Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Update on Otitis Media Otitis media is a complex disorder. Both genetic and environmental factors have been found to be involved, and the highest incidence are among infants and children. And even today, in 2005, otitis media still remains a major health issue for children in this country and for others in the family. Unfortunately, the pathophysiology is still not fully understood, and there is a potential long-term detrimental impact on hearing and language development, as well as significant economic consequences in this country. I would like to define some basic terms at the beginning. Otitis media is an inflammation of the middle ear. Acute otitis media is an acute infection of the middle ear space. It is usually associated with a rapid onset of symptoms and signs including fever, otalgia, inflammation, or bulging of the tympanic membrane, and purulent middle ear effusion. There is no constellation of signs and symptoms that have been universally accepted in establishing this diagnosis. Otitis media with effusion is an inflammation of the middle ear with a collection of fluid in the middle ear space. It is the presence of serous mucoid or purulent fluid without acute symptoms. And finally, chronic suppurative otitis media is an infection of the middle ear of several weeks duration associated with purulent otorrhea through a perforation or through a tympanostomy tube. Many issues currently exist in this disease. Many primary care practitioners still struggle with the diagnosis of otitis media and often recommend medical and surgical intervention inappropriately. There is increasing antimicrobial resistance and questions about the length and type of therapy that should be given, and despite years of clinical experience with this disorder, all the risk factors for otitis media are still not fully understood, and its management continues to evolve. This is a very broad topic. Today I want to focus on the recent developments and research in this area, specifically new data on the risk factors for otitis media and the impact on children in society. This new data has been published during the past five years and there is increasing evidence that heredity and reflux are risk factors for otitis media. Wide-spread use of vaccines may be efficacious, particularly the pneumococcal and influenza vaccines. The management of otitis media is constantly evolving, based on research from a variety of medical subspecialties. It is critical that we understand the epidemiology, diagnoses and treatment of this common pediatric infection. The otolaryngologist treating otitis media must keep pace with and synthesize these new findings into a rational approach to treatment. Despite advances in pubic health and medical care, middle ear infections are still prevalent around the world, and the incidence in the United States has actually increased over the past ten to twenty years. Otitis media remains the most common bacterial infection of childhood and the most common indication for antimicrobial therapy in this age group. Two-thirds of all American children have had at least one episode of acute otitis media prior to 1 year of age, and 80% have had one by 3 years of age. There are direct costs of treatment and medical care, and indirect costs, as in parental time lost from work. The total direct and indirect cost of each episode of otitis media has been estimated to be $1300. The annual cost of the medical and surgical treatment of otitis media in the United States has been estimated to be $3.5 billion. Otitis media is the most frequent diagnosis made by pediatricians in an ill child, second only to the common cold. It accounts for as many as 30 million office visits annually. Approximately 45 million prescriptions are written for oral antimicrobial agents each year in the United States for children under 10 years of age. One-half of all antibiotic prescriptions for children under 10 years of age are for otitis media, and it is estimated that approximately 600,000 myringotomy and tympanostomy tube operations are performed in the United States each year. Myringotomy with insertion of a tympanostomy tube is the most common surgical procedure performed in children. All of us are aware of the medical impact of otitis media. In otitis media with effusion, for instance, the average hearing loss is estimated at 27 dB. Sequelae of otitis media manifested in a tympanic membrane include atrophy, mryingosclerosis, retraction, adhesion, and perforation. Cholesteatoma is a serious possible sequela of otitis media, and ossicular problems due to either fixation, discontinuity, or absorption can cause a further conductive hearing loss. There has been growing interest in studying quality of life as an outcome measure in otitis media. Recurrent or chronic otitis media has been reported to have a substantial and negative effect on the various domains of functional health status and health-related quality of life. There is still incomplete data on these instruments’ validity and liability. Dr. Richards and Dr. Gianonni published a study in 2002. The participants were a consecutive series of 123 children referred for the surgical treatment of either recurrent acute otitis media, and/or chronic otitis media with effusion, who are undergoing either a tympanostomy tube placement alone, or with adenoidectomy. An otitis media disease specific questionnaire was administered to these children’s parents before and after surgical intervention. These children scored significantly poorer on the questionnaire than did children without a significant history of ear problems. Hearing and vestibular symptoms, speech, and social effects were the most severely affected. The mean percentage change for these children in the total ear symptoms score was a 75% improvement at one month follow-up after a tube placement and possible adenoidectomy, and at 60% improvement at the six month follow-up. Parental worry related to the child’s ear problems were also significantly decreased postoperatively. In most cases, otitis media begins with a viral infection of the upper respiratory tract that then causes congestion of the Eustachian tube and impairment of normal tubal function. Thus, there is not good middle ear ventilation, ciliary clearance, or drainage. Pathogens colonizing the nasopharynx may gain access to the middle ear space and multiply. The immune system most of the time will eradicate the infection and the acute symptoms, but the effusion may persist until normal tubal function returns. The bacterial species involved in acute otitis media have not changed significantly over the last two decades. Streptococcus pneumoniae, as shown here, continues to be the most common pathogen, accounting for 40% of cases, approximately. It is the organism most likely to produce otalgia and fever and least likely to resolve without medical management. The other two most common organisms are Haemophilus influenza, and Moraxella catarrhalis. Bacterial biofilmsare the new buzz words today. Viable bacteria are believed to organize through complex intracellular communication. They form an exopoly-saccharide matrix, and are thus protected from phagocytosis. This results in reduced metabolism and relative resistance to antibiotics, and to growth and tissue culture. And biofilms today are believed to account for the persistence of middle ear disease. The pathogenesis of middle ear infections in children is multifactorial. Age, allergy conditions and asthma are all associated with increased risk of otitis media, early onset of otitis media, and repeated episodes. Other factors have been extensively studied, including poor hygiene, poor nutrition, and impaired immune system. The presence of siblings means more exposure to respiratory pathogens, and hence, first-born children have lower rates of acute otitis media than do children witholder siblings. All of these factors listed here have been studied at length and are well known. What new findings have been discovered during the past five years? And what can we tell our patients who we see in clinic to reduce their children’s risk of developing acute otitis media? Acute otitis media is primarily a disease of infancy and early childhood, with the highest incidents between 6 and 18 months of age. The early onset of otitis media also predicts later recurrent episodes, so children who have their first episode during their first 6 months of life are five times more likely to develop more infections. The incidence, of course, varies with seasons, and it is greatest in winter, and the prevalence of upper respiratory infections is highest. The incidence is lowest during the summer in temperate climates. If a child is born during the fall, it has a slightly higher risk of early onset and recurrent otitis media. Maternal antibody levels will have declined from the periods of highest exposure in the previous winter and thus reach their nadir in the fall of the infant’s birth. So infants born in the fall then enter winter time, peak respiratory disease season, when their passive antibody levels are low and they are not yet producing their own antibodies. Otis media is nearly universal among children with unrepaired clefts of the palate. The occurrence is then reduced following surgical repair of the palate, because the Eustachian tube can then function better. Children with Down’s syndrome have been found to have poor active opening function of the Eustachian tube, and also a very low resistance at the tube, so secretions from the nasopharynx easily enter the middle ear. Immune defects include deficient immunoglobulin IgA, or decreased levels of IgG2. And HIV infected children have a significantly higher recurrence rate of acute otitis media than normal children. In the US, otitis media is most common among Native Americans and Alaskan Eskimos. And in these groups, otitis media is more frequently complicated by perforation of the tympanic membrane and persistence of purulent drainage. Otitis media was diagnosed by the age of 4 months in over half of Australian Aborigine children, and among Native American and Alaskan children, less than 1 year old, our patient visit rates were nearly three times higher than those for all American infants. Among Native American and Alaskan children ages 1 to 5 years old, the outpatient otitis media visit rate was 1.5 times higher than the rate for age-matched American children. During the past five years, there has been much research into the effect of race and socioeconomic factors. Studies during the 1970s and 80s have suggested that Caucasians were more likely to develop otitis media than African-Americans. Newer studies, however, suggest that there is no effect of race in these two groups on the development of otitis media, but rather, the treatment. Otitis media is more likely to be accurately detected earlier in Caucasian children, since they have better access to and use healthcare more. No difference was found between black children and white children, when children were from the same socioeconomic background, or examined at monthly intervals and received the same treatment for ear disease, from age birth to 2 years of age. Two studies in 2000 and 2002 used National Health Service data to evaluate healthcare among children with otitis media. Both studies assessed factors associated with tympanostomy tube insertion. One study suggested that children with continuing health coverage for more than seven months were more likely to be treated with tubes, and Caucasian children were more likely than African-American children to be treated with tubes. The second study reported that African-American children had a lower likelihood of seeing a specialist or of having tympanostomy tubes than did Caucasian children. And again, this difference is felt to be because of inequalities in healthcare today. Acute otitis media and tympanostomy tube placement are much more common in children in daycare facilities, as we all know. The risk increases if the child enters daycare the first year of life, and larger daycare size is also significantly associated with higher levels of risk. The prevalence of upper respiratory infections and otitis media was higher among child care settings with at least six children than among those in settings with fewer children, for once the children are more than 3 years of age, the incidents including of illness, including otitis media and upper respiratory infections, is unrelated to the number of hours per day spent in childcare. And although children in large daycare facilities tended to manifest more episodes of upper respiratory illnesses, daycare may provide a protective effect against common cold viruses once they actually enter school. In 1999, Dr. Kristjansson, in Australia, published a study of 5000 mothers. He asked mothers at their first prenatal visit how many cigarettes they smoked per day, and then tracked if their children developed their first episode of otitis media by six months of age. He found that the relative risk was 1.6 times higher if the mother smoked 1 to 9 cigarettes per day, and the risk of an infant developing otitis media by six months of age increased by a factor of 3.3 if the mother smoked 20 or more cigarettes per day at her first prenatal visit. The child’s risk of otitis media was found to be independent of maternal smoking at six month’s postpartum. Environmental tobacco smoke may affect children’s ears in several ways. It can directly cause an irritant effect on middle ear mucosa and the Eustachian tube. It can damage the mucociliary clearance mechanism. It indirectly causes irritation of adenoid tissue, and increases the risk of histamine, which in turn leads to production of middle ear effusion. Histopathological studies of adenoid tissue in passive smoking children, children who are exposed to smoke, indicates that there are significant differences in the adenoid tissue histopathologically, compared to children not exposed to cigarette smoke. Environmental smoke is also thought to depress immune function and render an infant more susceptible to bacterial and viral infection. It may also directly affect their susceptibility to respiratory disease by decreasing their lung function. In conclusion, passive exposure to cigarette smoke is a risk factor for otitis media. All of these studies, however, can be difficult to interpret, since investigators have different definitions of passive exposure, as well as the parents. Parents often say that they only smoke outside, or while they are in the car. And some studies include older children, which make accurate parental recall of otitis media difficult. The main question at this point is what duration and intensity of smoke exposure is needed to increase the risk of otitis media. We don’t know the answer to that yet. Most studies have found that breast feeding has a protective effective against middle ear disease. In 1993, 1000 infants were followed in a one-year study. Infants exclusively breast-fed for four months or longer had half the number of acute otitis media episodes, compared to infants who were not breast-fed at all. And they had 40% less episodes than infants who were breast-fed for less than four months. This breast-feeding is believed to protect the child from occurrence of otitis media during the first year of life. The protective effects of breast milk appear to be through immunological factors provided through the breast milk, especially secretory IgA, which has antibody activity against respiratory tract viruses and bacteria. A breast-feeding infant also uses a different assortment of muscles and generates less negative pressure than a bottle-fed infant, especially if the child goes to bed with a bottle. Bottle-fed children may aspirate fluids in the middle ear with the higher intraoral pressures, and if they are horizontal in bed while they are taking their bottle, it could predispose them to reflux, as well. Genes have been found to contribute to otitis media, and their predisposition to recurrent episodes may have a significant genetic component. The antigen HOAA2has been shown to occur more frequently in children with recurrent otitis media than in healthy controls. A large Norwegian twin study published in 2003 confirmed a substantial genetic effect. They found children and twins who developed recurrent childhood otitis media and found that there is an inheritability estimate of .72 for boys and there is 1.61 for girls. This discrepancy in gender effects may be explained by differences in the distribution of genes linked to otitis media. There is a good likelihood that subsequent large scale association studies will identify genes contributing to common liability for otitis media. For instance, genes controlling fatty acid production and function may be identified as important in otitis media susceptibility. Hopefully, future genetic studies will be conducted in high risk populations especially prone to otitis media: American- Canadian Indian, Alaskan and Greenland Inuits, and Australian Aborigines. Interestingly, two years ago, Dr. Hunt sought to define the effects of supine sleeping on infant health. His study included more than 3000 infants, and those who regularly sleep supine were found to have a 35% lower risk of otitis media at three and six months than did infants who slept prone or on their sides. He speculated that prone sleeping causes higher airway temperatures, which could increase the likelihood of bacterial colonization. Supine sleeping may also promote the clearance of nasopharyngeal secretion, resulting in less Eustachian tube obstruction and otitis media. It is important to note though, in light of the Back to Sleep campaign during the last decade, that this position does decrease the risk of SIDS (Sudden Infant Death Syndrome). But this was still a very interesting finding. Three years ago, Dr. Tasker and Dr. Koufman studied the relationship between gastroesophageal reflux and otitis media. They took middle ear effusions from 54 children, 2 to 8 years of age, who were undergoing myringotomies. Pepsin concentrations were measured, using ELISA and enzyme activity assays. 83% of these middle ear effusions contained pepsin concentrations of up to 1000 fold greater than blood serum levels. The controls, albumin and fibrinogen levels, were similar in middle ear samples and blood serum. GERD is believed to be an important inflammatory co-factor in many adult and pediatric disorders of the upper aerodigestive tract. The angle of the immature Eustachian tube in children may allow reflux from acid and pepsin from the nasopharynx into the middle ear. This can cause inflammation and damage to the nasopharynx and the Eustachian tube, leading to Eustachian tube dysfunction. The current data is not sufficient to support antireflux therapy in children with refractory and middle ear infections. More prospective randomized placebo control studies are needed. Many people have noted that those children with severe allergic symptoms, asthma, and refractory sinusitis, when put on reflux meds, do better with their ear symptoms, as their symptoms also improve. Finally, pacifier use has been associated with increased occurrence of acute otitis media among children in daycare. In 1999, Dr. Jackson evaluated risk factors for otitis media among 200 children 12 months of age or younger, and it was found that the rate of acute otitis media increased by two fold if pacifiers were used. And for children aged two to three years old attending daycare, the risk of recurrent attacks was increased by a risk factor of 2.9. The method by which pacifier use increases susceptiblity to acute otitis media is not fully known. Pacifiers may alter the pressure equilibrium around the middle ear cavity and the nasopharynx, impairing the function of the Eustachian tube. As this disease continues to be prevalent, more and more studies are focused on acute otitis media prevention. Approaches include immunization, using preventative agents such as Xylitol and probiotics, and risk factor reductions. Xylitol is a five-carbon alcohol widely distributed in plants found in strawberries, plums, and raspberries. Xylitol is a polyol that has been found to inhibit the growth of streptococcus pneumoniae and its adherence to epithelial cells. The use of Xylitol gum and syrup has been found to reduce pneumococcal carriage in the nasopharynx. The usefulness of this study was first initially discovered in Europe in studies in dental caries. This sugar cannot be eaten by Lactobacillus, and as children were ingesting the Xylitol, it was found that they had a lower incidence of ear infections. Two separate studies have been published in Europe. When given as a gum or syrup regularly, five times a day after meals, Xylitol was found to lower the occurrence of otitis media. And another study in Europe found that once-a-day bedtime administration could also reduce the incidence of acute otitis media in infants. However, there is one separate randomized control trial where Xylitol consumed only during upper respiratory episodes was ineffective in preventing acute otitis media. The use of probiotic bacteria also has shown promise for otitis media prevention in children in Europe. It is believed that this bacteria stimulates antibody production and enhances the phagocytic activity of blood leukocytes. A study was done of 571 children in daycare in winter time in Finland. All of these children were given milk three times a day. Half of them drank milk containing lactobacillus. The effects were modest, but consistently in the same direction. Children who drank milk with lactobacillus had fewer days absent from daycare: 4.9 versus 5.8 days over seven months, which is an 11% difference between the groups. Children drinking the lactobacillus had a reduction in the number of respiratory infections, including otitis media, as well as a reduction in antibiotic treatments. Further investigation is warranted here in the United States to confirm these findings, and double-blind randomized control trials are needed to verify their use. The pneumococcal vaccine is now being used in the fight against otitis media. The heptavalent pneumococcal conjugate vaccine was approved by the Food & Drug Administration in 2002 for prevention of invasive infections caused by strep pneumo. The serotypes in this vaccine are responsible for approximately two-thirds of cases of pneumococcal otitis media in the United States. Current recommendations offer universal immunization of children younger than two years of age, and selective vaccination of older children with significant risk factors for recurrent acute otitis media. In his landmark study five years ago, Dr. Black conducted a double-blind trial of 37,868 infants randomized either to the heptavalent pneumococcal vaccine or to the meningo-type conjugate at 2, 4, 6 and 12 to 15 months of age. The pneumococcal vaccine was found to reduce the incidents of pneumococcal invasive disease by 89%. Otitis media visits were reduced by 9%, and otitis media episodes were reduced by 7%. Children who had received the pneumococcal vaccine were found to be 20% less likely to require tube placements than were the controls. The pneumococcal vaccine was found to cause no serious adverse effects in this study, and the local and systemic reactions observed were generally mild. Dr. Escola published his follow-up findings on this vaccine in the New England Journal of Medicine four years ago. This was a double-blind, multi-center trial of 2497 healthy Finnish infants who were randomized to either the pneumococcal vaccine or the hepatitis B vaccine at 2, 4, 6 and 12 months of age. Infants were then followed for two years and when they developed symptoms of recurrent respiratory infections and were diagnosed with acute otitis media, they underwent tympanocentesis. The number of episodes of otitis media attributed to serotypes cross-reactive with those in the vaccine was reduced by 51%, while the number of episodes caused by all the other serotypes increased by 33%. He speculated that the vaccination for pneumococcus thus may be altering the serotypes responsible for otitis media. Non-vaccine serotypes may be playing a role in otitis media in vaccinated children. Currently, vaccine candidates for other middle ear pathogens are under investigation. Vaccination against influenza may reduce influenza related otitis media, and vaccines for nontypable H.flu, Haemophilus, in the early stages of development. We have discussed risk factor reduction and some prevention strategies, but invariably, some of our patients are going to develop middle ear infections. We can tell parents that the natural history of an individual episode of acute otitis media is quite favorable. In observational studies and randomized clinical trials, 80% of children with acute otitis media treated with placebo or no drug demonstrated spontaneous clinical resolution in seven to fourteen days. The persistence of middle ear effusion is 40% at one month and 26% at three months, and you can see here on this graph the decline several weeks after an episode of acute otitis media, and how it is roughly 10% persistent in effusion at twelve weeks after development of acute otitis media. The development of bacterial resistance, the expense, and the potential for side effects, have led clinicians to reconsider the need for antibiotics. In 1999, the report issued by the Drug Resistant Streptococcus Pneumoniae Therapeutic Work Group concluded that amoxicillin is the most appropriate first-line therapy. Amoxicillin has the longest time above MIC against drug resistant strep-pneumo. It is relatively inexpensive, and it has a long history of safety and efficacy in the treatment of acute otitis media. In cases of treatment failure, second-line agents are amoxicillin/clavulanate, cefuroxime and ceftriaxone. Children with severe otalgia, sepsis, and immunocompromised or suppurative complications of otitis media may benefit from tympanocentesis to identify the causative organism, or tympanostomy tube placement. Generally, tympanostomy tubes are recommended for children with severe symptoms and history of at least three or four episodes per six months. They are also considered in patients with craniofacial abnormalities, developmental delay, and febrile seizures. There is still a need for large, well-planned prospective studies to research otitis media causation and pathogenesis, but today I briefly sought to present some recent concepts and controversies from the medical literature. Otitis media does have considerable impact, both medically on children, and economically on our society. New data does show that some risk factors can be modified and patients should be urged to follow through with current immunization recommendations. Heredity and reflux continue to be interesting new factors that need to be further elucidated. The pathophysiology of this disease is still not fully understood, since multiple interrelated factors all contribute to the development of these episodes. The management of otitis media continues to evolve constantly. Case Presentation: The patient is a 19-month-old Caucasian male infant referred from his pediatrician. He had had five ear infections over the past ten months, three over the past six months. His parents reported that his ear infections were characterized by physical ear discomfort, fever, and poor sleep, and that they had all been treated with oral courses of amoxicillin. He was in a day care setting with seven other children. He had no older siblings. He was breast-fed for the first six months of life and used a pacifier intermittently during the first year of life. His parents denied allergy symptoms, speech delay, or exposure to passive smoke. His past medical history and birth history were unremarkable. He had not been diagnosed with asthma or immunodeficiency. On physical exam, his tympanic membranes were clear. His ear canals were patent, and he did not have any dysmorphic features. He underwent tympanostomy tube placement in late 2004 and subsequently has had only one episode of otorrhea that resolved with drops. Bibliography: Auinger P, Lanphear B, Kalkwarf HJ, Mansour ME. Trends in otitis media among children in the United States. Pediatrics 2003;112:514-520. Black S, Shinefield H, Fireman B, et al. Efficacy, safety, and immunogenicity of heptavalent pneumoccal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000;19:187-195. Brower CNM, Maille AR, Rovers MM, et al. Health-related quality of life in children in otitis media. Int J Pediatr Otorhinolaryngol 2005;69:1031-1041. Casby MW. Otitis media and language development: a meta-analysis. AM J Speech Lang Pathol 2001;10:65-80. Casselbrant ML, Mandel EM, Kurs-Lasky, et al. Otitis media in a population of black American and white American infants, 0-2 years of age. Int J Pediatr Otorhinolaryngol 1995;33:1-16. Curns AT, Holman RC, Shay DK, et al. Outpatient and hospital visits associated with otitis media among American Indian and Alaska Native children younger than 5 years. Pediatrics 2002;109:E41-1. Darrow DH, Dash N, Derkay CS. Otitis media: concepts and controversies. Curr Opin Otolaryngol Head Neck Surg 2003;11:416-423. Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344:403-409. Golz A, Netzer A, Westerman T, et al. Reading performance in children with otitis media. Otolaryngol Head and Neck Surg 2005;132:495-499. Grycznkska D, Kobos J, Zakrewska A. Relationship between passive smoking, recurrent respiratory tract infections, and otitis media in children. Int J Pediatr Otorhinolaryngol 1999; (Suppl 49):S275-S278. Hatakka K, Savilahti E, Ponka A, et al. Effect of long term consumption of probiotic milk on infections in children attending day care centers: double blind, randomized trial. BMJ 2001;322: 1327. Hunt CE, Lesko SM, Vezina RM, et al. Infant sleep position and associated health outcomes. Arch Pediatr Adoles Med 2003;157:469-474. Jackson JM, Mourino AP. Pacifier use and otitis media in infants twelve months of age or younger. Pediatr Dent 1999;21:255-260. Karkos PD, Assimakopoulos D, Issing WJ. Pediatric middle ear infections and gastroesophageal reflux. Int J Pediatr Otorhinolaryngol 2004;68:1489-1492. Kogan MD, Overpeck MD, Hoffman HJ, Casselbrant ML. Factors associated with tympanostomy tube insertion among preschool-aged children in the United States. Am J Public Health 2000;90:245-250. Lieu JE, Feinstein AR. Effect of gestational and passive smoke exposure on ear infections in children. Arch Pediatr Adol Med 2002;156:147-154. Minter KR, Roberts JE, Hooper SR, et al. Early childhood otitis media in relationship to children’s attention-related behavior in the first six years of life. Pediatrics 2001;107:1037-1042. Niemala M, Pihakari O, Pokka T, Uhari M. Pacifier as a risk factor for acute otitis media: a randomized, controlled trial of parental counseling. Pediatrics 2000;106:463-468. Paradise JL, Feldman HM, Colborn DK, et al. Parental stress and parent-related child behavior in relation to otitis media in the first three years of life. Pediatrics 1999;104:1264-1273. Paradise JL, Feldman HM, Campbell TF, et al. Effect of early or delayed insertion of tympanostomy tubes for persistent otitis media on developmental outcomes at the age of three years. N Engl J Med 2001;344:1179-1187. Paradise JL, Rockett HE, Colborn DK, et al. Otitis media in 2253 Pittsburgh-area infants: prevalence and risk factors during the first two years of life. Pediatrics 1997;99:318. Park CH, Kogan MD, Overpeck MD, Casselbrant ML. Black-white differences in health care utilization among US children with frequent ear infections. Pediatrics 2002;109:E84-E90. Praveen CV, Terry RM. Does passive smoking affect the outcome of grommet insertion in children? J Laryngol Otol 2005;119:448-454. Richards M, Giannoni C. Quality of life outcomes after surgical intervention for otitis media. Arch Otolaryngol Head Neck Surg 2002;128:776-782. Roberts JE, Burchinal MR, Jackson SC, et al. Otitis media in early childhood in relation to preschool language and school readiness skills among black children. Pediatrics 2000;106:725-735. Tapiainen T, Luotonen L, Kntiokari T, Renko M, Uhari M. Xylitol administered only during respiratory infections failed to prevent acute otitis media. Pediatrics 2002;109:E19. Tasker A, Dettmar PW, Panetti M, Koufman JA, Birchall JP, Pearson JP. Is gastric reflux a cause of otitis media with effusion in children? Laryngoscope 2002;112:1930-1934. Wiertsema SP, Veenhoven RH, Sanders EA, et al. Immunologic screening of children with recurrent otitis media. Curr Allergy Asthma Rep 2005;5:302-307. 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