in the case-control study: 1) met the case definitions of "definite" or "probable" invasive H. influenzae type b disease (see below); 2) resident of Los Angeles County for at least 1 month prior to onset of H. influenzae type b disease; 3) age between 18 and 59 months at onset of H. influenzae type b disease; and 4) accessible by home telephone (95 percent). A total of 88 cases met these criteria. For each case, the primary physician was interviewed by telephone to obtain additional information on clinical illness, concurrent medical conditions, and vaccination status and to obtain permission to contact the case's parent. Cases were classified as "definite," "probable," or "suspected" invasive H. influenzae type b disease using the following case definitions: 1) definite case: clinical findings consistent with invasive H. influenzae type b infection plus cultures positive for H. influenzae type b from a normally sterile body site, or clinical signs and symptoms consis-
tent with epiglottitis plus a positive culture from the pharynx, epiglottis, or blood; 2) probable case: clinical findings consistent with invasive H. influenzae type b infection plus H. influenzae type b antigen (by latex particle agglutination test) positive in cerebrospinal fluid, blood, joint fluid, or fluid from other normally sterile body site; 3) suspected case: other clinically suspected cases. Only definite and probable cases were included in this study. All H. influenzae type b strains were shown to be serotype b by slide agglutination, counterimmunoelectrophoresis, and/or type b capsular gene probe analysis (courtesy of E. Richard Moxon, Oxford, England). Selection of controls
Controls were obtained by random digit dialing of telephone numbers throughout Los Angeles County. A series of random telephone numbers was generated by computer, using randomly selected Los Angeles County prefixes and randomly generated suffixes. Each number was called systematically to identify households containing at least one child between 18 and 60 months of age. Each number was called until it was either resolved or until at least 12 calls were made, over a span of 6 weeks and covering days, nights, and weekends. Since vaccination practices changed over the course of the study, controls were indexed by month of illness of the case, with the goal of obtaining approximately 2-3 age-appropriate controls for each case stratified for time of illness. In families with more than one eligible control child, the youngest was used as the control. Case and control survey
After obtaining verbal consent, we interviewed parents of cases and controls using a standardized telephone questionnaire (in English or Spanish) to obtain further details of the child's H. influenzae type b illness (cases only), names and addresses of all physicians/clinics caring for the child, and information about possible risk factors for H. influenzae type b disease. Specifically, information was obtained on sex and date of
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Vadheim et al.
birth of the child, breast-feeding history, general health, concurrent medical conditions, day-care attendance (size, number of hours attended per week), parental ethnicity, parental education and occupation, total yearly household income, household composition, number of persons sleeping in the same room as the case/control, number of smokers in the household, and the source and method of payment for the child's usual medical care. For cases and controls, all questions were based on conditions during the 2-week period prior to onset of//, influenzae type b disease or the 2 weeks prior to the first of the month for which they served as a control (index period). For purposes of the study, day-care attendance was defined as any child care arrangement involving at least two nonrelated children and lasting at least 4 hours per week in the 2 weeks prior to diagnosis (beginning of index month for controls). Day care was further categorized as day-care home, small day-care center (less than five children), and large day-care center. Maternal and paternal occupations and socioeconomic status were categorized using the method of Green (20), which was developed for scoring socioeconomic status for health behavior research. To determine vaccination history, we interviewed all physicians/clinics caring for cases and controls by telephone to obtain the date, manufacturer, and lot number (when possible) of any H. influenzae type b vaccination (//. influenzae type b polysaccharide vaccine (PRP), PRP-diphtheria toxoid conjugate vaccine (PRP-D; Prohibit; Connaught Laboratories, Inc., Swiftwater, Pennsylvania), Haemophilus b oligosaccharide conjugate vaccine (Hboc; Hib TITER; Lederle/Praxis, Rochester, New York)) and measles/mumps/rubella vaccination. A case child was defined as being vaccinated if he/ she had received a vaccine prior to the date of onset of disease. A control child was defined as vaccinated if he/she had received a vaccine prior to the first day of the month for which he/she served as a control. Information on measles/mumps/rubella vaccination was obtained to provide an independent assessment of potential differences in
vaccination practices between cases and controls. Analytical methods
Cases and controls were initially compared for the presence of several known or suspected risk factors for H. influenzae type b disease by univariate analysis. These variables included sex, history of being breastfed, day-care attendance during the 2 weeks before disease onset/index period, number of persons sleeping in the same room as the case/control child, total household size, number of children less than 5 or 10 years of age. residing in the household, number of persons who smoke in the home, general health prior to disease/index date, concurrent chronic disease or genetic defect, type of facility providing usual medical care for the child, usual method of payment for health care, maternal and paternal ethnicity, maternal and paternal educational level, annual household income, PRP vaccination, PRP-D vaccination (children vaccinated with both PRP-D and PRP removed from analysis), and measles/mumps/rubella vaccination. Each potential risk factor was individually examined with Mantel-Haenszel x2 tests, adjusting (by stratification) for age group (18-23 months, 24-35 months, 3659 months) and index month. Unadjusted comparisons were also made with Fisher's exact test. We verified adjusted univariate results in simple logistic regression models before embarking on the modeling of interactions and confounding of risk factors, which have mathematics assumptions and no parallel in stratification methods. Statistically significant differences between cases and controls were observed for several variables in the univariate analyses. As some of these variables were highly interrelated, we then fit a logistic regression model with two variables at a time to gain a better understanding of the pairwise interaction of these factors and risk for H. influenzae type b disease. For the final analysis of risk factors and for calculation of adjusted odds ratio estimates (OR), a conditional logistic regression
Risk Factors for Invasive Haemophilus influenzae
model was utilized (21). All regression analyses were corrected for age in months (1823 months, 24-35 months, 36-60 months) and month of illness/index month, both known to be significantly related to H. influenzae type b disease risk and probability of vaccination. Of other potential variables, only those found to provide significant independent risk for H. influenzae type b disease in the previous analytical step (pairwise analyses) were used in the model, in order to avoid unstable estimates due to correlated risk factors and multicollinearity. Odds ratio estimates (OR), adjusted for age group, month of disease, vaccination status, and the other independent risk factors, were thus computed for maternal ethnicity, exposure to smoking in the home, and household size. Finally, to confirm that no substantial confounding was overlooked, each factor not in the model was temporarily added to the model on an individual basis to examine the resulting changes in the odds ratio estimates.
RESULTS H. influenzae type b cases and disease incidence
Between July 1, 1988, and July 31, 1989, a total of 380 cases of definite or probable H. influenzae type b occurred in Los Angeles County residents. Of these, 88 were eligible for the study based on study criteria (see Materials and Methods). The annual incidence of invasive H. influenzae type b disease in Los Angeles County for 1988-1989 was 29.9/100,000 children aged 18-23 months, 14.8/100,000 children aged 24-35 months, and 7.8/100,000 children aged 3660 months. Of the 88 eligible cases, 47 (59 percent) had meningitis, 14 (18 percent) had pneumonia, six (8 percent) had epiglottitis, four (5 percent) had facial cellulitis, three (4 percent) had bacteremia alone, two (3 percent) had septic arthritis, and three (4 percent) had multiple sites of H. influenzae type b infection. There was a 4/88 case/fatality ratio (4.5 percent).
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For 80 (91 percent) of the 88 potentially eligible case children, parents were interviewed by telephone, and for 79 (90 percent), vaccination status was verified by independent physician/clinic interview. Of the remaining eight potentially eligible cases, four could not be contacted even by the visiting public health nurse (one was found not to have a telephone), and an additional four could not be interviewed despite numerous telephone attempts and letters sent to the home. Of the eight noninterviewed cases, more were Hispanic (66 percent of those of known ethnicity vs. 27 percent of interviewed cases), female (75 percent vs. 54 percent of interviewed cases), and hospitalized in a county hospital (88 percent vs. 37 percent of interviewed cases). Controls
A total of 15,299 random telephone numbers were used to obtain controls. Of these, only 34 percent (5,224 numbers) were residential numbers. Of the residential numbers, 92 percent (4,806 numbers) belonged to residences with no children 18-60 months of age, and 1 percent (54 numbers) belonged to families who spoke neither English nor Spanish. Two percent of all households refused the interview. The remainder resulted in 237 control interviews, 223 with sufficient data for inclusion in the current study. Univariate analyses of risk factors
Several basic univariate comparisons of cases and controls are shown in table 1. For the overall study population, cases and controls were similar in sex ratio, proportion attending day care, general health, level of maternal education, prior history of breast feeding, and proportions vaccinated with measles/mumps/rubella and H. influenzae type b PRP vaccine (22). In contrast, cases differed from controls on several other factors, including presence of underlying medical conditions, maternal ethnicity, number of persons or children residing in the home, use of Medicare, smoking in the home, and vaccination with PRP-D vaccine (22).
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Vadheim et al.
TABLE 1. Selected risk and protedve factors for Haemophlhjs Influenzae type b (Hib) disease: univariate comparisons of cases and controls among Los Angeles County, California, children, 1988-1989 Cases*
Controls*
%
Adjusted p value*
0/211
0
2
36/69 23/69 10/69
52 33 14
143/211 63/211 5/211
68 30 2
Breast-fed (history) Vaccinated with PRP§ Vaccinated with PRP-D§ Vaccinated with MMR§
32/69 16/76 3/76 52/71
46 21 4 73
114/209 49/201 48/209 159/201
55 24 23 79
Factor
Nat
%
No.
9/76
12
Attend day care
25/70
Maternal ethnicity Caucasian Black Hispanic Other Total household size 1-3 persons 4-6 persons >6 persons
Concurrent disease^
Children
