Auris Nasus Larynx 44 (2017) 390–397
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Auris Nasus Larynx
journal homepage: www.elsevier.com/locate/anl

Randomized controlled trial of juzen-taiho-to in children withrecurrent acute otitis media§
Makoto Ito a, Yumiko Maruyama b, Ken Kitamura c, Toshimitsu Kobayashi d,Haruo Takahashi e, Noboru Yamanaka f, Yasuaki Harabuchi g, Hideki Origasa h,Tomokazu Yoshizaki i,*a

Department of Pediatric Otolaryngology, Tochigi Children’s Hospital, Jichi Medical University, Tochigi, Japan
Department of Otolaryngology, Kurobe Civic Hospital, Kurobe, Japanc
Department of Otolaryngology-Head and Neck Surgery, Tokyo Medical & Dental University, Tokyo, Japand
Department of Otolaryngology-Head and Neck Surgery, Tohoku University School of Medicine, Sendai, Japane
Department of Otolaryngology-Head and Neck Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japanf
Department of Otolaryngology-Head and Neck Surgery, Wakayama Medical University, Wakayama, Japang
Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japanh
Biostatistics and Clinical Epidemiology, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japani
Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Japanb

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 22 May 2016
Accepted 6 October 2016
Available online 31 October 2016

Objective: Recurrent acute otitis media (AOM) in young children is rapidly increasing worldwide.
Repeated antibiotic use leads to antibiotic-resistant pathogen development. Complementary andalternative medicine approaches have been suggested as a supplemental treatment option toconventional antimicrobial medicine. This randomized, parallel-group, open-label, non-herbal
medicine controlled trial assessed the efficacy of a traditional Japanese herbal medicine, juzentaiho-to (JTT) for AOM prevention in otitis-prone children.
Methods: Children prone to recurrent AOM aged 6–48 months were recruited from
26 otolaryngology clinics in Japan and received conventional AOM treatment based on Japaneseguidelines with or without 2 daily oral doses of JTT (0.10–0.25 g/kg/day). The mean number of
AOM episodes, coryza episodes, and duration of total antibiotic administration per month werecompared during 3-month intervention.
Results: At least one episode of AOM was diagnosed in 71% of JTT-group and 92% of control
participants during follow-up. JTT administration reduced the frequency of AOM episodes by 57%
compared with children who received conventional treatment alone (0.61  0.54 vs.
1.07  0.72 AOM instances/month; P = 0.005) and also significantly decreased number of coryza
episodes (P = 0.015) and total antibiotic administration (P = 0.024).
Conclusions: This is the first report of recurrent AOM prevention by herbal medication. JTT appears
to effectively prevent recurrent AOM in children. Subsequent double-blind studies are needed toconfirm the beneficial effects of JTT on recurrent AOM and upper respiratory tract infections.
ß 2016 Published by Elsevier Ireland Ltd.

Keywords:
Recurrent acute otitis media
Randomized controlled trial
Juzen-taiho-toJapanese herbal medicine (Kampo)§

Clinical Trial Registration: UMIN-CTR: ID: UMIN000002871.
Abbreviations: AOM, acute otitis media; CAM, complementary and alternative medicine; JTT, juzen-taiho-to; MEE, middle ear effusion; NKT, natural killer cells;
URT, upper respiratory tract.
* Corresponding author at: Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takaramachi,
Ishikawa, Kanazawa, Japan. Fax: +81 72 234 4265.
E-mail address: tomoy@med.kanazawa-u.ac.jp (T. Yoshizaki).
http://dx.doi.org/10.1016/j.anl.2016.10.002
0385-8146/ß 2016 Published by Elsevier Ireland Ltd.

M. Ito et al. / Auris Nasus Larynx 44 (2017) 390–397

1. Introduction
Otitis media is very common in children. By 2 years of age,most children (70%) experience at least one episode of acuteotitis media (AOM) [1–5]. A subpopulation of children,
representing 5–10% of the general population, are otitis-prone,
having experienced at least 3 separate episodes of AOM within
a 6 months, or more than 4 episodes in 1 year [6–8].
The increase in the number of otitis-prone children and therapid emergence of drug-resistant bacteria associated with
AOM are now generating increasing concern. b-Lactamasenonproducing ampicillin-resistant strains of Haemophilus
influenzae and penicillin-resistant Streptococcus pneumoniae
are particularly common and cause recurrent AOM in Japan [9–11]. In otitis-prone children, the effectiveness of repeatedantibiotic therapy for each new infection and prophylactic
antibiotic therapy to prevent AOM relapse is quite limited.
Furthermore, recurrent use of antibiotics leads to thedevelopment of antibiotic-resistant pathogens [12,13] and theimbalance of the normal nasopharyngeal bacterial flora[14]. Surgical insertion of a tympanostomy tube can have asignificant role in maintaining a ‘disease-free’ state [15–17],
but clinicians should consider the possible adverse effects ofgrommet insertion, such as transient or recurrent otorrhea,
tympanosclerosis, focal atrophy and persistent perforations
which may require repair.
In addition to these conventional treatments for AOM,
complementary and alternative medicine (CAM) approaches
have been suggested as a supplementary choice for thetreatment of recurrent AOM [18–20], because CAM treatments
such as herbal medicine and probiotics are commonly used totreat pediatric upper respiratory tract (URT) viral infections in
Europe, United States and Asia [21–23]. Viruses play animportant role in middle ear viral and following bacterial
infection because a URT viral infection usually precedes AOM.
Echinacea, Lactobacillus rhamnosus GG (probiotic), mao-to
and kakkon-to (herbal medicine) are considered to reduce therisk of acute URT infections [21,23–25], but no confirmative
evidence has shown that these products reduce the incidence ofrecurrent AOM [24,25].
The unique role played by traditional Japanese herbal
medicine, a type of pharmaceutical-grade multi-herbal medicine, is gradually attracting worldwide attention. More than
100 herbal medicines have been used clinically for centuries totreat a wide variety of diseases with very few side effects.
Despite, safety and tolerability of most CAM treatments are notprecisely defined, all Japanese herbal medicines are standardized and manufactured on a modern industrial scale under strict
scientific quality controls. Juzen-taiho-to (JTT) is one of theJapanese herbal medicines that comprises 10 different herbs,
and is administered to patients in various weakened conditions,
including post-surgery patients and patients with chronic
illnesses, where it can alleviate general symptoms such as
fatigue, pale complexion, anemia and loss of appetite[26,27]. JTT is used clinically to strengthen the immune
functions of patients with various diseases, including cancer,
hepatitis. JTT has been suggested to upregulate the hostimmune system [28–30] and reported to have therapeutic391

effects against bacterial infection such as perianal abscess[31]. A recent report suggested the beneficial effects of JTT in
reducing the episodes of AOM in otitis-prone children[32,33]. JTT has been known for lipopolysaccharides (LPS)like immunostimulatory activity [34,35]. JTT and LPS induce
similar gene expression profiles in monocytes [36,37]. Montenegro et al. suggested the emerging theory of bacterial
contribution to the immune-boosting activity of JTT, called‘‘herbal probiotics’’ [38].
JTT is composed of ten crude drugs, of which the quality iscontrolled by Japanese Pharmacopia XIII. JTT was prepared asfollows. A mixture of Astragali radix (3.0 g), Cinnamomi
cortex (3.0 g), Rehmanniae radix (3.0 g), Paeoniae radix(3.0 g), Cnidii rhizome (3.0 g), Atractylodis Lanceae rhizome(3.0 g), Angelicae radix (3.0 g), Ginseng radix (3.0 g), Hoelen(3.0 g), and Glycyrrhizae radix (1.5 g) was added to 285 ml ofwater and extracted at 100 8C for 1 h. The extracted solution
was filtered and the filtrate was spray-dried to obtain the dry
extract powder (2.3 g).
The aim of this study was to examine the possible effect of
JTT in reducing the incidences of recurrent AOM in young
children in a strict diagnostic framework. The primary andsecondary endpoints were to investigate whether JTT could
reduce the number of infectious episodes of AOM (primary
endpoint) as well as URT infection (coryza), the duration of
antibiotic administration and the number of children who
underwent tympanostomy tube insertion and time (days) until
tympanostomy tube insertion during the intervention in otitisprone children (secondary endpoints). We conducted arandomized, parallel-group, open-label, non-herbal medicine(conventional treatment only) controlled trial between December 2009 and October 2011 to assess the efficacy of JTT for theprevention of AOM in children with recurrent AOM.
2. Methods
2.1. Study settings
The study was conducted according to the principles of the
Declaration of Helsinki (as amended in Somerset West, South
Africa 1996) and was approved by the Institutional Review
Board at each participating university and hospital (Approval
No. 2009-032 5587). An independent external group was
appointed to monitor the study progress and the safety of theparticipants.
2.2. Subjects
Children aged 6–48 months who were otitis prone (asdocumented in their medical records) were recruited from
26 otolaryngology clinics including university hospitals, general
hospitals, and private clinics in Japan during December 2009 to
October 2011. Children with unwillingness to participate;congenital malformations of the ears, nose, or throat; known
allergy to JTT; or receiving immune therapy (e.g., immunoglobulin and steroids) or other Japanese herbal medicine were
excluded from the study. Children with tympanostomy tube
insertions were also excluded from the study.

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M. Ito et al. / Auris Nasus Larynx 44 (2017) 390–397

2.3. Randomization and intervention
After obtaining informed consent and assent, randomization
was performed. Children were randomly assigned to one of
2 groups by permuted block design using an Internet-based
central registration system (Captool, Mebix Inc., Tokyo,
Japan). One group received JTT and conventional treatment
based on the Japanese guidelines for AOM [33], and the control
group received conventional treatment only. JTT (Tsumura &Co. Ltd., Tokyo) at 0.10–0.25 g/kg/day was orally administered
twice per day for 3 months. No restrictions were imposed onconventional treatments for AOM, including tympanostomy
tube insertion or any other disease. After enrollment, children
were prospectively followed for 3 months while JTT was
administered. The intervention was considered failed if thechild received tympanic ventilation tube insertion within
1 month after enrollment (Fig. 1).
2.4. Clinical definition of AOM and treatment
Before starting the study, background information on eachchild’s health, nutrition, day care attendance, passive smoking,and history of respiratory disease was acquired through aquestionnaire. AOM was diagnosed by an otolaryngology
specialist based on examination of general and tympanic
findings according to Japanese clinical practice guidelines for
AOM [26]. AOM was diagnosed when one of the following
tympanic membrane findings were recognized: hyperemia,
protrusion, diminishment of the light reflex, thickening, bullae
formation, cloudiness (turbidity), perforation of the tympanic

membrane, middle ear effusion (MEE), otorrhea, and edema of
middle-ear mucosa. Symptoms indicative of acute middle ear
inflammation were otalgia, otorrhea, fever, and crying and/or
bad temper.
Recurrent AOM, ‘‘Otitis-prone’’, was defined as experiencing at least 3 separate episodes of AOM within a 6-month
period or more than 4 episodes in 1 year [6–8]. Children
received confirmation follow-up examination by otolaryngologist to ensure recovery of the AOM. A new episode of AOM
was diagnosed when the child, after completing treatment with
antibiotics and experiencing a period with no clinical signs ofAOM, presented new symptoms and otoscopic findings of
AOM. Throughout the study, the parents kept a daily diary toreport the symptoms of acute URT inflammation, coryza (fever,cough, rhinitis, nasal discharge, sore throat), and middle ear
infections; the use of medication including antibiotics; andvisits to doctors.
The treatment of AOM was based on Japanese clinicalpractice guidelines throughout the study period, including
recommended antibiotics for AOM (amoxicillin is the first-line
antibiotic) in all children [33].
2.5. Outcomes
The primary study outcome was the mean number of AOM
episodes per month during the 3-month intervention. As
secondary outcomes, we assessed the mean number of coryza
episodes, mean duration (days) of total antibiotic administration, and the number of children who underwent tympanostomy
tube insertion and time (days) until tympanostomy tube[(Fig._1)TD$IG]

Fig. 1. Flow chart showing the enrollment of subjects. Eighty-seven children who fulfilled the criteria were enrolled in the study. Thirteen children dropped out due tothe lost to follow-up (n = 10), adverse effects (n = 1), and refusal from a patient (n = 2) during the 12 week follow-up period. Additionally, a total of 4 children
dropped out due to non-compliance (n = 2), tympanostomy (n = 1), and adverse effects (mild diarrhea) (n = 1).

M. Ito et al. / Auris Nasus Larynx 44 (2017) 390–397

insertion. Each parameter was calculated as the mean number
in 30 days (number per month). Because insertion of
tympanostomy tubes was effective in preventing recurrent
AOM, the value of each parameter before tube insertion was
calculated in cases with tube insertion at least 1 month after
enrollment.
2.6. Statistical analysis
The mean number of recurrent AOM episodes in Japan was
expected to be 4.75 times per month according to previous
data (bilateral AOM was counted as 2 times in the study)[32]. Use of JTT would reduce it to 3 times per month with arelative reduction of 37%. Assuming that the standard
deviation is 3 times per month, a total of 94 participants
were necessary to detect the difference with 80% power.
Analysis was performed according to the intention-to-treat
principle.
Student’s t-test or chi-square test was applied forcomparisons of baseline characteristics between the 2 groups.
Endpoints were compared between the 2 groups by using
Wilcoxon’s rank-sum test, except for the number of tube
insertions, which was tested by using Fisher’s exact test, and theduration until tube insertion, which was tested by using logrank test. P < 0.05 was considered significant. Data wereanalyzed using SAS software version 9.2 (SAS Institute, Tokyo,
Japan) by Clinical Study Support, Inc. (Nagoya, Japan). We
also analyzed the independent association between AOM
episodes (primary study outcome) and several factors using themultivariate logistic regression analysis. Odds ratios (ORs)with 95% confidence intervals (CI) were presented. Statisticalanalyses were carried out by using Esumi Excel multivariate
analysis, version 5.0 (Esumi Corp, Tokyo, Japan), with asignificance threshold of 0.05.

393

3. Results
3.1. Participant flow
Eighty-seven children who fulfilled the criteria wereenrolled in the study (47 boys, 40 girls; median age,
17.0 months; mean age, 18.71 months; range 8–41 months)
and randomly allocated to one of the treatment groups (Fig. 1).
A total of 13 children dropped out owing to the lost to follow-up(n = 10), adverse effects (n = 1), and refusal from a patient(n = 2) during the 12 week follow-up period. One child in JTT
treatment group dropped out with an adverse effect of slightskin eruption, but no apparent side effects were observed during
the study. Additionally, a total of 4 children dropped out due tonon-compliance (n = 2), tympanostomy (n = 1), and adverse
effects (mild diarrhea) (n = 1).
The groups demonstrated no differences in pre-treatment
characteristics including number of participants in each group,
sex, mean age, mean weight, frequency of AOM episodes, typeof day care, or passive smoking in the household. Table 1-1
shows pre-treatment characteristics in intention-to-treat (ITT)cases and Table 1-2 shows protocol compatible (PC) cases.
3.2. The effect of JTT treatment on the occurrence of recurrent
AOM and coryza
3.2.1. Primary outcome
At least one episode of AOM was diagnosed in 71% of JTTgroup and 92% of control participants during follow-up. The
mean number of AOM episodes in each month (1M; 0–4 w, 2M;
5–8 w, 3M; 9–12 w) was 0.81, 0.58, and 0.39 in the JTT groupand 1.31, 0.72, and 0.93 in the control group. The frequency of
AOM gradually decreased during the administration of JTT(Fig. 2a).

Table 1Baseline characteristics and the number of AOM episodes before the intervention. (1-1) shows pre-treatment characteristics in intention-to-treat (ITT) cases and (1-2)
shows protocol compatible (PC) cases.

(1-1)
Sex (male:female)
Mean age (months)
Mean weight (kg)
AOM episodes (instances/month)Type of day careDay-care center
Smoking in the household(1-2)
Sex (male:female)
Mean age (months)
Mean weight (kg)
AOM episodes (instances/month)Type of day careDay-care center
Smoking in the household

JTT group ITT (n = 39)

Control group ITT (n = 48)

P value*

17:22
17.87  6.17
10.28  1.57
1.17  0.60

30:18
19.40  7.64
10.41  1.87
0.98  0.57

0.08
0.31
0.72
0.10

21
11

30
14

0.73
0.99

JTT group PC (n = 31)

Control group PC (n = 39)

P value*

14:17
17.29  5.28
10.22  1.38
1.17  0.60

25:14
20.13  8.03
10.73  1.94
0.98  0.57

0.15
0.29
0.21
0.10

18
10

27
14

0.27
0.81

The study groups did not significantly differ in pre-treatment characteristics including number of patients in each group, sex, mean age, mean weight, instances of
AOM episodes, type of day care, or passive smoking in the household[1_TD$IF].
*
P 0.05 was considered significant.

[(Fig._2)TD$IG]

M. Ito et al. / Auris Nasus Larynx 44 (2017) 390–397

394

Fig. 2. Mean number of infection episodes of AOM and coryza and duration of antibiotic administration during the intervention. The frequency of AOM and coryza
and the duration of antibiotic administration gradually decreased during administration of JTT.

Table 2
Mean number of episodes of the primary and the secondary outcome after the 3-month intervention in the JTT and control groups.

AOM episodes (instances/month)Coryza episodes (instances/month)
Antibiotic treatment (days/month)
Number of tube insertions
Duration until tube insertion

JTT group PC (n = 31)

Control group PC (n = 39)

P value*

0.61  0.54
1.10  0.62
4.99  3.21
2
81.8  0.27

1.07  0.72
1.56  0.83
8.10  5.87
4
67.1  0.84

[2_TD$IF]0.005*[3_TD$IF]0.015*[4_TD$IF]0.024*
0.68
0.46

Oral administration of JTT for 3 months reduced the frequency 1 of AOM episodes by 57% compared with the control group. JTT also reduced both the number ofcoryza episodes and total days of antibiotic administration after the 3-month administration of JTT[.5_TD$IF]*
P 0.05 was considered significant.

Children in the JTT group had significantly fewer total
episodes of AOM than the control group after the 3-monthintervention. (Wilcoxon rank-sum test, P = 0.005) (Table 2).
Mean and standard deviation of the frequency of AOM in the
JTT and control groups were 0.61  0.54 and1.07  0.72 instances/month, respectively (Fig. 2a). Oraladministration of JTT for 3 months reduced the frequency of
AOM episodes by 57% compared with children who received
only conventional treatment.

Table 3
Multivariate logistic regression analysis of AOM episodes and several factors
including JTT treatment, sex, age, weight, type of day car e and passive smoking
in the household.
OR[6_TD$IF]Treatment ([7_TD$IF]JTT: [8_TD$IF]Control)Sex (male:female)Age (months): pre-treatment
Weight (kg): pre-treatment
Type of day careDay-care center
Smoking in the household

P value*

95% CI
Lower

Upper

6.76
0.90
0.92
0.95

1.17
0.19
0.79
0.53

38.93
4.40
1.07
1.70

[9_TD$IF]0.032*
0.900
0.298
0.873

1.96
1.75

0.30
0.36

12.76
8.42

0.481
0.485

Multivariate analysis showed that JTT treatment (OR = 6.76, P = 0.032) was the
only independent factor of reducing AOM episodes[10_TD$IF].
*
P 0.05 was considered significant.

Multivariate analysis showed that JTT treatment(OR = 6.76, P = 0.032) was the only independent factor of
reducing AOM episodes (Table 3).
3.2.2. Secondary outcomes
The secondary outcomes were mean number of coryza
episodes, mean duration of total antibiotic administration, andthe number of children who underwent tympanostomy tube
insertion. The frequency of coryza and duration of antibiotic
administration tended to gradually decrease during the oral
administration of JTT (Fig. 2b and c).
The mean number and standard deviation of coryza episodes
and the mean duration of antibiotic administration after the 3month intervention were 1.10  0.62 instances/month and4.99  3.21 days/month in the JTT group compared to1.56  0.83 instances/month and 8.10  5.87 days/month in
the control group, respectively. The use of JTT significantly
decreased both the number of coryza episodes (Wilcoxon ranksum test, P = 0.015) and the total days of antibiotic
administration after the administration of JTT for 3 months(Wilcoxon rank-sum test, P = 0.024) (Table 2).
Two patients in the JTT group and 4 patients in the control
group received ventilation tube insertion due to recurrent AOM
during the follow-up period. The mean duration (days) until
tube insertion was 81.8 days in the JTT group and 67.1 days in
the control group. No significant difference was observed in theM. Ito et al. / Auris Nasus Larynx 44 (2017) 390–397

median number of ventilation tube insertions (Fisher’s exact
test, P = 0.68) or the duration until tube insertion (log-rank test,
P = 0.46) between the JTT and control groups (Table 2).
4. Discussion
The rapid increase of otitis-prone young children is now
emerging worldwide. In such children, the effectiveness of
repeated antibiotic therapy for each new infection andprophylactic antibiotic therapy for the prevention of AOM
relapse is quite limited. We found that prophylactic 3-months
treatment with JTT significantly reduced the risk of recurrent
AOM (primary endpoint), coryza, and the mean duration of
antibiotics administration in children (secondary endpoints)
younger than 4 years old. Our study recommends that it isvaluable to treat otitis-prone young children with JTT for
3 months.
Most episodes of AOM are preceded after URT infections,and AOM is the most common diagnosis for which antibiotics
are prescribed for children [39]. In our study, the frequency ofrecurrent AOM decreased in the JTT cohort, and simultaneously the JTT cohort showed significant improvement incoryza and total antibiotic administration. Nasopharyngeal
colonization with resistant strains of 3 major AOM pathogens,
Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis is frequent in otitis-prone
children and is directly associated with the frequency of AOM.
Thus, with conventional antimicrobial treatment for AOM,
some patients still suffer from recurrent AOM infection.
Antibody responses to the 3 pathogens following AOM aregenerally reduced in the first 2 years of life and rise rapidly
thereafter. Consequently, there is a role in using such additional
treatments including herbal medication along with conventional antibiotics in children with recurrent AOM under 2 years old.
Otitis-prone children appear to display a subtle immunologic abnormality that predisposes them to recurrent infections.
Otitis-prone children, during the first several years of life, havebeen reported to demonstrate poor immune system response
and the development and immaturity of the acquired immune
system, such as lower serum IgG2 levels [40] and low
concentration of serum anti-P6 IgG [41]. Immaturity ofacquired immune function is a major reason why the majorityof otitis-prone patients are under 2 years of age. The
pneumococcal conjugate vaccine (PCV 7) is effective in young
children, but only 7 serotypes are covered with this conjugate
vaccine. Therefore, vaccine strategies are not yet consideredsuccessful for AOM and recurrent AOM in children. Although
tympanostomy tube insertion is effective for the prevention ofrecurrent AOM in children [12,13], it is accompanied by thepossible adverse effects of tympanostomy tube insertion, suchas transient or recurrent otorrhea, tympanosclerosis, focal
atrophy and persistent perforations which may require surgicalrepair.
JTT is one of the traditiona1 Japanese herbal medicines thathas been used among Japanese people for long time to treat
patients in various weakened conditions. The Japanese Ministryof Health and Welfare has approved 148 Japanese herbal
prescription drugs including JTT for reimbursement under the395

National Health Insurance system. Recently, basic and clinicalresearch has demonstrated the effect of Japanese herbal
medicines that justify their wider use [29,42,43]. JTT is known
to increase immunity by enhancing immuno-associatedmechanisms such as phagocytosis, cytokine production,
antibody production, and the mitogenic activity. Moreover,accumulating evidence indicates that JTT upregulates a varietyof immune system functions by modulating the production ofcytokines, including IL-12 in macrophages and IL-2, 4, 5, andIFN-g in lymphocytes [28,29,42]. JTT has been known for
lipopolysaccharides (LPS)-like immunostimulatory activity[34,35]. JTT promotes LPS-induced IL-12 production andincreases natural killer (NKT) cells population [28,29].
JTT positively affects not only acquired immunity but also
innate immunity [29]. Recently, Muranaka et al. suggested that
JTT affects general immunity indirectly, presumably throughinteraction with the gut local immune system [44]. The
intestinal microflora might be considered to play a certain rolein eliciting the beneficial effects of JTT and other herbal
medicines. Furthermore, the current study supports the newtheory of the bacterial contribution in immune-boosting herbs(so called ‘‘herbal probiotics’’ theory). Montenegro et al.
suggested a possibility that Rahnella species are enriched in
JTT and contribute to its immunostimulatory activity [38].
Although the mechanism of JTT against recurrent AOM has
not yet been clarified, further investigations are needed to verify
the mechanisms of JTT. In the onset and progression ofbacterial and viral infections, increased host immune function
may be a viable alternative approach for treatment.
The current results of our study indicate that JTT provides a
new strategy for the treatment of otitis-prone children. The
limitation of this study was that it was an open label trial. In
addition, we could not use a blind assessor in the present study,
because there was only one doctor in each participating private
clinic. Although the beneficial results of JTT could be due to a
Hawthorne (placebo) effect, this situation stresses theimportance of continued investigations with placebo-controlled trials. We are preparing subsequent double-blindstudies to clarify the effect of JTT on recurrent AOM and
URT infections.
5. Conclusion
JTT appears to be an effective treatment for otitis-prone
children, and avoiding the overuse of antibiotics will help
prevent the emergence of drug-resistant bacteria. This study isthe first to report that the incidence of recurrent AOM is reducedby herbal medicine. JTT does not completely prevent the risk ofrecurrent AOM, but even reducing the incidence can be helpful
not only for the child but also for the family. We hope our next
study will further identify the mechanisms and confirm thebeneficial effects of this herbal medicine.
Funding sourceThis study was supported by Grants-in-Aid from the
Ministry of Health, Labor and Welfare (#H21-clinicalresearch-general-007).

M. Ito et al. / Auris Nasus Larynx 44 (2017) 390–397

396

Financial disclosure statement
The authors have no financial relationships to disclose.
Conflict of interest statement
The authors have no conflict of interest with any otherpeople or organizations.
Acknowledgments
We wish to thank Drs Tatsuya Hayashi, Isamu Kunibe,
Yoshihiro Noguchi, Muneki Hotomi, Akihisa Togawa, Satomi
Fukuda, Naohiro Okitsu, Atsuko Nakano, Yukiko Arimoto,Takayo Omura, Yoshihiro Manabe, Yukako Goto, Yosuke
Kamide, Fumihiro Kamide, Shigeki Matubara, Yoshifumi Uno,
Keiko Kanesada, Akihiro Uchizono, Akimitsu Kawai, Isao
Horikawa, Chikako Kayama, Noriko Morimoto, Fumiyo Kudo,
Yoshito Honma, Yasunari Iwanaga, Yukio Watanabe, andKoichi Sakamoto for their valuable efforts, and the participating children and their parents for allowing us to conduct the
study. Mebix Inc. (Tokyo, Japan) coordinated as data
coordinating center.
We also thank the Data and Safety Monitoring Board(DSMB), which includes Kenji Suzuki (Department ofOtolaryngology, Banbuntane Houtokukai Hospital, Fujita
Health University), Shingo Murakami (Department of
Neuro-otolaryngology, Nagogo City University Graduate
School of Medical Science), and Tatsuya Isomura (ClinicalStudy Support (CSS), Inc. Nagoya, Japan).
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