Risk factors for primary invasive Haemophilus influenzae disease: Increased risk from day care attendance and school-aged household members

Risk factors for primary invasive Haemophilus influenzae disease: Increased risk from day care attendance and school-aged household members From November 1, 1981, through April 30, 1982, we performed a case-control study of primary invasive Haemophilus influenzae infections in children in Colorado. Information was collected fo~ 121 (83 %) of 146 children with positive cultures and for 196 (67 %) of 292 age-matched controls selected at random from birth certificates. Infected children were more likely to have attended a day care center or nursery (DCC/N) and to have an elementary school-aged household member. For attendance at DCC/N, the relative risk was significantly increased only for children 12 months of age or older, and increased with the size of the DCC/N. After controlling for DCC/N attendance and school-aged siblings, children younger than 6 months of age with infection were significantly less likely to have been breast-fed, suggesting a protective effect of breast-feeding. We identified DCC/N attendees, especially those older than 1 year of age, to be at increased risk of primary H. influenzae disease. They could benefit from immunization. (J PEDIATR 106:190, 1985)

Gregory R. Istre, M.D., Judy S. Conner, Claire V. Broome, M.D., Allen Hightower, M.S., and Richard S. Hopkins, M.D. A t l a n t a , Georgia, a n d Denver, C o l o r a d o

HAEMOPHILUS INFLUENZAE accounts for 8000 to 11,000 cases of meningitis yearly ~ and almost as many cases of other invasive diseases, such as epiglottitis, arthritis, pneumonia, and cellulitis? Several reports have documented clusters of 1t. influenzae infections in households and in day care centers,~-5and another shows that children living in households in which such infection has occurred are at increased risk of secondary spread. 6 However, secondary cases account for only 1% or 2% of H. influenzae infections, and risk factors for the remaining cases that have no recognized source (the so-called primary cases of infection) have not been defined in a controlled study. We studied risk factors for primary invasive 11. influenzae infections, using a case-control approach. From the Division of Field Services, Epidemiology Program Office, and the Division of Bacterial Diseases, Center for Infectious Diseases, Centers for Disease Control; and the Colorado Department of Health. Submitted for publication June 18, 1984; accepted Aug. 10, 1984. Reprint requests: Gregory R. lstre, M.D., Epidemiology Service, Oklahoma State Department of Health, 1000 N.E. lOth St., Oklahoma City, OK 73152_

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METHODS Case findings. We established a surveillance system for invasive H. influenzae infections in Colorado through hospital infection control practitioners and bacteriology laboratory directors, who reported all cases of invasive H. influenzae infection from November 1, 1981, through April 30, 1982. All hospital infection control practitioners and laboratory directors in Colorado were contacted and asked to participate; each was provided with monthly updates of statewide surveillance and of cases reported DCC/N OR CL CDC

Day care center or nursery Odds ratio Confidence limits Centers for Disease Control

from their hospital. We asked each laboratory director to forward all H. influenzae isolates for confirmation; isolates were also used to verify that reports had been received from infection control practitioners. Infection control practitioners reported cases using a modified CDC bacterial meningitis form. To determine completeness of reporting, we reviewed laboratory records of a 10% random sample of

Volume 106 Number 2

R i s k factors f o r primary H. influenzae infections

19 1

Table I. Frequency of selected variables and odds ratios, univariate matched analysis,

Persons in household 3 to 5 years old 6 to 10 years old Elementary school-aged Crowding index (persons/bedrooms) DCC/nursery attendance >__4 Children Visits to physician Upper respiratory tract infection Ear infection Pneumonia Throat infection Income>$20,000/yr

Children with H. influenzae infection (n = 1 I0)

Controls (n = 166}

Univariate matched analysis odds ratio

4.3 + 1.7 0.5 + 0.6 0.4 + 0.7 0.5 +_ 0.9 1.5 _+ 0.6 55 (50%) 45 (41%) 3.2 +_ 4.1 0.8 +_ 1.3 1.8 _+ 3.2 0.1 _+ 0.5 0.4 _+ 0.9 55 (50%)

3.9 + 1.1 0.4 ___0.6 0.2 + 0.5 0.2 + 0.6 1.5 _+ 0.6 59 (35%) 36 (22%) 3.1 + 4.0 1.2 _+ 1.9 1.6 _+ 2.9 0.1 _+ 0.3 0.3 + 0.7 80 (48%)

1.2 1.2 2.0 1.7 1.0 1.9 2.5 1.0 0.9 1.0 1.4 1.1 1.1

Colorado hospital laboratories and of the three hospitals with the largest pediatric bed capacity. A case was defined as any person who had a culture positive for H. influenzae from a normally sterile body site in the presence of signs of infection. All reported children younger than 6 years of age were eligible for the study. Questionnaires. Each infected child was matched with two potential controls who were born on the same day. Controls were selected using a random number table from a systematic sample of all births in Colorado. Within 1 week of a report of a case, parents of each infected child and each control were mailed identical questionnaires requesting the following information: (1) day care center or nursery attendance in the previous 3 months (including size of D C C / N , number of hours attended per week, and number of weeks of attendance); (2) number of persons in the household in various age groups; (3) number of rooms (bedrooms, living areas, bathrooms) in the house; (4) number of preschool children (other than household and D C C / N contacts) with whom the child had regular contact; (5) number of visits to a physician for various illnesses since birth (ear infections, pneumonia, upper respiratory tract infections, throat infections); (6) antibiotics administered in the previous 3 months; (7) immunization dates; (8) number of other children in the household who attend D C C / N or elementary school; (9) and family income. F o r infected and control infants younger than 1 year of age, we administered an additional questionnaire concerning breast-feeding and formula use for each 3-month interval in the first year of life up to the time of onset of infection. In addition to the questionnaire data, we obtained, from birth certificates, information on race, gender, parental education, the month prenatal care began, and the mother's age. Second and third mailings were sent to nonrespon-

95% Confidence interval 1.0 to 0.8 to 1.2 to 1.1 to 0.6 to 1.2 to 1.5 to 0.9 to 0.8 to 0.9 to 0.7 to 0.8 to 0.6 to

1.5 1.8 3.3 2.5 1.5 3.2 4.5 1.1 1.1 1.1 2.7 1.6 2.1

dents. After the study period ended, we attempted to establish telephone contact with nonrespondents, to administer the same questionnaire by telephone. These responses were analyzed separately. To verify information about antibiotic use as reported by parents, we contacted a 50% systematic sample of physicians who cared for children whose parents stated that antibiotics had been used in the previous 3 months. Statistical analysis. Data were analyzed using a matched univariate analysis to identify variables associated with infection. Potential risk factors, confounding variables and effect-modifying variables were evaluated using a matched linear logistic regression model. 7 This analysis yields a point estimate of the odds ratios for associated variables. For diseases of low incidence, such as invasive H. influenzae infections, the O R calculation from a case-control study closely approximates the relative risk (risk ratio) that would have been derived from a cohort study comparing groups with and without the exposure under investigation? From the results of a case-control study, we can calculate the percent attributable risk of disease for various risk factors, using the relative risk estimate and the prevalence of exposure to that risk factor in the population? RESULTS Surveillance. During the study, 173 cases of invasive H. influenzae infection were reported. One hundred fortyeight (86%) were in children younger than 6 years of age. Two cases occurred within 1 month of contact with another infected child ('secondary cases); both were members of households in which there was a primary case and were excluded from the study. For 122 (83%) patients, at least one 1-1. influenzae isolate was forwarded for laboratory confirmation; all were H. influenzae type b. The retrospec-

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14

13 12

(1.4-124)** P<0.02

E]

= < 12 months of age {1.1-1~0) 9 P<0.03

= ~> 12 months of age

lO 9 E) C--.

8 7

e-, 6 0 5 ( 1,2"11.5) 9* P
4

(1.3-7.31"" (1,1-8,5)** P
3 2 By Definition

(0.3-3.1)*" P=NS (0,1-3.8)**

(0.5-2,9)'* P=NS

;lira

NO DCC/N

1k3

4-10

11-20

21 +

DCC/N SIZE (No. of other children attending DCC/N)

School-Age

Household Member

Fig. 1. Odds ratios for presence of elementary school-aged household member and for attendance at day care center or nursery (adjusted for presence of elementary school-aged household member), stratified by size of DCC/N. Invasive H. influenzae disease case-control study, Colorado, 1981-1982. NS, Not significant; **95% confidenceinterval.

tive review of records from the sample of participating laboratories showed that 88 (97%) of 91 patients with culture-confirmed H. influenzae infection identified in the review sample had been reported through the surveillance system. For the age group birth to 4 years, the overall rate of invasive 1-1. influenzae infection for Colorado was 64 per 100,000 for the 6 months of the study (128/100,000 per year). In the previous 5 years, 57% of H. influenzae meningitis cases reported to the Colorado Department of Health were reported between November and April? ~ If the same seasonal distribution is assumed, the adjusted yearly rate of invasive H. influenzae disease is 112/100,000 children up to age 4 years. Based on this adjustment, the incidence of meningitis was 68/100,000 and for other infection, 44/100,000. Questionnaires. Questionnaires were completed and returned by the parents of 121 (83%) of the infected children and 196 (67%) of the controls. Telephone and personalfollow-up attempts resulted in information from an additional eight children and 19 controls, for a total of 86% of cases and 74% of controls. The matched analysis was conducted by including only those matched sets (a case and at least one control) for which the questionnaire had been completed. One hundred ten matched pairs or triplets (1 i0 cases, 166 controls) were reviewed.

We analyzed birth certificate data to evaluate differences between respondents and nonrespondents. Parents of white race, with >12 years of education, and with earlier maternal prenatal care were more likely to respond; this trend was similar for cases and controls. Hispanic parents of children with infection, however, were significantly less likely to respond than those of matched controls, but Hispanics comprised only 10% of the cases. Two groups of variables were significantly associated with disease in the univariate analysis: those that measured exposure to D C C / N in different ways (any D C C / N attendance, size of DCC/N, length of attendance at D C C / N , and number of children in the DCC/N), and those related to the number of children in the household who were attending elementary school (the number of children 6 to 10 years of age or the number of children attending elementary school) (Table I). School-aged household member. The presence of an elementary school-aged household member and that of a 6- to 10-year-old household member were closely correlated. In the multivariate analysis, the presence of a school-aged household member was most closely associated with an infected child (OR 3.1, 95% confidence limits 1.6, 5.8). There was no additional risk associated with the presence of more than one household member of this age, and the association did not vary significantly with the age of the infected child.

Volume 106 Number 2

Day care center/nursery attendance. Children who did not attend a D C C / N showed a rather typical age distribution for H. influenzae disease, with a peak among the 6- to 11-month-old group, but those who did attend a D C C / N were mostly older ( > 18 months). In the univariate matched analysis, infected children were more likely to have attended a D C C / N (OR 1.9,95% CL 1.2, 3.2). For the group >_12 months of age, the ratio for any D C C / N attendance was 3.7 (95% C1 1.6, 8.5). and that for attendance at D C C / N serving at least four children was 5.9 (95% CL 2.3, 15.3). When the analysis was stratified both by the age of the child and by the size of the D C C / N and adjusted for the presence of an elementary school-aged household member, the OR was significantly increased only for children > 1 2 months of age who attended a D C C / N with four or more children (Fig. 1), and reached a peak OR of 13.1 for attendance at a DCCt'N with >--21 children. The risk for the smallest units (one to three children) was the same as that for children not attending a DCC/N. In Table II the raw numbers (in unmatched fashion) are stratified by presence of a household member in elementary school, age, and D C C / N attendance. In subsequent multivariate statistical modeling the group in a D C C / N with one to three children was combined with the group not attending a DCC/N. For purposes of statistical modeling, we assumed a linear increase m the log of the OR with each increasing D C C / N category.The multivariate model yielded estimates showing a clear trend of increasing OR with increasing age and increasing size of D C C / N (Fig. 2). The ratios for the various strata of D C C / N size were not increased for children younger than 6 months of age, modestly increased for those 6 to 11 months old, and significantly increased for the two older groups. The association of infected children with D C C / N attendance and the presence of a school-aged household member remained significant when meningitis and all other cases were analyzed separately, when D C C / N attendance was redefined as >4 per week or as >8 hours per week, or when D C C / N attendance of other household members Was added into the multivariate model. Restricting the analysis to infected Children born in Colorado and their corresponding controls resulted in similar findings. The addition of cases and controls who were originally unmatched or did not respond to the three mailings did not affect the results. In fact, those who were not included in the original matched analysis were even more likely to have attended a D C C / N than those infected children who were included, and the controls who were not included in the original matched analysis were less likely to have attended D C C / N than controls who were included. Breast-feeding. For the entire group younger than 1 year

Risk factors for primary H. influenzae infections

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Table II. Distribution of cases and controls, stratified by presence of elementary school-aged household members, age, and D C C / N attendance

-Age (too)

Cases

Controls

I

(DCc/NOR unmatched)

With elementary school-aged household members 0 to 11 DCC/N* 6 3 No DCC/Nt 15 14 ~12 DCC/N 10 3 No DCC/N 8 11 Without elementary school-aged household members 0 to 11 DCC/N 9 18 No DCC/N 31 59 >~12 DCC/N 20 12 No DCC/N 11 46

1.9

4.6

1.0 7.0

Overall Mantel-HaenszelChi = 3.4; ORM-Hfor DCC/N attendance= 2.5 (95% CI, 1.5, 4.3). *DCC/N attendancewith four or moreother children. tNo DCC/N attendance,or fewer than four other children.

of age, there was no significant difference in the prevalence of breast-feeding between cases and controls. However, among infants younger than 6 months of age, those with infection were significantly less likely to have been exclusively breast-fed in the most recent 3-month period (3/24 cases vs 16/45 controls, OR 0.1, 95% CL 0.01, 0.96), adjusted for presence of school-aged household members and D C C / N attendance. Attributable risk calculations. Using the prevalence of exposure to day care among our randomly selected control population (35%), and the overall OR for D C C / N attendance for children in the study (1.9), the calculated percent attributable risk to day care attendance is 24%. Twenty-seven percent of H. influenzae infections may be attributable to the presence of a school-aged Sibling in the household. For children older than 18 months, the attributable risk related to day care attendance is >75%. DISCUSSION The estimated yearly rate for invasive H. influenzae disease in Colorado (112/i 00,000 children up to years of age) was similar to rates based on an active surveillance system in Fresno, California.~ Using this surveillance system, hospital infection control practitioners and bacteriology laboratories reported twice the number of cases of meningitis to the Colorado Department of Health as during the previous year. The Subsequent review of a sample of laboratory-confirmed cases of H. influenzae infection demonstrated that reporting Nas virtually complete during the study, minimizing the chance of ascertainment bias in determining children eligible for inclusion in the study. We chose controls born on the same day as the infected

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q

Size of DCC/N (No. of children):

%.

~]

0-3

~

4-10

~]

11-20

l~

>~20

3o:0,105,,

14 om 12 I-< " 10 (3 a

o

8 2.3(1.1-5.2) p=0.04

0.8(0.2-2.8)** p=NS

1.3(0.7-2.6)** p=NS

, 0-5 mos,

6-11 mos,

12-17 mos.

I> 18 mos.

AGE IN MONTHS

Fig. 2. Odds ratios (adjusted for presence of elementary school aged household member; OR 3.0, 95% confidencelimits 1.6, 5.7, P= 0.002) for day care center or nursery attendance, by size of DCC/N and age of child. InvasiveH. influenzae disease, Colorado, 1981-1982. NS, Not significant. **Change in OR for each increase in DCC/N size category, with 95% confidence intervals in parentheses.

child, selected at random from Colorado birth certificates. We chose not to match for other factors such as race and socioeconomic status so that we could analyze these as potential risk factors. Neither was significant, although the large proportion of whites in Colorado made it difficult to evaluate the effect of race. The matching of some of the children born outside Colorado with controls born in the state did not affect the results; limiting the analysis to those infants born in Colorado and their controls showed a similar trend with regard to both the day care and household risk factors. Although parents who responded to the questionnaire were more likely to be white, to have more education, and to have received earlier prenatal care, this trend was similar among both Cases and controls, making it riot likely that this bias had an important effect. Inclusion of nonrespondents who were later reached by telephone or in personal interviews strengthened the associations found in the original analysis. Only two significant risk factors for invasive H. influenzae infection were identified: attendance at a D C C / N and the presence of an elementary school-aged household member. Using stricter definitions of D C C / N attendance (>4 hours per week or >8 hours per week) did not affect the results. Although D C C / N attendance has been sus-

pected, on the basis of anecdotal reports, to increase the risk of primary H. influenzae disease, our data give evidence for the increased risk. With the exception of gastrointestinal tract infections and hepatiti s A, H primary infections with few other diseases, if any, have been shown to be associated with D C C / N attendance. The striking relationship between age and risk from D C C / N attendance may be similar to that seen with other diseases. Hadler et al. H have shown that hepatitis A infections in day care settings are most frequent among children between 1 and 3 years of age. Sealy and Schuman ~2 showed that infection with Giardia in D C C / N attendees was highest in children 2 and 3 years old, and the prevalence of cytomegalovirus excretion among children in day care settings is higher for toddlers older than 1 year than for younger infants/3 This age-dependent risk may be related to the degree of shared secretions and direct physical contact among D C C / N attendees, which is probably minimal for infants who are too young to walk or crawl. In our study the group of children likely to be able to crawl (6 to 11 months old) had a risk intermediate between the younger and the older children. It is possible that other risk factors are important for the younger groups, and a larger study is necessary to detect an effect of D C C / N attendance.

Volume 106 Number 2 The other significant risk factor was the presence of a school-aged child in the household. A previous study found that children with 11. influenzae meningitis were more likely to have older siblings younger than 12 years of age.14 Nasopharyngeal colonization rates among school-aged contacts of persons with H. influenzae disease is 15% to 20%15; introduction of H. influenzae into a household could take place from such carriers and could represent the source of acquisition for their susceptible younger siblings. Exclusive breast-feeding was a significant protective factor for children younger than 6 months, after controlling for D C C / N attendance and for the presence of a school-aged household member. Lure et a l l 6 showed that among Alaskan Eskimos, children with invasive H. influenzae infection were significantly less likel~r to have been predominantly breast-fed than controls. The protection may be the result of H. influenzae anticapsular antibody in human milk, but the mechanism needs clarification. 16 Regardless, the data support the general recommendation to breast-feed infants. If the risk factors identified are Verified in other areas of the United States, children older than 1 year who attend a D C C / N may be a readily identifiable group for whom effective preventive measures, such as immunization, could be implemented. Such measures could prevent more than half of the cases of invasive H. influenzae disease in this age group. Day care has become an integral part of our society and is likely to remain common in the foreseeable future. In addition to efforts to make 1-1. influenzae vaccine available, it is incumbent on medical and public health investigators to identify aspects Of day care that may be improved or altered to decrease the risk of 1-1. influenzae infection. ADDENDUM Since this article was prepared, a study showing an increased rate of H. influenzae infections among D C C / N attendees in Monroe County, N e w York, has been published. 17 In that study, children 0 to 5 years of age who attended a D C C / N were 1.7 times more likely to develop H. influenzae infections than were children who did not attend, a relative risk similar to that found in our study, 1.9. However, the risk in the Monroe County study was highest for children younger than 1 year. We thank all infection control practitioners and bacteriology laboratory directors in Colorado hospitals for reporting cases;

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Mary Ann Welling, R.N., and Marti Roe, R.T.; Mimi Glode, M.D., for valuable ideas regarding questionnaire design; and Robert Gunn, M.D.; and Loraine Good for reviewing the manuscript, and Mary Schwartz for typing it. REFERENCES

1. Fraser DW, Geil CC, Feldman RA: Bacterial meningitis in Bernalillo County, New Mexico: A comparison with three other American populations. Am J Epidemiol 100:29, 1974. 2. 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 141:40, 1980. 3. Ginsburg CM, McCracken GH Jr, Rae S, Parke JC Jr: Haemophilus influenzae type b disease: Incidence in a day-care center. JAMA 238:604, 1977. 4. Ward Jl, Gorman G, Phillips C, Fraser DW: Hemophilus influenzae type b disease in a day-care center: Report of an outbreak. J PEDIATR92:713, 1978. 5. Melish ME, Nelson A J, Martin TE, et al: Epidemic spread of H. influenzae type b in a day-care center. Pediatr Res 10:348, 1976. 6. Ward Jl, Fraser DW, Baraff L J, Plikaytis BD: Haemophilus influenzae meningitis: A national study of secondary spread in household contacts. N Engl J Med 301:122, 1979. 7. Breslow NE, Day NE: Statistical methods in cancer research, vol 1. The analysis of case-control studies. Lyon, France, 1980, International Agency for Research on Cancer, pp 162-189 (IARC Scientific Publications No. 32). 8. Cornfield J: A method of estimating comparative rates from clinciM data: Applications to cancer of the tung, breast and cervix. J Natl Cancer Inst 11:1269, 1951. 9. Lillienfeld AM, Lillienfeld DE: Foundations of Epidemiology. New York, 1980, Oxford University Press, pp 217-218. 10. Istre GR, Conner JS, Glode MP, HoPkins RS: Increasing ampicillin resistance rates in Haemophilus influenzae meningitis. Am J Dis Child 138:366, 1984. 11. Hadler SC, Webster HM, Erben J J, et al: Hepatitis in day care centers: A community-wide assessment. N Engl J Med 302:1222, 1980. 12. Sealy DP, Schuman SH: Endemic giardiasis and day care. Pediatrics 73:154, 1983. 13. Pass RF, Hutto SC, Reynolds DW, Polhill RB: Increased frequency of cytomegaloviras excretion in children in group day care. Pediatrics 74:121, 1984. 14. Ounsted C: Haemophilus influenzae meningitis: A possible ecological factor. Lancet 1"161, 1950. 15. Band JD, Fraser DW, Ajello G: Prevention of Haemophilus influenzae type b disease by rifampin. JAMA 251:2381 , 1984. 16. Lum MK, Ward JI, Bender TR: Protective influence of breast feeding on the risk of developing invasive 1-1.influenzae type b disease. Pediatr Res 16:151-A, 1982. 17. Redmond SR, Pichichero ME: Haemophilus influenzae type b disease: An epidemiologic study with special reference to day-care centers. JAMA 252:258I, 1984.