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Primary invasive Haemophilus influenzae type b disease: A population-based assessment of risk factors
Primary invasive Haemophilus influenzae type b disease: A population-based assessment of risk factors We performed a population-based case-control study of risk factors for primary invasive Haemophilus influenzae type b (Hib) disease in metropolitan Atlanta from July I, 1983, through June 30, 1984. Active surveillance identified 102 cases in children <5 years of age, 89 of whom lived in households with telephones. We used random digit dialing to select 530 controls who were postmatched to cases by age. Multivariate analysis showed a significant association between Hib disease and two independent exposure factors, household crowding (odds ratio [OR] 2.7, 95% confidence limits [CL] 1.3 to 5.6) and day-care attendance. For day-care attendance, relative risk was highest in 2- to 5-month-old infants (OR 17.7, 95% CL 5.8 to 54.4) and declined to 9.4 (4.3 to 20.9) at ages 6 to 11 months, 5.0 (2.7 to 9.3) at 12 to 23 months, 2.7 (1.3 to 5.5) at 24 to 35 months, and 1.4 (0.5 to 4.0) in 36- to 59-month-old children. Fifty percent of all invasive Hib disease that occurred during the study period was attributable to exposure to day-care; the attributable risk for household crowding was 18%. Dose-response effects were observed for hours per week of day-care attendance and extent of household crowding. Breast-feeding was protective for infants <6 months of age (OR 0.08, 95% CL 0.01 to 0.59). After controlling for socioeconomic and o t h e r confounding factors, we could demonstrate no effect of black race on cumulative risk of invasive Hib disease. Our study defines high-risk groups and provides a population-based model of the interrelationship between risk factors associated with invasive Hib disease. (J PEDIAI"R1986;108:887-896) Stephen L. Cochi, M.D., David W. Fleming, M.D., Allen W. Hightower, M.S., Khanchit Limpakarnjanarat, M.D., M.P.H,, Richard R. Facklam, Ph.D., J. David Smith, B.S,, R. Keith Sikes, D.V.M., M.P.H,, a n d Claire V. Broome, M.D. From the Meningitis and Special Pathogens Branch, Statistical Services Activity, and Respiratory Diseases Branch, Division of Bacterial Diseases, and the Division of Field Services, Epidemiology Program Office, Centers for Disease Control; and the Office of Epidemiology, Georgia Department of Human Resources, Atlanta
Haemophilus influenzae type b is the leading cause of bacterial meningitis in the United States and accounts for an estimated 12,000 cases per year, primarily in children <5 years of age. Nonmeningitic invasive forms of Hib
Submitted for publication Aug. 20, 1985; accepted Dec. 27, 1985. Reprint requests: Stephen L. Cochi, M.D., Division of Immunization, Centers for Disease Control, Freeway Park, Room 367, Atlanta, GA 30333.
infection increase this annual burden to nearly 20,000 cases per year. ~ Although invasive Hib disease occurring in multiple members of a household was reported as long ago as 1909, 2 only within the last decade has documented evidence
CL Hib OR
Confidencelimits
Haemophilusinfluenzae type b Odds ratio
887
888
Cochi et al.
The Journal of Pediatrics June 1986
,300-
5
:"
"..
ATLANTA -- ALL RACES
250 /
//~ - " ~
REFERENCE
..............
U.S.*
l:z
200
>o o o o o
150
c..
(/3 i,i O3 <
\ \ '".....
1 O0
50-
0-5
6-11
AGE
J 12-17
' 18-23
(MONTHS)
~
I
l
'
2
'
'
AGE
3
J
'
4
'
(YEARS)
"SOURCE: JAMA 1985;253:521--9
Figure. Age- and race-specific incidence of invasiveH. influenzae disease, Atlanta, July 1983 through June 1984.
become available that invasive Hib disease is contagious. Published studies of secondary spread of Hib disease in contacts of index cases have documented a significant increase in the risk of illness in both household and day-care classroom contacts, 3-9 although unpublished data!0, H have made the issue of day-care contacts controversial. However, secondary invasive Hib disease occurring in any setting accounts for only 1% to 2% of all invasive Hib disease? Defining risk factors for acquisition of primary disease, therefore, assumes considerable public health importance. Several risk factors have been linked with the occurrence of invasive Hib disease. 12 Young age is associated with the highest incidence, but passive protection of some infants bY transplacentally acquired maternal antibody is thought to delay peak attack rates until age 6 or 7 months? The age-specific incidence curve may be shifted to the left in populations with especially high incidences of Hib disease ~3~6or to the right in populations with lower attack ratesJT,,8 Gender has not been an important predictor of disease in most studies; however, one population-based study x9 and national surveillance data ~~show attack rates to be substantially higher in boys than in girls. In several studies, the incidence of Hib meningitis in children <5
years of age was two to four times higher in black children than in white children, 19,2~27 and the incidence of all invasive Hib disease four times higher in blacks than in whites? High incidences of invasive Hib disease have also been observed in Hispanics3,24 and Native Americans.*13-]6 Although some investigators have suggested that these racial and ethnic differences in incidence of disease may be related to genetically determined differences in host susceptibility,28-35 this conclusion i s uncertain because of possible confounding socioeconomic variables. For example, increased attack rates of Hib meningitis have been observed in association with increased household size36,37 and population density,27and with low family income22,23,27 and education level. 23,~7 Increased use of child day-care facilities has focused attention on the role of this exposure as a risk factor for acquisition of primary Hib disease.3~, 39 Finally, breast-feeding of infants has been shown to be a significant protective factor. 39'4~ An approach that assesses the relative importance of *Readersoutsidethe UnitedStates mayneedan explanationof this term which currentlyis beingappliedby the U.S. CensusBureauto American Indians.--J.M.G.
Volume 108 Number 6 these many factors and determines which associations are affected by confounding variables has been lacking. The purpose of our study was to examine risk factors for primary invasive Hib disease by using a population-based case-control approach, and to synthesize a disease model that describes how these risk factors interact to produce the pattern of primary Hib disease observed in the study population. METHODS Study population. The study area consisted of the seven-county metropolitan area of Atlanta (1980 U.S. census population: 1,779,226), which has a racial-ethnic distribution of 73% white, 26% black, and 1% other racial or ethnic groups. Case finding. From July 1, 1983, through June 30, 1984, we conducted active surveillance for invasive Hib disease using two independent reporting systems: hospital infection control practitioners and bacteriology laboratories. All infection control practitioners and bacteriology laboratory directors in the study area (37 hospitals) were contacted and enrolled. Hospital infection control practitioners reported cases every week to the Georgia Department of Human Resources, Office of Epidemiology. Bacteriology laboratories independently filed case reports of all H. influenzae isolates from normally sterile body sites and forwarded these isolates to the CDC for bacteriologic confirmation and serotyping. Completeness of reporting was validated by reviewing the bacteriology records at all hospitals in the study area for the first 6 months of the study period and at the two hospitals with the largest pediatric services for the entire 12 months. Case definition. A case was defined as any child <5 years of age residing in the seven-county metropolitan Atlanta area from whom H. influenzae was cultured from a normally sterile body site, and who had clinical signs of infection. Any children whose clinical isolates were other than serotype b were excluded. A child was considered to have secondary Hib disease if onset of illness occurred from 1 to 60 days after exposure to a primary case in the same household or day-care facility and the outer membrane protein profile of the second case matched the profile of the primary case, if both were available? Only the first episodes in children with recurrent disease were included in the case-control study. Case survey. We contacted a parent of each case child by telephone or home visit from 1 to 6 months (median 57 days) after onset of illness and administered a questionnaire after obtaining informed consent. The following information was obtained: age, gender, and race or ethnicity of all children <5 years of age in the household, age and race or ethnicity of other persons in the household, number
R i s k factors in Hib disease
889
Table I. Frequency of selected variables for cases and controls, Atlanta, 1983 to 1984
Cases (n = 89) n
Controls (n = 530)
%
n
%
58 42
286 244
54 46
58 39 2 65
387 134 9 205
73 25 2 39
15 36 48 1
51 165 311 3
10 31 59 1
12 27 22 38
98 161 133 135 3
18 30 25 25 1
10 25 19 18 20 7 1
29 87 117 133 83 60 21
5 16 22 25 16 11 4
47 53 12
299 227 4 48/138
56 43 1 35
49
229
43
Sex
Male 52 Female 37 Race White 52 Black 35 Other 2 Day-care or nursery 58 attendance Mother's education (yr) <12 13 12 32 13+ 43 Missing 1 Crowding (persons per room) 0-0.45 11 0.451-0.60 24 0.61-0.79 20 0.80+ 34 Missing Family income <$5,000 9 $ 5,000-$14,999 22 $15,000-$24,999 17 $25,000-$34,999 16 $35,000:$49,999 18 $50,000 6 Missing 1 Other persons sleeping in same room 0 42 1+ 47 Missing Breast-feeding at 5/42 reference month Parent smoking 44
of rooms in the house, presence of a telephone, family income, and education level of parents. The format of these questions was taken directly from the 1980 U.S. census long-form questionnaire. Information was also obtained on the child's breast-feeding history, number of persons sleeping in the same room as the child, parental smoking, day-care or nursery school attendance since the beginning of the study period, and frequency of such attendance. Day-care was defined as any regular (>4 hr/wk) supervised care of at least two unrelated children. A child was
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The Journal of Pediatrics June 1986
T a b l e II. Age-specific relative risks for primary Hib disease by selected exposure variables, univariate matched analysis, Atlanta, 1983 to 1984 Odds ratio" by a g e group (mo) 2-5 Black race Mean Range Day-care Mean Range Extreme crowding ( E l person per room) Mean Range Low family income (<$15,ooo) Mean Range Breast-feeding (
0.3
6-11
12-23
24-35
36-59
All ages
1.3
5.0t 1.9-13.2
3.2
1.1
1.7t 1.0-2.9~
12.8t 3.3-5.0
5.4"~ 1.8-17.0
3.2t 1.2-8.4
3.5
0.9
3.9t 2.3-6.6
1.1
6.6~ 1.6-26.0
2.7
3.5
1.9
2.6t 1.5-4.5
0.8
1.7
2.0
7.8I" 1.8-35.0
1.2
1.8t 1.1-3.0
0.21 0.04-0.96
0.3
NA
NA
NA
0.3t 0.1-0.8
0.8
1.2
3.7t 1.3-10.0
0.4
0.9
1.2 0.8-2.0
0.8
1.0
2.5I" 1.0-6.5
1.1
1.6
1.4 0.8-2.2
0.7
2.0
2.0
1.8
1.1
1.5 0.9-2.4
1.7
1.2
1.7
1.3
0.5
1.3
0.8-2.0
NA, Not available, *Age- and reference month matched. tConfidence limits indicate statistically significant association. :[:95%confidencelimits.
classified as a day-care attendee if he or she attended for at least 16 hours in the month before, or 4 hours in the week before illness. 9 Control survey. A t the conclusion of the study period, we identified a random sample of children <5 years of age residing in the study area, using simple random digit dialing procedures. 41,4~ Each telephone number was contacted eight times before being discarded, of which six calls were during evening and weekend hours. After obtaining informed consent, a questionnaire was administered to the parent of each of the 557 children selected, with a format similar to that of the case survey. Data were collected for all children <5 years of age in a given household. A 15% sample of questionnaires was validated by having one of the investigators contact the parents again by telephone to
verify that the respondent was interviewed and to readminister parts of the survey instrument. Postmatching. After all information had been collected, controls were postmatched to cases by date of birth within 6-month age categories for all case-control pairs <2 years of age (0 to 5, 6 to 11, 12 to 17, and 18 to 23 months), and within 12-month age categories for pairs ~ 2 years of age. The method of minimum distance case-control matching 43 was used, and the matching ratio followed a variablematching ratio plan\. 44 Because no case children were <2 months of age, 27 control children who were <2 months of age at the time of postmatching were excluded to maximize the comparability of cases and controls; data for the remaining 530 children were analyzed. The onset month of Hib disease in the case was used as the reference month for
Volume 108 Number 6 determining day-care and breast-feeding status in matched controls. Laboratory methods. H. influenzae isolates were confirmed by standard procedures 45 and serotyped by slide agglutination with specific antisera. When secondary cases were suspected, we tested isolates in a blinded fashion to determine biotype and outer membrane protein type; outer membrane protein preparations were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in two gel systems as previously described by Barenkamp et al.46 Statistical methods. Potential risk factors, confounders, and effect modifiers were evaluated in conditional logistic regression models.47 The general modeling strategy was as follows: (1) to use backward elimination procedures whenever possible, (2) to eliminate nonsignificant effect-modification terms before any confounders or risk factors were evaluated, and (3) to keep low-order interaction terms regardless of significance when a higher-order term was significant:4 Indicator variables were used in models that examined the relationship between age, which had five categories, and day-care attendance and race, to verify the linear (for day-care) or quadratic (for race) relationship with the log-odds ratio and increasing age category before incorporating these assumptions into the final multivariate model. All computations of etiologic fractions, prevented fractions, and etiologic or prevented fractions in the exposed cases used the OR estimates obtained from the final multivariate model.44 RESULTS Surveillance. During the 12-month study period, 159 cases of invasive H. influenzae disease were identified; 135 cases were in children who resided in the study area and 114 (84%) of these were in children <5 years of age. Retrospective review of bacteriology laboratory records showed that only five (3%) of 159 cases were not reported through the surveillance system. The annual incidence of invasive H. influenzae disease was 82 cases per 100,000 children <5 years of age. The incidence of meningitis was 57/100,000 and of other invasive disease, 25/100,000. Age-specific attack rates were similar to rates observed in other studies in which active surveillance was conducted t (Figure). Serotyping information was available from CDC for 99 (87%) of 114 isolates: 97 were serotype b, one isolate was serotype a, and one isolate was nontypeable. For analysis of risk factors for primary Hib disease, we excluded the two non-serotype b cases, four cases (3.6%) with secondary invasive Hib disease, and three cases (3%) with recurrent disease. We were unsuccessful in contacting three families (3%) of case children. Thus, 102 (97%) of
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Table III. Dose-response relationship of primary Hib disease to day-care attendance and crowding Cases
O d d s of disease
Odds ratio
325 58 41 79 27
0.10 0.12 0.20 0.39 0.44
1.0" 1.3 2.0 4.1 4.7
98 161 133 135
0.! 1 0.15 0.15 0.25
1.0" 1.3 1.3 2.2
Controls
Day-care attendance (hr/wk) 0-4 31 5-19 7 20-39 8 40-49 31 50+ 12 Crowding (persons/room) 0-0.45 11 0.451-0.60 24 0.61-0.79 20 0.80+ 34 *Reference group.
105 case children with primary invasive Hib disease were enrolled in the case-control study. Case-control surveys. For the case survey, 42 (41%) of the 102 case families enrolled were interviewed during a home visit, including all 13 case families without telephones; the remainder were interviewed by telephone. The main case-control analysis included only the 89 cases in which the families had telephones. For the population control survey, we identified 3977 households from 11,525 randomly selected telephone numbers; 96% of telephones were answered. Ninety-eight percent of households cooperated with telephone screening to identify whether they contained children <5 years of age; such households comprised 13% of all households screened. The interview response rate of households selected was 93%. The frequency of selected study variables obtained from the case and control surveys is shown in Table I. Risk factors: Univariate analysis. Univariate analysis revealed that a number of exposure and host susceptibility factors were apparently associated with primary Hib disease (Table II). Black race, day-care attendance, household crowding, and low family income were associated with increased relative risk for Hib disease; breast-feeding was protective for infants 2 to 5 months of age. No significant differences in these effects were observed when the analyses were stratified by meningitic vs nonmeningitic disease; all clinical syndromes were, therefore, considered together for the remaining analyses. Race. Black children were at significantly increased relative risk of primary Hib disease compared with white children (OR 1.7, 95% CL 1.0 to 2.9). This increased relative risk seemed to be limited primarily to blacks 12 to 35 months of age. The age distribution of the 35 cases in black children was as follows: 2 to 5 months of age three, 6
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T a b l e IV. Multivariate model of relative risks for primary Hib disease, Atlanta, 1983 to 1984 Risk factor
Day-care
Black race
Extreme crowding Low family income Breast-feeding
A g e group
Relative risk
95% C o n f i d e n c e limits
P value
2-5 mo 6-11 mo 12-23 mo 24-35 mo 36-59 mo 2-5 mo 6-11 mo 12-23 mo 24-35 mo 36-59 mo 0-4 yr 0-4 yr 2-5 mo 6-11 mo
17.7 9.4 5.0 2.7 1.4 0.05 0.8 3.3 3.1 0.7 2.7 1,6 0.08 0.68
5.8-54.4 4.3-20.9 2,7-9.3 1.3-5.5 0.5-4.0 0.01-0.36 0.3-2.1 1.3-8.1 1.3-7.5 0.2-2.7 1,3-5.6 0;8-3.3 0.01-0.59 0.15-3.2
<0.0001 <0,0001 <0.0001 <0.004 NS <0.007 NS <0.005 <0.005 NS <0.004 NS <0.007 NS
NS, Not significant. to 11 months nine, 12 to 23 months 15, 24 to 35 months five, and 36 to 59 months three. Gender. The distribution of cases by gender (58% male) was not statistically different than the distribution in the study population (54% male). Day-care/nursery attendance. At the time of illness, 65% of case children attended day-care facilities compared with 39% of controls (OR 3.9, 95% CL 2.3 to 6.6, age and reference month matched). The magnitude of the association of day-care attendance with primary Hib disease was highly age dependent. The peak OR was 12.8 for children 2 tO 5 months of age; ORs decreased with increasing age (Table II). An increasing number of hours per week of attendance at day-care was associated with an increasing relative risk of disease when the data were examined in an unmatched fashion (Table III). Crowding. Twenty-six (29%) of 89 case children resided in households containing >__1 person per room, compared with 68 (13%) of 527 controls (OR 2.6, 95% CL 1.5 to 4.5) (Table II). The magnitude of risk associated with crowding increased as the extent of crowding increased, when an unmatched analysis was performed (Table III). Income and other socioeconomic variables. Family income of <$15,000 was reported by a greater percentage of case families (35%) than of control families (21%) and was significantly associated with risk for Hib disease (OR 1.8, 95% CL 1.1 to 3.0). The presence of other persons sleeping in the same room as a child was not associated with a significantly increased relative risk for Hib disease in the univariate matched analysis (OR 1.5, 95% CL 0.9 to 2.4). Children whose mothers had 12 or fewer years of education were not significantly more likely to be cases (51%) than controls (41%). Large household size and the presence of school-aged household members were not associated with risk for Hib disease.
Breast-feeding. Control children < 1 year of age had a significantly higher prevalence of breast-feeding (35%) than case children (12%) (Table II). The apparent protective effect of breast-feeding was greatest for infants <6 months of age and was not statistically significant in 6 to 11-month-old infants alone. Smoking. No effect of exposure to smoking by parents was evident. Risk factors: Multivariate model. Multivariate statistical modeling was used to control for potential confounding variables as well as to account for effect modification, and thereby improve the precision of our estimates of relative risks for Hib disease. Variables included in the final multivariate model are listed in Table IV. Exposure factors. Confirming the results of the univariate analysis, the model showed that attendance at daycare was most strongly associated with risk for Hib disease for children 2 to 5 months of age, and that relative risk decreased with increasing age of the child (Table IV). Risk was not significantly elevated for children >_3 years of age. Extreme household crowding remained significantly associated with Hib disease in the multivariate model (OR 2.7, 95% CL 1.3 to 5.7). In contrast, low family income, which was highly correlated with household crowding among controls (X2 = 57.2, P <10-"), did not demonstrate a significant association with Hib disease after adjustment (Table IV). Other socioeconomic variables that correlated strongly with household crowding demonstrated no independent association with risk for Hib disease when entered individually into the multivariate model. These variables included household size (OR 1.13, 95% CL 0.95 to 1.33), presence of other persons sleeping in the same room as a study child (OR 1.3, 95% CL 0.7 to 2.5), other children <5 years of age in the household (OR 0.8, 95% CL 0.5 to 1.5),
Volume 108 Number 6
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893
T a b l e V. Attributable risk for primary Hib disease, by exposure variable, Atlanta, 1983 to 1984 Prevalence of exposure (%)
Etiologic fraction
Odds ratio es|imates
or
Exposure variable Day-care attendance 0-4 yr 2-5 mo 6-11 mo 12-23 mo 24-35 mo 36-59 mo Black race 0-4 yr 2-5 mo 6-11 mo 12-23 mo 24-35 mo 36-59 mo Extreme crowding Low family income Breast-feeding <1 yr 2-5 mo 6-11 mo
Cases
Controls
Univariate
Multivariate
EF~
prevented fraction (%)
65 71 56 71 60 55
39 15 21 43 29 53
3.9 12.8 5.4 3.2 (3.5)* (0.9)
-17.7 9.4 5.0 2.7 (1.4)
0.77 0.94 0.89 0.80 0.63 0.33
5O 67 5O 57 38 16
39 19 35 58 50 27 29 35
25 31 33 21 23 24 13 2l
1.7 (0.3) (1.3) 5.0 (3.2) (1.1) 2.6 1.8
-0.05 (0.8) 3.3 3.1 (0.7) 2.7 (1.6)
0.01 -0.95]. -0.20]" -0.70 0.68 -0.30]" 0.63 0.38
0 -78t -St 41 34 -lOt 18 !3
12 13 12
35 43 25
0.3 0.2 (0:3)
-0.08 (0.68)
-0.55t -0.92]" -0.32]"
-59t -5t
-25?
EFt, Etiologic fraction among exposed cases, or proportion of exposed cases that are caused by risk factor. *Parentheses indicate O R not significantly above or below 1. ]'Negative sign indicates prevented fraction or prevented fraction among exposed cases for factors that are protective.
elementary school-aged children in the household (OR 1.2, 95% CL 0.8 to 1.9), and school-aged Children 5 to 18 years of age in the household (OR 1.1, 95% CL 0.8 to 1.6). Among controls, two variables correlated strongly with mothers who had 12 years or fewer of education: low family income (X2 = 51.4, P <10 -~2) and household crowding (X2 = 27.6, P <10-6). After controlling for confounding, no independent protective effect of high maternal education level (i.e., at least 1 year of college) could be demonstrated (OR 0.6, 95% CL 0.3 to 1.1). Host factors. The association of black race with risk for Hib disease was quadratic by age group (Table IV). Black children 2 to 5 months of age had a significantly lower relative risk for Hib disease than white Children; however, the relative risk was increased for black children 12 to 35 months of age, as was observed in the univariate analysis. M u c h o f the decrease in the adjusted relative risk for 2- to 5-m0nth-old black children calculated in the multivariate model resulted from controlling for the protective effect of breast-feeding, a praQtice that was absent among cases in blacks in that age group. The protective effect of breast-feeding among children 2 to 5 months of age was still evlden!! in .the multivariate model (OR 0.08, 95% CL 0.01 to 0.59)i but in 6- to 11-month,old children, the effect of breast-feeding was not significant (Table IV).
Two other study variables demonstrated no association with risk for Hib disease when entered individually into the multivariate model: male sex (OR 1.3, 95% CL 0.8 to 2.3) and parental smoking (OR 1.0, 95% CL 0.6 to 1.8). Of the 13 case children who lived in households without telephones, eight were male, six were black, 11 had family income of <$15,000 per year, seven lived in households with one or more persons per room, and three attended day-care. Including these 13 case children in the multivariate model had no substantial effect on the OR estimates for any risk factors except low family income. By including these cases, low family income became a statistically significant risk factor (OR 2.2, 95% CL 1.2 to 4.2). This confirmed our decision to exclude these cases from the a.nalysis to preserve the comparability of our cases and controls. However, exclusion of cases i0 low-income families may have minimized our ability to detect a significant association of low income with Hib disease. DISCUSSION In this study, cases of primary invasive Hib disease identified by prospective disease surveillance were compared with a control group randomly selected from the same study poPUlation by random digit dialing. We evaluated the aSsociation of both exposure variables and host susceptibility factors with risk for primary invasive Hib
894
Cochi et al.
disease, first by matched univariate analysis and then in a multivariate model. Two host susceptibility factors were related to disease risk: breast-feeding was protective for infants 2 to 5 months of age, and black race was protective in certain age groups and a risk factor in others. Two exposure factors, day-care attendance and household crowding, were associated with increased risk for Hib disease. For day-care, increased relative risk was highest in 2 to 5-month-old infants and exhibited a linear decline with increasing age; relative risk was not significantly elevated in children 3 years or older. Both day-care and household crowding exhibited dose-response effects in the univariate analysis, although these effects were unstable and could not be clearly demonstrated in the multivariate model. These two risk factors may operate by increasing the likelihood of exposure to sources of acquisition of Hib bacteria. The results of our risk factor analysis can be placed in the broader public health perspective. Because our control subjects were a random sample of the entire study population, we can calculate the proportion of all cases attributable to a given risk factor (the etiologic fraction). The etiologic fraction thus provides an estimate of the expected reduction in disease in the population after removal of the risk factor. An analogous measure, the prevented fraction, or the proportion of potential new cases that would have occurred in the absence of a protective exposure, can be applied to protective factors such as breast-feeding. Using these measures, we calculate that 50% of invasive Hib disease that occurred during the study period was attributable to exposure to day-care (Table V), and daycare had the highest attributable risks for children <24 months of age. Similarly, extreme household crowding, the other exposure variable that was significantly associated with risk for Hib disease in our study, had an attributable risk of 18%. The etiologic fraction may also be defined specifically for the exposed population as the proportion of exposed cases that are caused by the risk factor, termed the etiologic fraction among the exposed (Table V). By this measure, the probability was 0.77 during the study period that a case child who attended day-care developed Hib disease as a direct result of exposure to day-care, and the probability was 0.63 that a case child who lived in a crowded household developed Hib disease as a direct consequence of this exposure. Our finding that 50% of all invasive Hib disease that occurred during the study period was attributable to exposure to day-care has important implications regarding the implementation of effective preventive measures, such as immunization, to control Hib disease. Children ~ 1 8 months of age who attend day-care constitute a readily identifiable high-risk target group for immunization with
The Journal of Pediatrics June 1986
the currently available Hib polysaccharide vaccine. Younger children should be targeted for immunization with any future Hib vaccine shown to be effective in infancy. Two host susceptibility factors, black race and breastfeeding, were found to be associated with risk for Hib disease in our study population. The relationship of black race with risk for Hib disease was complex; after controlling for breast-feeding, day-care, household crowding, and family income, no overall increased risk attributable to black race could be demonstrated (Table V). The observation that black children 2 to 5 months of age had significantly lower risk and black children 12 to 35 months of age had significantly higher risk compared with white children remains unexplained. Other studies have also demonstrated that excess risk in blacks may be restricted to children >1 year of age. 12,19In our study, this excess risk may be related either to an exposure associated with race and Hib disease not measured or to genetically determined differences in host susceptibility to disease that affect the age distribution of disease. Previous uncontrolled studies have observed a higher incidence of invasive Hib disease in blacks than in whites, and this difference has been attributed to a genetic predisposition of a subpopulation of blacks to invasive Hib disease? ~ Potential differences b y race in level of passively acquired maternal antibody13that might affect risk for Hib disease during the first 6 months of life were not examined in our study, and may be a partial explanation for the decreased relative risk in black children <6 months of age compared with white children that was observed in our study population. Our study also supports the observation that breastfeeding confers protection against invasive Hib disease in infants 2 to 5 months of age. 39'4~In our study population, breast-feeding led to a 59% reduction in the number of cases in this age group, and breast-feeding all children <6 months of age could potentially reduce the risk for Hib disease by 92% in t h e m ( T a b l e V). It remains unclear whether some protection against disease may be conferred by breast-feeding children 6 to 11 months of age, an age group in whom the peak incidence of Hib disease occurs. The striking relationship between age and risk of Hib disease from day-care attendance is similar to that observed in Rochester, New York, 38 but contrasts with findings in Colorado, 39 where the relative risk increased with increasing age of the child. The explanation for these observed differences is not yet clear, but may relate to differences in the characteristics of day-care facilities and use in different geographic areas. Elucidating what daycare characteristics are associated with a higher risk of developing primary Hib disease is an appropriate next step, so that risk for children who attend day-care can be minimized.
Volume 108 Number 6
We thank metropolitan Atlanta hospital infection control practitioners and bacteriology laboratory directors for reporting cases; Rose Horsley for statistical support; and Patricia Adams, Lela Baughman, Unice Davis, Suzanne Gaventa, and Rubbina Mamdani for telephone interviewing. REFERENCES
1. Cochi SL, Broome CV, Hightower AW. Immunization of U.S. children with Hemophilus influenzae type b polysaccharide vaccine: a cost-effectiveness model of strategy assessment. JAMA 1985;253:521-529. 2. Davis DJ. Influenzal meningitis. Arch Intern Med 1909; 4:323-329. 3. Granoff DM, Basden M. Haemophilus influenzae infections in Fresno County, California: A prospective study of the effects of age, race, and contact with a case on incidence of disease. J Infect Dis i980;140:40-46. 4. Filice GA, Andrews JS Jr, Hudgins MP, Fraser DW. Spread of Haemophilus influenzae: secondary illness in household contacts of patients with H. influenzae meningitis. Am J Dis Child 1978;132:757-759. 5. Ward JI, Fraser DW, Baraff L J, Plikaytis BD. Haemophilus influenzae meningitis: a national study of secondary spread in household contacts. N Engl J Med 1979;301 : 122-126. 6. Glode MP, Daum RS, Goldmann DA, Leclair J, Smith A. Haemophilus influenzae type b meningitis: a contagious disease of children. Br Med J 1980;280:899-901. 7. Campbell LR, Zedd A J, Michaels RH. Household spread of infection due to Haemophilus influenzae type b. Pediatrics 1980;66:115-117. 8. Band JD, Fraser DW, Ajello G. Haemophilus influenzae Disease Study Group. Prevention of Haemophilus influenzae type b disease by rifampin prophylaxis. JAMA 1984; 251:2381-2386. 9. Fleming DW, Liebenhaut MH, Albanes D, et al. Secondary Haemophilus infiuenzae type b in day-care facilities: risk factors and prevention. JAMA 1985;254:509-514. 10. Osterholm MT, Kuritsky JN, Pierson LN, et al. Risk of secondary Haemophilus influenzae type b disease in day care [abstr]. Pediatr Res 1984;18:282A. 11. Murphy TV, Breedlove JA, Fritz EH, et al. County-wide surveillance of invasive Haemophilus infections: risk of associated cases in child care programs [abstr 229]. Presented at the Twenty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, Las Vegas, Oct. 24 to 26, 1983. 12. Fraser DW. Haemophilus influenzae in the community and the home. In: Sell SH, Wright PF, eds. Haemophilus influenzae. New York: Elsevier Science Publishing Co., 1982;1122. 13. Ward Jl, Lum MK, Margolis HS, et al. Haemophilus influenzae disease in Alaskan Eskimos: characteristics of a population with an unusual incidence of invasive disease. Lancet 1982;1:1281-1285. 14. Coulehan JL, Michaels RH, Williams KE, et al. Bacterial meningitis in Navajo Indians. Public Health Rep 1976; 91:464-468. 15. Coulehan JL, Michaels RH, Hallowell C, et al. Epidemiology of Haemophilus influenzae type b disease among Navajo Indians. Public Health Rep 1984;99:404-409. 16. Losonsky GA, Santosham M, Sehgal VM, et al. Haemophilus influenzae in the White Mountain Apaches: molecular
Risk factors in Hib disease
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22.
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24.
895
epidemiology of a high risk population. Pediatr Infect Dis 1984;3:539-547. Peltola H, Kayhty H, Virtanen M, Makela PH. Prevention of Hemophilus influenzae bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 1984;310:15611566. Claesson B, Trollfors B, Jodal U, Rosenhall U. Incidence and prognosis of Haemophilus influenzae meningitis in children in a Swedish region. Pediatr Infect Dis 1984;3:35-39. Santosham M, Kallman CH, Neff JM, Moxon ER. Absence of increasing incidence of meningitis caused by Haemophilus i~Tfluenzae type b. J Infect Dis 1979;140:1009-1012. Schlech WF, Band JD, Ward JI, et al. Bacterial meningitis in the United States, 1978-1981 : the national bacterial meningitis surveillance study. JAMA 1985;253:1749-1754. Parke JC Jr, Schneerson R, Robbins JB. The attack rate, age incidence, racial distribution, and case fatality rate of Haemophilus influenzae type b meningitis in Mecklenburg County, North Carolina. J PEDIATR 1972;81:765-769. Fraser DW, Darby CP, Koehler RE, et al. Risk factors in bacterial meningitis: Charleston County, South Carolina. J lnfect Dis 1973;127:271-277. Fraser DW, Geil CC, Feldman RA. Bacterial meningitis in Bernalillo County, New Mexico: A comparison with three other American populations. Am J Epiderhiol 1974;100:2934. Baraff L, Wehrle PF. Epidemiology of pediatric meningitis: Los Angeles County, 1975 [abstr]. Pediatr Res 1977; 11:434.
25. Tart PI, Peter G. Demographic factors in the epidemiology of Hemophilus influenzae meningitis in young children. J PEDIATR 1978;92:884-888. 26. Smith EWP Jr, Haynes RE. Changing incidence of Hemophilus influenzae meningitis. Pediatrics 1972;50:723-727. 27. Floyd RF, Federspiel CF, Schaffner W. Bacterial meningitis in urban and rural Tennessee. Am J Epidemiol 1974;99:395397. 28. Granoff DM, Squires JE, Munson RS, Suarez B. Siblings of patients with Haemophilus meningitis have impaired anticapsular antibody responses to Haemophilus vaccine. J PEDIATR 1983;103:185-191. 29. Pandey JP, Virella G, Loadholt CB, et al. Association between immunoglobulin allotypes and immune responses to Haemophilus influenzae and meningococcus polysaceharides. Lancet I979;1:190-192. 30. Granoff DM, Pandey JP, Fudenberg HH. lmmunoglobulin allotypes and race in relation to age of onset of invasive Haemophilus influenzae type b (HIB) infections [abstr]. Pediatr Res 1980;14:558. 31. Granoff DM, Pandey JP, Boles E, et al. Response to immunization with Haemophilus influenzae type polysaccharidepertussis vaccine and risk of Haemophilus meningitis in children with the Kin(l) immunoglobulin allotype. J Clin Invest 1984;74:1708-1714. 32. Granoff DM, Boies EG, Squires JE, et al. Histocompatibility leukocyte antigen and erythrocyte MNSs specificities in patients with meningitis or epiglottitis due to Haemophilus influenzae type b. J Infect Dis 1984;149:373-377. 33. Whisnant JK, Mann DL, Rogentine GN, Robbins JB. Human cell-surface structures related to Haemophilus influenzae type b disease. Lancet 1971 ;2:895-897. 34. Whisnant JK, Rogentine GN, Gralnick MA, et al. Host
896
35. 36. 37.
38.
39.
40.
Cochi et al.
factors and antibody response in Haemophilus influenzae type b meningitis and epiglottitis. J Infect Dis 1976;133:448455, Tejani A, Fotine M, Khan R, et al. HLA and Haemophilus influenzae disease. Tissue Antigens 1977;9:132. Ounsted C. Haemophilus influenzae meningitis: a possible ecological factor. Lancet 1950;1 : 161 - i 62. Michaeis RH, Schultz WF. The frequency of ttemophilus influenzae infections: analysis of racial and envlror~mental |'actors. In: Sell SHW, Karzon DT, eds: Hemophilus influenzae, proceedings of a conference on antigen-antibody systems, epidemiology, and immunoprophylaxis. Nashvilli~, Tenn.: Vanderbilt University Press, 1973; 243-250. Redmond SR, Pichichero ME. Hemophilus influenzae type b disease: an epidemiologic study with special ~eference to day-care centers. JAMA 1984;252:2581-2584. lstre GR, Conner JS, Broome CV, et al. Risk factors for primary invasive Haemophilus influenzae disease: increased risk from day Care attendance and school-aged household members. J PEDIATR 1985;106:190-195. Lure MK, Ward Jl, Bender TR. Protective inflttence of breast feeding on the risk of developing invasive H. influenzae type b disease [abstr]. Pediatr Res 1982;16:436.
The Journal of Pediatrics June 1986 41. Glasser G J, Metzger GD. Random digit dialing as a method of teiephone sampling. J Marketing Res 1972;9:59-64. 42. Hartge P, Brinton LA, Rosenthal JF, et al. Random digit dialing in selecting a population-based control group. Am J Epidemi01 1984;120:825-833. 43. Smith AH, Kark JD, C/issel JC, Spears GFS. Analysls of prospective epidemiologie studies by minimum distance Case~ control matching. Am J Epidemiot 1977;105:567-574. 44. Kleinbaum DG, Kupper LL, Morgensterri H. Epidemiologic research: principles and quantitative methods. Belmont, Calif.: Wadsworth, lnc, 1982;380, 449. 45. Kilian M. Haemophilus. In: Lennette EH, Balows A, Hausler W J, Shad0my H J, eds. Manual of Clinical microbiology, 4th ed. Washington, D.C.: American Society for Microbiology, 1985;387-393. 46. Barenkamp S J, Munson RS, Granoff DM. Subtyping isolates of Haemophilus influenzae type b by outer-membrane protein profiles. J Infect Dis 1981 ;143:668-676. 47. Breslow NE, Day NE, Halvorsen KT, et al. Estimation of multiple relative risk functions in matched case-control studies. Am J Epidemiol 1978;108:299-307.
Haemophilus influenzae type b is the leading cause of bacterial meningitis in the United States and accounts for an estimated 12,000 cases per year, primarily in children <5 years of age. Nonmeningitic invasive forms of Hib
Submitted for publication Aug. 20, 1985; accepted Dec. 27, 1985. Reprint requests: Stephen L. Cochi, M.D., Division of Immunization, Centers for Disease Control, Freeway Park, Room 367, Atlanta, GA 30333.
infection increase this annual burden to nearly 20,000 cases per year. ~ Although invasive Hib disease occurring in multiple members of a household was reported as long ago as 1909, 2 only within the last decade has documented evidence
CL Hib OR
Confidencelimits
Haemophilusinfluenzae type b Odds ratio
887
888
Cochi et al.
The Journal of Pediatrics June 1986
,300-
5
:"
"..
ATLANTA -- ALL RACES
250 /
//~ - " ~
REFERENCE
..............
U.S.*
l:z
200
>o o o o o
150
c..
(/3 i,i O3 <
\ \ '".....
1 O0
50-
0-5
6-11
AGE
J 12-17
' 18-23
(MONTHS)
~
I
l
'
2
'
'
AGE
3
J
'
4
'
(YEARS)
"SOURCE: JAMA 1985;253:521--9
Figure. Age- and race-specific incidence of invasiveH. influenzae disease, Atlanta, July 1983 through June 1984.
become available that invasive Hib disease is contagious. Published studies of secondary spread of Hib disease in contacts of index cases have documented a significant increase in the risk of illness in both household and day-care classroom contacts, 3-9 although unpublished data!0, H have made the issue of day-care contacts controversial. However, secondary invasive Hib disease occurring in any setting accounts for only 1% to 2% of all invasive Hib disease? Defining risk factors for acquisition of primary disease, therefore, assumes considerable public health importance. Several risk factors have been linked with the occurrence of invasive Hib disease. 12 Young age is associated with the highest incidence, but passive protection of some infants bY transplacentally acquired maternal antibody is thought to delay peak attack rates until age 6 or 7 months? The age-specific incidence curve may be shifted to the left in populations with especially high incidences of Hib disease ~3~6or to the right in populations with lower attack ratesJT,,8 Gender has not been an important predictor of disease in most studies; however, one population-based study x9 and national surveillance data ~~show attack rates to be substantially higher in boys than in girls. In several studies, the incidence of Hib meningitis in children <5
years of age was two to four times higher in black children than in white children, 19,2~27 and the incidence of all invasive Hib disease four times higher in blacks than in whites? High incidences of invasive Hib disease have also been observed in Hispanics3,24 and Native Americans.*13-]6 Although some investigators have suggested that these racial and ethnic differences in incidence of disease may be related to genetically determined differences in host susceptibility,28-35 this conclusion i s uncertain because of possible confounding socioeconomic variables. For example, increased attack rates of Hib meningitis have been observed in association with increased household size36,37 and population density,27and with low family income22,23,27 and education level. 23,~7 Increased use of child day-care facilities has focused attention on the role of this exposure as a risk factor for acquisition of primary Hib disease.3~, 39 Finally, breast-feeding of infants has been shown to be a significant protective factor. 39'4~ An approach that assesses the relative importance of *Readersoutsidethe UnitedStates mayneedan explanationof this term which currentlyis beingappliedby the U.S. CensusBureauto American Indians.--J.M.G.
Volume 108 Number 6 these many factors and determines which associations are affected by confounding variables has been lacking. The purpose of our study was to examine risk factors for primary invasive Hib disease by using a population-based case-control approach, and to synthesize a disease model that describes how these risk factors interact to produce the pattern of primary Hib disease observed in the study population. METHODS Study population. The study area consisted of the seven-county metropolitan area of Atlanta (1980 U.S. census population: 1,779,226), which has a racial-ethnic distribution of 73% white, 26% black, and 1% other racial or ethnic groups. Case finding. From July 1, 1983, through June 30, 1984, we conducted active surveillance for invasive Hib disease using two independent reporting systems: hospital infection control practitioners and bacteriology laboratories. All infection control practitioners and bacteriology laboratory directors in the study area (37 hospitals) were contacted and enrolled. Hospital infection control practitioners reported cases every week to the Georgia Department of Human Resources, Office of Epidemiology. Bacteriology laboratories independently filed case reports of all H. influenzae isolates from normally sterile body sites and forwarded these isolates to the CDC for bacteriologic confirmation and serotyping. Completeness of reporting was validated by reviewing the bacteriology records at all hospitals in the study area for the first 6 months of the study period and at the two hospitals with the largest pediatric services for the entire 12 months. Case definition. A case was defined as any child <5 years of age residing in the seven-county metropolitan Atlanta area from whom H. influenzae was cultured from a normally sterile body site, and who had clinical signs of infection. Any children whose clinical isolates were other than serotype b were excluded. A child was considered to have secondary Hib disease if onset of illness occurred from 1 to 60 days after exposure to a primary case in the same household or day-care facility and the outer membrane protein profile of the second case matched the profile of the primary case, if both were available? Only the first episodes in children with recurrent disease were included in the case-control study. Case survey. We contacted a parent of each case child by telephone or home visit from 1 to 6 months (median 57 days) after onset of illness and administered a questionnaire after obtaining informed consent. The following information was obtained: age, gender, and race or ethnicity of all children <5 years of age in the household, age and race or ethnicity of other persons in the household, number
R i s k factors in Hib disease
889
Table I. Frequency of selected variables for cases and controls, Atlanta, 1983 to 1984
Cases (n = 89) n
Controls (n = 530)
%
n
%
58 42
286 244
54 46
58 39 2 65
387 134 9 205
73 25 2 39
15 36 48 1
51 165 311 3
10 31 59 1
12 27 22 38
98 161 133 135 3
18 30 25 25 1
10 25 19 18 20 7 1
29 87 117 133 83 60 21
5 16 22 25 16 11 4
47 53 12
299 227 4 48/138
56 43 1 35
49
229
43
Sex
Male 52 Female 37 Race White 52 Black 35 Other 2 Day-care or nursery 58 attendance Mother's education (yr) <12 13 12 32 13+ 43 Missing 1 Crowding (persons per room) 0-0.45 11 0.451-0.60 24 0.61-0.79 20 0.80+ 34 Missing Family income <$5,000 9 $ 5,000-$14,999 22 $15,000-$24,999 17 $25,000-$34,999 16 $35,000:$49,999 18 $50,000 6 Missing 1 Other persons sleeping in same room 0 42 1+ 47 Missing Breast-feeding at 5/42 reference month Parent smoking 44
of rooms in the house, presence of a telephone, family income, and education level of parents. The format of these questions was taken directly from the 1980 U.S. census long-form questionnaire. Information was also obtained on the child's breast-feeding history, number of persons sleeping in the same room as the child, parental smoking, day-care or nursery school attendance since the beginning of the study period, and frequency of such attendance. Day-care was defined as any regular (>4 hr/wk) supervised care of at least two unrelated children. A child was
890
Cochi et al.
The Journal of Pediatrics June 1986
T a b l e II. Age-specific relative risks for primary Hib disease by selected exposure variables, univariate matched analysis, Atlanta, 1983 to 1984 Odds ratio" by a g e group (mo) 2-5 Black race Mean Range Day-care Mean Range Extreme crowding ( E l person per room) Mean Range Low family income (<$15,ooo) Mean Range Breast-feeding (
0.3
6-11
12-23
24-35
36-59
All ages
1.3
5.0t 1.9-13.2
3.2
1.1
1.7t 1.0-2.9~
12.8t 3.3-5.0
5.4"~ 1.8-17.0
3.2t 1.2-8.4
3.5
0.9
3.9t 2.3-6.6
1.1
6.6~ 1.6-26.0
2.7
3.5
1.9
2.6t 1.5-4.5
0.8
1.7
2.0
7.8I" 1.8-35.0
1.2
1.8t 1.1-3.0
0.21 0.04-0.96
0.3
NA
NA
NA
0.3t 0.1-0.8
0.8
1.2
3.7t 1.3-10.0
0.4
0.9
1.2 0.8-2.0
0.8
1.0
2.5I" 1.0-6.5
1.1
1.6
1.4 0.8-2.2
0.7
2.0
2.0
1.8
1.1
1.5 0.9-2.4
1.7
1.2
1.7
1.3
0.5
1.3
0.8-2.0
NA, Not available, *Age- and reference month matched. tConfidence limits indicate statistically significant association. :[:95%confidencelimits.
classified as a day-care attendee if he or she attended for at least 16 hours in the month before, or 4 hours in the week before illness. 9 Control survey. A t the conclusion of the study period, we identified a random sample of children <5 years of age residing in the study area, using simple random digit dialing procedures. 41,4~ Each telephone number was contacted eight times before being discarded, of which six calls were during evening and weekend hours. After obtaining informed consent, a questionnaire was administered to the parent of each of the 557 children selected, with a format similar to that of the case survey. Data were collected for all children <5 years of age in a given household. A 15% sample of questionnaires was validated by having one of the investigators contact the parents again by telephone to
verify that the respondent was interviewed and to readminister parts of the survey instrument. Postmatching. After all information had been collected, controls were postmatched to cases by date of birth within 6-month age categories for all case-control pairs <2 years of age (0 to 5, 6 to 11, 12 to 17, and 18 to 23 months), and within 12-month age categories for pairs ~ 2 years of age. The method of minimum distance case-control matching 43 was used, and the matching ratio followed a variablematching ratio plan\. 44 Because no case children were <2 months of age, 27 control children who were <2 months of age at the time of postmatching were excluded to maximize the comparability of cases and controls; data for the remaining 530 children were analyzed. The onset month of Hib disease in the case was used as the reference month for
Volume 108 Number 6 determining day-care and breast-feeding status in matched controls. Laboratory methods. H. influenzae isolates were confirmed by standard procedures 45 and serotyped by slide agglutination with specific antisera. When secondary cases were suspected, we tested isolates in a blinded fashion to determine biotype and outer membrane protein type; outer membrane protein preparations were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in two gel systems as previously described by Barenkamp et al.46 Statistical methods. Potential risk factors, confounders, and effect modifiers were evaluated in conditional logistic regression models.47 The general modeling strategy was as follows: (1) to use backward elimination procedures whenever possible, (2) to eliminate nonsignificant effect-modification terms before any confounders or risk factors were evaluated, and (3) to keep low-order interaction terms regardless of significance when a higher-order term was significant:4 Indicator variables were used in models that examined the relationship between age, which had five categories, and day-care attendance and race, to verify the linear (for day-care) or quadratic (for race) relationship with the log-odds ratio and increasing age category before incorporating these assumptions into the final multivariate model. All computations of etiologic fractions, prevented fractions, and etiologic or prevented fractions in the exposed cases used the OR estimates obtained from the final multivariate model.44 RESULTS Surveillance. During the 12-month study period, 159 cases of invasive H. influenzae disease were identified; 135 cases were in children who resided in the study area and 114 (84%) of these were in children <5 years of age. Retrospective review of bacteriology laboratory records showed that only five (3%) of 159 cases were not reported through the surveillance system. The annual incidence of invasive H. influenzae disease was 82 cases per 100,000 children <5 years of age. The incidence of meningitis was 57/100,000 and of other invasive disease, 25/100,000. Age-specific attack rates were similar to rates observed in other studies in which active surveillance was conducted t (Figure). Serotyping information was available from CDC for 99 (87%) of 114 isolates: 97 were serotype b, one isolate was serotype a, and one isolate was nontypeable. For analysis of risk factors for primary Hib disease, we excluded the two non-serotype b cases, four cases (3.6%) with secondary invasive Hib disease, and three cases (3%) with recurrent disease. We were unsuccessful in contacting three families (3%) of case children. Thus, 102 (97%) of
R i s k factors in Hib disease
891
Table III. Dose-response relationship of primary Hib disease to day-care attendance and crowding Cases
O d d s of disease
Odds ratio
325 58 41 79 27
0.10 0.12 0.20 0.39 0.44
1.0" 1.3 2.0 4.1 4.7
98 161 133 135
0.! 1 0.15 0.15 0.25
1.0" 1.3 1.3 2.2
Controls
Day-care attendance (hr/wk) 0-4 31 5-19 7 20-39 8 40-49 31 50+ 12 Crowding (persons/room) 0-0.45 11 0.451-0.60 24 0.61-0.79 20 0.80+ 34 *Reference group.
105 case children with primary invasive Hib disease were enrolled in the case-control study. Case-control surveys. For the case survey, 42 (41%) of the 102 case families enrolled were interviewed during a home visit, including all 13 case families without telephones; the remainder were interviewed by telephone. The main case-control analysis included only the 89 cases in which the families had telephones. For the population control survey, we identified 3977 households from 11,525 randomly selected telephone numbers; 96% of telephones were answered. Ninety-eight percent of households cooperated with telephone screening to identify whether they contained children <5 years of age; such households comprised 13% of all households screened. The interview response rate of households selected was 93%. The frequency of selected study variables obtained from the case and control surveys is shown in Table I. Risk factors: Univariate analysis. Univariate analysis revealed that a number of exposure and host susceptibility factors were apparently associated with primary Hib disease (Table II). Black race, day-care attendance, household crowding, and low family income were associated with increased relative risk for Hib disease; breast-feeding was protective for infants 2 to 5 months of age. No significant differences in these effects were observed when the analyses were stratified by meningitic vs nonmeningitic disease; all clinical syndromes were, therefore, considered together for the remaining analyses. Race. Black children were at significantly increased relative risk of primary Hib disease compared with white children (OR 1.7, 95% CL 1.0 to 2.9). This increased relative risk seemed to be limited primarily to blacks 12 to 35 months of age. The age distribution of the 35 cases in black children was as follows: 2 to 5 months of age three, 6
892
Cochi et al.
The Journal of Pediatrics June 1986
T a b l e IV. Multivariate model of relative risks for primary Hib disease, Atlanta, 1983 to 1984 Risk factor
Day-care
Black race
Extreme crowding Low family income Breast-feeding
A g e group
Relative risk
95% C o n f i d e n c e limits
P value
2-5 mo 6-11 mo 12-23 mo 24-35 mo 36-59 mo 2-5 mo 6-11 mo 12-23 mo 24-35 mo 36-59 mo 0-4 yr 0-4 yr 2-5 mo 6-11 mo
17.7 9.4 5.0 2.7 1.4 0.05 0.8 3.3 3.1 0.7 2.7 1,6 0.08 0.68
5.8-54.4 4.3-20.9 2,7-9.3 1.3-5.5 0.5-4.0 0.01-0.36 0.3-2.1 1.3-8.1 1.3-7.5 0.2-2.7 1,3-5.6 0;8-3.3 0.01-0.59 0.15-3.2
<0.0001 <0,0001 <0.0001 <0.004 NS <0.007 NS <0.005 <0.005 NS <0.004 NS <0.007 NS
NS, Not significant. to 11 months nine, 12 to 23 months 15, 24 to 35 months five, and 36 to 59 months three. Gender. The distribution of cases by gender (58% male) was not statistically different than the distribution in the study population (54% male). Day-care/nursery attendance. At the time of illness, 65% of case children attended day-care facilities compared with 39% of controls (OR 3.9, 95% CL 2.3 to 6.6, age and reference month matched). The magnitude of the association of day-care attendance with primary Hib disease was highly age dependent. The peak OR was 12.8 for children 2 tO 5 months of age; ORs decreased with increasing age (Table II). An increasing number of hours per week of attendance at day-care was associated with an increasing relative risk of disease when the data were examined in an unmatched fashion (Table III). Crowding. Twenty-six (29%) of 89 case children resided in households containing >__1 person per room, compared with 68 (13%) of 527 controls (OR 2.6, 95% CL 1.5 to 4.5) (Table II). The magnitude of risk associated with crowding increased as the extent of crowding increased, when an unmatched analysis was performed (Table III). Income and other socioeconomic variables. Family income of <$15,000 was reported by a greater percentage of case families (35%) than of control families (21%) and was significantly associated with risk for Hib disease (OR 1.8, 95% CL 1.1 to 3.0). The presence of other persons sleeping in the same room as a child was not associated with a significantly increased relative risk for Hib disease in the univariate matched analysis (OR 1.5, 95% CL 0.9 to 2.4). Children whose mothers had 12 or fewer years of education were not significantly more likely to be cases (51%) than controls (41%). Large household size and the presence of school-aged household members were not associated with risk for Hib disease.
Breast-feeding. Control children < 1 year of age had a significantly higher prevalence of breast-feeding (35%) than case children (12%) (Table II). The apparent protective effect of breast-feeding was greatest for infants <6 months of age and was not statistically significant in 6 to 11-month-old infants alone. Smoking. No effect of exposure to smoking by parents was evident. Risk factors: Multivariate model. Multivariate statistical modeling was used to control for potential confounding variables as well as to account for effect modification, and thereby improve the precision of our estimates of relative risks for Hib disease. Variables included in the final multivariate model are listed in Table IV. Exposure factors. Confirming the results of the univariate analysis, the model showed that attendance at daycare was most strongly associated with risk for Hib disease for children 2 to 5 months of age, and that relative risk decreased with increasing age of the child (Table IV). Risk was not significantly elevated for children >_3 years of age. Extreme household crowding remained significantly associated with Hib disease in the multivariate model (OR 2.7, 95% CL 1.3 to 5.7). In contrast, low family income, which was highly correlated with household crowding among controls (X2 = 57.2, P <10-"), did not demonstrate a significant association with Hib disease after adjustment (Table IV). Other socioeconomic variables that correlated strongly with household crowding demonstrated no independent association with risk for Hib disease when entered individually into the multivariate model. These variables included household size (OR 1.13, 95% CL 0.95 to 1.33), presence of other persons sleeping in the same room as a study child (OR 1.3, 95% CL 0.7 to 2.5), other children <5 years of age in the household (OR 0.8, 95% CL 0.5 to 1.5),
Volume 108 Number 6
R i s k factors in Hib disease
893
T a b l e V. Attributable risk for primary Hib disease, by exposure variable, Atlanta, 1983 to 1984 Prevalence of exposure (%)
Etiologic fraction
Odds ratio es|imates
or
Exposure variable Day-care attendance 0-4 yr 2-5 mo 6-11 mo 12-23 mo 24-35 mo 36-59 mo Black race 0-4 yr 2-5 mo 6-11 mo 12-23 mo 24-35 mo 36-59 mo Extreme crowding Low family income Breast-feeding <1 yr 2-5 mo 6-11 mo
Cases
Controls
Univariate
Multivariate
EF~
prevented fraction (%)
65 71 56 71 60 55
39 15 21 43 29 53
3.9 12.8 5.4 3.2 (3.5)* (0.9)
-17.7 9.4 5.0 2.7 (1.4)
0.77 0.94 0.89 0.80 0.63 0.33
5O 67 5O 57 38 16
39 19 35 58 50 27 29 35
25 31 33 21 23 24 13 2l
1.7 (0.3) (1.3) 5.0 (3.2) (1.1) 2.6 1.8
-0.05 (0.8) 3.3 3.1 (0.7) 2.7 (1.6)
0.01 -0.95]. -0.20]" -0.70 0.68 -0.30]" 0.63 0.38
0 -78t -St 41 34 -lOt 18 !3
12 13 12
35 43 25
0.3 0.2 (0:3)
-0.08 (0.68)
-0.55t -0.92]" -0.32]"
-59t -5t
-25?
EFt, Etiologic fraction among exposed cases, or proportion of exposed cases that are caused by risk factor. *Parentheses indicate O R not significantly above or below 1. ]'Negative sign indicates prevented fraction or prevented fraction among exposed cases for factors that are protective.
elementary school-aged children in the household (OR 1.2, 95% CL 0.8 to 1.9), and school-aged Children 5 to 18 years of age in the household (OR 1.1, 95% CL 0.8 to 1.6). Among controls, two variables correlated strongly with mothers who had 12 years or fewer of education: low family income (X2 = 51.4, P <10 -~2) and household crowding (X2 = 27.6, P <10-6). After controlling for confounding, no independent protective effect of high maternal education level (i.e., at least 1 year of college) could be demonstrated (OR 0.6, 95% CL 0.3 to 1.1). Host factors. The association of black race with risk for Hib disease was quadratic by age group (Table IV). Black children 2 to 5 months of age had a significantly lower relative risk for Hib disease than white Children; however, the relative risk was increased for black children 12 to 35 months of age, as was observed in the univariate analysis. M u c h o f the decrease in the adjusted relative risk for 2- to 5-m0nth-old black children calculated in the multivariate model resulted from controlling for the protective effect of breast-feeding, a praQtice that was absent among cases in blacks in that age group. The protective effect of breast-feeding among children 2 to 5 months of age was still evlden!! in .the multivariate model (OR 0.08, 95% CL 0.01 to 0.59)i but in 6- to 11-month,old children, the effect of breast-feeding was not significant (Table IV).
Two other study variables demonstrated no association with risk for Hib disease when entered individually into the multivariate model: male sex (OR 1.3, 95% CL 0.8 to 2.3) and parental smoking (OR 1.0, 95% CL 0.6 to 1.8). Of the 13 case children who lived in households without telephones, eight were male, six were black, 11 had family income of <$15,000 per year, seven lived in households with one or more persons per room, and three attended day-care. Including these 13 case children in the multivariate model had no substantial effect on the OR estimates for any risk factors except low family income. By including these cases, low family income became a statistically significant risk factor (OR 2.2, 95% CL 1.2 to 4.2). This confirmed our decision to exclude these cases from the a.nalysis to preserve the comparability of our cases and controls. However, exclusion of cases i0 low-income families may have minimized our ability to detect a significant association of low income with Hib disease. DISCUSSION In this study, cases of primary invasive Hib disease identified by prospective disease surveillance were compared with a control group randomly selected from the same study poPUlation by random digit dialing. We evaluated the aSsociation of both exposure variables and host susceptibility factors with risk for primary invasive Hib
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disease, first by matched univariate analysis and then in a multivariate model. Two host susceptibility factors were related to disease risk: breast-feeding was protective for infants 2 to 5 months of age, and black race was protective in certain age groups and a risk factor in others. Two exposure factors, day-care attendance and household crowding, were associated with increased risk for Hib disease. For day-care, increased relative risk was highest in 2 to 5-month-old infants and exhibited a linear decline with increasing age; relative risk was not significantly elevated in children 3 years or older. Both day-care and household crowding exhibited dose-response effects in the univariate analysis, although these effects were unstable and could not be clearly demonstrated in the multivariate model. These two risk factors may operate by increasing the likelihood of exposure to sources of acquisition of Hib bacteria. The results of our risk factor analysis can be placed in the broader public health perspective. Because our control subjects were a random sample of the entire study population, we can calculate the proportion of all cases attributable to a given risk factor (the etiologic fraction). The etiologic fraction thus provides an estimate of the expected reduction in disease in the population after removal of the risk factor. An analogous measure, the prevented fraction, or the proportion of potential new cases that would have occurred in the absence of a protective exposure, can be applied to protective factors such as breast-feeding. Using these measures, we calculate that 50% of invasive Hib disease that occurred during the study period was attributable to exposure to day-care (Table V), and daycare had the highest attributable risks for children <24 months of age. Similarly, extreme household crowding, the other exposure variable that was significantly associated with risk for Hib disease in our study, had an attributable risk of 18%. The etiologic fraction may also be defined specifically for the exposed population as the proportion of exposed cases that are caused by the risk factor, termed the etiologic fraction among the exposed (Table V). By this measure, the probability was 0.77 during the study period that a case child who attended day-care developed Hib disease as a direct result of exposure to day-care, and the probability was 0.63 that a case child who lived in a crowded household developed Hib disease as a direct consequence of this exposure. Our finding that 50% of all invasive Hib disease that occurred during the study period was attributable to exposure to day-care has important implications regarding the implementation of effective preventive measures, such as immunization, to control Hib disease. Children ~ 1 8 months of age who attend day-care constitute a readily identifiable high-risk target group for immunization with
The Journal of Pediatrics June 1986
the currently available Hib polysaccharide vaccine. Younger children should be targeted for immunization with any future Hib vaccine shown to be effective in infancy. Two host susceptibility factors, black race and breastfeeding, were found to be associated with risk for Hib disease in our study population. The relationship of black race with risk for Hib disease was complex; after controlling for breast-feeding, day-care, household crowding, and family income, no overall increased risk attributable to black race could be demonstrated (Table V). The observation that black children 2 to 5 months of age had significantly lower risk and black children 12 to 35 months of age had significantly higher risk compared with white children remains unexplained. Other studies have also demonstrated that excess risk in blacks may be restricted to children >1 year of age. 12,19In our study, this excess risk may be related either to an exposure associated with race and Hib disease not measured or to genetically determined differences in host susceptibility to disease that affect the age distribution of disease. Previous uncontrolled studies have observed a higher incidence of invasive Hib disease in blacks than in whites, and this difference has been attributed to a genetic predisposition of a subpopulation of blacks to invasive Hib disease? ~ Potential differences b y race in level of passively acquired maternal antibody13that might affect risk for Hib disease during the first 6 months of life were not examined in our study, and may be a partial explanation for the decreased relative risk in black children <6 months of age compared with white children that was observed in our study population. Our study also supports the observation that breastfeeding confers protection against invasive Hib disease in infants 2 to 5 months of age. 39'4~In our study population, breast-feeding led to a 59% reduction in the number of cases in this age group, and breast-feeding all children <6 months of age could potentially reduce the risk for Hib disease by 92% in t h e m ( T a b l e V). It remains unclear whether some protection against disease may be conferred by breast-feeding children 6 to 11 months of age, an age group in whom the peak incidence of Hib disease occurs. The striking relationship between age and risk of Hib disease from day-care attendance is similar to that observed in Rochester, New York, 38 but contrasts with findings in Colorado, 39 where the relative risk increased with increasing age of the child. The explanation for these observed differences is not yet clear, but may relate to differences in the characteristics of day-care facilities and use in different geographic areas. Elucidating what daycare characteristics are associated with a higher risk of developing primary Hib disease is an appropriate next step, so that risk for children who attend day-care can be minimized.
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We thank metropolitan Atlanta hospital infection control practitioners and bacteriology laboratory directors for reporting cases; Rose Horsley for statistical support; and Patricia Adams, Lela Baughman, Unice Davis, Suzanne Gaventa, and Rubbina Mamdani for telephone interviewing. REFERENCES
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