Treatment of Acute Otitis Media in Young Children
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- Mandel, E.M. & Casselbrant, M.L. Curr Allergy Asthma Rep (2012) 12: 559. doi:10.1007/s11882-012-0309-9
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Although acute otitis media (AOM) is one of the most common pediatric problems, the debate over treatment, especially in young children, continues. The 2004 Guideline on treatment of AOM stated that observation without antimicrobial therapy was an option for selected children 6−24 months of age with AOM. Two recent randomized trials sought to determine the necessity of antimicrobial treatment in young children; both studies found modest, statistically significant, positive effects of treatment. However, these studies provoked a flurry of discussion in the literature and the issue remains unsettled. That prevention is preferable to treatment is not controversial. Eliminating or modifying risk factors and use of vaccines, both bacterial and viral, may help decrease the number of AOM episodes. The discussion on treatment of AOM in young children must also take into account side effects of treatment and effect of treatment on possible long-lasting sequelae of AOM, such as developmental outcomes.
KeywordsOtitisOtitis mediaAcute otitis mediaChildrenPediatricsAntibioticsTympanostomy tubeAdenoidectomyTreatmentAntimicrobial treatmentPrevention
Although it is one of the most common pediatric problems, the debate over treatment of acute otitis media (AOM) continues. Not only is the treatment of an individual episode unsettled, but the definition of the disease and the goals of treatment are also not agreed upon. Prior to the 2004 Guideline , antibiotic treatment for children with AOM was the standard of care. In the 1990s, with the emergence of antibiotic-resistant strains of the bacteria involved in AOM, such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and the recognition that the prescription of antibiotics was not standard in all countries , the routine prescription of antibiotics for all children with AOM was questioned. The 2004 Guideline stated that “observation without use of antibacterial agents in a child with uncomplicated AOM is an option for selected children based on diagnostic certainty, age, illness severity, and assurance of follow-up.” For children 6−24 months of age, antibacterial therapy was recommended in those with a “certain diagnosis” and those with an “uncertain diagnosis and severe illness”, but for those with “uncertain diagnosis” and non-severe illness, observation was an option. Two recent randomized trials sought to settle the controversy over whether young children should be treated with an antimicrobial for AOM, but this controversy remains far from settled.
Antimicrobial Treatment for AOM
Hoberman et al. [3••] randomly assigned 291 children 6−23 months of age with AOM to either a 10-day course of amoxicillin-clavulanate (90 mg/kg/day amoxicillin/6.4 mg/kg/day clavulanate, divided into two doses per day) or placebo. Subjects had to have received at least two doses of pneumococcal conjugate vaccine previously, and were stratified by whether they had a history of recurrent AOM and whether they had exposure to three or more children for at least 10 h per week. Children were re-examined on Day 4−5 and again on Day 10−12; daily phone calls to the parents were made until the first follow-up visit. AOM at entry was defined by: onset of symptoms of a certain severity [defined by an Acute Otitis Media Severity of Symptoms (AOM-SOS) scale] within the previous 48 h; presence of middle-ear effusion; and moderate or marked bulging of the tympanic membrane (TM) or slight bulging accompanied by either otalgia or marked erythema of the TM. Clinical failure at or before the Day 4−5 visit was defined as either a lack of substantial improvement in symptoms, a worsening of signs on otoscopic examination, or both; clinical failure at the Day 10−12 visit was defined as failure to achieve complete or nearly complete resolution of symptoms and of otoscopic signs, without regard to the presence or absence of middle-ear effusion. Diagnosis at each point was only by otoscopy by validated otoscopists.
Data for symptomatic outcome were presented by time to first recording of an AOM-SOS score of 0 or 1 by days 2, 4, and 7; this occurred in 35, 61, and 80 %, respectively, in the amoxicillin−clavulanate group, and in 28, 54, and 74 % in the placebo group. For two successive AOM-SOS scores of 0 or 1, the values were 20, 41, and 67 % at the same time-points in the amoxicillin−clavulanate group compared to 14, 36, and 53 % in the placebo group (P = 0.04). Clinical failure by Day 4−5, as defined above, occurred in 4 % of the amoxicillin-clavulanate group compared to 23 % in the placebo group (95 % CI, 12−27; P < 0.001) and in 16 versus 51 %, respectively, by Day 10−12. No child was categorized as a treatment failure because of symptoms alone, which means that they had a combination of symptoms and otoscopic signs or otoscopic signs alone. Relapse at or before the Day 21−25 visit occurred in 16 % in the amoxicillin−clavulanate group and in 19 % of the placebo group. Middle-ear effusion at the Day 21−27 visit occurred in 50 % in the amoxicillin-clavulanate group and in 63 % of the placebo group (P = 0.05). Not surprisingly, “unfavorable characteristics” marking subjects more likely to be treatment failures by Day 10−12 included highest symptom scores at entry, exposure to three or more children for 10 or more hours per week, bilateral disease, and marked bulging of the tympanic membrane at entry.
The authors stated that resolution of symptoms was the primary outcome of interest, and found the differences in symptom scores between the antibiotic-treated group and the placebo group “modest but consistent through the first 10 days of follow-up”, favoring the antibiotic-treated group. They concluded that treatment with amoxicillin-clavulanate in the 6−23 months age group afforded short-term benefit, to be weighed against side effects of the medication, mainly diarrhea, and the contribution of treatment to emergence of resistant bacterial strains.
The other study was done in Finland in 319 children 6−35 months of age randomized to receive either amoxicillin-clavulanate (40 mg/kg/day amoxicillin and 5.7 mg/kg/day clavulanate, divided into two doses daily) or placebo for 7 days [4••]. AOM in this study was defined as meeting three criteria: (1) middle-ear fluid had to be present on otoscopy with at least two of the following: bulging of the tympanic membrane, decreased or absent mobility, abnormal color or opacity not due to scarring, or air-fluid levels; (2) at least one acute inflammatory sign had to be present in the tympanic membrane: “distinct erythematous patches or streaks or increased vascularity over full, bulging, or yellow tympanic membrane”; and (3) had to have acute symptoms such as fever, ear pain, or respiratory symptoms. Subjects were re-examined on Day 3 and on Day 8, which was 1 day after completing the study drug. The primary outcome was time to treatment failure which was a composite of six parts: no improvement in overall condition by Day 3, a worsening of the child’s overall condition at any time, no improvement in otoscopic signs by the Day 8 visit, perforation of the tympanic membrane at any time, severe infection (such as mastoiditis or pneumonia) for which systemic antimicrobial treatment was necessary, or any other reason that the study drug had to be discontinued (adverse event or noncompliance with study drug). By the Day 3 visit, 13.7 % of subjects in the amoxicillin-clavulanate group and 25.3 % of subjects in the placebo group were considered treatment failures. Overall, 30 (18.6 %) of 161subjects in the amoxicillin−clavulanate group and 71 (44.9 %) of 158 subjects in the placebo group were considered treatment failures. “Overall condition” was the basis for treatment failure in 27 subjects in the amoxicillin-clavulanate group and for 48 in the placebo group, “overall condition” and otoscopic signs in no children in the antibiotic-treated group but in 6 children in the placebo group, and otoscopic signs alone in 2 and 15 children in the antibiotic group and the placebo group, respectively. A change in treatment was required in 6.8 % of the amoxicillin−clavulanate group and 33.5 % in the placebo group. The authors felt that treatment with amoxicillin−clavulanate improved the symptoms of poor appetite, decreased activity, irritability and fever faster, although there was no effect on resolution of ear pain reported by parents or by children, ear rubbing, restless sleep, or excessive crying.
These studies provoked a flurry of discussion in the literature [5–23]. The use of multiple primary endpoints [5, 7, 19], use of amoxicillin−clavulanate rather than amoxicillin as recommended by the guidelines [6, 11, 17], and the subsequent finding of substantial numbers of subjects with adverse events, especially diarrhea [7, 17], were criticized. Several authors commented that the definition of AOM was more stringent than what is possible in clinical practice, and that the benefit seemed greater in these “sicker” patients [9, 10, 17]. Some authors were also critical of the use of persistence of otoscopic signs with resolution of symptoms as a criterion for “treatment failure”, thus inflating the numbers of subjects who failed with placebo [5, 7, 9, 11, 12, 18]. Even with all the criticisms, it remains clear that many of these young children, even with “stringent” criteria for the diagnosis of AOM, recovered without the need for antibiotic treatment and that antibiotics provided modest improvement in time to symptomatic improvement at a cost of side effects and possibly adding to the problem of antibiotic resistance. This is in keeping with previous studies in mainly older age groups [24, 25•] One could argue over the details of the studies, but all seem to support that not all patients with AOM require treatment and a physician/health care provider may select, based on their clinical impression of the patient and assessment of family situation and preferences, to provide immediate antibiotic treatment or defer treatment, either with re-examination or a “wait-and-see prescription”, to be filled if symptoms do not improve. Being able to predict which patients would benefit from antibiotic treatment and which would not require antibiotics to achieve a satisfactory outcome seems to be key to treatment of AOM in young children.
Prevention of AOM
All would agree that the best way to “treat” AOM would be to prevent it in the first place. Ameliorating the known or suspected environmental risk factors such as decreasing exposure to tobacco smoke, breast-feeding the infant, limiting pacifier use, and removing a child from high-density daycare may be tried. However, vaccines seem particularly effective, as seen in the use of the 7-valent pneumococcal vaccine which contained the serotypes 4,6B, 9V, 14, 18C, 19F, and 23F . This vaccine was shown to have a modest effect on AOM, reducing the incidence by about 6 %  but having a greater effect as the frequency of episodes increased and reducing the placement of tympanostomy tubes by 20 % . In 2010, PCV13, which includes the additional pneumococcal serotypes 1, 3, 5, 6A, 7F, and 19A, was licensed in the US. Decreased nasopharyngeal carriage of vaccine strains in immunized children has been shown , which hopefully will translate into less OM, but that has not yet been established.
Even though there is strong evidence that viruses play a crucial role in the pathogenesis of OM [29, 30], there is no viral vaccine for the prevention of OM except for the influenza vaccine. It is thought that, in most children, viral infection of the upper respiratory tract mucosa initiates the cascade of events that finally leads to the development of AOM. Until the introduction of PCR (polymerase chain reaction), viruses were not considered a major factor in the etiology of OM due to technical difficulties in isolating the viruses. However, using the PCR technique, it has been possible to identify respiratory syncytial virus (RSV), influenza, adenovirus, parainfluenza, and rhinoviruses in middle-ear effusions [29, 31]. Virus-induced inflammation of the nasopharynx and Eustachian tube may allow bacteria to infect the middle ear . Recently, studies have reported the risk for developing an episode of OM from a URI which varies with the specific virus isolated in the nasopharynx. Winter et al.  enrolled 60 children (24 families with at least 2 children) between the ages of 1 and 5 years who were followed from October 2003 through April 2004 by daily parental recording of illness signs, weekly pneumatic otoscopy, and viral PCR of nasal secretions collected during “colds” or when middle-ear effusion was noted or from enrolled siblings without these conditions. One or more viruses were identified from 73 % of secretions collected during a “cold” but from only 18 % collected at a time without a “cold”. Of 93 episodes of OM, which includes AOM and OME, 70 % occurred during a “cold”, and nasal secretions from 77 % of children at the time of these episodes were positive for virus. For OM episodes both with a “cold” and without, rhinovirus was the virus found most frequently; influenza and RSV were not found in episodes not associated with a “cold”. When a virus was isolated from the nasopharynx with a cold or not, an associated episode of OM was classified as AOM in 8 % of rhinovirus detections, but in 33 and 38 % of detections of RSV and influenza A virus, respectively . In a cohort of 294 children 6 months to 3 years of age, whose parents were instructed to present to the study when the child had a URI or AOM, the overall incidence of OM complicating URI was 61 %, 37 % being AOM and 24 % OME. Rhinovirus and adenovirus were the most commonly detected viruses during URI. Young age was the most important predictor for AOM complicating a URI .
By using viral vaccines, it is possible that AOM as a complication of URI could be prevented. At present, the only commercially available viral vaccine for the prevention of OM is the influenza vaccine, which is recommended for all children 6 months and older . Two types of vaccine are currently available for children. The trivalent inactivated vaccine (TIV) contains killed viruses and is given intramuscularly to children 6 months and older and to adults, while the live-attenuated influenza vaccine (LAIV) is given intranasally and is for healthy individuals 2 through 49 years of age.
Importance of Treating OM in Young Children
A great concern in treating AOM in children, in addition to the child’s pain and discomfort as well as the loss of sleep and working time for the parent, is the effect of residual middle-ear effusion on development. While most episodes of AOM are short-lived, middle-ear effusion may persist for weeks to months after an episode [36, 37]. Paradise and co-workers  found no difference in regard to hearing, speech-language, and behavioral testing through the ages of 9−11 years in children who were randomly assigned to early versus late tympanostomy tube insertion as young children less than 3 years of age (early defined as after 3 months of bilateral middle-ear effusion, late after 9 months of bilateral effusion; various other time requirements were given for unilateral or intermittent episodes). This was felt to be re-assuring to health care providers and parents, and surgical treatment for residual effusions could be delayed or avoided. Recently, Whitton and Polley [39•] reviewed the literature on the effect of OM on development and proposed that OM , or more exactly, hearing loss as a result of OM, during critical periods of brain development leads to “amblyaudia”, the auditory equivalent of amblyopia. They describe amblyaudia as a “cluster of neurological sequelae”, abnormal brainstem physiology, and deficits in spatial hearing as well as receptive language skills that persist for years after the middle ear pathology has resolved. They proposed that most clinical studies have used OM to represent hearing loss instead of looking at development in those with documented hearing loss, particularly during critical periods. They conclude that, by “looking only at studies that relate poor auditory processing and language skills to a history of hearing loss and OM rather than OM alone, the evidence unambiguously shows that early conductive hearing loss increases a child’s risk for abnormalities in brainstem physiology, binaural hearing and receptive language skills.”
The management of AOM in young children is not straightforward. While studies show that antibiotic treatment can improve symptoms faster and lead to fewer treatment failures, the same studies show that not all young children require antibiotic treatment to recover. The difficulty is in deciding who requires treatment and who can be observed with treatment at a later time if necessary. One must weigh the benefits of treatment, including prevention of sequelae, with the possible side effects and potential increase in resistant organisms. Vaccines, both bacterial and viral, as well as modification of risk factors, may prevent some episodes of OM.
No potential conflicts of interest relevant to this article were reported.