The highest incidence of AOM occurs between 6 and 11 months of age (20), and onset of the first episode of AOM before 6 months (20) or 12 months of age is a powerful predictor of recurrence (25). The risk of persistent MEE after an episode of AOM is inversely correlated with age (20), and children who experience their first episode of MEE before 2 months of age are at a higher risk for persistent fluid during their first year of life than are children having their first episode later (26).

Most investigators have reported no apparent sex-based difference in the incidence of OME. Some studies have found a significantly higher incidence of AOM in males as well as more recurrent episodes than in females, but others have not found this (24).

Previous studies have suggested a lower incidence of OM in black children compared to white children. However, more recent studies in which the children were followed prospectively with examinations of the ears every 6 weeks showed no difference between the black and white children in their experience with OM (27,28). One study, part of an American population-based sample survey evaluating school children ages 6 to 10 years with tympanometry, also reported no difference between black and white children. However, the prevalence of OME was significantly higher in Hispanic children compared to white children (29).

Controversy remains regarding the role of allergy in the pathogenesis of OM as allergy is a common problem in children, occurring at a time when respiratory infections and OM are common. Most, but not all, of the epidemiologic studies have supported an association. Pukander and Karma (30) found, in 707 children with AOM, that in children with atopic manifestations, the persistence of MEE for 2 months or longer was greater than in children without allergy. However, in another study, atopic diathesis was not found to predispose a child to the development of AOM (31). Tomonaga et al. (32) determined that allergic rhinitis was present in 50% of 259 patients (mean age of 6 years) in whom OME had been diagnosed while OME was present in 21% of 605 patients (mean age of 9 years) in whom allergic rhinitis had been diagnosed. Among 108 children (ages 5 to 8 years, mean age of 6 years) in whom neither condition had been diagnosed, the incidences of allergic rhinitis, OME, and both of these conditions were 17%, 6%, and 2%, respectively. Another investigative group (33) compared 76 children with MEE admitted for bilateral myringotomy with tube insertion (M&T) to 76 controls matched by age, gender, and season of admission for a general surgical procedure. Results showed a nearly fourfold increase in the risk of persistent MEE in children who had atopic symptoms for more than 15 days per month. In another study, Bernstein and Reisman (34) determined the allergy status of a group of 200 children who had undergone one or more M&T procedures. They diagnosed allergy in 23% of the entire group but found that the frequency was 35% among the 88 children with multiple myringotomies with tube insertions. The frequency of allergy in these patients was higher than that reported for children of similar age in the general population. The above studies generally found a higher frequency of OME in allergic children compared with age-matched nonallergic children, as well as higher frequencies of allergy in children with OME compared with children without OME. Skoner et al. (35) suggested that if significant allergic rhinitis is diagnosed in a patient with OME, it should be treated aggressively. More studies are needed to evaluate the relationship between these two conditions.

Children with recurrent OM as well as other recurrent infections may have a defect in the immune system such as a defect in phagocyte function, humoral immunity, local
immunity, or other immune defects (36). Immunologic screening is indicated to exclude an immunodeficiency in children with frequent episodes of OM or an abnormal course of disease (37). While agammaglobulinemia and hypogammaglobulinemia are rare, deficient or lowered immunoglobulin (Ig)A or decreased levels of one or more IgG subclasses, in particular IgG2, are more common. The specific antibody response to bacterial capsular polysaccharides is often low. Kaur et al. (38) reported finding that, after an episode of AOM due to Streptococcus pneumoniae, otitis-prone children and children who failed treatment for AOM had less of an IgG serum antibody response compared to non-otitis-prone children to proteins of S. pneumoniae. Children infected with the human immunodeficiency virus have a significantly higher recurrence rate than normal children or children who have seroconverted (39).

To date, no evidence suggests an effect of cleft palate/cleft lip type or laterality on OME prevalence (40), and an equally high OME prevalence was reported in patients with diagnosed submucosal cleft palate (41) but not in patients with bifid uvula (42,43). OM is considered “universal” in infants less than 2 years of age with unrepaired cleft palate (44). After surgical repair of the palate, the occurrence of OM is reduced, which is most likely due to improvement of eustachian tube function. In a prospective study of 150 children with cleft lip and palate, enrolled between 2 and 18 months of age, Robinson et al. (45) reported a 92% prevalence of OME before palate repair, no short-term change after palate repair, but a reduced prevalence to 70% at 4 years of age. Many children continue to have problems up into the teens. A reduction of middle-ear disease by newer palatoplasty procedures has been suggested (46). OM is also common in children with other craniofacial abnormalities also due to anatomical or functional eustachian tube dysfunction (47). Down syndrome children have, in addition to poor active eustachian tube function, low resistance of the eustachian tube, which predisposes to reflux of nasal secretions into the middle ear (48).

The frequency of the occurrence of one episode of OM is so high that a genetic predisposition cannot be expected. However, a predisposition to recurrent episodes of OM and chronic MEE may have a significant genetic component. The etiology of OM is multifactorial, involving environmental as well as genetic factors. A large number of genes may be involved, each contributing to a particular increase in disease risk.

Twin and triplet studies have been used to assess the heritability of OM. Two retrospective studies using questionnaires have been published. The first study, using 2,750 Norwegian twin pairs, estimated the heritability at 0.74 in females and 0.45 in males (49). In the second study, the estimated heritability was, on average, 0.57 at ages 2, 3, and 4 years (50). In a prospective twin/triplet study from Pittsburgh with monthly assessments of middle-ear status, the heritability estimate for OM at age 2 years was 0.79 in females and 0.64 in males (51). Heritability is a population statistic to ascertain if a trait is heritable, while link-age and association studies may identify genetic regions or specific genes influencing the particular trait or disease. Daly et al. (52), using genome-wide linkage analysis, have suggested that regions of chromosomes 19q and 10q contain genes contributing to the susceptibility to chronic OME/recurrent AOM. Subsequent fine mapping of both regions further strengthened the evidence for this link-age (53). A second genome-wide linkage analysis demonstrated linkage regions with plausible candidate genes in 17q12 (AP2B1, CCL5, and a cluster of other CCL genes) and in 10q22.3 (SFTPA2) (54). Polymorphisms in mannose binding proteins (55), surfactant protein (56), mucin expression (57), and cytokines (58,59) have been associated with mucosal immunity and development of disease. In addition, polymorphisms in three genes (FBXIIO, TLR4, and PAII) originally identified in mouse models of OM have shown evidence of susceptibility to childhood OM in cohort studies (60,61,62).

Both epidemiologic evidence and clinical experience strongly suggest that OM is frequently a complication of an URI. The incidence of AOM is highest during the fall and winter months and lowest during spring and summer months, which parallels the incidence of URI (22). This supports the hypothesis that an episode of URI plays an important role in the etiology of OM. Rhinovirus, RSV, adenovirus, and coronavirus have been detected in MEE during episodes of AOM (64,65). Winther et al. (66) reported that the OM complication rate of a cold-like illness was 33%. The predominant virus in this population was the rhinovirus.

Almost universally, day care center attendance remains a very important risk factor for development of OM. For example, prevalence of high negative middle-ear pressure
and flat tympanograms (type B), indicative of MEE, have been shown to be highest in children cared for in day care centers with many children, intermediate in children in family day care with fewer children, and lowest in children cared for at home (67). Data from the United States ECLS-B, including more than 8,000 children studied at 9 months and 2 years of age, showed a significant increased risk for recurrent AOM and tube insertion for children attending day care (5).

Birth order has been shown to be associated with episodes of OM and percentage of time with MEE (22). Firstborn children had a lower rate of episodes of AOM and less time with MEE during the first two years of life than children with older siblings. Also, having more than one sibling was significantly related to early onset of OM (30), and the presence of more children in the household was related to more time with MEE (28).

The reason for the higher morbidity in children in day care centers and in children with older siblings may be related to the greater opportunity for exposure to viral URI, which may cause eustachian tube dysfunction leading to the development of OM.

An association between OM and passive exposure to smoking has been reported by many investigators, while others have not been able to demonstrate such an association. In most studies, the information regarding smoke exposure has been obtained from the parents. A few studies have measured cotinine, a metabolite of nicotine, in blood, urine, or saliva of the child and have been able to more accurately determine the association between OM and smoke exposure (21,68). More information about the pathogenesis, duration, and intensity of exposure is needed to clarify this association. Two studies have shown an association between middle-ear status and parental smoking. In children exposed to parental smoking, tympanostomy tubes stayed in place for 59 weeks compared to 86 weeks in children who were not exposed to smoking (69). Also, myringosclerosis was more prevalent in children with two smoking parents compared to those with no smoking parents (64% vs. 20%), and maternal smoking was associated with a highly increased risk of recurrent OM after insertion of tympanostomy tubes (70).

Breast-feeding for 6 months exclusively is recommended by most national and international authorities, including the American Academy of Pediatrics and the American Academy of Family Physicians, the World Health Organization (WHO), and the United Nations Children’s Fund. In 2002, Kramer and Kakuma (71) published a comprehensive review of the world literature to determine health benefits of exclusive breast-feeding for 6 months compared to 3 to 4 months. They reported a decrease in the risk for gastrointestinal infection even in developed areas. It had not been shown previously that exclusive breast-feeding for 6 months or longer compared to 4 to less than 6 months in the United States provided greater protections against respiratory infections. Therefore, a secondary analysis of data from the National Health and Nutrition Examination Survey III, a population-based cross-sectional home survey conducted from 1988 to 1994, was undertaken (72). After adjusting for demographic variables, child care and smoke exposure, the data revealed statistically significant increased risk for both pneumonia (OR: 4.27; 95% CI: 1.27 to 14.35) and three or more episodes of OM (OR: 1.95; 95% CI: 1.06 to 3.59) in those children breast-fed 4 to less than 6 months. These findings further support the current recommendations that infants receive breast milk exclusively during the first 6 months of life.

Socioeconomic status and access to health care are factors that may affect the incidence of OM. It has been generally thought that OM is more common among the lower socioeconomic strata due to poor sanitary conditions and crowding. Paradise et al. (28) followed 2,253 infants for 2 years in the United States and found an inverse relationship between the cumulative proportion of days with MEE and socioeconomic status. However, many studies have not revealed any correlation between socioeconomic status of the child’s family and the incidence of MEE.

Niemelä et al. (73) reported that pacifier use increased the annual incidence of AOM and calculated that pacifier use was responsible for 25% of AOM episodes in children younger than 3 years. They reported the results of an intervention trial in which parents in various well-baby clinics were taught that pacifier use was harmful and should be limited, while parents in other clinics were not provided with this information. This led to a 29% decrease in AOM in the group provided with pacifier information. Pacifier use has been theorized to contribute to the development of OM, possibly due to the sucking action of the child propelling nasopharyngeal secretions into the middle ear or by the pacifier acting as a fomite. However, Brook and Gober (74) cultured the surface of pacifiers from children with AOM but found no pathogens typical of AOM. The role of pacifier use in AOM remains unclear.

Recent studies have indicated that there may be an association between OM and body mass index (BMI). Tympanostomy tube insertion and overweight were studied in a predominantly white cohort of children (97%) followed from birth to 2 years of age (75). Weight for length and BMI
for age were calculated using well-child visit data. A history of tympanostomy tube insertion significantly predicted risk of BMI index at both greater than 95th percentile and greater than 85th percentile at 2 years of age after controlling for risk factors and confounders. However, early weight status was not related to later OM, recurrent OM, or tympanostomy tube insertion. In another cohort of American Indian children, a history of recurrent AOM increased the likelihood of weight-for-length index greater than 95th percentile (76). The mechanisms are not clear, but it was suggested that inflammatory changes in the middle ear can result in objective gustatory changes.

Pneumovax is a 23-valent polysaccharide vaccine [PPSV23], which is not efficacious in children 2 years or younger due to poor antibody production. Prevnar is a conjugated vaccine in which pneumococcal polysaccharides are conjugated to a nontoxic mutant of diphtheria toxin. The 7-valent vaccine (PCV7, serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) was licensed for use in the United States in 2000 and recommended for use in children less than 6 years of age by the American Academy of Pediatrics (103). Prevnar 13 (PCV13) replaces PCV7. It was licensed for use in 2010 and includes six additional serotypes (1, 3, 5, 6A, 7F, and 19A) that can cause invasive pneumococcal disease, including the increasingly drug-resistant serotype 19A. The PCV 13 vaccine is recommended for all children 2 to 59 months of age and for children 60 to 71 months of age with an underlying condition that makes them more susceptible to pneumococcal disease. Children up to age 59 months who are fully (four doses) vaccinated with PCV7 should receive one dose of PCV13. (For further guidance by the American Academy of Pediatrics on use of PCV13 and PPSV23, see the Policy Statement, www.pediatrics.org/cgi/doi/10.1542/peds.2010-1280.)

There was great hope that the introduction and subsequent use of PCV7 for infants and young children would lead to a substantial decrease in AOM. Data from vaccine trials conducted in California (104) and Finland (105) revealed only a 7% and a 6% relative reduction, respectively, in AOM episodes. However, in the California study, children with recurrent OM benefited from the vaccine with a reduction of OM episodes varying from 9.3% to 22.8%, increasing as the frequency of episodes of AOM increased. In addition, immunized children were 20.1% less likely to require tube placement than controls. The PCV7 vaccine demonstrated a much higher efficacy (greater than 80%) in reducing invasive pneumococcal disease than reducing the burden of OM. Additional follow-up of the study subjects continued to demonstrate a modest amount of protection against episodes of AOM and tympanostomy tube insertion (106). Reduction in need for tympanostomy tubes after introduction of PCV7 was also shown in Tennessee and New York (107) and in Finland (108).

With use of the vaccine, pneumococcal colonization in the nasopharynx has changed as the vaccine has caused a reduction in the carriage rate of vaccine serotypes and replacement with nonvaccine serotypes (84,109). It should be noted that a reduction in nasopharyngeal carriage of vaccine serotypes and an increase in nonvaccine serotypes have also been seen in children younger than 7 months of age (83).

In the United States and Finland, the initial immunization with PCV7 is at age 2 months based on the results from the clinical trials. However, the question of whether or not the results obtained in the Finnish and US trials could be extrapolated to older children who already had a history of recurrent episodes of AOM was addressed by Dutch and Belgian trials (110,111). Seventy-eight and three hundred and eighty-three children with documented histories of recurrent AOM were enrolled in the Belgian and Dutch studies, respectively. In both trials, children between 1 and 7 years were immunized at entry with PCV7 followed by a booster immunization with a 23-valent pneumococcal polysaccharide vaccine 7 months later and followed up for a total of 18 months in the Dutch and 26 months in the Belgian trial. The results from these two studies did not lend any support to the use of pneumococcal conjugate vaccine to prevent AOM in previously unvaccinated toddlers and children with a history of recurrent AOM. In the infant studies, the PCV7 immunization may prevent or delay nasopharyngeal colonization of the most frequent pneumococcal serotypes and consequently delay pneumococcal episodes of AOM until a later age. In older children, who already are carriers of pneumococci, there is rapid replacement of pneumococcal vaccine serotypes with nonvaccine serotypes.

An 11-valent polysaccharide pneumococcal serotype vaccine conjugated to H. influenzae-derived protein D was evaluated in a clinical trial conducted in the Czech Republic enrolling a total of 4,968 children who were followed to the end of the second year of life with middle-ear cultures when episodes of AOM were diagnosed (112

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