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.
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 [
[143]- 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 [
[144]- 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.
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 [
[21]- 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 [
[145]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 [
[146]- 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 [
[147]- 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.
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 [
[148]- 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) [
[149]- 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 [
[150]- 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 [
[151]- 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 [
[152]- 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 [
[33]- 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. [
[19]- 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) [
[20]- 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 [
[77]- 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 [
[153]- 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 [
[142]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.
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 [
[9]- 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 [
[154]- 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 [
[15]- 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 [
[14]- 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 [
[87]- 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 [
155- 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.
,
156- Del Mar C.
- Glasziou P.
- Hayem M.
Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis.
,
157The 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 [
[158]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 [
[77]- 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 [
[21]- 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) [
[33]- 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 [
[159]- 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% [
[160]- 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% [
[18]- 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.
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 [
[161]- 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 [
[162]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 [
[163]- 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. [
[9]- 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 [
[83]- 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 [
[31]- 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 [
[164]- 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 [
[33]- 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 [
[165]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 [
[166]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.
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 [
[167]- 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 [
[168]- 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 [
[169]- 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 [
[170]- 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 [
[171]- 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 [
[172]- 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.
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 [
[173]- 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 [
[174]- 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 [
[175]- 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 [
[176]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 [
[177]Histamine H1 antagonists and clinical characteristics of febrile seizures.
]. Furthermore, antihistamines have been listed among potential candidate causes of acute encephalopathy in children [
[178]- 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
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 [
[179]- 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 [
[180]- 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 [
[181]- 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 [
[182]- 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 [
[179]- 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 [
[32]- 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.
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 [
[183]- 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 [
184- 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.
,
185- 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.
,
186- 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 [
[187]- 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 [
[163]- 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 [
[188]Effects of long-term tympanostomy tubes in children with intractable otitis media.
,
[189]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) [
[190]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 [
[191]- 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 [
[98]- 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 [
[192]Tympanostomy tubes in the otitis media prone child.
,
[193]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 [
[194]- 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.
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 [
[102]- 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) [
[101]- 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.
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) [
[195]- 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 [
[94]- 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 [
[196]- 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 [
[196]- Suetake M.
- Endo H.
- Shimoda H.
- Oyama K.
- Irumada M.
- Wataya H.
- Hozawa K.
- Kobayashi T.
- Tkasaka T.
Immunoglobulin therapy for otitis-prone children.
,
[197]- 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.