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Clinical practice guidelines for the diagnosis and management of acute otitis media in children—2018 update

Open AccessPublished:June 20, 2020DOI:https://doi.org/10.1016/j.anl.2020.05.019

      Abstract

      Objective

      “Clinical Practice Guidelines for the Diagnosis and Management of Acute Otitis Media in Children—2018 update (2018 Guidelines)” aim to provide appropriate recommendations about the diagnosis and management of children with acute otitis media (AOM), including recurrent acute otitis media (recurrent AOM), in children under 15 years of age. These evidence-based recommendations were created with the consensus of the subcommittee members, taking into consideration unique characteristics of bacteriology and antimicrobial susceptibilities of AOM pathogens in Japan, as well as global advances in vaccines.

      Methods

      The subcommittee re-evaluated key clinical issues based on SCOPE (a master plan of the guidelines) and created clinical questions (CQ) about the diagnosis and management of AOM patients. A literature search of the publications from 2013 to 2016 were added to the Guidelines 2013, not only to assess the evidence on the effectiveness of vaccines, but also to provide up to date information of the bacteriology and antimicrobial susceptibilities of AOM causative pathogens in Japan.

      Results

      We have proposed guidelines for disease severity-based management of AOM patients, after classifying AOM severity into mild, moderate, and severe, based on age, clinical manifestations, and otoscopic findings.

      Conclusions

      Precise otoscopic findings are essential for judging AOM severity, which can lead to appropriate management of AOM patients.

      Keywords

      1. Introduction

      The Clinical Practice Guidelines for Management of Acute Otitis Media in Children–2018 (the Guidelines 2018) are the 4th edition of the guidelines in Japan. Subcommittee on the Guidelines published the first edition in 2006 to respond to the increasing demand for the solution of the prevalence of intractable acute otitis media (AOM) in children since the late 1990s in Japan. The aim of the Guidelines has been to provide appropriate recommendations about diagnosis and optimal management for the pediatric patients under 15 years of age with acute otitis media. These evidence-based recommendations were created with the consensus of the subcommittee members, taking into consideration unique characteristics of bacteriology and antimicrobial susceptibilities of AOM pathogens in Japan. The first revision was made in 2009 mainly to improve the assessment method of disease severity and to reflect that on the treatment algorithm. The 3rd edition introduced new treatment algorithm with new oral antimicrobial agents for intractable acute otitis media in 2013.
      The Guidelines 2018 have included the clinical questions and the recommendations about recurrent acute otitis media (recurrent AOM) and pneumococcal conjugate vaccines, by which routine vaccination has started in April 2013 in Japan. Furthermore, this edition is the first one that has adopted the AAP (American Academy of Pediatrics) method, which has been widely used in several guidelines in recent years, for the evaluation of the evidence quality and strength of the recommendation.
      We have proposed the guidelines for disease severity-based management of AOM patients, after classifying AOM severity into mild, moderate, and severe, based on age, clinical manifestations, and otoscopic findings. Precise otoscopic findings are essential for judging AOM severity, which can lead to appropriate management of AOM patients.

      2. Authors

      The members of the Subcommittee on Clinical Practice Guidelines for the Diagnosis and Management of Acute Otitis Media (AOM) in Children is shown in Table 1. This committee (AOM Guideline Committee of Japan) is composed of three academic organizations: Japan Otological Society (JOS), Japan Society for Infection and Aerosol in Otorhinolaryngology (JSIAO), and Japan Society for Pediatric Otorhinolaryngology (JSPO). The first committee meeting was held on January 8, 2003, and the 2006 Guidelines were published in March 2006 on the website of the Japan Society for Infectious Diseases in Otorhinolaryngology (reorganized into JSIAO in 2013), in the journals of the JOS and the JSPO, on the website of the Japan Council for Quality Healthcare, and in printed form [
      Japan Otological Society,
      Japan Society for Pediatric Otorhinolaryngology, Japan Society for Infectious Diseases in Otolaryngology, Clinical practice guideline for diagnosis and management of acute otitis media in children 2006.
      ,
      Japan Otological Society,
      Japan Society for Pediatric Otorhinolaryngology, Japan Society for Infectious Diseases in Otolaryngology, Clinical practice guideline for diagnosis and management of acute otitis media in children.
      ,

      Japan Council for Quality Health Care (Minds). 2006; Available from:http://minds.jcqhc.or.jp/[in Japanese].

      ,
      Japan Otological Society,
      Japan Society for Pediatric Otorhinolaryngology, Japan Society for Infectious Diseases in Otolaryngology, Clinical practice guideline for diagnosis and management of acute otitis media in children 2006.
      ]. The 2006 Guidelines underwent evaluation, and work on the production of a revised edition began at the 13th committee meeting on January 7, 2007. The revised Guidelines were published in January 2009 as the 2009 Guidelines [
      Japan Otological Society,
      Japan Society for Pediatric Otorhinolaryngology, Japan Society for Infectious Diseases in Otolaryngology, Clinical practice guideline for diagnosis and management of acute otitis media in children 2009.
      ]. The committee started revision of the 2013 Guidelines in May 2010, and it was released in July 2013 [
      Japan Otological Society,
      Japan Society for Pediatric Otorhinolaryngology, Japan Society for Infectious Diseases in Otolaryngology, Clinical practice guideline for diagnosis and management of acute otitis media in children 2013.
      ]. The newly organized committee began preparatory work for the 2018 version in November 2015. The collaborators who offered critical evaluations and supportive advice as independent experts, and the members of the systematic review team are listed in Tables 2 and 3, respectively.
      Table 1The membership of the subcommittee of clinical practice guidelines.
      NameAffiliation
      Haruo TakahashiDept. of Otolaryngology Head and Neck Surgery, Nagasaki University
      Sho HashimotoDept. of Otolaryngology Head and Neck Surgery, National Hospital Organization Sendai Medical Center
      Hiromi KojimaDept. of Otolaryngology, Tokyo Jikei University School of Medicine
      Tatsuya Hayashi (Chair)Dept. Otolaryngology-Head and Neck Surgery, Asahikawa Medical University
      Fumiyo KudoAlice ENT Clinic
      Yoshifumi UnoUno ENT Clinic
      Shoichi SawadaSawada ENT and Eye Clinic
      Hidenobu TaijiDept. of Otolaryngology, Saiseikai Central Hospital
      Muneki HotomiDept. of Otolaryngology Head and Neck Surgery, Wakayama Medical University
      Hisakazu YanoDept. of Microbiology and Infectious Diseases, Nara Medical University
      Goro TakahashiYamahoshi ENT Clinic
      Ken KitamuraShonan University of Medical Sciences
      Table 2Collaborators.
      NameAffiliation
      Toshihiko IshiwadaDivision of Infection Control, Medical Mycology Research Center, Chiba University
      Akiyoshi NariaiDept. of Pediatrics, Shimane Prefecural Central Hospital
      Table 3Systematic review team.
      NameAffiliation
      Goro TakahashiYamahoshi ENT Clinic
      Seigo UedaOtolaryngology-Head and Neck Surgery, Asahikawa Medical University
      Ryuki OtakaOtolaryngology-Head and Neck Surgery, Asahikawa Medical University
      Kyoko KitaokaDept. of Otolaryngology Head and Neck Surgery, Nagasaki University
      Manabu KomoriDept. of Otolaryngology, Tokyo Jikei University School of Medicine
      Shunju TamagawaDept. of Otolaryngology Head and Neck Surgery, Wakayama Medical University
      Akihisa TogawaDept. of Otolaryngology Head and Neck Surgery, Wakayama Medical University
      Tsunetaro MorinoDept. of Otolaryngology, Tokyo Jikei University School of Medicine
      Haruo YoshidaDept. of Otolaryngology Head and Neck Surgery, Nagasaki University

      3. Background and history

      AOM is one of the most common upper respiratory infectious diseases in young children. Patients with AOM usually visit Ear–Nose–Throat (ENT) clinics in Japan, although they are also treated by pediatricians and emergency department physicians. However, the exact incidence of this disease in Japan has not yet been clarified. According to reports from Europe and the US, 62% to 75% of children suffer from at least one episode of AOM in their first year of life, and 83% of children have at least one episode in the first 3 years of life [
      • Teele D.W.
      • Klein J.O.
      • Rosner B.
      Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study.
      ,
      • Faden H.
      • Duffy L.
      • Boeve M.
      Otitis media: back to basics.
      ].

      3.1 The role of antimicrobial agents

      It has been reported from Europe and the US that clinicians do not need to prescribe antimicrobial agents for patients with AOM. Some reports from the Netherlands revealed that more than 90% of AOM cases resolved spontaneously without antimicrobial agents, and advocated initial observation without antimicrobial agents for 3–4 days from onset of the condition [
      • van Buchem F.L.
      • Peeters M.F.
      • van 't Hof M.A.
      Acute otitis media: a new treatment strategy.
      ,
      • Damoiseaux R.A.
      • van Balen F.A.
      • Hoes A.W.
      • Verheij T.J.
      • de Melker R.A.
      Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years.
      ]. Rosenfeld et al. have also reported observation as a management option [
      • Rosenfeld R.M.
      • Bluestone C.D.
      ,
      • Rosenfeld R.M.
      • Kay D.
      Natural history of untreated otitis media.
      ,
      • Rosenfeld R.M.
      • Kay D.
      Natural history of untreated otitis media.
      ], and more recent studies also found no significant difference in clinical outcome if antimicrobial agents are not given immediately, but are rather prescribed only when there is no improvement in symptoms after 48 or 72 h [
      • Spiro D.M.
      • Tay K.Y.
      • Arnold D.H.
      • Dziura J.D.
      • Baker M.D.
      • Shapiro E.D.
      Wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial.
      ,
      • Little P.
      • Moore M.
      • Warner G.
      • Dunleavy J.
      • Williamson I.
      Longer term outcomes from a randomised trial of prescribing strategies in otitis media.
      ]. A Cochrane review that examined randomized controlled trials (RCTs) of antimicrobial agent administration versus placebo also found that antimicrobial agents had little effect on childhood AOM [
      • Glasziou P.P.
      • Del Mar C.B.
      • Sanders S.L.
      • Hayem M.
      Antibiotics for acute otitis media in children.
      ]. In addition, a double-blind randomized controlled trial of amoxicillin (AMPC) and a placebo found no significant difference in the therapeutic efficacy between these two approaches [
      • Le Saux N.
      • Gaboury I.
      • Baird M.
      • Klassen T.P.
      • MacCormick J.
      • Blanchard C.
      • Pitters C.
      • Sampson M.
      • Moher D.
      A randomized, double-blind, placebo-controlled noninferiority trial of amoxicillin for clinically diagnosed acute otitis media in children 6 months to 5 years of age.
      ,
      • McCormick D.P.
      • Chonmaitree T.
      • Pittman C.
      • Saeed K.
      • Friedman N.R.
      • Uchida T.
      • Baldwin C.D.
      Nonsevere acute otitis media: a clinical trial comparing outcomes of watchful waiting versus immediate antibiotic treatment.
      ].
      As mentioned above, negative evidence on the clinical efficacy in AOM has accumulated. Two large RCTs published in succession in 2011, however, showed evident treatment effects of antimicrobial agents in AOM management. Tähtinen et al. performed a randomized, placebo-controlled study on clavulanate (CVA)/AMPC versus placebo, and have reported that CVA/AMPC yielded a significantly increased improvement rate based on otoscopic findings, and reduced the progression to treatment failure and the need for rescue treatment [
      • Tähtinen P.A.
      • Laine M.K.
      • Huovinen P.
      • Jalava J.
      • Ruuskanen O.
      • Ruohola A.
      A placebo-controlled trial of antimicrobial treatment for acute otitis media.
      ]. Hoberman et al. also reported another large RCT, in which CVA/AMPC treatment significantly shortened the period of time required for resolution of symptoms and the duration of residual abnormal otoscopic findings [
      • Hoberman A.
      • Paradise J.L.
      • Rockette H.E.
      • Shaikh N.
      • Wald E.R.
      • Kearney D.H.
      • Colborn D.K.
      • Kurs-Lasky M.
      • Bhatnagar S.
      • Haralam M.A.
      • Zoffel L.M.
      • Jenkins C.
      • Pope M.A.
      • Balentine T.L.
      • Barbadora K.A.
      Treatment of acute otitis media in children under 2 years of age.
      ].
      The above two RCTs adopted stringent criteria in terms of otoscopic findings for diagnosing AOM, which differed from those of other RCTs. These criteria avoid inclusion of patients misdiagnosed with AOM because of viral upper respiratory infection and nonspecific otalgia, allowing fair evaluation of the efficacy of antimicrobial agents.
      A Cochrane review included these results in a systematic review of 13 RCTs, and reported that antimicrobial therapy revealed positive effects on residual abnormal tympanometry findings, tympanic perforations, and occurrence of contralateral AOM [
      • Venekamp R.P.
      • Sanders S.L.
      • Glasziou P.P.
      • Del Mar C.B.
      • Rovers M.M.
      Antibiotics for acute otitis media in children.
      ]. However, they concluded that the effect was limited, because antimicrobial agents were most beneficial in children below the age of 2 years with bilateral AOM and in children with otorrhea, and did not show a significant effect on early pain relief and late AOM recurrence as compared with placebo.
      Dagan et al. as well as Toltzis et al. recommended decreased administration of antimicrobial agents, because antimicrobial agents resulted in an increase in antimicrobial-resistant Streptococcus pneumoniae in the nasopharynx and superinfection of S. pneumoniae resistant to the administered drug in the middle ear effusion (MEE) in a review and case–control studies [
      • Dagan R.
      Treatment of acute otitis media - challenges in the era of antibiotic resistance.
      ,
      • Dagan R.
      • Leibovitz E.
      • Cheletz G.
      • Leiberman A.
      • Porat N.
      Antibiotic treatment in acute otitis media promotes superinfection with resistant Streptococcus pneumoniae carried before initiation of treatment.
      ,
      • Toltzis P.
      • Dul M.
      • O'Riordan M.A.
      • Toltzis H.
      • Blumer J.L.
      Impact of amoxicillin on pneumococcal colonization compared with other therapies for acute otitis media.
      ].
      These results indicate the importance of a stringent diagnosis, based on a precise examination of the tympanic membrane, to distinguish patients who are likely to benefit from antimicrobial agents from those who do not need antimicrobial agents.

      3.2 History of the guidelines

      In Japan, AOM in children had become refractory to treatment before the first edition of Guidelines were published in 2006. Regular nationwide surveillance of causative pathogens of AOM, acute sinusitis, acute tonsillitis, and peritonsillar abscess indicated an increase in the prevalence of resistant organisms and a difference in resistance patterns from those in Europe and the US [
      • Suzuki K.
      The status quo of drug-resistant bacteria in pediatric otolaryngological infectious diseases.
      ,
      • Nishimura T.
      • Suzuki K.
      • Oda M.
      • Kobayashi T.
      • Yajin K.
      • Yamanaka N.
      • Ubukata K.
      • Fujisawa T.
      • Baba S.
      The third nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]. Demands for guidelines for the management of AOM increased under these circumstances. Unlike Europe and the US, ENT specialists play a major role in the treatment of AOM in Japan; stringent diagnosis of AOM, based on precise otoscopic findings, had already been established in this country. Based on this perspective, the JOS, the JSIDO, and the JSPO created the 2006 Clinical Practice Guidelines, consistent with evidence-based medicine (EBM) to support the management of childhood AOM, and adopted a classification of AOM severity based on stringent otoscopic examination, to decide whether and which antimicrobial agents should be used [
      • Nakayama T.
      Clinical practice guideline consistent with evidence-based medicine: manual for development and application.
      ].
      A survey of otolaryngologists and pediatricians in Ishikawa Prefecture showed that 85% of otolaryngologists and 52% of pediatricians had some knowledge of the 2006 Guidelines, with 56% of those otolaryngologists and 49% of those pediatricians reporting that they used them in daily practice [
      • Ito M.
      • Furukawa M.
      Usefulness of the guideline of diagnosis and management of acute otitis media.
      ]. Treatment outcomes of clinical practice in accordance with the guidelines were also satisfactory [
      • Hayashi T.
      • Abe Y.
      • Ueda S.
      • Otaka R.
      • Bandoh N.
      • Katada A.
      • Harabuchi Y.
      Treatment outcome of acute otitis media in children treated with the newly released guideline in Japan.
      ,
      • Sugahara K.
      • Yamashita Y.
      Treatment based on the guidelines for pediatric acute otitis media.
      ]. Taking these results into account, the JOS, JSIDO, and JSPO decided to revise the 2006 Guidelines and issued a new edition in 2009.
      Soon after publication of the 2009 Guidelines, clinical practice guidelines for pediatric AOM were reported from Canada in 2009 [
      • Forgie S.
      • Zhanel G.
      • Robinson J.
      Management of acute otitis media.
      ], and from Italy in 2010 [
      • Marchisio P.
      • Bellussi L.
      • Di Mauro G.
      • Doria M.
      • Felisati G.
      • Longhi R.
      • Novelli A.
      • Speciale A.
      • Mansi N.
      • Principi N.
      Acute otitis media: From diagnosis to prevention. Summary of the Italian guideline.
      ]. The Italian guidelines mentioned the importance of precise otoscopic examination and recording it; furthermore, it offered a management option for referring the patient to otolaryngologists who were able to make stringent otoscopic examinations with a microscope and/or endoscope if pediatricians were not able to obtain precise otoscopic findings and/or record it. Moreover, the US guidelines, revised in 2013, also began to emphasize the importance of a detailed otoscopic examination [
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ]. The recent guidelines for AOM share the basic concept that a detailed otoscopic examination is essential for the management of AOM. In fact, in Japan, the guidelines were founded on this basic concept since their first edition in 2006.
      The 2013 edition was revised based on changes in the prevalence of causative pathogens and their resistance patterns and the re-evaluation of scoring items for determining disease severity, with addition of descriptions of new items for AOM management, such as a rapid antigen detection kit for identifying pneumococci, pneumococcal conjugate vaccine, new antimicrobial agents, and Japanese herbal medicine approved for children, as well as the definition of refractory AOM and recurrent AOM. Treatment outcomes of clinical practice in accordance with the 2013 Guidelines were reportedly also sufficient [
      • Uno Y.
      • Kudo F.
      Verification of clinical practice guidelines for the diagnosis and management of pediatric acute otitis media in Japan-2013 update.
      ].
      The committee for the 2018 Guidelines has changed the evaluation method for the quality of evidence and the strength of recommendations of recent advances in methodology in the guideline development. In the process of selecting the evaluation method, the committee referred to a proposal described in “Minds (Medical Information Network Distribution Service Japan) Handbook for Clinical Practice Guideline Development 2014, Minds ed.” [
      • Fukui T.
      • Yamaguchi N.
      • Morizane T.
      • Yoshida M.
      • Kojimahara N.
      Minds Handbook for clinical practice guideline development 2014.
      ]. The Guideline Committee searched for the most appropriate evaluation method; the method should be able to assess the quality of evidence of the significant outcome comprehensively, and also placed a high priority on the balance of benefit and harm for patients when evaluating recommendations. Additionally, the method had to make it easy to make a recommendation about diagnosis as well as about treatment. The method recommended by the American Academy of Pediatrics (AAP) fits the above conditions best, and the committee finally decided to apply it to the latest guidelines. During the revision process, the committee re-evaluated some CQs and added new CQs about the diagnosis and treatment of recurrent AOM, which had been requested by many guideline users. The overall structure of the guidelines was re-organized for the convenience of guideline users; for example, a list explaining the technical or unusual terms was added at the end of the guidelines as a glossary.
      The guidelines in Japan were created with the main aim of spreading information about the appropriate antimicrobial usage since the first edition. To achieve this goal, as a basic policy, the guidelines have retained the recommendation to avoid using antimicrobial agents initially in mild cases, and to use a penicillin class agent as the first-line antimicrobial agent in moderate or severe cases. This policy fits “the Global Action Plan on Antimicrobial Resistance” that has recently attracted much attention. The decrease in the prevalence of penicillin-resistant Streptococcus pneumoniae observed after the guidelines were published is considered to be a significant achievement of the guidelines. However, Haemophilus influenzae has been showing high resistance rates; it therefore remains important to ensure that the guidelines are implemented more widely in order to spread information on the optimal antimicrobial use, and it is still necessary to update the guidelines to ensure further improvement of treatment outcomes.
      These clinical practice guidelines are intended to support the clinical practice of all clinicians but are not intended to restrict the clinical judgement of individual clinicians in the management of AOM. Clinicians can decide how to apply these guidelines to the patients in various clinical settings, based on their knowledge and experience, with consideration of parent and patient intentions and preferences. A lack of sufficient evidence on the efficacy of a treatment does not always directly imply that the treatment is not effective or that clinicians should not provide that treatment to patients. However, it is necessary to pay more attention to assessing the validity of the clinical efficacy and to communicating with patients when applying management options that are not included in the guidelines. It is necessary to emphasize that each recommendation in the guidelines does not have legal binding force for individual medical practice for patient with specific medical circumstances [
      • Hurwitz B.
      Legal and political considerations of clinical practice guidelines.
      ]. The 2018 Guidelines will be periodically revised, reflecting not only the opinions of guideline-users and patients, but also the results of external evaluations, as well as the 2006, 2009, and 2013 Guidelines.
      NOTE: The position of the guidelines
      Regulations > directives > recommendations ≥ guidelines
      (From A Dictionary of Epidemiology, Last JM ed., trans. Japan Epidemiological Association)

      4. Objectives and goal of the guidelines

      The aim of the guidelines is to provide a means for appropriate diagnosis and to offer optimal management for pediatric patients, under 15 years of age (see NOTE), with AOM, including recurrent AOM. They are based on several evidence-based recommendations, with the consensus of committee members for the guideline, and are based on the bacteriological background in Japan and focus on the balance of benefits and harms for the patients and their parents. The guidelines aim to be useful for decision-making by all clinicians in terms of the diagnosis and management of pediatric patients with AOM.
      NOTE: December 15, 2000, PMSB/ELD* Notification No. 1334. “Clinical Investigation of Medicinal Products in the Pediatric Population” has advocated the following definitions for each age category: preterm newborn infants, term newborn infants (0 to 27 days), infants and toddlers (28 days to 23 months), children (2 to 11 years), adolescents (12 to 16 or 18 years) [

      The Ministry of Health, Labour and Welfare's Pharmaceutical Affairs Bureau,. Guidance concerning clinical trials of drugs in pediatric populations Notification No. 1334, released on December 15, 2000.

      ]. In the guidelines, “children” are defined as anyone under 15 years old, which is well accepted in Japanese society.
      *PMSB/ELD: Evaluating and Licensing Division of the Pharmaceutical and Medical Safety Bureau

      5. Users

      The 2018 Guidelines is intended for all clinicians who treat pediatric patients with AOM. The guidelines include some recommendations about surgical treatment, which is usually performed by otolaryngologists. Clinicians should be prepared to refer to specialists in case they cannot offer the recommended management options by themselves, even when necessary.

      6. Subjects

      The target population of the 2018 Guidelines are otherwise healthy children, aged under 15 years, with AOM and recurrent AOM. The guidelines do not cover patients with otitis media with effusion (OME), with a ventilation tube already inserted, craniofacial abnormalities, severe immunodeficiency, complications, including facial palsy and inner ear disorders, acute mastoiditis, and intracranial purulent complications. It may be difficult to distinguish between AOM and bullous myringitis, but the latter is not covered by the guidelines.
      There are some recurrent AOM patients with temporary low serum levels of IgG2. Young children with such temporal immunodeficiency during the normal growth process are included in the guidelines.

      7. Definition of AOM

      The definition of acute otitis media in the guidelines is a middle ear infection, with acute onset of symptoms and signs, often including otalgia, fever, and otorrhea. See the following NOTE for additional details.
      NOTE:
      • (1)
        Acute onset is defined in the case where patients visit the clinic with persisting acute symptoms that are recognized by patients’ complaint or parents. There is no definite evidence about duration of “acute onset.” The guidelines have adopted the definition of “no more than 3 weeks” since this is widely accepted [
        • Senturia B.
        • Paparella M.
        • HW. L.
        • Klein J.
        • Arnold W.
        • Lim D.
        • Axelsson G.
        • Paradise J.
        • Bluestone C.
        • Sade J.
        • Howie V.
        • Woods R.
        • Hussl B.
        • Wullstein H.
        • Ingelstedt S.
        • SR. W.
        Panel I—definition and classification.
        ]. The guidelines do not cover acute exacerbation of chronic suppurative otitis media, because this is a different pathological condition.
      • (2)
        Clinical practice guideline for AOM children by the AAP in 2004 (Subcommittee on Management of Acute Otitis Media 2004) advocated the following criteria for the diagnosis of AOM: (1) rapid onset of symptoms, (2) presence of MEE, (3) otoscopic findings of acute inflammation [
        M
        American Academy of Pediatrics Subcommittee on Management of Acute Otitis, Diagnosis and management of acute otitis media.
        ]. In the revised version of 2013, AOM was defined as signs and symptoms of acute onset caused by middle ear inflammation (AAP Guidelines 2013) and the following three items have been recommended for diagnosis of AOM [
        • Lieberthal A.S.
        • Carroll A.E.
        • Chonmaitree T.
        • Ganiats T.G.
        • Hoberman A.
        • Jackson M.A.
        • Joffe M.D.
        • Miller D.T.
        • Rosenfeld R.M.
        • Sevilla X.D.
        • Schwartz R.H.
        • Thomas P.A.
        • Tunkel D.E.
        The diagnosis and management of acute otitis media.
        ]:
        • (1)
          Moderate to severe bulging of the tympanic membrane (TM) or new onset of otorrhea, not due to acute otitis externa.
        • (2)
          Mild bulging of the TM and recent (less than 48 h) onset of otalgia (holding, tugging, rubbing of the ear in a nonverbal child) or otalgia of acute onset with intense erythema of the TM.
        • (3)
          Clinicians should not diagnose AOM in children who do not have MEE (demonstrated by pneumatic otoscopy and/or tympanometry).

      8. Increase in treatment-resistant AOM in Japan and its bacteriological background

      When the first edition of AOM Guidelines in Japan was issued in 2006, the increase in treatment-resistant AOM had become a major problem. Because of the increasing numbers of manuscripts in which the main pathogens of AOM, such as S. pneumoniae and H. influenzae, were reported to have become antimicrobial-resistant during the same period of time, one of the significant factors was considered to be derived from worsened antimicrobial susceptibility of AOM pathogens, requiring urgent management of this issue. Since the publication of the guidelines, drug susceptibility of S. pneumoniae has improved to some extent, along with changes in circumstances related to AOM pathogens, such as appropriate administration of antimicrobial agents, periodical inoculation with pneumococcal conjugate vaccine (first 7-valent, followed by 13-valent vaccine), and newly available antibiotic agents.
      However, no obvious improvement in prevalence of resistant H. influenzae has been observed. It is important to know the difference in the bacteriological background in Japan as compared to that of many European countries and the US, as these differences make it difficult to apply foreign guidelines directly to Japan; this necessitates guidelines specifically developed for patients in Japan.
      Data collection on drug susceptibilities of AOM pathogens provides a basis 1) for reviewing past medical practices, including appropriate administration of antimicrobial agents, and 2) for creating new strategies for AOM management.

      8.1 Bacteria isolated from children with AOM

      The Fifth Nationwide Surveillance of Clinical Isolates from Patients with Otorhinolaryngological Infections was conducted from January 2011 through June 2012 [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ] as part of a joint project by the Japanese Association for Infectious Diseases, Japanese Society of Chemotherapy and the Japanese Society for Clinical Microbiology [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Iwamoto A.
      • Totsuka K.
      • Kaku M.
      • Iwata S.
      • Kadota J.
      • Hanaki H.
      Nationwide surveillance of 6 otorhinolaryngological infectious diseases and antimicrobial susceptibility pattern in the isolated pathogens in Japan.
      ]. It was reported that 195 bacterial isolates were obtained from patients with AOM; among these, S. pneumoniae (29.2%), H. influenzae (26.7%), and Moraxella catarrhalis (11.3%) accounted for almost 70% of all isolates. One- hundred-and-fifty-four isolates were obtained from children aged 15 years and younger: S. pneumoniae (31.2%), H. influenzae (32.5%), and M. catarrhalis (12.3%). The recent isolation rate of S. pneumoniae from otorhinolaryngological infections in patients of all ages has decreased and that of H. influenzae has increased to some extent, as compared with four previous surveillances conduced in 1994, 1998, 2003, and 2007 ( ) [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]. From the age-dependent point of view, the rates of H. influenzae isolation from patients aged less than 12 months and aged one-year-old were as high as 48.3% and 43.8%, respectively. Furthermore, the older patients demonstrated lower isolation rates. On the other hand, the isolation rates of S. pneumoniae remained almost the same at any age (Table 4) [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ].
      Fig. 1
      Fig. 1Bacteria isolated from AOM patients
      [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]
      .
      Table 4Bacterial isolates from AOM patients in each age group.
      Bacteria<24 m.o.1 y.o.2–5 y.o.6–15 y.o.16 y.o~
      n%n%n%n%n%
      S. pneumoniae620.72035.11831.1550922
      H. influenzae1448.32543.81220.711012.4
      M. catarrhalis26.9610.51017.311037.3
      m.o.: months old, y.o.: years old.

      8.2 Antimicrobial susceptibility of S. pneumoniae and H. influenzae

      S. pneumoniae is classified according to its minimum inhibitory concentration (MIC) of penicillin G (PCG). S. pneumoniae with a PCG MIC ≤ 0.06 µg/mL is classified as penicillin-susceptible S. pneumoniae (PSSP), that with an MIC of 0.125–1.0 µg/mL as penicillin-intermediate-resistant S. pneumoniae (PISP), and that with an MIC ≥ 2 µg/mL as penicillin-resistant S. pneumoniae (PRSP). H. influenzae without production of β-lactamase and with an ampicillin MIC ≤ 1 µg/mL is classified as β-lactamase-non-producing ampicillin-susceptible H. influenzae (BLNAS), that with an MIC = 2 µg/mL as β-lactamase-non-producing ampicillin-intermediate-resistant H. influenzae (BLNAI), and that with an MIC ≥ 4 µg/mL as β-lactamase-non-producing ampicillin-resistant H. influenzae (BLNAR). H. influenzae with production of β-lactamase and with an MIC for CVA/AMPC ≥ 4/8 µg/mL is classified as β-lactamase-producing amoxicillin clavulanate-resistant H. influenzae (BLPACR), and that with and MIC ≤ 2/4 µg/mL as β-lactamase-producing ampicillin-resistant H. influenzae (BLPAR).

      8.2.1 S. pneumoniae

      The proportions of PSSP, PISP, and PRSP of all S. pneumoniae isolated during the first to fifth surveillance are demonstrated in Fig. 2 [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]. However, these data included those from all age groups, with all otorhinolaryngological diseases; therefore, data not related to pediatric AOM are included. No significant change was observed in the proportion of PSSP, PISP, and PRSP. However, a slight decrease in the prevalence of PRSP has been observed since 2003. Ozawa et al. studied the prevalence rate of resistant S. pneumoniae strains isolated from pediatric patients with AOM from 2001 to 2012. They reported that the prevalence of PRSP decreased from 43.4% in 2010 to 27.5% in 2011 and 13.3% in 2013 [
      • Ozawa D.
      • Yano H.
      • Hidaka H.
      • Kakuta R.
      • Komatsu M.
      • Endo S.
      • Kanamori H.
      • Kaku M.
      • Katori Y.
      Twelve-year survey (2001-2012) of the antimicrobial susceptibility of Streptococcus pneumoniae isolates from otorhinolaryngology clinics in Miyagi Prefecture, Japan.
      ]. Hoshino et al. reported changes in the frequency of PRSP isolated from the MEE of AOM patients aged ≤ 15 years between the periods 2007–2010 and 2011–2014. The rate of PRSP decreased from 25% to 4.5% [
      • Hoshino T.
      • Takeuchi N.
      • Fukasawa C.
      • Hirose S.
      • Okui H.
      • Sato H.
      • Sato M.
      • Arimoto Y.
      • Nakano A.
      • Ishiwada N.
      Analysis of Streptococcus pneumoniae and Haemophilus influenzae isolated from middle ear fluid before and after the introduction of government subsidies for pneumococcal and H. influenzae type b vaccines in Japan.
      ]. These results suggested that the prevalence of PRSP shows a declining tendency in Japan.
      Fig. 2
      Fig. 2Antimicrobial susceptibility of S. pneumoniae
      [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]
      .
      The isolation rate of PRSP in each age group was investigated in the fifth surveillance. The younger age group demonstrated higher rates of PRSP: 77.8% in children aged < 12 months, 58.5% in children aged ≥ 1 and ≤ 5 years, and 37.7% in children aged ≥ 6 years. These data suggested that the high prevalence of PRSP in the younger age group was one of the major factors of intractable AOM in young children. Thus, because the prevalence of PRSP is age-dependent, more attention should be paid when comparing the different age groups.
      The MIC90 of each antimicrobial agent for S. pneumoniae in the fourth and fifth nationwide surveillance is demonstrated in Table 5 [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]. No marked change in the MIC90 of ß-lactams, including PCG, was noted; however, there was a marked decrease in susceptibility to macrolides.
      Table 5MIC90 of various antimicrobial agents against S. pneumoniae from the Nationwide surveillance on clinical isolates in 2007 & 2012
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      .
      Antimicrobials20072012
      n = 78n = 113
      PCG22
      AMPC22
      CVA/AMPC22
      FRPM0.50.5
      CDTR10.5
      CFPN11
      CTRX0.51
      TBPM≤0.06
      LVFX22
      TFLX0.250.25
      CAM128≥128
      AZM32≥128

      8.2.2 H. influenzae

      The fifth nationwide surveillance revealed the proportion of BLNAS, BLNAI, BLNAR, BLPAR, and BLPACR among 106 isolates of H. influenzae as 34.0%, 15.1%, 35.8%, 10.3%, and 4.7%, respectively (Fig. 3) [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]. These data included those from all age groups, with all otorhinolaryngological diseases. The younger age group demonstrated higher isolation rates of antimicrobial-resistant H. influenzae as well as S. pneumoniae. Resistant strains accounted for 71.4% of isolates from patients aged < 2 years. Kakuta et al. studied 157 strains of H. influenzae isolated from MEE of AOM children ≤ 3 years old throughout Japan. They reported that 31.2% of 157 H. influenzae isolates were BLNAS, 26.8% were BLNAI, 33.8% were BLNAR, 4.5% were BLPAR, and 3.8% were BLPACR. The resistance rates were almost the same as those observed in the fifth surveillance [
      • Kakuta R.
      • Yano H.
      • Hidaka H.
      • Kanamori H.
      • Endo S.
      • Ichimura S.
      • Ogawa M.
      • Shimojima M.
      • Ozawa D.
      • Inomata S.
      • Tanouchi A.
      • Kaku M.
      • Katori Y.
      Molecular epidemiology of ampicillin-resistant Haemophilus influenzae causing acute otitis media in Japanese infants and young children.
      ].
      Fig. 3
      Fig. 3Antimicrobial susceptibility of H. influenzae
      [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]
      .
      The rates of isolation of resistant H. influenzae have been increasing year by year in Japan. The total incidence of BLNAI and BLNAR in each surveillance tended to increase, that is, starting from 23.3% in the second surveillance, 47.2% in the third, 52.4% in the fourth, and 50.9% in the fifth surveillance. The prevalence of ß-lactamase-producing resistant H. influenzae strains (BLPACR and BLPAR) has tended to increase, particularly in recent years (6.8%, 3.1%, 6.3%, and 15.1% between the second and fifth surveillance). Therefore, the proportion of susceptible H. influenzae has declined (69.9% in the second, 49.7% in the third, 41.3% in the fourth, and 34.0% in the fifth surveillance).
      The MIC90 of each antimicrobial agent for H. influenzae in the fourth and fifth nationwide surveillance is listed in Table 6 [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]. There was no marked change in the MIC90 for ß-lactams and fluoroquinolones between 2007 and 2012.
      Table 6MIC90 of various antimicrobial agents against H. influenzae from the Nationwide surveillance on clinical isolates in 2007 & 2012
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      .
      Antimicrobials20072012
      n = 63n = 106
      ABPC12832
      CVA/AMPC168
      CDTR0.50.5
      CFPN42
      CTRX0.250.5
      MEPM0.50.5
      TBPM1
      LVFX≤0.06≤0.06
      TFLX≤0.06≤0.06
      CAM168
      AZM42
      MINO0.51

      9. Literature search

      During the preparation of these guidelines, existing evidence (literature) was gathered with respect to the following clinical issues, as described below:
      • (a)
        Diagnosis
      • (b)
        Testing methods
      • (c)
        Treatment

      9.1 Databases used

      For the 2006 Guidelines, PubMed and Japan Centra Revuo Medicina Web version 3 were used, and for the 2009, 2013, and 2018 Guidelines, PubMed, the Cochrane library, and Japan Centra Revuo Medicina Web versions 4 and 5 were used.

      9.2 Search period

      For the 2006 Guidelines, database searches of the literature published during 2000–2004 were performed. For the 2009 Guidelines, articles published in 2004 that had not been included in the 2006 Guidelines were added, along with articles published after 2005 and that were searchable on April 10, 2008. For the 2013 Guidelines, articles published during 2008–2012 were added. For the 2018 Guidelines, articles published during 2013–2017 were added.

      9.3 Criteria for use

      Priority was given to articles that comprised systematic reviews of RCTs or that described individual RCTs, and if these were not available, then observational studies, such as cohort studies and case–control studies, were used. If these were insufficient, the scope was widened to include articles describing case series. Articles concerning animal experiments and basic science were excluded.

      9.4 Method of use

      For the 2006 Guidelines, the keyword “chujien” (otitis media) was used to search the Japan Centra Revuo Medicina Web version 3 database, with the “meta-analysis,” “randomized controlled trial,” “controlled clinical trial,” and “comparative research” research design tags checked, but no articles suitable for use in these Clinical Practice Guidelines were found. In PubMed, searches were performed with the following keywords: i) otitis media, treatment; ii) otitis media, antibiotics; iii) acute otitis media, treatment; and iv) acute otitis media, antibiotics. For meta-analyses and systematic reviews, using the Cochrane Collaboration, the search format “English [la] AND otitis media[ti] AND (Cochrane Database Syst Rev[jour] OR meta-analysis[pt]) AND 2000:2004[dp]” was used. Articles cited in the AAP Guidelines 2004 were also analyzed. In addition to the literature searches described above, articles published before 2000, those published during 2003–2005 while the Guidelines were in preparation, and those published in Japanese and international journals that were considered to be required for the preparation of the guidelines were also identified, resulting in a total of 82 articles for investigation.
      For the 2009 and 2013 Guidelines, the search format (chujien (otitis media)/TH or chujien (otitis media)/AL) and (PT = “NOT conference repot” and RD = “meta-analysis”, “randomized control trial”, “semi-randomized control study,” “controlled study,” and “clinical practice guidelines”) was used to search Japan Centra Revuo Medicina Web versions 4 or 5, yielding hits for 104 articles (2003–2008) and 233 articles (2008–2013). As the abstracts or main texts of these articles were studied, seven articles for the 2009 Guidelines and 50 articles for the 2013 Guidelines were selected for inclusion.
      In PubMed, searches were performed using the following keywords: Search (English[la] OR Japanese[la]) AND (otitis media) AND (treatment OR antibiotics) AND (randomized controlled trial[pt]) AND 2004:2007[dp]; and Search (English[la] OR Japanese[la]) AND (otitis media) AND (treatment OR antibiotics) AND (meta-analysis[pt] OR Cochrane Database Syst Rev[ta]) AND 2004:2007[dp], yielding 118 articles. A further 268 articles published between 2004 and April 2007 and containing “otitis media” in their title, abstract, or keywords were also identified from the Cochrane Reviews, Clinical Trials, Other Reviews, Technology Assessments, and Economic Evaluations included in the Cochrane Library. A total of 386 articles found by the above searches were studied and 60 of 386 articles were added to the 2009 Guidelines, excluding those already used in the 2006 Guidelines. In addition, with the cooperation of the Japan Council for Quality Healthcare Medical Information Network Distribution System EBM Medical Information Department, a search of PubMed for articles published after April 1, 2007, was performed on April 10, 2008, using the search format ((“otitis media”[MeSH] AND “therapy”[Subheading]) OR (“otitis media”[MeSH] AND antibiotics) OR (“acute otitis media” AND “therapy”[Subheading]) OR (“acute otitis media” AND antibiotics)) AND ((“meta-analysis”[pt] OR “randomized controlled trial”[pt]) NOT “Cochrane database of systematic reviews (Online)”[Jour] AND “humans”[MeSH] AND (english[la] OR japanese[la]) AND 2007/4/1[edat]: 2008/3/31[edat]. This identified 11 articles, of which five were selected for study. In addition to the literature searches described above, three other articles that were considered required for preparation of the guidelines were added, resulting in 75 articles being added to those used in the 2006 Guidelines and yielding a final total of 157 articles in the new guidelines (Abstract Table not attached). In the 2013 Guidelines, 650 articles were extracted by the same search method (PubMed, the Cochrane Library, and Japan Centra Revuo Medicina), and 208 articles were added. Since the 2013 version, the abstract table was published only on the Japan Otological Society website (http://www.otology.gr.jp). In the 2018 Guidelines, 2257 articles were extracted by the same search method and 311 articles were added.

      10. Quality of evidence and strength of recommendation

      10.1 Quality of evidence

      This clinical practice guideline was developed using the evaluation method proposed by the AAP [
      I
      American Academy of Pediatrics Steering Committee on Quality, Management, Classifying recommendations for clinical practice guidelines.
      ].
      The quality of evidence was evaluated based on the proposal of the AAP and “Minds Handbook for Clinical Practice Guideline Development 2014″ [
      • Fukui T.
      • Yamaguchi N.
      • Morizane T.
      • Yoshida M.
      • Kojimahara N.
      Minds Handbook for clinical practice guideline development 2014.
      ]. The quality of evidence of each individual study was evaluated based on not only the type of study (Table 7), but on various factors that may reduce the quality, as follows:
      • (1)
        Risk of bias (selection bias, performance bias [blinding of participants and personnel], detection bias [blinding of outcome assessors], attrition bias [against intention-to-treat (ITT) analysis or incomplete outcome data], selective outcome reporting bias, early stopping bias and other biases [conflict of interest (COI) etc.]).
      • (2)
        Directness (external validity, generalizability applicability) In the next steps, studies were integrated in each group with the same outcome and the same study design to decide a quality of the aggregate evidence as a body of evidence. In this process, other bias factors, such as inconsistency, imprecision, and publication bias, were evaluated, in addition to risk of bias and indirectness.
      • (3)
        Consistency (support from multiple studies)
      • (4)
        Imprecision. In the case of the observational study, factors as demonstrated bellow that may upgrade the quality of evidence were taken into consideration.
      • (5)
        A large effect of the intervention
      • (6)
        A dose-dependent gradient
      • (7)
        Plausible confounders that reduced the effects. Finally, the quality of evidence of the recommendation for each clinical question was rated across outcomes as a summary of evidence.
      Table 7Quality of Evidence
      I
      American Academy of Pediatrics Steering Committee on Quality, Management, Classifying recommendations for clinical practice guidelines.
      .
      A.Well-designed, randomized controlled trials or diagnostic studies on relevant populations.
      B.RCTs or diagnostic studies with minor limitations; overwhelmingly consistent evidence from observational studies.
      C.Observational Studies (case control and cohort design).
      D.Expert opinion, case reports, reasoning from first principles.
      X.Exceptional situations where validating studies cannot be performed and there is a clear preponderance of benefit or harm.

      10.2 Strength of recommendation

      One of the most important functions of clinical practice guidelines is to demonstrate the strength of recommendations. The methodology for deciding optimal grading of recommendations has been controversial. The Guideline Committee of this clinical practice guideline used the proposal of Minds as reference to create SCOPE. Decisions about the strength of recommendations were made based on both the quality of evidence and the ratio of the potential benefit to harm, as recommended by the AAP (Tables 8 & 9).
      Table 8Strength of Recommendation
      I
      American Academy of Pediatrics Steering Committee on Quality, Management, Classifying recommendations for clinical practice guidelines.
      .
      Strong recommendation: A strong recommendation means the benefits of the recommended approach clearly exceed the harms (or that the harms clearly exceed the benefits in the case of a strong negative recommendation) and that the quality of the supporting evidence is excellent (grade A or B). In some clearly identified circumstances, strong recommendations may be made when high-quality evidence is impossible to obtain (X) and the anticipated benefits strongly outweigh the harms.
      Recommendation: A recommendation means the benefits exceed the harms (or that the harms clearly exceed the benefits in the case of a strong negative recommendation) but the quality of evidence is not as strong (grade B or C). In some clearly identified circumstances, strong recommendations may be made when high-quality evidence is impossible to obtain (X) and the anticipated benefits strongly outweigh the harms.
      Option: An option means that either the quality of evidence that exists is suspect (grade D) or that well-done studies (A, B, or C) show little clear advantage to one approach over another.
      No recommendation: No recommendation means there is both a lack of pertinent evidence (grade D) and unclear balance between benefits and harms.
      Table 9Relationship of evidence quality and benefit-harm balance in determining the strength of recommendation
      I
      American Academy of Pediatrics Steering Committee on Quality, Management, Classifying recommendations for clinical practice guidelines.
      .
      The strength of recommendations and the statements of recommendation required a consensus from all members of the Guideline Committee. However, the selection of diagnostic items and each specific score of the scoring system used to decide the disease severity in CQ1–4 were determined by the Delphi method.
      NOTE: The Delphi method is a communication technique used to reach agreement about initially unsolved matters, in which process experts express their opinions independently and/or anonymously, a facilitator provides the summary of opinions of all participants; then, individual members revise their opinions by reference to other experts’ answers, and finally members obtain consensus by repeating this process several times.

      10.3 Evaluation and presentation of quality of evidence and strength of recommendation

      10.3.1 Methodology for creating clinical practice guidelines

      The AOM Guideline Committee of Japan had used a method for evaluating the quality of evidence proposed by the Japan Stroke Society since the first edition of the guidelines were published in 2006. The new members of the committee began to revise the guidelines based on newly proposed assessment of evidence and recommendation by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system since 2015.
      In the GRADE system, the evidence from individual studies were integrated according to the outcomes, some of which compose a CQ, into the body of evidence. The quality of evidence of the recommendation for each CQ was evaluated across outcomes as a summary of evidence. In the GRADE system, RCTs are not always assessed as high-quality evidence. The quality of evidence of RCTs may be downgraded by various factors, including study-related biases. On the other hand, this evaluation system includes a mechanism that allows upgrading of the quality of evidence, even if it is an observational study [
      • Atkins D.
      • Best D.
      • Briss P.A.
      • Eccles M.
      • Falck-Ytter Y.
      • Flottorp S.
      • Guyatt G.H.
      • Harbour R.T.
      • Haugh M.C.
      • Henry D.
      • Hill S.
      • Jaeschke R.
      • Leng G.
      • Liberati A.
      • Magrini N.
      • Mason J.
      • Middleton P.
      • Mrukowicz J.
      • O'Connell D.
      • Oxman A.D.
      • Phillips B.
      • Schunemann H.J.
      • Edejer T.
      • Varonen H.
      • Vist G.E.
      • Williams Jr., J.W.
      • Zaza S.
      • Group G.W.
      Grading quality of evidence and strength of recommendations.
      ].
      The Guideline Committee described the SCOPE (a master plan of the guideline) first, and re-evaluated clinical key issues on the pediatric AOM, based on the SCOPE. CQs that include key clinical issues were carefully selected and written in accordance with the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) framework. Otological specialists were organized into a systematic review (SR) team to perform a systematic review related to each CQ. The team investigated whether the GRADE method could be used for creating the guidelines. The team found some problems:
      GRADE is a very powerful tool for evaluating a clinical issue on the treatment choice: for example, assessing which of surgery or medicine is the better treatment. Evaluation with the GRADE method requires several studies on a common outcome, even if their study designs are different.
      Because diagnostic and treatment issues of pediatric AOM are closely related, the guidelines of Japan have included many sections or CQs on diagnostic issues, since their first edition. Moreover, one of the most important missions of the Guidelines should be to prevent unnecessary treatment interventions based on uncertain diagnoses. The widespread use of precise diagnostic procedures could provide a basis for appropriate management of AOM patients. Therefore, these guidelines need to include the evaluation of diagnostic issues.
      There have been several studies about the effectiveness of antimicrobial agents in patients with AOM. However, there are a limited number of studies about the effectiveness of each antimicrobial agent for each causative pathogen in terms of the bacteriology and antimicrobial resistance pattern in Japan, which differs markedly from that in Europe and the US.
      After intensive discussions, the Guideline Committee concluded that the GRADE method is not the best approach for establishing AOM guidelines in Japan at this time, because it is not optimal if the guidelines cannot make a recommendation regarding some key clinical issues due to insufficient evidence, even when it is clear that the recommendation can provide major benefits to the patients.

      10.3.2 Adopted method for evaluation

      Several guidelines that used AAP proposals [
      I
      American Academy of Pediatrics Steering Committee on Quality, Management, Classifying recommendations for clinical practice guidelines.
      ] to evaluate the evidence quality and strength of the recommendation have been published in recent years [
      • Tunkel D.E.
      • Bauer C.A.
      • Sun G.H.
      • Rosenfeld R.M.
      • Chandrasekhar S.S.
      • Cunningham Jr., E.R.
      • Archer S.M.
      • Blakley B.W.
      • Carter J.M.
      • Granieri E.C.
      • Henry J.A.
      • Hollingsworth D.
      • Khan F.A.
      • Mitchell S.
      • Monfared A.
      • Newman C.W.
      • Omole F.S.
      • Phillips C.D.
      • Robinson S.K.
      • Taw M.B.
      • Tyler R.S.
      • Waguespack R.
      • Whamond E.J.
      Clinical practice guideline: tinnitus.
      ,
      • Stachler R.J.
      • Chandrasekhar S.S.
      • Archer S.M.
      • Rosenfeld R.M.
      • Schwartz S.R.
      • Barrs D.M.
      • Brown S.R.
      • Fife T.D.
      • Ford P.
      • Ganiats T.G.
      • Hollingsworth D.B.
      • Lewandowski C.A.
      • Montano J.J.
      • Saunders J.E.
      • Tucci D.L.
      • Valente M.
      • Warren B.E.
      • Yaremchuk K.L.
      • Robertson P.J.
      American Academy of, S. Neck, Clinical practice guideline: sudden hearing loss.
      ,
      • Seidman M.D.
      • Gurgel R.K.
      • Lin S.Y.
      • Schwartz S.R.
      • Baroody F.M.
      • Bonner J.R.
      • Dawson D.E.
      • Dykewicz M.S.
      • Hackell J.M.
      • Han J.K.
      • Ishman S.L.
      • Krouse H.J.
      • Malekzadeh S.
      • Mims J.W.
      • Omole F.S.
      • Reddy W.D.
      • Wallace D.V.
      • Walsh S.A.
      • Warren B.E.
      • Wilson M.N.
      • Nnacheta L.C.
      A.-H. Guideline Otolaryngology Development Group
      Clinical practice guideline: Allergic rhinitis.
      ]. All target diseases include key clinical issues about diagnosis per se. The US AOM guidelines (AAP guidelines) also used the AAP method [
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ]. This method helps to evaluate the quality of evidence of outcomes related to diagnosis as well as treatment. The same criteria as used in the GRADE system can be used for evaluation of a case if the reported evidence is sufficient. The criteria of Quality Assessment of Diagnostic Accuracy Studies (QUADAS) [
      • Whiting P.
      • Rutjes A.W.
      • Reitsma J.B.
      • Bossuyt P.M.
      • Kleijnen J.
      The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews.
      ] are available for diagnosis-related evaluation. Thus, the AAP method seems sufficiently flexible to allow evaluation of various types of issues. Furthermore, this method, as well as the GRADE system, emphasizes the balance of benefits and harms when judging the strength of recommendation as well as the evidence quality. Thus, strong recommendation is possible in clinical practice when the anticipated benefits strongly outweigh the harms, even when the evidence is poor because it is not possible to perform a high-quality study, as shown in Table 9.
      These features of the AAP method fit members’ philosophy well, and the Guideline Committee reached a consensus to use this method. Finally, the Guideline Committee determined the evidence quality and the strength of recommendation for each CQ by reference to the SR report produced by the SR team.

      11. Summary of evidence

      The quality of evidence for each study was assessed first. Evidence from several studies about the same outcome are integrated into an aggregate quality of evidence for the body of evidence as a whole. The quality of evidence regarding the recommendation for the CQ, which is composed of several outcomes, is determined across outcomes as a summary of the evidence.

      12. Pre-release review

      The 2018 Guidelines were qualified by two pediatricians (Table 2) before publication, using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instruments [
      Appraisal of Guidelines, Research, and Evaluation in Europe (AGREE) Collaborative Group
      Guideline development in Europe. An international comparison.
      ,

      AGREE Next Steps Consortium. Appraisal of guidelines for research & evaluation II (AGREE II)2009; Available from:https://www.agreetrust.org/agree-ii/.

      ,

      Council for Quality Health Care, Department of EBM and Guidelines,, AGREE II (Japanese translation), (2016) [in Japanese].

      ] and finally obtained their recommendations as a high-quality guideline.

      13. Future updates

      It is planned to update the guidelines around every 3–5 years to maintain the validity of the recommendations. After publication of the guidelines, new members will organize a new subcommittee to provide updates. Newly published evidence will be systematically assessed and reviewed. Urgent and significant updates may be published to the websites of the JOS, the JSIAO, and the JSPO.

      14. Recommendations and evidence-based reasons

      The 2018 Guidelines are intended to be useful for decision-making related to diagnosis and treatment of pediatric patients with AOM, by all clinicians, with various backgrounds, including otolaryngologists and pediatricians, etc., across a wide variety of practical settings. The relationships of recommendations and the evidence-based reasons, from published literature, are described in each CQ section. Nevertheless, it should be restated that none of the recommendations in the guidelines can replace the judgement of experienced clinicians; it only can support their decision-making.

      15. Patient preference

      Recommendations in the guidelines should not apply to all patients, given their individually different backgrounds and clinical conditions. Clinicians should make clinical decisions comprehensively, using evidence and recommendations, including the guidelines, the experience and specialty of each clinician, the preferences of patients and their parents/guardians, and their values. In the 2018 Guidelines, the balance of benefits and harms for the patients and patient preferences, in addition to the evidence quality, were emphasized and described as the reason for the recommendations.

      16. Practical considerations in implementation of the guidelines

      Generic names are used for brand names in the Guidelines, to ensure fairness. Moreover, because generic drugs have become popular in recent years, there is a plethora of product names. Hence, clinicians should pay attention to the generics available in their own practical settings, to follow the recommendations of the guidelines.

      17. Clinical questions (CQ)

      17.1 Diagnosis and examination

      CQ 1–1: Under what conditions is AOM diagnosed?
      Recommendation:
      Precise otoscopic examination and evaluation is strongly recommended for a definite diagnosis of AOM (typical otoscopic findings are shown in Fig. 4 [
      • Kamide Y.
      Classification of tympanic membrane findings on acute otitis media in children and their verification.
      ]).
      • Representative otoscopic findings of AOM are as follows: redness (erythema, hyperemia), bulging (protrusion), and otorrhea; nevertheless, all these findings are not always observed. An unclear light reflex of the TM, thickening of the TM, bullous formations on the TM, a cloudy (dull or opaque) TM, and perforation of the TM are supportive findings for AOM.
      • Although an edematous middle ear mucosa may be observed through the perforation of the TM by myringotomy, which would indicate severe inflammation of the middle ear mucosa, this finding can be used only as a reference, as it may not be observed in every case with AOM.
      • It is highly desirable to use an otomicroscope and/or otoendoscope for precise evaluation of TM findings. A pneumatic otoscope could be an alternative device.
      Fig. 4
      Fig. 4Typical otoscopic findings of AOM
      [
      • Kamide Y.
      Classification of tympanic membrane findings on acute otitis media in children and their verification.
      ]
      .
      ♦ Recommendation Strength: Strong Recommendation, Evidence Quality: B
      Background:
      AOM is an acute inflammation of the middle ear mucosa. MEE caused by inflammation as well as other acute inflammatory findings of the TM identified by precise otoscopic examination is essential for definite diagnosis of AOM.
      Aggregate evidence quality:
      • Benefits for children: Definite diagnosis based on precise examinations can avoid unnecessary treatment interventions and can help to reduce treatment failures.
      • Risks and harms for children: Precise examinations of the TM potentially require an uncomfortable process for children, such as ear wax removal with/without some physical restraint.
      • Benefit–harm assessment: Benefits exceed the harms, because a diagnosis based only on symptoms without precise otoscopic examinations would lead to administration of unnecessary antimicrobial agents, inducing adverse effects for individual patients, and would also result in a social disadvantage, such as an increase in antimicrobial-resistant pathogens in the community.
      • Patient preference: None
      • Exclusions: None.
      Comments:
      A wide variety of descriptive terms for TM findings related to AOM have been used in many reports and text books, including redness (erythema, hyperemia), opaque (cloudy, dull), bulging (protrusion), thickening, bullous formation, perforation, and abnormal appearance of the light reflex of the TM. There seems no standardized terminology. Bulging is frequently observed in AOM and is the most important factor for distinguishing it from OME [
      • Shaikh N.
      • Hoberman A.
      • Rockette H.E.
      • Kurs-Lasky M.
      Development of an algorithm for the diagnosis of otitis media.
      ]. Therefore, bulging is considered to be the most important finding for a diagnosis of bacterial AOM, particularly if it occurs along with discoloration and impaired mobility [
      • Shaikh N.
      • Hoberman A.
      • Rockette H.E.
      • Kurs-Lasky M.
      Development of an algorithm for the diagnosis of otitis media.
      ,
      • Karma P.H.
      • Penttila M.A.
      • Sipila M.M.
      • Kataja M.J.
      Otoscopic diagnosis of middle ear effusion in acute and non-acute otitis media. I. The value of different otoscopic findings.
      ,
      • Pelton S.I.
      Otoscopy for the diagnosis of otitis media.
      ,
      • Pichichero M.E.
      Acute otitis media: Part I. Improving diagnostic accuracy.
      ]. An opaque TM usually indicates edematous changes of the TM, except when it is due to scar formation. Redness is also frequently observed in AOM; however, clinicians should consider whether this is induced by crying and/or high fever in the patients, and note that it is also observed in viral AOM [
      • Weiss J.C.
      • Yates G.R.
      • Quinn L.D.
      Acute otitis media: making an accurate diagnosis.
      ]. Furthermore, pediatric patients under 12 months of age with bulging TMs may not show distinct redness. If symptoms have a rapid onset and there is proof of MEE, suggested from a bulging TM and/or otorrhea from the middle ear, then a definite diagnosis of AOM can be made [
      • Lee H.J.
      • Park S.K.
      • Choi K.Y.
      • Park S.E.
      • Chun Y.M.
      • Kim K.S.
      • Park S.N.
      • Cho Y.S.
      • Kim Y.J.
      • Kim H.J.
      • Korean Otologic S.
      Korean clinical practice guidelines: otitis media in children.
      ]. Clinical practice guidelines for AOM children by the AAP in 2013 (AAP Guidelines 2013) include the following recommendations for a diagnosis of AOM [
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ].
      • (1)
        Clinicians should diagnose AOM in children who present with moderate to severe bulging of the TM or with new onset otorrhea not due to acute otitis externa.
      • (2)
        Clinicians should diagnose AOM in children who present with mild bulging of the TM and recent (less than 48 h) onset of ear pain (holding, tugging, or rubbing of the ear in a nonverbal child) or intense erythema of the TM.
      • (3)
        Clinicians should not diagnose AOM in children who do not have MEE (based on pneumatic otoscopy and/or tympanometry).
      When otoscopic findings of MEE and acute inflammation related to AOM are observed simultaneously, the diagnosis of AOM is almost definite [
      • Rosenfeld R.M.
      • Casselbrant M.L.
      • Hannley M.T.
      Implications of the AHRQ evidence report on acute otitis media.
      ]. Impaired or absent mobility of the TM is strong positive evidence of MEE. Guideline users in Japan should pay attention to the fact that the recommendations in AAP Guidelines 2013 were created to select those patients who require antimicrobial agents and who receive benefits from them, that is, to select severe AOMs caused by bacteria, for which antimicrobial agents can make a big contribution. Clinicians sometimes need to remove ear wax and always need to use appropriate illumination to obtain a clear vision of the TM.
      As the external ear canals of children under 24 months, who frequently suffer from AOM, are sometimes extremely narrow, a magnifying otoscope with sufficient illumination is required for precise inspection of the TM. Although it has been reported that the use of an otomicrospcope did not improve the diagnostic accuracy of AOM, compared to a magnifying otoscope [
      • Hemlin C.
      • Hassler E.
      • Hultcrantz M.
      • Papatziamos G.
      • Krakau I.
      Aspects of diagnosis of acute otitis media.
      ], observation of the TM by an otomicroscope or an otoendoscope, particularly one equipped with a CCD video camera, is desirable for precise TM examinations, and for a time-course of recordings for creating each patient's database. A prospective clinical trial has reported that video endoscopy was the best approach for identifying MEE among other examinations, such as pneumatic otoscopy, tympanometry, or acoustic reflectometry [
      • Guo Y.C.
      • Shiao A.S.
      Diagnostic methods for otitis media with effusion in children.
      ].
      In Japan, where optical instruments are highly developed and widely distributed, TM inspection by using a surgical microscope and/or a rigid endoscope equipped with a CCD video camera is recommended. On the other hand, pneumatic otoscopy is strongly recommended for clinicians other than otolaryngologists who often do not have these instruments.
      CQ 1–2: Is it necessary to acquire the patient's history when diagnosing AOM?
      Recommendation:
      Clinicians should take a patient's history to confirm acute onset for the diagnosis of AOM. It is very important to know the patient's background and the history in order to assess whether the patient is otitis prone and/or whether the pathogens are resistant to antimicrobials.
      • Recommendation Strength: Recommendation, Evidence Quality: C
      Background:
      The information about acute onset is essential for the diagnosis of AOM because of its disease definition in the guidelines. The medical interviews also play an important role for understanding various risk factors. An appropriate medical interview is recommended for diagnosis and management of AOM (Table 10).
      Table 10Medical interview sheet for a child with AOM.
      Aggregate evidence quality:
      • Benefits for children: Appropriate history-taking could prevent unnecessary treatment interventions, which may arise from an uncertain diagnosis. Furthermore, it could predict the risk of antimicrobial-resistant pathogens and intractability of AOM and promote proper treatment interventions based on the patient's complaints.
      • Risks and harms for children: Appropriate assessments of patients’ complaints could be very difficult in cases of preverbal children, whose crying and/or irritability (bad temper) may not be due to otological symptoms.
      • Benefit–harms assessment: Benefits exceed the harms for every patient because not only the signs, but also the symptoms and histories obtained are clearly important for making a definite diagnosis of AOM, which enables appropriate treatment interventions.
      • Patient preference: N/A.
      • Exclusions: None.
      Comments:
      Clinicians should confirm acute onset of the disease, which forms part of the disease definition, from history-taking. Young, preverbal children cannot complain of otalgia (ear pain) by themselves, although this is the most common symptom of AOM. Holding, rubbing, or tugging of the ear for them could be alternative expressions of otalgia; however, they are not specific to AOM. It has been reported that a diagnosis based on only history-taking, including the present history and symptoms alone, may lead to misdiagnosis of AOM, followed by unnecessary antimicrobial use; for example, patients with OME who happen to have otalgia that is not related to AOM, could be diagnosed as AOM [
      • Shaikh N.
      • Hoberman A.
      • Rockette H.E.
      • Kurs-Lasky M.
      Development of an algorithm for the diagnosis of otitis media.
      ,
      • Laine M.K.
      • Tahtinen P.A.
      • Ruuskanen O.
      • Huovinen P.
      • Ruohola A.
      Symptoms or symptom-based scores cannot predict acute otitis media at otitis-prone age.
      ]. On the other hand, either otalgia or fever, or the combination of these, can increase the accuracy of diagnosis of AOM requiring treatment [
      • Rovers M.M.
      • Glasziou P.
      • Appelman C.L.
      • Burke P.
      • McCormick D.P.
      • Damoiseaux R.A.
      • Gaboury I.
      • Little P.
      • Hoes A.W.
      Antibiotics for acute otitis media: a meta-analysis with individual patient data.
      ].
      Patients who attend day-care centers are frequently infected with antimicrobial-resistant pathogens [
      • Ito M.
      • Shirai A.
      • Tatsumi A.
      • Yoshizaki T.
      • Nishimura T.
      • Furukawa M.
      Incidence of penicillin resistant Streptococcus pneumoniae in a nursery school.
      ]. Home-based patients also suffer from antimicrobial-resistant bacterial infection if their siblings attend day-care centers. Young children are more likely to develop severe AOM in Japan and in Western countries [
      • Hotomi M.
      • Yamanaka N.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Factors associated with clinical outcomes in acute otitis media.
      ,
      • Rovers M.M.
      • Schilder A.G.
      • Zielhuis G.A.
      • Rosenfeld R.M.
      Otitis media.
      ]. A history of recurrent AOM may suggest drug-resistance of the pathogens or immunological problems of the patients. These data can be provided by detailed history-taking, which is valuable for predicting the severity of AOM and the presence of an immunological condition in patients.
      CQ 1–3: Is tympanometry beneficial for diagnosis of AOM?
      Recommendation:
      Tympanometry is recommended because it offers objective data for the presence of MEE, particularly when a thick and/or non-transparent TM disturbs the precise otoscopic examination.
      • Recommendation Strength: Recommendation, Evidence Quality: B
      Background:
      Tympanometry is a reliable objective measurement that can evaluate the presence of MEE. Acoustic reflectometry cannot be recommended in these guidelines even though it is recommended in Western countries [
      • Laine M.K.
      • Tahtinen P.A.
      • Helenius K.K.
      • Luoto R.
      • Ruohola A.
      Acoustic reflectometry in discrimination of otoscopic diagnoses in young ambulatory children.
      ], because this device has been commercially unavailable in Japan since 1994.
      Aggregate evidence quality:
      • Benefits for children: Tympanometry facilitates reliable assessment of MEE, even when otoscopic examinations are difficult through thick and non-transparent TMs, and can thereby avoid unnecessary treatments based on uncertain diagnosis.
      • Risks and harms for children: It is necessary to prove MEE, but this is not sufficient to make a diagnosis of AOM. Tympanometry costs more than using a pneumatic otoscope to prove MEE.
      • Benefit–harms assessment: Benefits exceed harms because a definite diagnosis by tympanometry in combination with precise otoscopic examination could enhance correct decision-making about treatment interventions.
      • Patient preference: N/A
      • Exclusions: Clinicians should not carry out tympanometry for patients with otorrhea.
      Comments:
      Clinicians should not diagnose AOM in children who do not have MEE based on pneumatic otoscopy and/or tympanometry [
      • Hoberman A.
      • Paradise J.L.
      • Rockette H.E.
      • Shaikh N.
      • Wald E.R.
      • Kearney D.H.
      • Colborn D.K.
      • Kurs-Lasky M.
      • Bhatnagar S.
      • Haralam M.A.
      • Zoffel L.M.
      • Jenkins C.
      • Pope M.A.
      • Balentine T.L.
      • Barbadora K.A.
      Treatment of acute otitis media in children under 2 years of age.
      ,
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ].
      Tympanometry measures the compliance changes in the middle ear system, including the TM, by continuously changing air pressure in the sealed external auditory canal. Type C and B tympanograms suggest negative pressure in the middle ear cavity and the presence of MEE, objectively [
      • Saeed K.
      • Coglianese C.L.
      • McCormick D.P.
      • Chonmaitree T.
      Otoscopic and tympanometric findings in acute otitis media yielding dry tap at tympanocentesis.
      ,
      • Sakaguchi M.
      • Taguchi K.
      • Ishiyama T.
      • Netsu K.
      • Katsuno S.
      Tympanometric changes following acute otitis media in Japanese children.
      ]. Tympanometry was found to be more reliable than pneumatic otoscopy for predicting the presence of MEE [
      • Abbott P.
      • Rosenkranz S.
      • Hu W.
      • Gunasekera H.
      • Reath J.
      The effect and acceptability of tympanometry and pneumatic otoscopy in general practitioner diagnosis and management of childhood ear disease.
      ].
      Tympanometry can only detect MEE, but cannot differentiate AOM from OME [
      • Rosenkranz S.
      • Abbott P.
      • Reath J.
      • Gunasekera H.
      • Hu W.
      Promoting diagnostic accuracy in general practitioner management of otitis media in children: findings from a multimodal, interactive workshop on tympanometry and pneumatic otoscopy.
      ], and a precise otoscopic examination is essential for stringent diagnosis of AOM. Moreover, patients with AOM are usually younger than those with OME, and it is sometimes difficult to apply tympanometry to younger patients who cannot remain still for a certain period of time because of ear pain and/or whose ear wax or sealing problems disturb the examination. Some clinicians have reported that the reliability of tympanometry was limited because there was no obvious change in the antimicrobial prescription rate between groups in which tympanometry was or was not used to evaluate MEE [
      • Spiro D.M.
      • King W.D.
      • Arnold D.H.
      • Johnston C.
      • Baldwin S.
      A randomized clinical trial to assess the effects of tympanometry on the diagnosis and treatment of acute otitis media.
      ].
      On the other hand, a randomized controlled study of children aged 6 to 35 months, whose AOM was primarily diagnosed by otoscopic findings by Tähtinen et al., has suggested that peaked tympanometry (types A and C) can be a predictive indicator for candidates that should undergo initial observation without antimicrobial prescription [
      • Tähtinen P.A.
      • Laine M.K.
      • Ruohola A.
      Prognostic factors for treatment failure in acute otitis media.
      ].
      It should be noted that tympanometry using a 226Hz probe tone, which had been widely used in Japan, is not reliable when patients are younger than 6 months [
      • Alaerts J.
      • Luts H.
      • Wouters J.
      Evaluation of middle ear function in young children: clinical guidelines for the use of 226- and 1,000-Hz tympanometry.
      ].
      CQ 1–4: How is the severity of AOM assessed?
      Recommendation:
      Severity is classified as mild, moderate, and severe according to the patient's age, otoscopic findings, and clinical manifestations.
      Otoscopic findings: redness (erythema, hyperemia), bulging (protrusion), otorrhea
      Clinical manifestations: otalgia (ear pain), fever, crying and/or irritability (bad temper)
      • Strength: Recommendation, Evidence Quality: C
      • Scores of symptoms and findings to determine disease severity (the Guideline Committee Proposal)
      • Scores for age
        • Age: a score of 0 or 3 is assigned.
          0: 24 months and older
          3: below the age of 24 months
      • Scores for clinical manifestations
        • Otalgia or ear pain: a score 0, 1, or 2 is assigned.
          0: no pain; 1: some pain; 2: long-lasting and severe pain
        • Fever (axillary temperature): a score 0, 1, or 2 is assigned.
          0: under 37.5 °Celsius (°C)
          1: 37.5 °C and higher but less than 38.5 °C
          2: 38.5 °C and higher.
        • Crying and/or irritability (bad temper): a score 0 or 1 is assigned.
          0: absent; 1: present
      • Scores for otoscopic findings
      • Redness (erythema, hyperemia): a score 0, 2, or 4 is assigned.
        0: absent,
        2: present along the manubrium of the malleus or limited to a part of the TM
        4: present over the whole TM
      • Bulging (protrusion): a score 0, 4, or 8 is assigned (typical otoscopic findings are shown in Fig. 5 [
        • Kamide Y.
        Classification of tympanic membrane findings on acute otitis media in children and their verification.
        ]).
        Fig. 5
        Fig. 5Bulging levels and scores
        [
        • Kamide Y.
        Classification of tympanic membrane findings on acute otitis media in children and their verification.
        ]
        .
        0: absent
        4: limited to a part of the TM
        8: involves the whole TM
      • Otorrhea: a score 0, 4, or 8 is assigned.
        0: absent
        4: present, but the TM is visible (a small amount)
        8: present, and the TM is obscured (a large amount)
      • Disease severity according to a total score
        • AOM severity is classified according to the total of the above scores, as follows,
          Mild: ≤ 5
          Moderate: 6–11
          Severe: ≥ 12
      A sample of the score chart used for assessing the severity of AOM in clinical practice is shown in Table 11.
      Table 11Scores of age, symptoms and findings to decide severities of AOM (2018).
      <Score chart>
      Age (below the age of 24 months?)0 (no)3 (yes)
      Otalgia or ear pain0 (no pain)1 (some pain)2 (long-lasting and severe pain)
      Fever (axillary temperature)0 (<37.5 °C)1 (37.5≤, <38.5 °C)2 (38.5 °C≤)
      Crying and/or irritability (bad temper)0 (absent)1 (present)
      Redness (erythema, hyperemia)0 (absent)2 (present along the manubrium of malleus or limited to a part of TM4 (present in the whole TM)
      Bulging (protrusion)0 (absent)4 (limited to a part of TM)8 (the whole TM)
      Otorrhea0 (absent)4 (present but tympanic membrane is visible (a small amount))8 (present and tympanic membrane is invisible (a large amount))
         * You can add a score for bulging of TM and that for otorrhea.
       Total score:
      <Assessment>
       Mild: ≤5,Moderate: 6 to11,Severe: ≥12
      Background:
      Clinicians should offer the appropriate management to the patients with a definite diagnosis of AOM, depending on the disease severity. Otoscopic findings and a younger age contribute markedly to the severity of AOM. Symptoms usually improve earlier than otoscopic findings [
      • Hotomi M.
      • Yamanaka N.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Factors associated with clinical outcomes in acute otitis media.
      ,
      • Hotomi M.
      • Yamanaka N.
      • Samukawa T.
      • Suzumot M.
      • Sakai A.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Treatment and outcome of severe and non-severe acute otitis media.
      ]; thus, precise otoscopic findings are more important for evaluating disease severity when choosing an appropriate treatment of AOM [
      • Friedman N.R.
      • McCormick D.P.
      • Pittman C.
      • Chonmaitree T.
      • Teichgraeber D.C.
      • Uchida T.
      • Baldwin C.D.
      • Saeed K.A.
      Development of a practical tool for assessing the severity of acute otitis media.
      ]. Because it has been reported that redness (erythema, hyperemia) alone is not a sufficient otoscopic finding for the diagnosis of AOM [
      • McConnochie K.M.
      Development of an algorithm for the diagnosis of otitis media.
      ,
      • Sibbald A.D.
      Acute otitis media in infants: the disease and the illness. Clinical distinctions for the new treatment paradigm.
      ], additional otoscopic findings of acute inflammation, such as bulging (protrusion), absence of landmarks, change in color, or decreased mobility of the TM are important for the diagnosis of AOM [

      Scottish Intercollegiate Guideline Network. Diagnosis and management of childhood otitis media in primary care Edinburgh, Scotland2000; Available from:www.sign.ac.uk/guidelines/fulltext/66/index.html.

      ].
      Since the 2013 version, the AAP Guidelines have changed, emphasizing the need for precise otoscopic findings. Their criteria for diagnosing AOM is either 1) moderate to severe bulging (protrusion) of the TM, or new onset of otorrhea not due to acute otitis externa, or 2) mild bulging (protrusion) of the TM and recent (less than 48 h) onset of ear pain (holding, tugging, or rubbing of the ear in a nonverbal child), or otalgia of acute onset with intense erythema of the TM. The need for antimicrobial prescription is decided according to age, whether bilateral or unilateral, and disease severity, based on the intensity and duration of otalgia, or the presence of high fever (39 °C or higher) [
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ].
      Every version of the AOM Guidelines in Japan has recommended disease severity-based management; precise otoscopic findings have priority when deciding on disease severity, followed by age and clinical manifestations. This also applies to deciding the optimal treatment choice for AOM, including myringotomy as a surgical intervention.
      The AAP and Japanese Guidelines have structural differences, but essentially follow the same principle when deciding on antimicrobial prescription according to the definite diagnosis of AOM based on a combination of patient age, clinical manifestations, and precise otoscopic findings.
      Aggregate evidence quality:
      • Benefits for children: Patients are easily and optimally managed for AOM according to the disease severity, based on objective assessment of the need for treatment.
      • Risks and harms for children: A patient with a diagnosis of mild AOM will not receive an antimicrobial agent for 3 days, and consequently, treatment could be delayed. There may still be unnecessary antimicrobial prescription, if patients with viral upper respiratory tract infection complains of unspecific otalgia not due to AOM.
      • Benefit–harms assessment: Benefits exceed harms for all patients because a definite diagnosis based on a combination of clinical manifestations and precise otoscopic findings could reduce unnecessary antimicrobial prescription and increase the opportunity for patients to undergo optimal treatment interventions for AOM.
      • Patient preference: N/A
      • Exclusions: none.
      Comments:
      In these Guidelines, patient age, clinical manifestations, and otoscopic findings are scored to assess the severity of AOM based on a total score of all these factors. Friedman et al. used a similar method; they assessed the severity of AOM by scores related to parent perception of the severity and the TM findings. They concluded that their scoring method was useful for an appropriate treatment choice [
      • Friedman N.R.
      • McCormick D.P.
      • Pittman C.
      • Chonmaitree T.
      • Teichgraeber D.C.
      • Uchida T.
      • Baldwin C.D.
      • Saeed K.A.
      Development of a practical tool for assessing the severity of acute otitis media.
      ]. Casey et al. also assessed the severity of AOM by using a scoring system for the diagnosis and evaluation of treatment efficacy. They scored clinical manifestations (otalgia and irritability of patients), otoscopic findings, and fever [
      • Casey J.R.
      • Block S.
      • Puthoor P.
      • Hedrick J.
      • Almudevar A.
      • Pichichero M.E.
      A simple scoring system to improve clinical assessment of acute otitis media.
      ].
      In the first Guidelines in Japan, issued in 2006, the Committee chose redness (erythema, hyperemia), bulging (protrusion), and otorrhea as scorable items. These items, and each score for this scoring system, were decided by the Delphi method. It is sometimes difficult to measure clinical manifestations in young children because clinicians can only assess these from their behavior and/or physical responses [
      • McConnochie K.M.
      Development of an algorithm for the diagnosis of otitis media.
      ]. There is a guideline that advocates that clinicians should not make a diagnosis of AOM based only on fever, otalgia, and irritability; however, a diagnosis can be made if it is based on intense otalgia and/or irritability with a duration of 24 h [
      • Lee H.J.
      • Park S.K.
      • Choi K.Y.
      • Park S.E.
      • Chun Y.M.
      • Kim K.S.
      • Park S.N.
      • Cho Y.S.
      • Kim Y.J.
      • Kim H.J.
      • Korean Otologic S.
      Korean clinical practice guidelines: otitis media in children.
      ].
      Kaleida et al. set a cutoff point for fever in mild and severe AOM as 39.0 °C (oral) and 39.5 °C (rectal) [
      • Kaleida P.H.
      • Casselbrant M.L.
      • Rockette H.E.
      • Paradise J.L.
      • Bluestone C.D.
      • Blatter M.M.
      • Reisinger K.S.
      • Wald E.R.
      • Supance J.S.
      Amoxicillin or myringotomy or both for acute otitis media: results of a randomized clinical trial.
      ]. In Japan, a patient's temperature is usually determined by axillary measurement. The Guideline Committee in Japan determined the criteria for mild, moderate, and severe fever as under 37.5 °C (axillary), 37.5 °C and higher but under 38.5 °C, and 38.5 °C and higher, respectively, by the Delphi method. In the process of diagnosis, fever is an essential symptom and a sign of acute febrile illnesses, including AOM, although it is thought by some that fever may not contribute much to disease severity. After intensive discussions, fever was chosen as a scoring item since the first version of the Guidelines in Japan. Casey et al. used the presence and level of fever in their scoring system in a study on the clinical assessment of AOM [
      • Casey J.R.
      • Block S.
      • Puthoor P.
      • Hedrick J.
      • Almudevar A.
      • Pichichero M.E.
      A simple scoring system to improve clinical assessment of acute otitis media.
      ]. However, it has been reported that 23% of patients with AOM have fever, and only 0.3% have a fever of 40.5 °C and over [
      • Lee H.
      • Kim J.
      • Nguyen V.
      Ear infections: otitis externa and otitis media.
      ]. On the other hand, it is also thought by some that fever of 38 °C and higher is related to the severity of AOM [
      • Lee H.J.
      • Park S.K.
      • Choi K.Y.
      • Park S.E.
      • Chun Y.M.
      • Kim K.S.
      • Park S.N.
      • Cho Y.S.
      • Kim Y.J.
      • Kim H.J.
      • Korean Otologic S.
      Korean clinical practice guidelines: otitis media in children.
      ]. Thus, it remains controversial whether fever should be included among the items for classifying disease severity.
      Younger age is a risk factor for aggravating and/or prolonging AOM [
      • Hotomi M.
      • Yamanaka N.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Factors associated with clinical outcomes in acute otitis media.
      ,
      • Rovers M.M.
      • Schilder A.G.
      • Zielhuis G.A.
      • Rosenfeld R.M.
      Otitis media.
      ,
      • Block S.L.
      • Kratzer J.
      • Nemeth M.A.
      • Tack K.J.
      Five-day cefdinir course vs. ten-day cefprozil course for treatment of acute otitis media.
      ,
      • Ovetchkine P.
      • Cohen R.
      Shortened course of antibacterial therapy for acute otitis media.
      ]. The Guideline Committee has adopted the < 24-months-old group as a high-risk group for the scoring system since the second version of the Guidelines in Japan, issued in 2009 [
      • Rovers M.M.
      • Schilder A.G.
      • Zielhuis G.A.
      • Rosenfeld R.M.
      Otitis media.
      ,
      • Block S.L.
      • Kratzer J.
      • Nemeth M.A.
      • Tack K.J.
      Five-day cefdinir course vs. ten-day cefprozil course for treatment of acute otitis media.
      ,
      • Ovetchkine P.
      • Cohen R.
      Shortened course of antibacterial therapy for acute otitis media.
      ,
      • Rovers M.M.
      • Glasziou P.
      • Appelman C.L.
      • Burke P.
      • McCormick D.P.
      • Damoiseaux R.A.
      • Little P.
      • Le Saux N.
      • Hoes A.W.
      Predictors of pain and/or fever at 3 to 7 days for children with acute otitis media not treated initially with antibiotics: a meta-analysis of individual patient data.
      ].
      It has been reported that bilateral AOM has a higher risk of longer persistence of disease than unilateral AOM, and bilateral vs. unilateral AOM has a more significant difference in terms of risk than the age factor [
      • Suzuki C.
      • Yamanaka N.
      Is bilateral acute otitis media clinically more refractory than unilateral acute otitis media?.
      ].
      The efficacy of the treatment based on severity has been reported by Uno et al. [
      • Uno Y.
      • Kudo F.
      Verification of clinical practice guidelines for the diagnosis and management of pediatric acute otitis media in Japan-2013 update.
      ]. They treated 735 AOM children according to the scoring system described in the third edition of the guidelines issued in 2013, which is almost the same that in the latest version. They reported that the treatment success rate was 98.3% in the mild, 86.8% in the moderate, and 71.4% in the severe disease group, and 84.5% overall. They mentioned that standardized criteria of treatment efficacy are needed to evaluate treatment.
      CQ1-5: Under what conditions is recurrent AOM diagnosed?
      Recommendation:
      Recurrent AOM is defined as three or more episodes of AOM in the previous 6 months, or four or more episodes of AOM in the previous 12 months.
      • Recommendation Strength: Recommendation, Evidence Quality: C
      Background:
      Recurrent AOM is a pathological condition of several repeated AOM episodes over a certain period of time. Although the definition has not been standardized globally yet, the Guideline Committee of Japan has adopted “three or more episodes of AOM in the previous 6 months, or four or more episodes in the previous 12 months” as the definition of recurrent AOM, referring to the proposals in previous publications. An insufficient immune response in the patients has been regarded as a causative factor of recurrent AOM. The immune system of infants is still under development, implying that the specific immune response to the causative pathogens is premature, and therefore infants easily suffer from recurrent AOM.
      Aggregate evidence quality:
      • Benefits for children: Because recurrence of AOM with more than a certain number of times is a predictive factor of further recurrences, patients can undergo appropriate management based on the appropriate diagnosis of recurrent AOM.
      • Risks and harms for children: None.
      • Benefit–harms assessment: Benefits exceed harms for all patients, because the diagnosis of recurrent AOM can offer standard treatment, preventing unnecessary and/or excessive treatment, and can promote optimal management.
      • Patient preference: N/A
      • Exclusions: None
      Comments:
      Recurrent otitis media is a disease concept proposed by Howie in 1975, and it is a pathological condition of repeated AOM episodes (Howie et al. 1975). Most of the following reports have focused on the number of recurrences, and can be classified into two types: 1) a definition based on the number of AOM recurrences up to a certain age, and 2) a definition based of the number of AOM recurrences within a certain period of time.

      17.1.1 The definition based on the number of AOM recurrences up to a certain age

      Howie et al. defined recurrent AOM as “six or more episodes of AOM before 6 months old” [
      • Howie V.M.
      • Ploussard J.H.
      • Sloyer J.
      The "otitis-prone" condition.
      ]. Alho et al. defined recurrent AOM as “four or more episodes of AOM before 9 months old” [
      • Alho O.P.
      • Koivu M.
      • Sorri M.
      What is an 'otitis-prone' child?.
      ]. Yamanaka et al. first defined recurrent AOM as “four or more episodes of AOM before 1 year old, or six or more episodes of AOM before 2 years old” [
      • Harimaya A.
      • Takada R.
      • Somekawa Y.
      • Fujii N.
      • Himi T.
      High frequency of alloiococcus otitidis in the nasopharynx and in the middle ear cavity of otitis-prone children.
      ,
      • Yamanaka N.
      • Faden H.
      Antibody response to outer membrane protein of nontypeable Haemophilus influenzae in otitis-prone children.
      ,
      • Yokota S.
      • Harimaya A.
      • Sato K.
      • Somekawa Y.
      • Himi T.
      • Fujii N.
      Colonization and turnover of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in otitis-prone children.
      ]. They later changed the definition to “five or more episodes of AOM before 2 years old, or six or more episodes of AOM before 6 months old, or five or more episodes of AOM in a year” [
      • Hotomi M.
      • Yamanaka N.
      • Saito T.
      • Shimada J.
      • Suzumoto M.
      • Suetake M.
      • Faden H.
      Antibody responses to the outer membrane protein P6 of non-typeable Haemophilus influenzae and pneumococcal capsular polysaccharides in otitis-prone children.
      ].

      17.1.2 The definition based on the number of AOM recurrences within a certain period of time

      Klein et al. defined recurrent AOM as “three or more episodes of AOM within 6 months, or four or more episodes of AOM in a year” [
      • Klein J.O.
      Antimicrobial prophylaxis for recurrent acute otitis media.
      ]. The definition by Harsten et al. was “six or more episodes of AOM in a year” [
      • Harsten G.
      • Prellner K.
      • Heldrup J.
      • Kalm O.
      • Kornfalt R.
      Recurrent acute otitis media. A prospective study of children during the first three years of life.
      ]. Goycoolea et al. added the following criteria to the same definition as that used by Kline et al.: “Acute inflammation has to be resolved between each episode” [
      • Goycoolea M.V.
      • Hueb M.M.
      • Ruah C.
      Otitis media: the pathogenesis approach. Definitions and terminology.
      ]. A Cochrane review has also adopted this definition [
      • McDonald S.
      • Langton Hewer C.D.
      • Nunez D.A.
      Grommets (ventilation tubes) for recurrent acute otitis media in children.
      ]. Furthermore, most authors utilized the definition of “three or more episodes of AOM within 6 months, or four or more episodes of AOM in a year” [
      • Ren D.
      • Murphy T.F.
      • Lafontaine E.R.
      • Pichichero M.E.
      Stringently Defined Otitis Prone Children Demonstrate Deficient Naturally Induced Mucosal Antibody Response to Moraxella catarrhalis Proteins.
      ,
      • Kirkham L.S.
      • Wiertsema S.P.
      • Corscadden K.J.
      • Mateus T.
      • Mullaney G.L.
      • Zhang G.
      • Richmond P.C.
      • Thornton R.B.
      Otitis-prone children produce functional antibodies to pneumolysin and pneumococcal polysaccharides.
      ,
      • Ito M.
      • Maruyama Y.
      • Kitamura K.
      • Kobayashi T.
      • Takahashi H.
      • Yamanaka N.
      • Harabuchi Y.
      • Origasa H.
      • Yoshizaki T.
      Randomized controlled trial of juzen-taiho-to in children with recurrent acute otitis media.
      ,
      • Maruyama Y.
      • Hoshida S.
      • Furukawa M.
      • Ito M.
      Effects of Japanese herbal medicine, Juzen-taiho-to, in otitis-prone children–a preliminary study.
      ,
      • Sher L.
      • Arguedas A.
      • Husseman M.
      • Pichichero M.
      • Hamed K.A.
      • Biswas D.
      • Pierce P.
      • Echols R.
      Randomized, investigator-blinded, multicenter, comparative study of gatifloxacin versus amoxicillin/clavulanate in recurrent otitis media and acute otitis media treatment failure in children.
      ,
      • Ables A.Z.
      • Warren P.K.
      High-dose azithromycin or amoxicillin-clavulanate for recurrent otitis media?.
      ,
      • Arrieta A.
      • Singh J.
      Management of recurrent and persistent acute otitis media: new options with familiar antibiotics.
      ,
      • Pichichero M.E.
      Ten-year study of the stringently defined otitis-prone child in Rochester, NY.
      ].
      Fifty to seventy percent of children experience their first episode of AOM before the age of 3 years. Moreover, most children experience at least one episode of AOM in the first 2 years of life, and 30–40% of them experience three or more episodes of AOM before 3 years of age [
      • Teele D.W.
      • Klein J.O.
      • Rosner B.
      Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study.
      ,
      • O'Neill P.
      • Roberts T.
      • Bradley Stevenson C.
      Otitis media in children (acute).
      ,
      • Froom J.
      • Culpepper L.
      • Jacobs M.
      • DeMelker R.A.
      • Green L.A.
      • van Buchem L.
      • Grob P.
      • Heeren T.
      Antimicrobials for acute otitis media? A review from the International Primary Care Network.
      ]. The age at the first episode of AOM is considered to be particularly important, as it is related to a predisposition to recurrent AOM. If children suffer from AOM within the first 12 months since birth, the likelihood of AOM occurring increases. Furthermore, it has become evident that children are more likely to have recurrent episodes of AOM if they suffered from AOM within the first 6 months since birth. The incidence of AOM recurrence before 2 years of age has been recognized as indicating a predisposition to susceptibility to recurrent AOM.
      An impaired immune response of the patient to the pathogens is considered to play a causal role in recurrent AOM [
      • Yamanaka N.
      • Faden H.
      Antibody response to outer membrane protein of nontypeable Haemophilus influenzae in otitis-prone children.
      ,
      • Hotomi M.
      • Yamanaka N.
      • Saito T.
      • Shimada J.
      • Suzumoto M.
      • Suetake M.
      • Faden H.
      Antibody responses to the outer membrane protein P6 of non-typeable Haemophilus influenzae and pneumococcal capsular polysaccharides in otitis-prone children.
      ]. Infants easily suffer from recurrent AOM because their immune systems are still developing; therefore, a specific immune response to the causative pathogen is premature. Measurement of the IgG2 subclass level, available as a standard laboratory test, offers useful information for understanding immunological issues in the patient with recurrent AOM (see “CQ3-11”).
      Referring to the proposals in prior publications, we have defined recurrent AOM as “three or more episodes of AOM in the previous 6 months, or four or more episodes of AOM in the previous 12 months.”
      NOTE: Immunoglobulin administration for patients with low serum IgG2, who suffer from recurrent AOM caused by S. pneumoniae or H. influenzae, has been covered by the National Health Insurance System of Japan since 2016. The attached document (package insert) states that four or more episodes of AOM is requisite for immunoglobulin administration. Therefore, it is necessary to pay attention to differences in the definitions of recurrent AOM between the attached document and the Guidelines (see CQ3-11 for more details).

      17.2 Prevention

      CQ2-1: Are pneumococcal conjugate vaccines (PCVs) effective in preventing pediatric AOM?
      Recommendation:
      PCVs are effective in preventing pediatric AOM.
      • Recommendation Strength: Recommendation, Evidence Quality: B
      Background
      PCVs are recommended for the prevention of pediatric AOM because there have been some reports indicating not only their preventative effects for AOM and recurrent AOM, but also their cost-effectiveness.
      On the other hand, the limitations of PCVs in terms of prophylactic effects, such as an increase in AOM caused by non-vaccine serotypes of S. pneumoniae and H. influenzae, have been pointed out.
      Aggregate evidence quality:
      • Benefits for patients: Patients can receive marked benefits from PCVs because they could prevent AOM caused by vaccine serotypes of S. pneumoniae, improve disease severity, and decrease AOM recurrence, etc.
      • Risks and harms for children: Potential adverse reactions associated with vaccination.
      • Benefit–harms assessment: Benefits exceed harms because there have been no reports of serious adverse reactions, and PVCs are cost-effective.
      • Patient preference: Take parents or guardians’ preferences into consideration when making a vaccine decision.
      • Exceptions: Do not inoculate if there is a known history of anaphylaxis caused by vaccine components or diphtheria toxoid.
      Comments:
      The preventive efficacies of 7-valent PCV (PCV7) on AOM has been studied in large-scale clinical studies. As the overall prevention of AOM by PCV7 was 6–7% [
      • Black S.
      • Shinefield H.
      • Fireman B.
      • Lewis E.
      • Ray P.
      • Hansen J.R.
      • Elvin L.
      • Ensor K.M.
      • Hackell J.
      • Siber G.
      • Malinoski F.
      • Madore D.
      • Chang I.
      • Kohberger R.
      • Watson W.
      • Austrian R.
      • Edwards K.
      Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group.
      ,
      • Eskola J.
      • Kilpi T.
      • Palmu A.
      • Jokinen J.
      • Haapakoski J.
      • Herva E.
      • Takala A.
      • Kayhty H.
      • Karma P.
      • Kohberger R.
      • Siber G.
      • Makela P.H.
      • Finnish Otitis Media Study G.
      Efficacy of a pneumococcal conjugate vaccine against acute otitis media.
      ,
      • Fireman B.
      • Black S.B.
      • Shinefield H.R.
      • Lee J.
      • Lewis E.
      • Ray P.
      Impact of the pneumococcal conjugate vaccine on otitis media.
      ], a Cochrane review in 2004 suggested that the efficacy of PCV7 for prevention of AOM was not sufficient and did not recommend PCV7 for preventing AOM [
      • Straetemans M.
      • Sanders E.A.
      • Veenhoven R.H.
      • Schilder A.G.
      • Damoiseaux R.A.
      • Zielhuis G.A.
      Pneumococcal vaccines for preventing otitis media.
      ]. Subsequently, in addition to previous large-scale clinical studies on the effectiveness of preventing AOM, there have been some clinical studies with high-quality evidence that proved the cost-effectiveness of PCVs [
      • Palmu A.A.
      • Saukkoriipi A.
      • Jokinen J.
      • Leinonen M.
      • Kilpi T.M.
      Efficacy of pneumococcal conjugate vaccine against PCR-positive acute otitis media.
      ,
      • Jansen A.G.
      • Sanders E.A.
      • Hoes A.W.
      • van Loon A.M.
      • Hak E.
      Effects of influenza plus pneumococcal conjugate vaccination versus influenza vaccination alone in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled trial.
      ,
      • Dinleyici E.C.
      Current status of pneumococcal vaccines: lessons to be learned and new insights.
      ,
      • Gisselsson-Solen M.
      • Melhus A.
      • Hermansson A.
      Pneumococcal vaccination in children at risk of developing recurrent acute otitis media - a randomized study.
      ,
      • Boonacker C.W.
      • Broos P.H.
      • Sanders E.A.
      • Schilder A.G.
      • Rovers M.M.
      Cost effectiveness of pneumococcal conjugate vaccination against acute otitis media in children: a review.
      ,
      • Tyo K.R.
      • Rosen M.M.
      • Zeng W.
      • Yap M.
      • Pwee K.H.
      • Ang L.W.
      • Shepard D.S.
      Cost-effectiveness of conjugate pneumococcal vaccination in Singapore: comparing estimates for 7-valent, 10-valent, and 13-valent vaccines.
      ]. Although there are some limitations, such as the incidence of mastoiditis, the number of mastoiditis cases caused by S. pneumoniae has not changed even after the introduction of PCV7 [
      • Kordeluk S.
      • Orgad R.
      • Kraus M.
      • Puterman M.
      • Kaplan D.M.
      • Novak L.
      • Dagan R.
      • Leibovitz E.
      Acute mastoiditis in children under 15 years of age in Southern Israel following the introduction of pneumococcal conjugate vaccines: a 4-year retrospective study (2009-2012).
      ]. The AOM guidelines from the US, revised in 2013 (AAP Guideline 2013), strongly recommends pneumococcal vaccination for all children [
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ]. In addition, according to the Cochrane review in 2014, although PCV7 has a low preventive efficacy in young children with a high risk of developing AOM and in children with a history of AOM, PCV7 has preventive efficacy for generally healthy children with a low risk of developing AOM [
      • Fortanier A.C.
      • Venekamp R.P.
      • Boonacker C.W.
      • Hak E.
      • Schilder A.G.
      • Sanders E.A.
      • Damoiseaux R.A.
      Pneumococcal conjugate vaccines for preventing otitis media.
      ].
      A drawback of PCV7 has been pointed out: there has been an increase in non-vaccine pneumococcal serotypes (19A and 16A) and H. influenza [
      • Taylor S.
      • Marchisio P.
      • Vergison A.
      • Harriague J.
      • Hausdorff W.P.
      • Haggard M.
      Impact of pneumococcal conjugate vaccination on otitis media: a systematic review.
      ,
      • Pichichero M.E.
      • Casey J.R.
      Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children.
      ]. To solve the problems associated with PCV7, the pneumococcal vaccine was changed from PCV7 to PCV13 (13-valent PCV). However, the preventive effect of PCV13 against AOM has not yet been fully established and required further study.
      The serotype coverage of PCV7 for pneumococci isolated from children with AOM in Japan was 60.6%, covering 87.0% of antimicrobial-resistant pneumococci [
      • Otsuka T.
      • Kitami O.
      • Kondo K.
      • Ota H.
      • Oshima S.
      • Tsuchiya A.
      • Shirai T.
      • Fujii K.
      • Nakamure M.
      • Shoji Y.
      • Nakamura H.
      • Masuda Y.
      • Komiyama K.
      • Yoshida K.
      • Ishikawa Y.
      • Iwaya A.
      • Takahashi S.
      • Okazaki M.
      • Hotomi M.
      • Yamanaka N.
      Incidence survey of acute otitis media in children in Sado Island, Japan–Sado Otitis Media Study (SADOMS).
      ,
      • Hotomi M.
      • Billal D.S.
      • Kamide Y.
      • Kanesada K.
      • Uno Y.
      • Kudo F.
      • Ito M.
      • Kakehata S.
      • Sugita R.
      • Ogami M.
      • Yamanaka N.
      G. Advanced Treatment for Otitis Media Study, Serotype distribution and penicillin resistance of Streptococcus pneumoniae isolates from middle ear fluids of pediatric patients with acute otitis media in Japan.
      ]. The preventive efficacy of PCV7 for AOM was estimated to be 7.4–9.1% for AOM as a whole, 33.1–41.0% of AOM caused by S. pneumoniae, and 40.1–49.4% of AOM caused by antimicrobial-resistant pneumococci. It was concluded that PCV7 was effective in suppressing the intractability of AOM [
      • Yamanaka N.
      • Htomi M.
      • Sugita R.
      Disease burden of acute pneumococcal otitis media in children and cost-effectoveness of 7-valent pneumococcal conjugate vaccine for children.
      ]. Furthermore, some reports demonstrated that the number of cases that required myringotomy in children ≤ 5 years old was reduced, and suggested that PCVs could prevent AOM in children under 1 year of age, the age group in which AOM is likely to become intractable [
      • Sugino H.
      • Tsumura S.
      • Kunimoto M.
      • Noda M.
      • Chikuie D.
      • Noda C.
      • Yamashita M.
      • Watanabe H.
      • Ishii H.
      • Tashiro T.
      • Iwata K.
      • Kono T.
      • Tsumura K.
      • Sumiya T.
      • Takeno S.
      • Hirakawa K.
      Influence of pneumococcal conjugate vaccine on acute otitis media with severe middle ear inflammation: a retrospective multicenter study.
      ,
      • Sasaki A.
      • Kunimoto M.
      • Takeno S.
      • Sumiya T.
      • Ishino T.
      • Sugino H.
      • Hirakawa K.
      Influence of pneumococcal conjugate vaccines on acute otitis media in Japan.
      ].
      NOTE: In Japan, voluntary vaccination by PCV7 (including serotypes 4, 6B, 9 V, 14, 18C, 19F, and 23F) started in February 2002, and public subsidies have expanded since February 2011. Routine vaccination by PCV7 became possible in April 2013. In November 2013, this was switched to PCV13 (including 1, 3, 5, 6A, 7F, and 19A in addition to the PCV7 serotypes).

      17.3 Treatment

      In the 2018 Guidelines, final treatment outcomes are assessed at 3 weeks after the onset, based on improvement of otoscopic findings (redness [erythema, hyperemia], bulging [protrusion], thickening, bullous formations, cloudy TM [dull or opaque], MEE, and otorrhea). AOM is judged as completely cured if both the scores for the clinical manifestations and otoscopic findings are 0.
      When patients have already undergone treatment by antimicrobial agents before visits, clinicians should evaluate the current disease severity (mild, moderate, or severe) from the otoscopic examinations. After the previous antimicrobial agents are taken into account, clinicians can apply the appropriate algorithm in the 2018 Guidelines.
      CQ 3–1: Which antimicrobial agents are appropriate for treating AOM children?
      Recommendation:
      AMPC or CVA/AMPC is recommended as the first-line antimicrobial agent, depending on disease severity. Cefditoren pivoxil (CDTR-PI), tosufloxacin (TFLX), and tebipenem pivoxil (TBPM-PI) are recommended as the second- or third-line oral antimicrobial agents, and ampicillin (ABPC) and ceftriaxone (CTRX) are recommended as parenteral antimicrobial agents, according to the causative pathogens and disease severity.
      • Recommendation Strength: Recommendation, Evidence Quality: B
      Background:
      AMPC and CVA/AMPC are recommended as the first-line antimicrobial agents, based on the recent bacteriological background in Japan, and the clinical efficacy of these antimicrobial agents in AOM treatment and the susceptibility of the two major pathogens, S. pneumoniae and H. influenzae. In terms of the bacteriological background in Japan, the rates of PRSP and BLNAR in 2012 were 12.3% and 35.8%, respectively [
      • Suzuki K.
      • Kurono Y.
      • Ikeda K.
      • Watanabe A.
      • Hanaki H.
      The fifth nationwide surveillance of clinical isolate from patients with otolaryngological field infections.
      ]. Clinicians should choose the optimal antimicrobial agents among those recommended above, depending on the causative pathogens and disease severity. This does not mean that other antimicrobial agents are not recommended, but rather that the above antimicrobial agents are recommended in consideration of the current antimicrobial susceptibility profile in Japan.
      Aggregate evidence quality:
      • Benefits for children: Appropriate antimicrobial administration is likely to provide more rapid treatment success for the present patient, and is likely to provide benefits to patients in future by minimizing the increase in antimicrobial-resistant pathogens.
      • Risks and harms for children: Antimicrobial administration can increase the risk of gastrointestinal adverse effects, such as diarrhea. All antimicrobial agents can be the cause of an increase in antimicrobial-resistant bacteria.
      • Benefit–harms assessment: Benefits exceed harms because the recommended antimicrobial agents have been selected based on major causative pathogens and the high prevalence of antimicrobial resistance in Japan.
      • Patient preference: N/A
      • Exclusions: Do not administer antimicrobial agents to cases with a history of allergies to them.
      Comments:

      17.3.1 Efficacy of antimicrobial treatment for pediatric AOM

      The validity of antimicrobial treatment and the efficacy of AMPC and/or CVA/AMPC for pediatric AOM were again emphasized by the results of two large RCTs reported in 2011. Tähtinen et al. performed a randomized, double-blind, placebo-controlled study on CVA/AMPC versus placebo. They reported that CVA/AMPC reduced the progression to treatment failure by 62% (hazard ratio, 0.38; 95% confidence interval [CI], 0.25–0.59; P < 0.001) and the need for rescue treatment by 81% (hazard ratio, 0.19; 95% CI, 0.10–0.36; P < 0.001) compared with the placebo group [
      • Tähtinen P.A.
      • Laine M.K.
      • Huovinen P.
      • Jalava J.
      • Ruuskanen O.
      • Ruohola A.
      A placebo-controlled trial of antimicrobial treatment for acute otitis media.
      ]. Hoberman et al. also conducted an RCT on CVA/AMPC versus placebo, in which 291 patients from 6 to 23 months of age were studied. CVA/AMPC treatment for 10 days shortened the time to resolution of symptoms as well as the time to residual abnormal otoscopic findings [
      • Hoberman A.
      • Paradise J.L.
      • Rockette H.E.
      • Shaikh N.
      • Wald E.R.
      • Kearney D.H.
      • Colborn D.K.
      • Kurs-Lasky M.
      • Bhatnagar S.
      • Haralam M.A.
      • Zoffel L.M.
      • Jenkins C.
      • Pope M.A.
      • Balentine T.L.
      • Barbadora K.A.
      Treatment of acute otitis media in children under 2 years of age.
      ]. Following these large clinical studies, a Cochrane review, including data from 13 RCTs (3401 children and 3938 episodes), concluded that antimicrobial agents had a modest benefit for abnormal tympanometry findings, perforation of the TM, and occurrence of contralateral AOM. However, antimicrobial agents had no effect on early pain relief and recurrence of AOM as compared with placebo. Additionally, they caused more adverse events (such as vomiting or diarrhea) than placebo. The systematic review suggested that antimicrobial agents were most beneficial in children younger than 2 years old with bilateral AOM and in AOM children with otorrhea. They also concluded that expectant observation (an observational approach in which prescriptions may or may not be provided) for children with mild AOM seemed justified [
      • Venekamp R.P.
      • Sanders S.L.
      • Glasziou P.P.
      • Del Mar C.B.
      • Rovers M.M.
      Antibiotics for acute otitis media in children.
      ].

      17.3.2 Appropriate first-line antimicrobial agents for pediatric AOM

      AMPC or CVA/AMPC is recommended as first-line antibiotics. The AAP Guideline revised in 2013 also recommended AMPC as the first-line antimicrobial agent [
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ]. Furthermore, guidelines from other countries adopted AMPC as the first-line antimicrobial treatment [
      • Ovnat Tamir S.
      • Shemesh S.
      • Oron Y.
      • Marom T.
      Acute otitis media guidelines in selected developed and developing countries: uniformity and diversity.
      ]. A prospective clinical study from Japan also reported the good clinical effects of AMPC [
      • Hotomi M.
      • Yamanaka N.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Factors associated with clinical outcomes in acute otitis media.
      ,
      • Hotomi M.
      • Yamanaka N.
      • Samukawa T.
      • Suzumot M.
      • Sakai A.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Treatment and outcome of severe and non-severe acute otitis media.
      ,
      • Harabuchi Y.
      • Kodama H.
      • Faden H.
      Outcome of acute otitis media and its relation to clinical features and nasopharyngeal colonization at the time of diagnosis.
      ].
      Wald et al. used the regular dose (45 mg/kg/day) of AMPC as the initial prescription [
      • Wald E.R.
      • DeMuri G.P.
      Commentary: Antibiotic recommendations for acute otitis media and acute bacterial sinusitis in 2013–the conundrum.
      ]. On the other hand, a prospective study by Piglansky et al. revealed the effectiveness of high-dose AMPC (80 mg/kg/day for 10 days) as the initial therapy [
      • Piglansky L.
      • Leibovitz E.
      • Raiz S.
      • Greenberg D.
      • Press J.
      • Leiberman A.
      • Dagan R.
      Bacteriologic and clinical efficacy of high dose amoxicillin for therapy of acute otitis media in children.
      ]. A multicenter RCT on the eradication rate of S. pneumoniae and H. influenzae revealed the effectiveness of high-dose CVA/AMPC (6.4/90 mg/kg/day for 10 days) [
      • Dagan R.
      • Hoberman A.
      • Johnson C.
      • Leibovitz E.L.
      • Arguedas A.
      • Rose F.V.
      • Wynne B.R.
      • Jacobs M.R.
      Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media.
      ].
      Damrikarnlert et al. compared two and three divided doses of CVA/AMPC per day and have reported that there was no significant difference between these two groups in terms of their efficacy [
      • Damrikarnlert L.
      • Jauregui A.C.
      • Kzadri M.
      Efficacy and safety of amoxycillin/clavulanate (Augmentin) twice daily versus three times daily in the treatment of acute otitis media in children. The Augmentin 454 Study Group.
      ].

      17.3.3 Efficacy of other antimicrobial agents for pediatric AOM (CDTR-PI)

      There have been a limited number of large clinical trials on the effects of ß-lactam antimicrobial agents, other than AMPC and CVA/AMPC. Against the recent bacteriological background in Japan (Fig. 3), where ampicillin-resistant strains of H. influenzae (BLNAR and/or BLPACR) are frequently isolated as causative pathogens of AOM in children, clinicians should use the antimicrobial agents for which H. influenzae shows sufficient susceptibility, and need to prepare second-line antimicrobial agents in the case of treatment failure after the first-line antimicrobial therapy. CDTR-PI is the better candidate treatment in these cases, because CDTR-PI has a better MIC than cefcapene pivoxil even though both are third generation cephalosporins to which H. influenzae demonstrates good susceptibility (Table 6). Hotomi et al. reported on prospective trials with good treatment outcomes when AMPC was prescribed as the first-line therapy, followed by CDTR-PI [
      • Hotomi M.
      • Yamanaka N.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Factors associated with clinical outcomes in acute otitis media.
      ,
      • Hotomi M.
      • Yamanaka N.
      • Samukawa T.
      • Suzumot M.
      • Sakai A.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Treatment and outcome of severe and non-severe acute otitis media.
      ].
      On the other hand, the poor tissue penetration ability is a known drawback of third-generation cephalosporins. However, a high-dose application can improve the penetration ability, and result in good clinical effects in patients with pediatric AOM [
      • Ito M.
      • Yoshizaki T.
      • Nishimura T.
      • Yamazaki Y.
      • Uramoto N.
      • Sakunaka K.
      • Himi Y.
      • Furukawa M.
      Therapeuutic and bacterial effect of CDTR-PI to acute otitis media.
      ,
      • Miyamoto N.
      • Suzuki M.
      • Murakami S.
      A comparative study of effectiveness of tebipenem pivoxil and high-dose cefditren pivoxil for the treatment of intractable acute otitis media in children.
      ]. High-dose CDTR-PI was used as a control in a non-inferiority trial of TBPM-PI, to which pathogens causing pediatric AOM are known to have marked susceptibility [
      • Suzuki K.
      • Baba S.
      • Totsuka K.
      • Hori S.
      • Ubukata K.
      • Nakashima M.
      • Sunakawa K.
      Double-blind comparative study of tebipenem pivoxil and high-dose cefditoren pivoxil in children with acute otitis media (Phase III).
      ].
      Based on the bacterial susceptibility profile background in Japan, CDTR-PI is recommended as an optimal treatment option in the 2018 Guidelines.

      17.3.4 Efficacy of other antimicrobial agents for pediatric AOM

      TFLX is the only quinolone-class antimicrobial agent that has been approved as safe in children. Furthermore, it has been shown not only to possess excellent pharmacokinetic and pharmacodynamic features, but also demonstrated good clinical effects in some trials [
      • Kobayashi T.
      • Baba S.
      • Suzuki K.
      • Shimada J.
      • Soyano K.
      • Maruo T.
      • Ito H.
      Laboratory and clinical studies on T-3262 in otorhinolaryngological infections.
      ]. High cure rates for AOM in children were also reported for TFLX [
      • Suzuki K.
      • Iino Y.
      • Kudo F.
      • Taiji H.
      • Sunakawa K.
      An uncontrolled, open label study of tosufloxacin granules 10% in pediatric acute otitis media (AOM).
      ,
      • Yamanaka N.
      • Sugita R.
      • Uno Y.
      • Matsubara S.
      • Hayashi Y.
      • Sawada S.
      Clinical efficacy of tosufloxacin tosilate hydrate for the treatment of acute otitis media in children.
      ].
      TBPM-PI is the only oral carbapenem-class antimicrobial agent with both broad-spectrum and strong bactericidal activity comparable with that of the parenteral carbapenems. It has been reported that TBPM-PI has good tissue penetration ability into the middle ear [
      • Baba S.
      • Kasahara H.
      • Morita J.
      • Aizawa K.
      • Sunakawa K.
      Tissue and aural discharge distribution of tebipenem pivoxil.
      ]. An RCT indicated that TBPM-PI had effects comparable with those of high-dose CDTR-PI [
      • Suzuki K.
      • Baba S.
      • Totsuka K.
      • Hori S.
      • Ubukata K.
      • Nakashima M.
      • Sunakawa K.
      Double-blind comparative study of tebipenem pivoxil and high-dose cefditoren pivoxil in children with acute otitis media (Phase III).
      ], and a multicenter clinical trial has shown excellent clinical efficacy of TBPM-PI against not only AOM, but against recurrent AOM and other intractable AOM [
      • Yamanaka N.
      • Suetake M.
      • Tomiyama M.
      • Sugita R.
      • Matsubara S.
      • Sawada S.
      • Uno Y.
      • Kanesada K.
      • Uchizono A.
      Efficacy evaluation of TBPM-PI, an oral carbapenem anticacterial agent, in children with acute otitis media including recurrent/persistent cases.
      ]. Faster improvement of otoscopic findings were reported in patients treated with high-dose TBPM-PI (12 mg/kg/day in two divided doses) than with low-dose TBPM-PI (8 mg/kg/day in two divided doses). Moreover, high-dose TBPM-PI shortened the period of time required for treatment [
      • Sawada S.
      Comparative effectiveness of high dose versus standard dose of Tebipenem-Pivoxil (TBPM-PI) in intractable acute otitis media in children.
      ].
      Nevertheless, it is important that clinicians should limit prescription of TFLX and TBPM-PI only to patients in which other oral antimicrobial agents have failed.

      17.3.5 Efficacy of parenteral antimicrobial agents for pediatric AOM

      It has been reported that the clinical effect of intravenous application of CTRX once a day was comparable to that of CVA/AMPC (AMPC 40 mg/kg/day) for 10 days [
      • Wang C.Y.
      • Lu C.Y.
      • Hsieh Y.C.
      • Lee C.Y.
      • Huang L.M.
      Intramuscular ceftriaxone in comparison with oral amoxicillin-clavulanate for the treatment of acute otitis media in infants and children.
      ]. Heikkinen and colleagues reported that intramuscular application of CTRX significantly reduced isolation rates of H. influenzae from the nasopharynx [
      • Heikkinen T.
      • Saeed K.A.
      • McCormick D.P.
      • Baldwin C.
      • Reisner B.S.
      • Chonmaitree T.
      A single intramuscular dose of ceftriaxone changes nasopharyngeal bacterial flora in children with acute otitis media.
      ]. Although intramuscular use of CTRX has not been approved in Japan, intravenous application once a day has been covered by the National Health Insurance System of Japan since November 13, 2007. Therefore, children and adults in Japan can undergo outpatient parenteral antimicrobial therapy (OPAT).
      CQ 3–2: Are antimicrobial agents useful for the analgesic treatment of AOM?
      Recommendation:
      Antimicrobial agents are not recommended for the purpose of reducing otalgia, because the efficacy of antimicrobial agents against otalgia remains unknown.
      • Recommendation Strength: Recommendation (Recommendation not to administer antimicrobial agents for analgesic treatment of AOM), Evidence Quality: B
      Background:
      Otalgia is the main clinical symptom of AOM that requires management; however, contradictory results concerning the analgesic effect of antimicrobial agents have been reported. Antimicrobial agents are not recommended for the purpose of reducing otalgia considering the benefits–harms assessment. Currently, in Japan, acetaminophen is the choice for analgesic treatment in infants.
      Aggregate evidence quality:
      • Benefits for children: Antimicrobial agents may reduce the duration of otalgia.
      • Risks, harms for children: Antimicrobial agents do not reduce ear pain within 24 h. Administration of antimicrobial agents might cause adverse gastorointestinal events, particularly diarrhea. Administration of any antimicrobial agents might cause bacterial resistance.
      • Benefit–harms assessment: Administration of antimicrobial agents might be unnecessary in cases with otalgia, whose diagnosis remains uncertain. Harms exceed benefits because antimicrobial agents do not have proven effects in reducing otalgia but may have adverse effects.
      • Patient preference: N/A
      • Exclusions: Administration of antimicrobial agents to patients with otalgia in order to treat AOM.
      Comments:
      Venecamp et al. reviewed 12 RCTs on the analgesic effect of antimicrobial agents in pediatric AOM. They reported that antimicrobial agents did not reduce otalgia within 24 h, and only a 5–6% reduction of otalgia was observed after 48 h [
      • Venekamp R.P.
      • Sanders S.L.
      • Glasziou P.P.
      • Del Mar C.B.
      • Rovers M.M.
      Antibiotics for acute otitis media in children.
      ]. In contrast, Bascelli et al. reported that, in an RCT, the duration of subjective otalgia was significantly shorter and the consumption of analgesics was significantly reduced in the antimicrobial agent-treated group to which antimicrobial agents were administered immediately after onset, in comparison to the group who received antimicrobial agents 3 days after onset, after no remission was observed [
      • Bascelli L.M.
      • Losh D.P.
      How does a "wait and see" approach to prescribing antibiotics for acute otitis media (AOM) compare with immediate antibiotic treatment?.
      ]. Therefore, the effect of antimicrobial agents on otalgia remains unclear. Harms exceed benefits, particularly when antimicrobial agents are administered for the purpose of reducing otalgia without precise otoscopic findings.
      The effect of analgesics on otalgia has also not been fully investigated. In a multicenter, double-blind RCT performed by Bertin et al., the effect of ibuprofen was significant compared to placebo, but no significant analgesic effect of acetaminophen was observed [
      • Bertin L.
      • Pons G.
      • d'Athis P.
      • Duhamel J.F.
      • Maudelonde C.
      • Lasfargues G.
      • Guillot M.
      • Marsac A.
      • Debregeas B.
      • Olive G.
      A randomized, double-blind, multicentre controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children.
      ]. In a Cochrane review, Sjoukes et al. reported that acetaminophen and ibuprofen may have limited analgesic effect on otalgia in pediatric AOM patients. However, they pointed out the necessity of more studies, as the evidence was not sufficient [
      • Sjoukes A.
      • Venekamp R.P.
      • van de Pol A.C.
      • Hay A.D.
      • Little P.
      • Schilder A.G.
      • Damoiseaux R.A.
      Paracetamol (acetaminophen) or non-steroidal anti-inflammatory drugs, alone or combined, for pain relief in acute otitis media in children.
      ]. At the present time in Japan, acetaminophen is the choice for analgesic treatment in infants.
      CQ 3–3: How long should an antimicrobial agent be administered?
      Recommendation:
      It is recommended to administer an antimicrobial agent for 5 days as the initial treatment to patients with moderate or severe AOM, along with observation on day 3 or day 4 to assess the treatment efficacy.
      • Recommendation Strength: Recommendation, Evidence Quality: B
      Background:
      The optimal duration of antimicrobial treatment for pediatric AOM has been reported to be 5–7 days or 10 days, but the duration should vary depending on the clinical effects and the causative pathogens. Five-day administration is recommended as the initial antimicrobial treatment for patients with moderate or severe AOM, along with observation on day 3 or day 4 to assess the treatment efficacy.
      Aggregate evidence quality:
      • Benefits for children: The probability of treatment success is increased by taking antimicrobial agents for a necessary and sufficient period.
      • Risks and harms for children: It may not be the optimal administration period for individual patients. It is possible that the patients will not be able to visit the clinic on the specified date.
      • Benefit–harms assessment: Five-day administration with adequate observation of the clinical course of AOM has greater benefits than harms.
      • Patient preference: Clinicians could propose the visit day for follow-up observation with some flexibility in consideration of parents’ preferences.
      • Exclusions: Clinicians can switch antimicrobial agents without waiting for the scheduled period of time if clinical findings on days 3–4 are not improved or are worsened.
      Comments:
      In a systematic review of 35 RCTs, the number of treatment failure cases significantly increased when the oral antimicrobial agent was administered for less than 4 days (short-term), as compared to being administered for 4 days or more. Because short-term administration increases the risk of treatment failure, they recommend that the antimicrobial treatment period should be 4 days or more [
      • Gulani A.
      • Sachdev H.P.
      • Qazi S.A.
      Efficacy of short course (<4 days) of antibiotics for treatment of acute otitis media in children: a systematic review of randomized controlled trials.
      ]. In addition, a meta-analysis of 32 RCTs revealed that 5-day administration was sufficient as a duration of antimicrobial treatment for AOM patients without complications, based on a comparison of administration for less than 7 days or 8 days or more (8–19 days) [
      • Kozyrskyj A.L.
      • Hildes-Ripstein G.E.
      • Longstaffe S.E.
      • Wincott J.L.
      • Sitar D.S.
      • Klassen T.P.
      • Moffatt M.E.
      Short course antibiotics for acute otitis media.
      ]. A prospective observational study of the duration of antimicrobial treatment in patients who did not receive antimicrobial agents in the initial treatment recommended 5 days of antimicrobial treatment for patients with AOM aged 2 years or older [
      • Manarey C.R.
      • Westerberg B.D.
      • Marion S.A.
      Clinical decision analysis in the treatment of acute otitis media in a child over 2 years of age.
      ].
      Pichichero et al. compared the effectiveness of 5-day, 7-day, and 10-day antimicrobial treatment in a prospective study of 2172 children with AOM (46.4% of the cases were younger than 2 years). They found no significant difference between duration periods. However, in a subgroup-analysis of patients with AOM, within 1 month of onset, the number of treatment failures were significantly less in the 10-days antimicrobial treatment group than in the 5-day treatment group [
      • Pichichero M.E.
      • Marsocci S.M.
      • Murphy M.L.
      • Hoeger W.
      • Francis A.B.
      • Green J.L.
      A prospective observational study of 5-, 7-, and 10-day antibiotic treatment for acute otitis media.
      ]. Hoberman et al. compared the clinical outcome of AOM treated with CVA/AMPC for 5 days or 10 days in 520 children aged from 6 to 23 months old. They reported favorable clinical outcomes in the 10-day treatment compared with the 5-day treatment (Treatment failure for 5-day treatment 34%; 10-day treatment 16%; 95% confidence interval 9–25%). The mean symptom score on days 6–14 and 12–14 was significantly better in the 10-day treatment than in the 5-day treatment group (p = 0.001). The ratio of cases with a symptom score improved by 50% or more was significantly higher at 10 days than at 5 days (80% vs. 91%, p = 0.003). In contrast, recurrence rates, adverse events, and detection rates of PRSP/PISP in the nasopharynx were not different significantly between the two treatment groups. The incidence of adverse events and antimicrobial-resistant bacteria did not decrease with short-term treatment. Based on these findings, it has been reported that children under 2 years of age require 10 days of treatment [
      • Hoberman A.
      • Paradise J.L.
      • Rockette H.E.
      • Kearney D.H.
      • Bhatnagar S.
      • Shope T.R.
      • Martin J.M.
      • Kurs-Lasky M.
      • Copelli S.J.
      • Colborn D.K.
      • Block S.L.
      • Labella J.J.
      • Lynch T.G.
      • Cohen N.L.
      • Haralam M.
      • Pope M.A.
      • Nagg J.P.
      • Green M.D.
      • Shaikh N.
      Shortened antimicrobial treatment for acute otitis media in young children.
      ].
      The AAP Guidelines 2013 recommend 10 days of antimicrobial treatment for patients less than 2 years of age or for severe cases, 7 days of treatment for patients 2–5 years of age with non-severe AOM, and 5–7 days of administration for patients with non-severe AOM who are older than 6 years of age. In addition, it is recommended to re-evaluate whether symptoms worsen within 2–3 days after the initial antimicrobial treatment [
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ]. Tähtinen et al. conducted an RCT on 7-day treatment with CVA/AMPC versus placebo and reported that there was a significant difference between the two groups in the treatment failure rate from the third day of antimicrobial treatment. [
      • Tähtinen P.A.
      • Laine M.K.
      • Huovinen P.
      • Jalava J.
      • Ruuskanen O.
      • Ruohola A.
      A placebo-controlled trial of antimicrobial treatment for acute otitis media.
      ]. Similarly, Hoberman et al. also performed an RCT on 10-day treatment with CVA/AMPC versus placebo, and reported a significant difference in treatment failure rates (4% and 23%, respectively) between the 4th and 5th day after administration (p < 0.001) [
      • Hoberman A.
      • Paradise J.L.
      • Rockette H.E.
      • Shaikh N.
      • Wald E.R.
      • Kearney D.H.
      • Colborn D.K.
      • Kurs-Lasky M.
      • Bhatnagar S.
      • Haralam M.A.
      • Zoffel L.M.
      • Jenkins C.
      • Pope M.A.
      • Balentine T.L.
      • Barbadora K.A.
      Treatment of acute otitis media in children under 2 years of age.
      ].
      In Japan, Hotomi et al. classified AOM into mild and severe disease, and examined the clinical course of AOM to ascertain the appropriate timing for determining the efficacy of antibacterial agents. Ninety-four percent of the patients showed recovered clinical symptoms, regardless of the initial severity. However, improvement in TM findings was reported for 55% of mild cases on day 5, but only in 10% of severe cases [
      • Hotomi M.
      • Yamanaka N.
      • Samukawa T.
      • Suzumot M.
      • Sakai A.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Treatment and outcome of severe and non-severe acute otitis media.
      ]. Yamanaka et al. also reported that the improvement rate in TM findings on the 3rd day of antimicrobial treatment was an indicator of subsequent healing in both uncomplicated AOM and refractory AOM [
      • Yamanaka N.
      • Suetake M.
      • Tomiyama M.
      • Sugita R.
      • Matsubara S.
      • Sawada S.
      • Uno Y.
      • Kanesada K.
      • Uchizono A.
      When and how should we swithch antimicrobial agents in the management of pediatric acute otitis media?.
      ].
      In addition, Sawada reported that improvement in TM findings was better in cases treated with high-dose TBPM-PI (6 mg/kg, twice a day) than in those treated with the normal dose (4 mg/kg, twice a day), on the 3rd to 4th day of treatment. They suggested that the administration period could be shortened [
      • Sawada S.
      Comparative effectiveness of high dose versus standard dose of Tebipenem-Pivoxil (TBPM-PI) in intractable acute otitis media in children.
      ].
      Taken together, it is recommended to administer an antimicrobial agent for 5 days as the initial treatment in patients with moderate or severe AOM, along with observation on day 3 or day 4 to assess the treatment efficacy.
      CQ 3–4 Is it reasonable not to administer antimicrobial agents for mild AOM?
      Recommendation:
      Observation with close follow-up is recommended for mild AOM for 3 days without use of antimicrobial agents.
      • Recommendation Strength: Recommendation, Evidence Quality: B
      Background:
      It is requisite for clinicians to diagnose mild AOM accurately, based on precise otoscopic examinations and to assure close follow-up when they do not administer antimicrobial agents, particularly in an environment in which the number of AOMs is increasing due to antimicrobial resistant pathogens in Japan.
      Aggregate evidence quality:
      • Benefits for children: This recommendation can avoid unnecessary antimicrobial treatment. It could reduce adverse effects, such as gastrointestinal effects, represented by diarrhea, and could reduce the likelihood of selecting antimicrobial-resistant bacteria.
      • Risks, harms for children: There is a potential risk that the patient will not receive necessary antimicrobial treatment for 3 days.
      • Benefit–harms assessment: Benefits exceed harms because the risk of adverse consequences of delayed antimicrobial treatment would be modest, even if antimicrobial treatment was eventually necessary after the 3-day follow-up.
      • Patient preference: An appropriate informed consent is required.
      • Exclusions: An observation policy without the use of antimicrobial agents requires assured re-evaluation of clinical findings in the patient at a follow-up after 3 days.
      Comments:
      Van Buchem et al. reported that 2.7% of 4860 children aged 2 years and older without antimicrobial treatment, who were followed-up closely, developed persistent fever, otalgia, or otorrhea for 3–4 days, and led to acute mastoiditis in two children [
      • van Buchem F.L.
      • Peeters M.F.
      • van 't Hof M.A.
      Acute otitis media: a new treatment strategy.
      ].
      Little et al. reported on a multicenter RCT in which antimicrobial agents were immediately prescribed in one group, and was only prescribed when symptom relief was not obtained in 72 h in the other group. Distress scores decreased in 21% of children with immediate use of antimicrobials, as compared to the delayed-use group among children with fever or vomiting; in contrast, distress scores decreased only 4% among children without fever or vomiting. They concluded that observation with close follow-up was appropriate [
      • Little P.
      • Gould C.
      • Williamson I.
      • Moore M.
      • Warner G.
      • Dunleavey J.
      Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media.
      ]. In addition, 76% of children who were closely followed-up eventually needed antimicrobial agents, while the duration of symptom, such as otalgia, restlessness at night, otorrhea, and crying decreased by 1 day. Moreover, there was no significant difference in school absence, relief of otalgia, or distress between these two groups [
      • Little P.
      • Moore M.
      • Warner G.
      • Dunleavy J.
      • Williamson I.
      Longer term outcomes from a randomised trial of prescribing strategies in otitis media.
      ]. Spiro et al. also reported that observation without prescription of antimicrobial agents was useful in patients whose symptoms had improved or had not worsened in 48 h [
      • Spiro D.M.
      • Tay K.Y.
      • Arnold D.H.
      • Dziura J.D.
      • Baker M.D.
      • Shapiro E.D.
      Wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial.
      ]. Rovers et al. conducted a meta-analysis of RCTs on the predictors of a prolonged course for children with AOM who did not receive an immediate prescription. They concluded that the symptoms in children with bilateral AOM who were younger than 2 years of age persisted twice as long as that in children with unilateral AOM, aged 2 years and older, based on an assessment of the treatment course with fever and/or pain at 3–7 days [
      • Rovers M.M.
      • Glasziou P.
      • Appelman C.L.
      • Burke P.
      • McCormick D.P.
      • Damoiseaux R.A.
      • Little P.
      • Le Saux N.
      • Hoes A.W.
      Predictors of pain and/or fever at 3 to 7 days for children with acute otitis media not treated initially with antibiotics: a meta-analysis of individual patient data.
      ].
      Some problems have been pointed out regarding the validity of observation without immediate antimicrobial prescription, from the outcome-setting point of view, in previous clinical studies and meta-analyses [
      • Rosenfeld R.M.
      • Vertrees J.E.
      • Carr J.
      • Cipolle R.J.
      • Uden D.L.
      • Giebink G.S.
      • Canafax D.M.
      Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials.
      ,
      • Del Mar C.
      • Glasziou P.
      • Hayem M.
      Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis.
      ,
      • Gisselsson-Solen M.
      The importance of being specific–a meta-analysis evaluating the effect of antibiotics in acute otitis media.
      ]. In those publications, the outcome of the clinical course of AOM has been evaluated mainly based on clinical symptoms, such as otalgia or fever. Consequently, the criteria for diagnosis of AOM remains ambiguous. Furthermore, the otoscopic findings were not included in the outcome measures in those publications. Babies and toddlers often demonstrate no symptoms and signs, or rarely complain of otalgia or fever, even when AOM was definitely diagnosed by tympanocentesis. Therefore, clinicians should take note that they could misdiagnose mild AOM and offer “watchful waiting” to patients in whom a definite assessment of disease severity, based on precise otoscopic evaluation, was not performed [
      • Paradise J.L.
      Short-course antimicrobial treatment for acute otitis media: not best for infants and young children.
      ]. In Japan, Hotomi et al. classified children with AOM into two categories, mild and severe, based on clinical symptoms and otoscopic findings, using a scoring system; children with mild AOM were not given antimicrobial agents at their first visit. They showed that it was possible to follow-up patients with mild AOM, without administration of antimicrobial agents for as long as 5 days after the first visit [
      • Hotomi M.
      • Yamanaka N.
      • Samukawa T.
      • Suzumot M.
      • Sakai A.
      • Shimada J.
      • Ikeda Y.
      • Faden H.
      Treatment and outcome of severe and non-severe acute otitis media.
      ].
      According to a Cochrane review in 2015, in developed countries, observation with close follow-up is reasonable for children with mild and moderate AOM, while antimicrobial agents would be most beneficial for children under the age of 2 years with bilateral AOM or otorrhea [
      • Venekamp R.P.
      • Sanders S.L.
      • Glasziou P.P.
      • Del Mar C.B.
      • Rovers M.M.
      Antibiotics for acute otitis media in children.
      ]. In the AAP Guidelines 2013, watchful waiting has been proposed as an option for unilateral AOM in children aged 6 months to 23 months, without severe signs or symptoms (i.e., mild otalgia for less than 48 h with a fever less than 39 °C) [
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ]. In contrast, Tähtinen et al. reported that watchful waiting might be associated with transient worsening of a child's condition, prolongation of symptoms, and economic losses [
      • Tahtinen P.A.
      • Laine M.K.
      • Ruuskanen O.
      • Ruohola A.
      Delayed versus immediate antimicrobial treatment for acute otitis media.
      ]. There were some reports about a safety-net antibiotic prescription, which is an approach in which parents or guardians decide to start antimicrobial treatment that was prescribed in advance, after judging the need for antimicrobial treatment by themselves, based on clinical symptoms. Those studies revealed that antimicrobial agents were eventually used in 31% [
      • Siegel R.M.
      • Kiely M.
      • Bien J.P.
      • Joseph E.C.
      • Davis J.B.
      • Mendel S.G.
      • Pestian J.P.
      • DeWitt T.G.
      Treatment of otitis media with observation and a safety-net antibiotic prescription.
      ] or 34% [
      • McCormick D.P.
      • Chonmaitree T.
      • Pittman C.
      • Saeed K.
      • Friedman N.R.
      • Uchida T.
      • Baldwin C.D.
      Nonsevere acute otitis media: a clinical trial comparing outcomes of watchful waiting versus immediate antibiotic treatment.
      ] of the children. When clinicians apply an observation policy, it is necessary to offer a close follow-up and to prepare for immediate antimicrobial treatment use in cases where the child fails to improve.
      Thus, observation with close follow-up is recommended for mild AOM for a period of 3 days without use of antimicrobial agents, if mild AOM is diagnosed based on accurate assessment of clinical and otoscopic findings, along with consideration of the patient's age (younger than 2 years) and other risk factors.
      CQ3-5 What are indications for myringotomy in children with AOM?
      Recommendation: A myringotomy is recommended depending on the severity of AOM.
      • Recommendation Strength: Recommendation, Evidence Quality: C
      Background:
      AOM is characterized by inflammation of the middle ear with MEE. Drainage through the TM is considered effective in promoting rapid improvement of the disease. However, there have been a limited number of reports offering high quality evidence that myringotomy provides significant treatment effects in AOM.
      Aggregate evidence quality:
      • Benefits for patients: To promote early improvement of clinical symptoms, such as otalgia, fever, and hearing impairment, early improvement of otoscopic findings, particularly in severe cases. To make it possible to identify causative pathogens, followed by appropriate antimicrobial treatment.
      • Risks and harms for children: Pain and discomfort, and the need for physical restraint during the procedure, and otorrhea and a risk of persistent perforation after the procedure, etc.
      • Benefit–harms assessment: Benefits exceed harms in selected patients, based on symptoms and otoscopic findings.
      • Patient preference: An appropriate informed consent is requisite.
      • Exclusions: Skills and equipment are essential; clinicians should not implement this procedure without these.
      Comments:
      There are some reports on the effectiveness of myringotomy. A retrospective observational study, in which myringotomy was performed in cases in which signs of infection had persisted even after 48-hour antimicrobial treatment, reported that clinical symptoms improved in all cases by 48 h after myringotomy [
      • Babin E.
      • Lemarchand V.
      • Moreau S.
      • Goullet de Rugy M.
      • Valdazo A.
      • Bequignon A.
      Failure of antibiotic therapy in acute otitis media.
      ]. Hotomi et al. concluded that myringotomy was necessary, depending on the severity of AOM [
      • Hotomi M.
      • Yamanaka N.
      Treatment of intractable otitis media caused by antimicrobiotic resistant bacteria.
      ]. Nomura et al. reported that myringotomy significantly reduced the frequency of progression to OME from AOM in a case–control study, but that it was not effective in preventing early relapse of AOM or development of recurrent AOM [
      • Nomura Y.
      • Ishibashi T.
      • Yano J.
      • Ichikawa T.
      • Shinogami M.
      • Monobe H.
      • Hirai R.
      • Kaga K.
      Effect of myringotomy on prognosis in pediatric acute otitis media.
      ]. On the other hand, an RCT on severe cases, which compared three groups: myringotomy vs. antimicrobial treatment vs. myringotomy with antimicrobial treatment, revealed no additional clinical effect of myringotomy when myringotomy was used with antimicrobial treatment. [
      • van Buchem F.L.
      • Peeters M.F.
      • van 't Hof M.A.
      Acute otitis media: a new treatment strategy.
      ]. Kaleida et al. conducted an RCT on severe cases aged 2 years or older, in which they compared three groups: those treated with AMPC, treated with AMPC and myringotomy, or treated with placebo and myringotomy. They reported that the myringotomy and placebo group showed significantly worse results than the other groups [
      • Kaleida P.H.
      • Casselbrant M.L.
      • Rockette H.E.
      • Paradise J.L.
      • Bluestone C.D.
      • Blatter M.M.
      • Reisinger K.S.
      • Wald E.R.
      • Supance J.S.
      Amoxicillin or myringotomy or both for acute otitis media: results of a randomized clinical trial.
      ]. Although they concluded that myringotomy alone was not an effective treatment, it does not mean that myringotomy is ineffective. The clinical practice guidelines for AOM from Canada, published in 2009 by the Canadian Pediatric Society, recommended that clinicians other than otolaryngologists should refer patients to otolaryngologists for the purpose of tympanocentesis if the second-line antimicrobial treatment fails or if the first-line antimicrobial treatment fails in patients who are allergic to ß-lactam-class antimicrobials [
      • Forgie S.
      • Zhanel G.
      • Robinson J.
      Management of acute otitis media.
      ]. In a recent report, myringotomy was described as a technique to prove MEE, rather than as a treatment [
      • Qureishi A.
      • Lee Y.
      • Belfield K.
      • Birchall J.P.
      • Daniel M.
      Update on otitis media - prevention and treatment.
      ]. A previous report mentioned that myringotomy was difficult to carry out in all pediatric patients. On the other hand, another report recommended myringotomy for patients showing no treatment effect of antimicrobial agents, even though most myringotomies are performed to identify causative pathogens [
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • Ganiats T.G.
      • Hoberman A.
      • Jackson M.A.
      • Joffe M.D.
      • Miller D.T.
      • Rosenfeld R.M.
      • Sevilla X.D.
      • Schwartz R.H.
      • Thomas P.A.
      • Tunkel D.E.
      The diagnosis and management of acute otitis media.
      ].
      However, because most evidence regarding myringotomy were obtained in places and at a time where antimicrobial resistant bacteria were not a marked concern, unlike in current Japan, intractable or persistent cases of AOM caused by PRSP or BLNAR were not included in those studies. Yamanaka et al. divided severe cases of AOM into two groups: one was treated with antimicrobial agents along with myringotomy and the other was treated with antimicrobial agents alone. They reported that the improvement in TM scores in the myringotomy group were significantly greater than those of the antimicrobials-alone group, after 2 weeks [

      N. Yamanaka, M. Hotomi, Is there no clinical difference between myringotomy and antimicrobial agent?, in: N. Yamanaka, M. Hotomi (eds), Management of acute otits media in children, Iyaku Journal, Osaka, 2006, pp. 73-76[in Japanese].

      ].
      In addition, Uno reported that patients with myringotomy demonstrated earlier improvement than did patients without myringotomy, in some specific cases, as follows: cases classified as severe AOM, cases with high scores for otalgia, cases with high fever, cases with simultaneous redness and bulging, and cases without otorrhea [
      • Uno Y.
      Current frequency and efficacy of myringotomy for acute Otis media in children.
      ]. In addition, although there was no difference in the final treatment outcome, rates of rapid improvement were higher when myringotomy was performed, and the rates of relapse or recurrence in severe cases were significantly lower in patients treated with myringotomy.
      From the viewpoint of action plans for antimicrobial-resistance (AMR), which have attracted public attention recently, myringotomy can play an important role as a treatment option that is independent of antimicrobial agents, and as a measure for identifying causative pathogens, which can help to establish susceptibility profiles that can, in turn, promote appropriate antimicrobial stewardship.
      Taken together, myringotomy is recommended in some specific cases, with consideration of parents’ or guardians’ preferences: patients classified as severe, patients with marked bulging TMs, with severe otalgia, or patients with marked bulging TMs with high fever. A unique healthcare environment in Japan that enables easy access to otolaryngologists supports this recommendation, which means that myringotomy is not recommended for clinicians other than otolaryngologists. Therefore, clinicians should prepare to refer patients to otolaryngologists who can offer myringotomy in cases where the clinicians cannot perform this technique by themselves, due to their specialties.
      CQ 3–6: Are ear drops effective for the treatment of AOM?
      Recommendation:
      Topical treatment is recommended for AOM children with an efficient, accessible route, such as tympanostomy tubes, for administering ear drops into the middle ear cavity. Ear drops should not be administered to patients without TM perforations, because they are ineffective.
      • Recommendation Strength: Recommendation, Evidence Quality: B
      Background:
      Topical antibiotic treatment can deliver high-concentration antimicrobials directly into the middle ear, and are indicated in selected cases.
      Aggregate evidence quality:
      • Benefits for children: Ear drops can be effective if a sufficient dose can reach the middle ear cavity. There are no systemic adverse side effects and there is less influence on the systemic bacterial flora, including the nasopharynx.
      • Risks, harms for children: The treatment might be difficult for one parent or guardian alone to perform without any support.
      • Benefit–harms assessment: Benefits exceed harms if there is a sufficient, accessible route for ear drops to reach the middle ear cavity, because adverse side effects are less than those of systemic administration of antimicrobial agents.
      • Patient preference: Guardians’ or parents’ circumstances and preferences need to be considered.
      • Exclusions: Patients without a perforation of the TM.
      Comments
      In a prospective study, administration of four drops of topical ciprofloxacin (CPFX; 0.3%)/dexamethasone (0.1%) through tympanostomy tubes, twice daily for 7 days, and an oral suspension of AMPC/CVA (600 mg/42.9 mg) every 12 h for 10 days were compared in AOM cases with otorrhea [
      • Dohar J.
      • Giles W.
      • Roland P.
      • Bikhazi N.
      • Carroll S.
      • Moe R.
      • Reese B.
      • Dupre S.
      • Wall M.
      • Stroman D.
      • McLean C.
      • Crenshaw K.
      Topical ciprofloxacin/dexamethasone superior to oral amoxicillin/clavulanic acid in acute otitis media with otorrhea through tympanostomy tubes.
      ]. Otic drops obtained a significantly earlier cure and otic treatment through tympanostomy tubes was found to be effective for earlier resolution of otorrhea. Van Dongen et al. conducted an RCT to compare topical treatment with hydrocortisone–bacitracin–colistin, CVA/AMPC (7.5 mg/30 mg/kg/day) for 7 days, and no treatment in AOM patients with otorrhea. By 2 weeks after starting treatment, otorrhea continued in 5% of patients treated with topical treatment, 44% in those treated with CVA/AMPC, and 55% in those with no treatment [
      • van Dongen T.M.
      • van der Heijden G.J.
      • Venekamp R.P.
      • Rovers M.M.
      • Schilder A.G.
      A trial of treatment for acute otorrhea in children with tympanostomy tubes.
      ]. In another RCT that compared types of otic treatments, such as CPFX/dexamethasone and ofloxacin (OFLX), CPFX/dexamethasone demonstrated significantly superior treatment outcomes [
      • Roland P.S.
      • Dohar J.E.
      • Lanier B.J.
      • Hekkenburg R.
      • Lane E.M.
      • Conroy P.J.
      • Wall G.M.
      • Dupre S.J.
      • Potts S.L.
      • Group C.A.S.
      Topical ciprofloxacin/dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of granulation tissue in children with acute otitis media with otorrhea through tympanostomy tubes.
      ]. Furthermore, Schmelzle et al. evaluated RCTs on the effect of topical treatment in pediatric AOM patients with tympanostomy tube insertions, and reported that topical treatment by fluoroquinolone, with or without corticosteroids, reduced the duration of otorrhea in pediatric AOM patients with tympanostomy tubes [
      • Schmelzle J.
      • Birtwhistle R.V.
      • Tan A.K.
      Acute otitis media in children with tympanostomy tubes.
      ].
      The effectiveness of topical treatment after myringotomy has not been established. The inner diameter of the tympanostomy ventilation tubes is 0.9–1.5 mm, When the size of the myringotomy is sufficiently large, topical treatment should be as effective as treatment with a tympanostomy tube insertion. In laser myringotomy, the perforation size ranges from 1.0 to 3.0 mm in diameter; therefore, the conditions are similar to those of tympanostomy tubes [
      • Silverstein H.
      • Kuhn J.
      • Choo D.
      • Krespi Y.P.
      • Rosenberg S.I.
      • Rowan P.T.
      Laser-assisted tympanostomy.
      ]. However, the size of the myringotomy will gradually shrink; thus, more studies on the effects of myringotomy combined with topical treatment are required to validate the effectiveness of this approach in pediatric AOM patients.
      NOTE: Aminoglycoside and antifungal agents should not be used as otic drops because of their ototoxicity [
      • Venekamp R.P.
      • Prasad V.
      • Hay A.D.
      Are topical antibiotics an alternative to oral antibiotics for children with acute otitis media and ear discharge?.
      ].
      CQ 3–7: Are antihistamines effective in the treatment of AOM?
      Recommendation:
      Clinicians should not prescribe antihistamines for AOM treatment because there is no evidence that antihistamines are effective in AOM treatment.
      • Recommendation Strength: Strong recommendation (Strong recommendation not to perform this treatment), Evidence Quality: A
      Background:
      Antihistamines have been believed to have some anti-inflammatory effects in inflammatory diseases, including AOM. However, there is currently no evidence indicating effectiveness of antihistamines for patients with AOM.
      Aggregate evidence quality:
      • Benefits for children: There is no benefit, because antihistamines are ineffective for AOM.
      • Risks, harms for children: Drowsiness, decrease in activities, adverse effects in terms of convulsions, unnecessary cost of medication
      • Benefit–harms assessment: Harms exceed benefits because antihistamines provide no beneficial effects, but have some obvious adverse effects, in the treatment of AOM.
      • Patient preference: N/A
      • Exclusions: None
      Comments:
      Both viruses and bacteria have additive effects on the production of histamines in pediatric AOM [
      • Chonmaitree T.
      • Patel J.A.
      • Lett-Brown M.A.
      • Uchida T.
      • Garofalo R.
      • Owen M.J.
      • Howie V.M.
      Virus and bacteria enhance histamine production in middle ear fluids of children with acute otitis media.
      ]. Chonmeitree et al. conducted a double-blind RCT of 179 children with AOM, aged 3 months to 6 years, and compared the clinical outcomes of treatment with placebo, steroids, antihistamines, or a combination of steroids and antihistamines [
      • Chonmaitree T.
      • Saeed K.
      • Uchida T.
      • Heikkinen T.
      • Baldwin C.D.
      • Freeman Jr., D.H.
      • McCormick D.P.
      A randomized, placebo-controlled trial of the effect of antihistamine or corticosteroid treatment in acute otitis media.
      ]. The study demonstrated that clinical outcomes and recurrence rates did not differ significantly among treatments, and that the children who received only antihistamines had a significantly longer duration of MEE. Flynn et al. conducted a meta-analysis of 13 RCTs and compared the effects of anti-inflammatory drugs, antihistamines, and a combination of both to those of placebo [
      • Flynn C.A.
      • Griffin G.
      • Tudiver F.
      Decongestants and antihistamines for acute otitis media in children.
      ]. The results of the analysis demonstrated that the groups treated with anti-inflammatory agents or antihistamines received no benefit. Furthermore, in another meta-analysis of 15 RCTs, Coleman et al. evaluated the treatment effectiveness of a combination of decongestants and antihistamines and found no beneficial effect or improvement in AOM. Therefore, routine administration of decongestants and antihistamine agents has not been recommended [
      • Coleman C.
      • Moore M.
      Decongestants and antihistamines for acute otitis media in children.
      ].
      Patients with AOM often have fever. According to a study of the relationship between antihistamines and febrile seizures, antihistamines shortened the duration from fever onset to seizure and the duration of seizures was significantly longer in the antihistamine group than in the non-antihistamine group [
      • Zolaly M.A.
      Histamine H1 antagonists and clinical characteristics of febrile seizures.
      ]. Furthermore, antihistamines have been listed among potential candidate causes of acute encephalopathy in children [
      • Yamauchi H.
      • Ichikawa T.
      • Osawa M.
      • Katsunuma T.
      • Takahashi T.
      • Niijima S.
      • Nagai T.
      • Mizuguchi M.
      • Yoshikawa H.
      Acute encephalopathy in children., in: Japan Pharmaceutical Information Center (JAPIC) (eds), The Manuals for management of individual serious adverse drug reactions, version 5.
      ]. Therefore, to avoid antihistamine use is strongly recommended for the treatment of pediatric AOM.
      CQ 3–8: Are topical nasal therapies effective for management of AOM patients?
      Recommendation:
      Topical nasal therapies for cleaning of the nasal cavity, such as saline nasal irrigation or nasal lavage, can be an adjunct treatment for patients with AOM along with rhinosinusitis
      • Recommendation Strength: Option, Evidence Quality: D
      Background:
      AOM often develops after upper respiratory tract infections and is strongly associated with rhinosinusitis. AOM and acute rhinosinusitis share the same causative pathogens. Furthermore, rhinosinusitis was reported to be an important risk factor for refractory AOM, relapse, or recurrence of AOM [
      • Yamanaka N.
      • Uchizono A.
      • Uno Y.
      • Kanesada K.
      • Sawada S.
      • Suetake M.
      • Sugita R.
      • Tomiyama M.
      • Hotomi M.
      • Matsubara S.
      Concomitant rhinosinusitis is a risk factor for refractory acute otitis media in children.
      ]. Although evidence is insufficient, topical nasal therapies are considered to facilitate patients’ recovery from AOM.
      Aggregate evidence quality:
      • Benefits for children: Topical nasal therapies potentially facilitate patients’ recovery from AOM.
      • Risks and harms for children: A potential risk of mucosal damage and related nasal bleeding. Medical costs as an outpatient if undergoing therapies at the outpatient clinic. Device costs if treatment is performed at home.
      • Benefit–harms assessment: Benefits exceed harms for the patients with rhinosinusitis because appropriate device selection, such as soft tubes or those with an olive-shaped tip, can sufficiently reduce the potential risk of mucosal damage. Moreover, topical nasal therapies are expected to facilitate patients’ recovery from AOM by improving Eustachian tube function through creation of a better nasopharyngeal environment.
      • Patient preference: Clinicians should consider parents or guardians’ preferences.
      • Exclusions: Patients without rhinosinusitis.
      Comments:
      There is not a sufficient number of studies to reveal the significance of the effect of topical nasal therapies in AOM patients. Ito et al. conducted a prospective study on nasopharyngeal bacteriology of children with AOM before and after nasal lavage. They reported eradication rates of PRSP and BLNAR of 57% and 60%, respectively [
      • Ito M.
      • Shirai A.
      • Yoshizaki T.
      • Nishimura T.
      • Miwa T.
      • Furukawa M.
      The efficacy of nasopharyngeal topical treatment.
      ]. Irumada et al. performed a prospective study to assess changes in the amount and bacteriology of the nasal discharge before and after nasal lavage for 2 weeks, without use of any antimicrobial agents. They reported that the amount of nasal discharge and post-nasal drip had returned to normal in 55% and 71% of the patients, respectively [
      • Irumada M.
      • Suetake M.
      • Takayanagi R.
      • Hndo H.
      The effectiveness of nasal irrigation in the treatment of infant nasal problems.
      ]. Furthermore, the amount of S. pneumoniae had reduced or completely disappeared in 80% of the cases, as did H. influenzae in 60% of cases. One prospective study reported on the effectiveness of the nasal aspirator in patients aged from 2 months to 2 years. They compared patients treated with both a nasal aspirator and saline lavage to patients treated with saline lavage alone, and found that the episodes of AOM decreased in the group treated with the nasal aspirator [
      • Montanari G.
      • Ceschin F.
      • Masotti S.
      • Bravi F.
      • Chinea B.
      • Quartarone G.
      Observational study on the performance of the Narhinel method (nasal aspirator and physiological saline solution) versus physiological saline solution in the prevention of recurrences of viral rhinitis and associated complications of the upper respiratory tract infections (URTI), with a special focus on acute rhinosinusitis and acute otitis of the middle ear.
      ]. Yamanaka et al. reported that AOM patients with failure of antimicrobial therapy significantly more often had rhinosinusitis as a background factor [
      • Yamanaka N.
      • Uchizono A.
      • Uno Y.
      • Kanesada K.
      • Sawada S.
      • Suetake M.
      • Sugita R.
      • Tomiyama M.
      • Hotomi M.
      • Matsubara S.
      Concomitant rhinosinusitis is a risk factor for refractory acute otitis media in children.
      ]. These outcomes suggest the important role of the topical nasal therapies for management AOM patients. It is suggested that topical nasal therapies have beneficial effects in the management of AOM patients by improving Eustachian tube function through normalization of the bacteriological environment of the nasopharynx.
      Additionally, although only the AOM Guidelines from Japan used to refer to topical nasal therapies, the recent guideline from Italy recommended removal of the nasal discharge by using saline nasal irrigation [
      • Marchisio P.
      • Bellussi L.
      • Di Mauro G.
      • Doria M.
      • Felisati G.
      • Longhi R.
      • Novelli A.
      • Speciale A.
      • Mansi N.
      • Principi N.
      Acute otitis media: From diagnosis to prevention. Summary of the Italian guideline.
      ]. Topical nasal therapies are now recognized as an important treatment for AOM patients not only in Japan, but also in other countries.
      CQ3-9: Is the tympanostomy tube effective for recurrent AOM?
      Recommendation:
      Tympanostomy tube placement is recommended as a treatment option for recurrent AOM.
      • Recommendation Strength: Recommendation, Evidence Quality: B
      Background:
      Recurrent AOM has been defined as three or more episodes of AOM within the previous 6 months, or four or more episodes within the previous 12 months (CQ1-5). There are two types of recurrent AOM. One is recurrent AOM with persistent MEE between each episode, and the other is recurrent AOM without effusion between episodes, due to resolution of the effusion with improvement of aeration of the middle ear. Among the above two categories, the treatment effects of a tympanostomy tube can be expected to play a role in the former type of recurrent AOM [
      • Rosenfeld R.M.
      • Schwartz S.R.
      • Pynnonen M.A.
      • Tunkel D.E.
      • Hussey H.M.
      • Fichera J.S.
      • Grimes A.M.
      • Hackell J.M.
      • Harrison M.F.
      • Haskell H.
      • Haynes D.S.
      • Kim T.W.
      • Lafreniere D.C.
      • LeBlanc K.
      • Mackey W.L.
      • Netterville J.L.
      • Pipan M.E.
      • Raol N.P.
      • Schellhase K.G.
      Clinical practice guideline: Tympanostomy tubes in children.
      ].
      Aggregate evidence quality:
      • Benefits for children: Decreased frequency of AOM; antimicrobial otic drops can be administered via the tubes.
      • Risks, harms for children: Pain, discomfort, and need for physical restraint during the surgical procedure under local anesthesia to the tympanic membrane. Potential risks of general anesthesia in cases of surgery performed under general anesthesia. Otorrhea while tubes are in place, and adverse events affecting the TM, including calcification and persistent perforations after extrusion or removal of tubes.
      • Benefit–harms assessment: Benefits exceed harms because adverse consequences, including the perforation of the TM, can decrease by choosing short-term tympanostomy tubes.
      • Patient preference: An appropriate informed consent is requisite.
      • Exclusions: None.
      Comments:
      Treatment of recurrent AOM is classified into conservative and surgical procedures. Surgical procedures include myringotomy, tympanostomy tube insertion, and tympanostomy tube insertion in conjunction with adenoidectomy. Adenoidectomy has not been demonstrated to reduce the incidence of or prevent recurrent AOM, based on RCTs [
      • Oomen K.P.
      • Rovers M.M.
      • van den Akker E.H.
      • van Staaij B.K.
      • Hoes A.W.
      • Schilder A.G.
      Effect of adenotonsillectomy on middle ear status in children.
      ,
      • Hammaren-Malmi S.
      • Saxen H.
      • Tarkkanen J.
      • Mattila P.S.
      Adenoidectomy does not significantly reduce the incidence of otitis media in conjunction with the insertion of tympanostomy tubes in children who are younger than 4 years: a randomized trial.
      ,
      • Koivunen P.
      • Uhari M.
      • Luotonen J.
      • Kristo A.
      • Raski R.
      • Pokka T.
      • Alho O.P.
      Adenoidectomy versus chemoprophylaxis and placebo for recurrent acute otitis media in children aged under 2 years: randomised controlled trial.
      ]. Adenoidectomy cannot be recommended because Kujala et al. reported that adenoidectomy did not provide any additional benefits to the effects of tympanostomy tube insertion [
      • Kujala T.
      • Alho O.P.
      • Luotonen J.
      • Kristo A.
      • Uhari M.
      • Renko M.
      • Kontiokari T.
      • Pokka T.
      • Koivunen P.
      Tympanostomy with and without adenoidectomy for the prevention of recurrences of acute otitis media: a randomized controlled trial.
      ].
      In a Japanese case–control study, myringotomy has been reported not to be effective in decreasing the incidence of recurrent AOM [
      • Nomura Y.
      • Ishibashi T.
      • Yano J.
      • Ichikawa T.
      • Shinogami M.
      • Monobe H.
      • Hirai R.
      • Kaga K.
      Effect of myringotomy on prognosis in pediatric acute otitis media.
      ]. In contrast, short-term placement of tympanostomy tubes for 1 year or 1 month has significantly reduced the frequency of recurrent AOM [
      • Uno Y.
      Effects of long-term tympanostomy tubes in children with intractable otitis media.
      ,
      • Uno Y.
      Effects of short-term tympanostomy tube on intractable recurrent otitis media in children.
      ]. Furthermore, the incidence of AOM was decreased for 1 year after tympanostomy tube insertion and the tympanostomy tube was effective for pain relief and for improving parents or guardians’ quality of life (QOL) [
      • Whittemore Jr., K.R.
      In response to what is the role of tympanostomy tubes in the treatment of recurrent acute otitis media?.
      ]. On the other hand, it has been reported that the QOL of the patient or parents/guardians did not change after tympanostomy tube insertion [
      • Kujala T.
      • Alho O.P.
      • Kristo A.
      • Uhari M.
      • Renko M.
      • Pokka T.
      • Koivunen P.
      Quality of life after surgery for recurrent otitis media in a randomized controlled trial.
      ]. Therefore, the effect of tympanostomy tube remains controversial. According to a Cochrane review [
      • McDonald S.
      • Langton Hewer C.D.
      • Nunez D.A.
      Grommets (ventilation tubes) for recurrent acute otitis media in children.
      ], two RCTs reported decreased occurrence of AOM within 6 months after tympanostomy tube insertion [
      • Gebhart D.E.
      Tympanostomy tubes in the otitis media prone child.
      ,
      • El-Sayed Y.
      Treatment of recurrent acute otitis media chemoprophylaxis versus ventilation tubes.
      ]. However, Gebhart demonstrated a statistically significant difference, while El-Sayed presented no statistically significant differences. These two studies included bias, because their randomization lacked accuracy. Therefore, the Cochrane review concluded that further studies are needed to determine the efficacy of tympanostomy tube insertion for recurrent AOM. Taken together, the long-term benefit of tympanostomy tube insertion for recurrent AOM is not yet conclusive, even if short-term benefit has been demonstrated with limited evidence.
      Several complications and sequelae occur during tympanostomy tubes placement and after their extrusion. Persistent TM perforations can cause significant clinical problems. Persistent perforations occur in 2.2% of cases with insertion of short-term tubes, while they occur in 16.6% of those with insertion of long-term tubes, according to a meta-analysis of tympanostomy tube sequelae [
      • Kay D.J.
      • Nelson M.
      • Rosenfeld R.M.
      Meta-analysis of tympanostomy tube sequelae.
      ].
      Long-term placement of tympanostomy tubes is rarely needed for treatment of recurrent AOM in comparison to that for OME. Persistent perforation of the TM is more common with long-term tympanostomy tubes than with short-term ones. Therefore, short-term tympanostomy tubes are recommended for recurrent AOM in consideration of the benefit–harms assessment.
      NOTE: The National Health Insurance System of Japan does not cover tympanostomy tube placement for treatment of AOM and recurrent AOM.
      CQ 3–10: Is Japanese herbal medicine effective for recurrent AOM?
      Recommendation:
      Juzen-taiho-to (JTT), a Japanese herbal medicine known as Hozai (formulations with tonic effects) that improves immune function and nutritional condition, is recommended for the treatment of children with recurrent AOM, because it was found to be effective for reducing the frequency of AOM.
      • Recommendation Strength: Recommendation, Evidence Quality: B
      Background:
      Children under 2 years of age more often suffer from recurrent AOM because of their immature immune systems. JTT, which is known to upregulate the host's immune system and improve nutritional status, is reported to be effective for children with recurrent AOM.
      Aggregate evidence quality:
      • Benefits for children: To decrease the frequency of recurrent AOM by therapies other than surgical interventions.
      • Risks and harms for children: Rare side effects (such as pseudohyperaldosteronism), drug costs.
      • Benefit–harms assessment: Benefits exceed harms because the risk of adverse effects of JTT is low enough.
      • Patient preference: Clinicians should consider parents or guardians’ preferences.
      • Exclusions: None.
      Comments:
      The unique role played by traditional Japanese herbal medicines (Kampo) is gradually attracting worldwide attention. In addition to conventional treatment, supplementary and alternative medicine approaches have been proposed as an additional choice for treatment of AOM. Hozai (formulations with tonic effects) are nourishing types of Japanese herbal medicines that is administered to patients in various weakened conditions, such as those with fatigue, appetite loss, and post-illness exhaustion, to improve disturbances and imbalances in homeostasis. JTT and Hochu-ekki-to are representative Hozai-type Japanese herbal medicines. Several basic and clinical studies have reported that Hozai increasing the immune and biophylactic function of the host and have efficacy against infectious diseases. Hozai have been reported to have inhibitory effects against rhinovirus infection. Several clinical studies have shown that Hozai reduce the frequency of the common cold and help patients with chronic obstructive pulmonary disease to gain weight, as well as improving the immune defense against MRSA infection, and showing treatment effects against Candida infections. JTT is also reported to be effective for infants with fistula-in ano and peri‑anal abscesses and is becoming one of the standard treatments in Japan. JTT is known to increase the production of IL-2 in macrophages, IL-2, 4, and 5 and IFN-γ in lymphocytes, and the activation of natural killer cells.
      Maruyama et al. reported that the frequency of AOM, duration of fever and antimicrobial administration, and the number of emergency department visits decreased significantly after JTT administration for 3 months for recurrent AOM in infants, leading to remission in 95.2% patients [
      • Maruyama Y.
      • Hoshida S.
      • Furukawa M.
      • Ito M.
      Effects of Japanese herbal medicine, Juzen-taiho-to, in otitis-prone children–a preliminary study.
      ]. Moreover, Ito et al. conducted an RCT for children aged 6–48 months with recurrent AOM, and reported that children who received conventional AOM treatment based on the Japanese Guidelines along with JTT had significantly fewer episodes of AOM (mean ± SD = 0.61 ± 0.54 episodes/month) than did the control group who received conventional treatment alone (1.07 ± 0.72) [
      • Ito M.
      • Maruyama Y.
      • Kitamura K.
      • Kobayashi T.
      • Takahashi H.
      • Yamanaka N.
      • Harabuchi Y.
      • Origasa H.
      • Yoshizaki T.
      Randomized controlled trial of juzen-taiho-to in children with recurrent acute otitis media.
      ]. They also reported that the use of JTT significantly decreased both the frequency of upper respiratory tract infection (coryza) and the duration of antimicrobial administration, but no significant difference was observed in terms of the median number of tympanostomy tube insertions.
      NOTE: Indications for JTT under the National Health Insurance System of Japan are “post-illness weakened condition, fatigue, loss of appetite, night sweats, cold hands and feet, and anemia” (as of July 2017).
      CQ 3–11: Is immunoglobulin administration effective for recurrent AOM?
      Recommendation:
      Immunoglobulin administration is recommended for patients with low serum IgG2 levels, whose recurrent AOM cannot be controlled by other available treatment modalities.
      • Recommendation Strength: Recommendation, Evidence Quality: C
      Background:
      Some patients with recurrent AOM demonstrate a low serum level of IgG2. Immunoglobulin administration is effective for some of these patients. Intravenous administration of immunoglobulin is recommended for patients with serum IgG2 under 80 mg/dL, whose recurrent AOM cannot be controlled by other treatment, with the utmost consideration for parents or guardians’ preferences.
      Aggregate evidence quality:
      • Benefits for children: The number of episodes of recurrent AOM caused by low serum IgG2 can decrease.
      • Risks and harms for children: There might be some risks of virus contamination, as known adverse events of blood products.
      • Benefit–harms assessment: Since sufficient systematic countermeasures against viral contamination have been established, the benefits exceed the harms for recurrent AOM patients with low serum levels of IgG2 whose recurrent AOM cannot be controlled by other available treatment modalities.
      • Patient preference: Clinicians should consider parents or guardians’ preferences and written informed consent is requisite.
      • Exclusions: Patients whose serum IgG2 levels exceed 80 mg/dL.
      Comments:
      There are four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4, and IgG2 includes antibodies against polysaccharides of S. pneumoniae and H. influenzae.
      Some patients with recurrent infectious diseases, such as recurrent AOM, demonstrate low serum levels of IgG2. S. pneumoniae and H. influenzae are common pathogens causing AOM, and protective antibodies against these bacteria belong to the IgG2 subclass. Low serum levels of IgG2 represent insufficient antibody production and it can be a cause of recurrent infections. For such cases, administration of immunoglobulin, including the IgG2 subclass, increases the serum IgG2 level of patients, helping to preventing infections.
      IgG2 hypogammaglobulinemia is defined as levels under 80 mg/dL, and its deficiency is defined as levels under 30 mg/dL. Decreased serum IgG2 includes not only permanently insufficient IgG2 production caused by congenital gene deletion, but also transient low serum IgG2 levels caused by delayed immunological development. It is sometimes difficult to differentiate these two at the early stage. Congenital IgG subclass deficiency is included in primary immunodeficiency (PID) and is specified as one of the specific pediatric chronic diseases, with public subsidy for medical costs in Japan.
      Immunoglobulin treatment for patients with a low serum level of IgG2 has been reported to be effective, irrespective of the cause of low serum IgG2. Clinicians should remember that IgG subclass deficiency could be the cause of recurrent AOM and/or other severe infectious diseases, and should plan for appropriate diagnostic examinations, if needed.
      The cutoff value of IgG2 hypogammaglobulinemia has been defined as 80 mg/dL based on the inclusion criteria of IgG2 levels in a multicenter trial performed by Sakiyama et al., which evaluated the prophylactic effects of infections by intravenous immunoglobulin therapy (IVIG) [
      • Sakiyama Y.
      • Komiyama A.
      • Shiraki K.
      • Taniguchi N.
      • Torii S.
      • Baba S.
      • Yada J.
      • Matsumoto S.
      Intravenous immunoglobulin for prophylaxis of recurrent acute otitis media and lower respiratory tract infection in infancy with IgG2 deficiency.
      ].
      Hotomi et al. reported that 13.9% of children with recurrent AOM had low levels of IgG2 [
      • Hotomi M.
      • Yamanaka N.
      • Saito T.
      • Shimada J.
      • Suzumoto M.
      • Suetake M.
      • Faden H.
      Antibody responses to the outer membrane protein P6 of non-typeable Haemophilus influenzae and pneumococcal capsular polysaccharides in otitis-prone children.
      ]. There have been some reports on the effectiveness of IVIG for recurrent AOM in Japan, including one from Suetake et al. They reported that the total number of episodes of AOM decreased from 162 times/147 months before IVIG treatment to 11 times/162 months after the treatment, and that the tympanogram was improved to type A in 76.3% of children with recurrent AOM [
      • Suetake M.
      • Endo H.
      • Shimoda H.
      • Oyama K.
      • Irumada M.
      • Wataya H.
      • Hozawa K.
      • Kobayashi T.
      • Tkasaka T.
      Immunoglobulin therapy for otitis-prone children.
      ]. It was also reported that the shorter the duration from the initial episode of AOM to the first IVIG treatment, the higher the rate of normalization of the tympanogram [
      • Suetake M.
      • Endo H.
      • Shimoda H.
      • Oyama K.
      • Irumada M.
      • Wataya H.
      • Hozawa K.
      • Kobayashi T.
      • Tkasaka T.
      Immunoglobulin therapy for otitis-prone children.
      ,
      • Ishizaka A.
      • Otsu M.
      • Kojima K.
      • Sakiyama Y.
      • Ozutsumi K.
      • Kikuta H.
      • Matsumoto S.
      Successful treatment of recurrent bacterial otitis media in infancy with intravenous immunoglobulin therapy.
      ].
      However, since immunoglobulin is a blood derivative, clinicians should respect parents or guardians’ preferences. It is requisite to obtain parents or guardian's consent, based on sufficient information, including information about the risk of viral contamination. In order to secure the safety of fractionated plasma products, the 2018 Guidelines conform to the Guidelines for Safety from Viral Contamination of Plasma Fractionated Products (August 30, 1999, Notification No. 1047 of the Pharmaceutical and Food Safety Bureau). Clinicians need to pay attention to the administration schedule of live vaccines as follows: clinicians should not inoculate live vaccines within 3 months after IVIG treatment, and when a patient has undergone IVIG within 14 days after administration of a live vaccine, additional live vaccines should be inoculated 3 months or more after the IVIG treatment.

      18. Treatment algorithms

      Generally recommended treatment algorithms, based on the severity of AOM, are shown in Fig. 6-8 and Table 12.
      Fig. 6
      Fig. 6Treatment algorithm for mild case (score 0–5).
      Fig. 7
      Fig. 7Treatment algorithm for moderate cases (score 6–11).
      Fig. 8
      Fig. 8Treatment algorithm for moderate cases (score 12≤).
      Table 12NOTE for treatment algorithms.
      • It is desirable to observe clinical findings on day 3 or day 4 to assess the treatment efficacy.
      • Acetaminophen (10–15 mg/dose) is the choice for children with otalgia or fever (≥ 38.5 °C ) .
      • Add topical nasal therapies for patients with rhinosinusitis (CQ 3–8).
      • Identify causative pathogens by a bacterial culture of the nasopharyngeal swab, MEE, or otorrhea.
      • Prescribe antimicrobial-resistant lactic acid bacteria preparation or clostridium butyricum preparation to prevent diarrhea along with antimicrobial prescription
      • Pay attention to hypoglycemia associated to secondary hypocarrnitinemia following treatment with pivoxil-containing antimicrobial agents.
      • * Consider myringotomy as a choice of treatment depending on clinicians’ specialty.
      • **Do not exceed 7 days of use (the regulation of the National Health Insurance System of Japan).
      • Do not exceed following dose;
        AMPC: 45/kg/dose, 90 mg/day
        CDTR-PI: 200 mg/dose, 600 mg/day
        TBPM-PI: 300 mg/dose, 600 mg/day
        TFLX: 180 mg/dose, 360 mg/day
      • Clinicians need to follow up the patients for at least 3 weeks from the first visit.
      Financial Support and Conflict of Interest
      Production of these Guidelines was funded by JOS operating expenses. The JOS does not receive support from any specific organizations or companies.
      All members of the committee conformed to the membership policies of clinical practice guidelines established by the Japanese Association of Medical Sciences (JAMS) [

      The Japanese Association of Medical Sciences. The JAMS COI management guidance on eligibility criteria for clinical practice guideline formulation2017; Available from:http://jams.med.or.jp/guideline/index.html.

      ], and there was no financial conflict in published research related to AOM.

      Acknowledgments

      The 2018 Guidelines were created by the members of the Subcommittee of Clinical Practice Guideline for Diagnosis and Management of Acute Otitis Media in Children composed of JOS, JSPO, and JSIAO.

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