Clinical Epidemiology of Otitis Media

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performed in hospitals during this time would vastlyunderestimate the true tube rate. Therefore twosources of national data, one on hospital dischargediagnoses and another on ambulatory surgery diag-noses, were used for this comparison.

Studies from Finland and the United States havereported increasing incidence of acute OM and recur-rent OM; both studies also reported an increase ingroup child care during the study period. 10, 11 Althoughincreased OM incidence would be consistent with theobserved increased attendance in group child care,changes in rates of breast-feeding and parental smok-ing are more complicated. Rates of breast-feeding at 6months peaked in the United States at 25% in 1982 (upfrom 5% in 1971), declined to 18% in 1989 and thenrose to 22% in 1995.12 Smoking rates for 20- to 44-year-olds have actually declined since 1974, with male ratesdropping more rapidly than female rates. 13 Receiving adiagnosis of OM depends on a number of variables, for

example, diagnostic criteria, parent and physicianawareness of OM and its risk factors and access to anduse of health care. Changes in factors that contribute tothe likelihood of OM diagnosis or ascertainment mayhave occurred over the same time period, resulting inan apparent increase in OM incidence.

Demographic factors. Difficulties arise when com-paring OM rates from studies of a homogenous group tomake judgments about differences in OM susceptibilityby race or ethnicity. Variability in study design, meth-odology or other population characteristics (e.g. socio-economic status, risk factor profiles) may contribute todifferences in OM rates that should not be attributed toethnicity. Previous clinic-based research and surveydata from national samples using parental report of childrens OM history revealed that African-Americanchildren were less likely to experience acute and recur-rent OM or OME than white children. 14, 15 However,Pittsburgh researchers using passive and active surveillance, monthly study visits and objective diagnosticcriteria among biracial study populations demon-strated comparable rates of acute OM, MEE and theproportion of time with MEE in African-American andwhite children during the first 2 years of life and astrong inverse association between OME duration and

socioeconomic status controlling for race.5, 16

Also, anational population-based study of school age childrenreported similar rates of OME for whites and African- Americans, whereas Hispanics experienced higherOME prevalence. 17

Inuit, Native American and Native Alaskan childrenhave considerably higher rates of chronic OM thanrates reported for similarly aged, predominantly whitepopulations, although only one study included morethan one ethnic group. 7 In contrast the few longitudi-nal studies of Native American or Alaskan Native

children in early life describe OM incidence ratessimilar to those of white and African-American chil-dren.

Young age clearly increases the risk of OM andOME, a finding established by a preponderance of evidence. Numerous studies have reported that malechildren are at higher risk of OM than female children,but several others have found no male-female disparityin rates. Socioeconomic status encompasses many in-dependent factors that affect both the risk of OM andthe likelihood of OM ascertainment. These includeaccessibility of medical care, race (often linked to socialclass), prevalence of risk factors (bottle-feeding, paren-tal smoking), exposure to viruses and bacteria impli-cated in OM at child care or in crowded living condi-tions. The complexity of socioeconomic status andfailure to adequately control for it in risk factor studiesmost likely accounts for contradictory findings aboutthe association between socioeconomic status and OM

risk. Additionally in studies using passive surveillance,middle and high income groups may appear to havehigher OM rates than lower income groups because useof health care increases the likelihood of having OMascertained.

Environmental factors. Child care attendance andexposure to other young children (including siblings)has been established by numerous researchers andconfirmed with metaanalysis as one of the major riskfactors for OM, recurrent OM, OME and tympanos-tomy tubes. According to one metaanalysis, child careoutside the home conferred a 2.5-fold risk of OM. 18 A critical review of studies investigating child care andOM reported odds ratios of 1.1 to 2.6 for family vs.home care and 1.6 to 4.0 for center care vs. home care. 19

Child care brings many children together in closecontact, increasing the risk of both respiratory tractinfection and OM. Several characteristics of the childcare experience are related to increased exposure toother children and provide additional risk. These in-clude center care, number of children in the setting orwith whom the child has regular contact, hours spentin child care, age at entry, use of center care for thefirst placement, changes in care settings and havingsiblings in child care (this has been reported from

Norway, where in contrast to the United States, in-fants do not enter child care until they are nearly 12months old). However, recent studies have shown thatamong children followed prospectively or studied cross-sectionally in child care centers, rates of OM andrespiratory disease diminish with age, with older pre-schoolers appearing to be less prone to respiratoryinfections and concomitant episodes of OM. Presum-ably decreasing OM susceptibility with increasing ageeven among children in center care occurs because of maturing immune systems accompanied by ameliorat-

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ing changes in the angle and width of the Eustachiantube, which reduces the effects of viral and bacterialinfections on the Eustachian tube and middle ear.

Infant carriage of bacterial and viral pathogens im-plicated in OM and upper respiratory tract infectionbegins in the first few months of life. These pathogenscan infect (or colonize) a child, and they are easilyspread to others in the child care environment. Pro-posed mechanisms of viral action include injury to themiddle ear and Eustachian tube epithelial cells, en-hanced bacterial adhesion to these cells, lessening of middle ear mucociliary clearance, deleterious effects oncellular immune function and phagocytosis, tubal dys-function resulting in negative pressure and seroustransudate in the middle ear (which is an excellentgrowth medium for invading bacteria) and reducedantibiotic distribution from plasma to the inflamedmiddle ear. Although those in child care are more likelythan other children to acquire active respiratory infec-

tions, they are also at higher risk of bacterial and viralcolonization of the nasopharynx, which independentlyincreases their OM risk.

Scores of researchers have studied the role of infantfeeding in OM. Many of these have reported thatbreast-feeding is protective, but recent studies havefound protective effects only for exclusive breast-feeding lasting for 3 to 6 months. A metaanalysis of risk factor studies reported a 13% reduction in OMassociated with breast-feeding of this duration. 18 Theeffect of breast-feeding on OM has been reported topersist 4 to 12 months after breast-feeding cessation,perhaps because it delays the onset of the first OMepisode and, thereby, reduces the frequency of OMrecurrence. In contrast numerous investigators havefailed to find an association between breast-feedingand OM or recurrent OM. Breast-feeding is a complexbehavioral variable, which cannot be adequately de-scribed with terms such as breast-feeding or bottle-feeding. Researchers classification of infant feedingshould include description of exclusivity of breast (orformula) feeding, duration of each specific feedingpractice (exclusive breast, exclusive formula, combina-tion feeding) and timing of introduction of supplemen-tal foods. 20 Another potential design problem is failure

to adequately control for smoking and social class. Bothare inversely related to breast-feeding but positivelyrelated to OM. In addition detection bias may exist if formula-feeding mothers are more likely than breast-feeding mothers to seek medical care for an ill child,thus increasing the likelihood of OM ascertainment. 20

If breast-feeding reduces OM incidence and preva-lence, several alternative explanations exist for itsbenefit. Lying flat during bottle feeding could causemilk to reflux into the middle ear, as first described byDuncan 21 in 1960. A more recent study demonstrated

that among bottle-fed infants, 60% fed supine and 15%fed in the upright position had abnormal tympano-grams suggestive of MEE after feeding. 22 Alternativelycomponents of breast milk have antimicrobial andimmunomodulating properties that could prevent mid-dle ear infections during and subsequent to breast-feeding. However, evidence about specific protectivemechanisms is lacking. One study showed that exclu-sive breast-feeding reduced nasopharyngeal coloniza-tion with the three major OM pathogens, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxellacatarrhalis, at 6 months of age, although others havereported no effect of breast-feeding duration or exclu-sivity on colonization with H. influenzae . Breast-feeding has not been shown to reduce adherence of H.influenzae to respiratory epithelium, and activity of breast milk pneumococcal antibodies was not corre-lated with colonization or prevention of acute OM.

Like breast-feeding, both positive and negative stud-

ies have been published on the role of exposure topassive smoke and childhood OM. Several studies haveshown a dose-response relationship or increased OMrisk only with heavy smoking. Two metaanalyses re-ported relative risks associated with exposure to pas-sive smoke of 1.2 to 1.7, with an estimated 350 000 to2 200 000 cases of middle ear disease attributable tothis exposure annually in the United States. 18, 23 A possible explanation for discrepancies in studies inves-tigating passive smoke and OM is assessment of childsexposure, which is usually determined by maternalreport of parents current smoking status and numberof cigarettes smoked per day. Other important deter-minants of actual exposure to passive smoke includeparents proximity to child when smoking, childs reg-ular exposure to other smokers and time away fromsmoking parents (e.g. child care). Furthermore smok-ing parents may understate the amount they smoke ordeny that they are smokers. Therefore quantification of a biomarker for smoke exposure is desirable to assessthe childs actual degree of exposure. Studies in whichcotinine have been assayed in the childs blood, salivaor urine have demonstrated a significant relationshipbetween the level of this nicotine metabolite and OMrisk. Probable mechanisms of the link between passive

smoke exposure and childhood OM include inflamma-tion of the mucosal surfaces of the nasopharynx, Eu-stachian tube and middle ear, rendering them more vulnerable to viral and bacterial infection; goblet cellhyperplasia, resulting in mucoid MEE, which is diffi-cult to clear because it is often accompanied by im-paired mucociliary clearance and Eustachian tubeobstruction; inflammation of the respiratory tract air-ways, which increases susceptibility to respiratory in-fection, an important antecedent of OM; and greaterexposure to respiratory infections, which are more

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common among smoking parents who then pass themon to their children.

Genetics. Research has demonstrated the familialclustering of OM, and data are emerging on the role of genes in OM susceptibility. Sibling, maternal and pa-ternal OM history has all been shown to be indepen-dently related to a childs OM risk. Shared OM historyamong siblings may be the result of inherited suscep-tibility and/or exposure to the same environmentalfactors and cultural practices. But when both parentand child develop OM, the likelihood of shared envi-ronmental exposure as the causative factor is notpersuasive because parent and child reside in differentenvironments during early childhood, the period of highest risk. To disentangle the role of heredity andenvironment, recent twin studies have examined theheritability of recurrent OM in 18- to 25-year-olds andtotal time with MEE in the first 2 years of life.Heritabilities of 72 to 75% were reported, with variabil-ity depending on gender and zygosity of the twinpairs. 24, 25

Given the large estimate of heritability and thelikelihood that heritability is multigenic, the next log-ical step is to identify genes linked to OM susceptibil-ity. Knowledge of specific genes involved in OM wouldprovide new insights into pathogenesis. A disease en-tity may arise from different etiologic pathways (genesat one locus or more, environmental factors or interac-tion of genes and environment). Subgrouping individ-uals based on molecular characteristics could elucidateknown mechanisms of causation and lead to the dis-

covery of previously unknown mechanisms, suggestingnew avenues of treatment. Knowledge of a childsgenetic susceptibility would impart more specific,DNA-based estimates of a childs risk to parents (aconsiderable improvement over knowledge of familyhistory). It could also lead to individualized treatmentstrategies. Population-based studies would clarify theimpact of susceptibility genes on disease burden andallow development and targeting of appropriate prevention activities, for example, eliminating environ-mental triggers and providing more aggressive surveil-lance for genetic susceptibles to prevent complications

earlier in disease progression.Prenatal and perinatal factors. Because OM hasits highest incidence in the first few years of life, it islogical to investigate risk factors from the prenatal andperinatal periods. A few studies have shown that lowerbirth weight and prematurity increased OM risk, al-though several others have reported no relationshipbetween birth weight, gestational age and OM. How-ever, more recent studies with large numbers of infantswith very low birth weight, very preterm birth orintrauterine growth retardation have shown these chil-

dren to be at higher risk for OME and recurrentOM.2628

Our recent study investigating the role of prenatalrisk factors for early OM onset demonstrated a signif-icant relationship between low levels of passivelytransferred maternal pneumococcal antibodies mea-sured in cord blood and early OM. 29 However, noassociations were found among maternal prenatal diet,dietary supplements, use of drugs, alcohol, medicationsand symptoms and illnesses during the last trimesterand early OM onset. 30

CLINICAL IMPLICATIONS OF OMEPIDEMIOLOGY

The epidemiologic information on OM gathered todate has led to important avenues for fruitful investi-gation. Identification of the importance of OM onset inthe first few months of life as a strong determinant of subsequent recurrent OM suggested environmentalinterventions (delayed or small group child care,breast-feeding advocacy) and immunologic strategies(maternal immunization against common infant OMpathogens). Identification of genetic determinants of OM susceptibility will yield a quantum leap in OMprevention through early detection of at risk infants.Racial and socioeconomic factors remain tightly inter-twined, and discriminating one from the other factor asOM determinants has been difficult. Clearly respira-tory viral infection remains one of the strongest infantand early childhood OM determinants, giving an incen-tive to develop immunoprophylaxis against these dis-eases.

It is time to expand the clinicians use of this epide-miologic information in patient care while awaitingrandomized trials to measure risk factor reduction ondecreased OM incidence. In primary OM prevention,breast-feeding and small child care size should bepromoted, household tobacco smoking should be dis-couraged and cleft (and submucous) palate should beidentified early in life. A sibling history of early infantor recurrent OM should be known early in life andshould lead to careful ear examinations during the firstyear.

Despite a great deal of progress in the developmentof vaccines to prevent OM, there has been little re-search on preventive strategies to reduce risk factorsas a method of primary prevention. As the ClinicalPractice Guideline for OME points out, no randomizedintervention studies have been conducted to learnwhether reducing traditional risk factors (bottle-feeding, passive smoke exposure, child care size andrespiratory infections) would impact OM incidence.However, two recent randomized intervention studiesshowed that: children of parents who received advice toreduce pacifier use had lower OM rates than controls, 31and children in child care who were randomly assigned



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to use xylitol gum or syrup for 3 months had loweracute OM rates than placebo recipients. 32 Many haveadvocated that physicians advise parents to controlenvironmental risk factors, although the typical physi-cian receives little training on effective strategies tocounsel parents about risk factor reduction. In ourrecent population-based study in Minnesota, only 25%of mothers of 8- to 12-month-old infants received advicefrom a physician or nurse about OM prevention, andthe presence of risk factors was not related to havingreceived this advice. 33 Carefully planned randomizedprevention trials are needed. They should be designedto measure risk factor reduction as an intermediatemeasure of intervention success, with decreased OMincidence as the outcome.

There is sufficient knowledge of secondary OM prevention strategies to promote these as well. With therising prevalence of antibiotic-resistant middle earbacterial pathogens, judicious use of antibiotics is war-

ranted. In particular the use of antibiotic chemopro-phylaxis for recurrent OM has only limited indicationstoday given the marginal impact ( 15% reduction) of this preventive strategy on recurrent OM. The childwho clears MEE between recurrent OM episodes, buthas three or more episodes in 6 months might beconsidered for chemoprophylaxis. Polyvalent pneumo-coccal vaccine [PneumoVax 23 (Merck & Co.); PnuIm-mune 23 (Lederle Laboratories)] is immunogenic inchildren older than 24 months and is likely to reduceOM incidence after this age. New pneumococcal conju-gate vaccines are likely to have an effect on both infantpneumococcal colonization and OM incidence at a

younger age. Surgical intervention (tube insertion,adenoidectomy) is also accepted secondary OM prophy-laxis, based on the epidemiologic linkage of abnormalEustachian tube function with recurrent OM.

CONCLUSIONS

OM, with its peak incidence in the first 2 years of life,is the most commonly diagnosed pediatric disease.Identified host characteristics are useful in targetinghigh risk children, and well-defined environmentalfactors present potential avenues of primary preven-tion. Advances in understanding the genetics of OMwill continue and will dramatically change OM man-agement in the future. Vaccines currently being field-tested offer promise for primary prevention, and strat-egies for risk factor reduction should be tested andimplemented. These strategies are complementary andprovide a well-balanced approach to the reduction of OM morbidity into the 21st century.

REFERENCES1. Freid VM, Mukuc DM, Rooks RN. Ambulatory health care

visits by children: principal diagnosis and place of visit. VitalHealth Stat 1998;13:123.

2. Myer CM III, France A. Ventilation tube placement in amanaged care population. Arch Otolaryngol Head Neck Surg 1997;123:2268.

3. Gates GA. Cost-effectiveness considerations in otitis mediatreatment. Otolaryngol Head Neck Surg 1996;114:52530.

4. Holt E, Guyer B, Hughart N, et al. The contribution of missedopportunities to childhood underimmunization in Baltimore.Pediatrics 1996;97:47480.

5. Paradise JL, Rockette HE, Colborn K, et al. Otitis media in2253 Pittsburgh-area infants: prevalence and risk factorsduring the first two years of life. Pediatrics 1997;99:31833.

6. Owen MJ, Baldwin CD, Swank PR, Pannu AK, Johnson DL,Howie VM. Relation of infant feeding practices, cigarettesmoke exposure, and group child care to the onset andduration of otitis media with effusion in the first two years of life. J Pediatr 1993;123:70211.

7. Homoe P, Christensen RB, Bretlau P. Prevalence of otitismedia in a survey of 591 unselected Greenlandic children. IntJ Pediatr Otorhinolaryngol 1996;36:21530.

8. Daly K. Definition and epidemiology of otitis media witheffusion. In: Roberts JE, Wallace I, Henderson F, eds. In:Otitis media, language, and learning in young children.Baltimore: Paul H. Brooks Publishing, 1997:341.

9. Daly KA, Hunter LL, Giebink GS. Chronic otitis media witheffusion. Pediatr Rev 1999;20:8594.

10. Joki-Erkkila VP, Laippala P, Pukander J. Increase in paedi-atric acute otitis media diagnosed by primary care in twoFinnish municipalities: 19945 versus 19789. EpidemiolInfect 1998;121:52934.

11. Lanphear BP, Byrd RS, Auinger P, Hall CB. Increasedprevalence of recurrent otitis media among children in theUnited States. Pediatrics 1997;99:E1.

12. Ryan AS. The resurgence of breastfeeding in the UnitedStates. Pediatrics 1997;99:E12.

13. Pechmann C, Dixon P, Layne N. An assessment of US andCanadian smoking reduction objectives for the year 2000. Am J Pub Health 1998;88:13627.

14. Shurin PA, Pelton SI, Donner A, Klein JO. Persistence of middle ear effusion after acute otitis media in children.N Engl J Med 1997;330:11213.

15. MacTurk RH, Hoffman HJ, Overpeck MD, Jackson E. Riskfactors forfrequentear infections in US children: results fromthe Third National Health and Nutrition Examination Sur- vey (NHAMES III). In: Abstracts of the Seventh Interna-tional Symposium on Recent Advances in Otitis Media, FortLauderdale, FL, June 1 to 5, 1999, p. 228.

16. Casselbrant ML, Mandel EM, Kurs-Lasky M, et al. Otitismedia in a population of black American and white Americaninfants, 0 2 years of age. Int J Pediatr Otorhinolaryngol1995;33:116.

17. Hoffman HJ, MacTurk RH, Gravel JS, Chiu MS, CosgroveCM. Epidemiological risk factors for otitis media and hearing loss in school age children based on NHANES III, 19881994.In: Abstracts of the Seventh International Symposium onRecent Advances in Otitis Media, Fort Lauderdale, FL, June1 to 5, 1999, p. 59.

18. Uhari M, Mantysaari K, Niemela M. A meta-analytic reviewof the risk factors for acute otitis media. Clin Infect Dis1996;22:107983.

19. Rovers MM, Zielhuis GA, Ingels K, et al. Day-care and otitismedia in young children: a critical overview. Eur J Pediatr1999;158:16.

20. Bauchner H, Leventhal JM, Shapiro ED. Studies of breast-feeding and infections: how good is the evidence? JAMA 1996;256:88792.

21. Duncan RB. Positional otitis media. Arch Otolaryngol 1960;72:45463.

22. Tully SB, Bar-Halm Y, Bradley RL. Abnormal tympanogra-phy after supine bottle feeding. J Pediatr 1995;126:S10511.

23. DiFranza JR, Lew RA. Morbidity and mortality in childrenassociated with the use of tobacco products by other people.Pediatrics 1996;97:5608.

24. Kvaerner KJ, Tambs K, Harris JR, Magnus P. Distributionand heritability of recurrent ear infections. Ann Otol Rhinol

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Laryngol 1997;106:62432.25. Casselbrant ML, Mandel EM, Fall PA, et al. The heritability

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26. Engel J, Anteunis L, Volovics A, Hendriks J, Marres E.Prevalence rates of otitis media with effusion from 0 to 2years of age: healthy-born versus high-risk-born infants. IntJ Pediatr Otorhinolaryngol 1999;47:24351.

27. Nalluswami K, Ko CW, Hou JR, Hoffman HJ. Very low birthweight (VLBW) infants are at increased risk for frequent earinfections [Abstract]. Am J Epidemiol 1998;147:S16.

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29. Salazar JC, Daly KA, Giebink, et al. Low cord blood pneumo-coccal immunoglobulin G (IgG) antibodies predict early onsetacute otitis media in infancy. Am J Epidemiol 1997;145:104856.

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31. Uhari M, Niemela M, Pihakari O, Pokka T. Pacifier as a riskfactor for acute otitis media. In: Abstracts of the SeventhInternational Symposium on Recent Advances in Otitis Me-dia, Fort Lauderdale, FL, June 1 to 5, 1999, p. 229.

32. Uhari M, Kontiokari T, Niemela M. A novel use of xylitolsugar in preventing acute otitis media. Pediatrics 1998;102:87984.

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QUESTIONS/ANSWERSQuestion: In a study of 2000 children from shortly

after birth to age 2 years, breast-feeding for 3 monthshad a carryover effect. Why does this occur? One theoryis that the immune system is activated resulting in thelong carryover protective effect.

Dr. Giebink: My bias is that the carryover effectexists simply because early OM is reduced. Data indi-

cate that early OM is the strongest determinant of

recurrent OM. Therefore, if you can delay the firstepisode 3 to 6 months, the incidence of recurrent OM isdramatically reduced.

Question: Why do you think that early OM predictsrecurrent OM? Is there any information and what isthe mechanism?

Dr. Giebink: There are many hypotheses. All stud-ies have shown that there is a very strong, independentrisk for recurrent OM with early OM.

Question: Is it not true that most OM occurs in thefirst year of life whether it recurs or not?

Dr. Giebink: Most recurrent OM that occurs in thefirst 6 months goes on. The vast majority of cases are inthe first 6 months of life. Studies have shown that if OM was diagnosed at the 2-month office visit, therewas over a 50% chance of having three or more episodesbefore the first birthday vs. a 20% chance ifOM wasnotpresent at the 2-month visit.

Question: Concerning breast-feeding, why is it aneffective prevention? Is it because of immunoglobulinsin the breast milk?

Dr. Giebink: That is a possibility, but other factorsmay be present. There is a lot of lactoferrin in milk andthere are other nonimmunologic mechanisms that mayhave a role. Let me add that bottle feeding results in anegative pressure in the bottle. Measurements of thatpressure plus the pressure in the pharynx suggest thatbabies struggle to suck the bottle. Also, sucking onpacifiers appears to be related to OM. The negativepressure adversely affects the Eustachian tube (also insupine vs. prone sleeping positions). Breast-feeding is

always under positive pressure.


Clinical Epidemiology of Otitis Media

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