Review

Medical prevention of
recurrent acute otitis media:
an updated overview
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14

Expert Rev. Anti infect. Ther. 12(5), 611–620 (2014)

Paola Marchisio1, Acute otitis media (AOM) is one of the most common pediatric diseases; almost all children
Erica Nazzari1, experience at least one episode, and a third have two or more episodes in the first three years
Sara Torretta2, of life. The disease burden of AOM has important medical, social and economic effects. AOM
requires considerable financial assistance due to needing at least one doctor visit and a
Susanna Esposito*1,2
prescription for antipyretics and/or antibiotics. AOM is also associated with high indirect costs,
and Nicola Principi1 which are mostly related to lost days of work for one parent. Moreover, due to its acute
1
Department of Pathophysiology and symptoms and frequent recurrences, AOM considerably impacts both the child and family’s
Transplantation, Pediatric Highly
quality of life. AOM prevention, particularly recurrent AOM (rAOM), is a primary goal of pediatric
Intensive Care Unit, Università degli
Studi di Milano, Fondazione IRCCS Ca’ practice. In this paper, we review current evidence regarding the efficacy of medical treatments
Granda Ospedale Maggiore Policlinico, and vaccines for preventing rAOM and suggest the best approaches for AOM-prone children.
Milan, Italy
2
For personal use only.

Department of Clinical Sciences and
Community Health, Otorhinolaryngology
Unit, Università degli Studi di Milano,
Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, Milan, Italy
*Author for correspondence:
Tel.: +39 025 503 2498
Fax: +39 025 032 0206
susanna.esposito@unimi.it
KEYWORDS: acute otitis media • antibiotic prophylaxis • complementary and alternative medicine • otitis media
• prevention • probiotics • recurrent acute otitis media • vaccine • vitamin D • xylitol
Acute otitis media (AOM) is one of the most
common pediatric diseases. By the age of 3,
almost all children have experienced at least
one episode of AOM and one-third experi-
enced two or more episodes [1,2]. In general,
single, isolated episodes of AOM have a mod-
erate clinical impact and do not cause social
and economic problems to both the child and
family. AOM is usually mild and often spon-
taneously resolves in a short period of time.
AOM complications are mainly due to tym-
panic membrane perforation, which usually
resolves itself in a few days without any rele-
vant sequelae. AOM complications are rarely
due to severe clinical problems such as mas-
toiditis, meningitis or brain abscesses.
AOM often recurs, however, resulting in sig-
nificant medical, social and economic effects. In
this case, the impact of AOM on health systems
is particularly significant due to the high num-
ber of AOM cases, which require many medical
visits as well as repeated antipyretic and antibi-
otic prescriptions and for the increased risk for
complications and hospitalization [3–5]. More-
over, repeated episodes of AOM are associated
with high indirect costs, which are related
primarily to lost work days for the parent stay-
ing home with the ill child [6]. Finally, the qual-
ity of life of both the child and family is
significantly reduced; a child that is frequently
ill cannot attend daycare or participate in typical
activities, and parents experience increasing con-
cern with each attack.
Thus, AOM prevention in subjects who have
already experienced several AOM episodes
remains a primary goal of pediatric care [7,8].
Conventionally, treatments for reducing the risk
for AOM are recommended for children who
have already suffered from three AOM episodes
in the last 6 months or four episodes in the last
year [9]. In these children, AOM is defined as
recurrent AOM (rAOM) [10], and several pro-
phylactic methods have been suggested. AOM
prophylaxis starts with a wait-and-see approach
by evaluating individual characteristics or envi-
ronmental factors that are frequently associated
with rAOM. Etiologic AOM characteristics
are also considered. Many medical or surgical
interventions for AOM are available, but their
importance remains controversial.
Here, we review the efficacy of current
AOM medical treatments, except for surgical
AOM prophylaxis [11], and vaccines.
Reducing child-specific risk factors
Certain child-specific risk factors are associated
with the onset of a first episode of AOM in a
child without previous ear problems or new

informahealthcare.com 10.1586/14787210.2014.899902
2014 Informa UK Ltd ISSN 1478-7210 611

 Review Marchisio, Nazzari, Torretta, Esposito & Principi
AOM episodes in children with rAOM. Specific interventions
can reduce these risk factors, thereby decreasing the risk for
developing AOM. Modifiable factors include daycare atten-
dance, bottle-feeding, secondhand smoke exposure and pacifier
use [12–14], and the reduction of these factors are part of a wait-
and-see approach. Unfortunately, the risk of other factors
associated with an increased AOM risk cannot be reduced,
including prematurity, the presence of siblings (i.e., family
size), allergies and craniofacial abnormalities.
Studies have shown that staying at home instead of attending
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14
daycare could prevent one of five AOM episodes in the general
pediatric population and two of five in children with
rAOM [15]. Moreover, when daycare center hygiene measures
(i.e., hand washing, use of alcoholic solutions) were systemati-
cally used, AOM episodes decreased by 27% [16].
Breastfeeding is also associated with reduced AOM inci-
dence. AOM incidence was shown to be inversely related to
breastfeeding rates after 3 months of age. A meta-analysis [12]
found that prolonged breastfeeding for at least 3 months
reduced the risk for AOM by 13% (relative risk [RR]: 0.87;
95% CI: 0.79–0.95). In addition, in one study, none of the
children who were breastfed until 6 months of age developed
AOM in the first year of life [17]. The cumulative incidence of
the first AOM episode between 6 and 12 months also increased
For personal use only.
from 25 to 51% in infants who were exclusively breastfed
compared to 54–76% in infants who were formula-fed [18].
However, quantifying the protective effect of breastfeeding is
not possible due to varying definitions of breastfeeding between
studies, and how long this protective effect persists after wean-
ing remains unknown. Additional studies are needed to address
these questions, but it should be noted that the global advan-
tages of breastfeeding suggest that children should be breastfed
for at least the first 6 months of life or as long as possible.
Several studies have also shown that exposure to secondhand
smoke increases the risk for AOM with the number of AOM
recurrences directly related to the amount of cigarettes smoked
by the parents. Strong exposures can increase the risk for
rAOM by 50–70% [19–21]. Because secondhand smoke is associ-
ated with several respiratory problems besides AOM, interven-
tions to reduce environmental tobacco smoke exposure among
children have been implemented worldwide [22,23]. Quantifying
the advantages of these interventions on rAOM incidence is
lacking but should not detract from the importance of address-
ing secondhand smoke.
The use of devices such as the pacifier and plastic push-and-
pull bottle caps can induce harmful nasopharyngeal pressure,
thereby increasing the reflux of secretions from the nasopharynx
into the Eustachian tube. This has also been associated with an
increased risk for AOM. Most of this data have been collected
in children using pacifiers. In one study, the risk for AOM in
children increased by 24% among those who routinely used
pacifiers (RR: 1.24; 95% CI: 1.06–1.46) [12]. This observation
was confirmed by another study that showed that pacifier use
often or sometimes was an AOM risk factor (RR: 1.3; 95% CI:
0.9–1.9) [24]. Last, among families that were given adequate
612
information on pacifier use, a 29% reduction in AOM inci-
dence was observed [25]. The habitual use of plastic push-and-
pull bottle caps was also more frequent among children with a
history of rAOM (50.0%) compared to a control group
(24.2%; p = 0.047) even after adjusting for age [26], which high-
lights the potential role of plastic push-and-pull caps as a
rAOM risk factor.
Reducing AOM-related etiology factors
Vaccines
AOM is caused by bacteria in more than 70% of the cases;
Streptococcus pneumoniae (Sp), in particular, is the pathogen
most frequently isolated from the middle-ear fluid of children
with AOM. Thus, the pneumococcal conjugate vaccine
(PCV7), which evoked protective immune responses in younger
children, was considered a good opportunity for preventing
AOM in general as well as rAOM [27]. Moreover, because
many AOM cases are preceded by viral respiratory infections
(such as influenza), influenza vaccines, which can prevent many
influenza episodes, could also limit the risk of AOM in chil-
dren, including those with rAOM [28]. However, data on
whether both these vaccines are effective for reducing AOM
risk in the pediatric population remain less than convincing.
Administering PCV7 in the first year of life (according to
recommended vaccination schedules) significantly reduced the
incidence of rAOM episodes as well as the number of required
pressure-equalizing tube insertions (a surgical procedure aimed
at preventing future AOM episodes in children with rAOM)
[28–32]. However, administering PCV7 later in children already
suffering from rAOM had no effect on AOM develop-
ment [33,34]. In this case, PCV7 inefficacy was ascribed to the
poor effect that late PCV7 administration has on pneumococci
nasopharyngeal colonization [34]. Recent studies have found
that suboptimal memory B- and T-cell responses and immature
antigen-presenting cells may play a significant role in the pro-
pensity for rAOM. One group has shown that the immuno-
logic characteristics of AOM-prone subjects resembled those of
neonates [35–37]. In particular, these children suffered from three
or more episodes of AOM in the past 6 months or four or
more in the past year despite individualized AOM care and
had defective immune responses to vaccines, including PCV7
[35,38]. This suggests that the rAOM risk reduction caused by
PCVs is limited to children who do not experience delayed
immune system maturation. However, it is reasonable to posit
that the recent introduction of PCVs with a greater number of
serotypes (PCV10 and PCV13) could further increase AOM
protection in all children, including those with rAOM and
delayed immune development through herd immunity. Prelimi-
nary data regarding general AOM prevention show promise
for these vaccines, particularly PCV13 [39]. PCV13 is the only
PCV that includes serotype 19A, a serotype recently identified
as the most important cause of severe pneumococcal disease,
including mastoiditis [40]. Moreover, PCV10 was shown
to modify pneumococcal nasopharyngeal carriage similarly to
PCV7, while PCV13 significantly reduced the carriage of
Expert Rev. Anti infect. Ther. 12(5), (2014)

serotypes 1, 6A, 7F, 6C, 19A and 19F [41]. Thus, the use of
PCV13 has been predicted to decrease the total number of
pneumococcal AOM cases from 53 to 19% in just few years,
and the global reduction in pneumococcal AOM could reach
as low as 2.7% [42].
Similar conclusions can be drawn from the studies evaluating
the impact of influenza vaccines on AOM incidence in chil-
dren. Most studies have examined all available influenza vaccine
preparations (i.e., the traditional inactivated trivalent vaccine
[TIV], some adjuvanted vaccines and the live attenuated vac-
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14
cine). Each preparation was able to reduce AOM incidence in
vaccinated subjects when they were administered before influ-
enza season began [43–46]. Despite the total number of children
with rAOM enrolled in these studies was low, the impact of
influenza vaccines on children with rAOM can be considered
positive. In a study using an intranasal inactivated influenza
vaccine (not currently marketed), vaccination prevented AOM
in 43.7% of children with rAOM (95% CI: 18.6–61.1%;
p = 0.002) [47]. Moreover, the cumulative duration of middle-
ear effusion was significantly lower in vaccinated children than
in controls. Another study using a virosomal-adjuvanted TIV
reported that significantly fewer vaccinated children with
rAOM experienced at least one AOM episode (49/90, 54.4%,
vs 74/90, 82.2%; p < 0.001). In addition, the mean number of
For personal use only.
AOM episodes, episodes without perforation, duration of bilat-
eral otitis media with effusion and antibiotic courses were all
significantly lower in the vaccinated children [48]. However,
some children with rAOM do not seem to adequately respond
to influenza vaccine administration. In the virosomal-adjuvanted
TIV study, a positive response to the vaccine occurred more fre-
quently in children with rAOM who had no history of tym-
panic membrane perforation compared to those who had
repeatedly experienced this complication (efficacy in children
with recurrent spontaneous othorrea: 19%; p = 0.07; efficacy in
children without recurrent spontaneous othorrea: 47.6%;
p < 0.001). This is consistent with the presence of various sub-
groups among children with rAOM who could experience
reduced global influenza vaccine efficacy. However, because a
defective antibody response to several vaccines has been found
in children with rAOM [35], it is also possible that those with
reduced antibody responses could more frequently experience
complicated disease and respond poorly to the administration of
influenza vaccines.
Probiotics
Oral probiotics
Probiotics are live microorganisms that offer health benefits by
modulating an individual’s microbial community and enhanc-
ing host immunity. Several such microorganisms have been
identified, but only a few have been extensively studied. The
available data suggest that each of these bacteria has different
properties and exerts different prophylactic actions [49,50]. Most
of probiotics are administered orally, and commercial prepara-
tions are based on single microorganisms of multiple bacteria.
Studies that have evaluated probiotic efficacy against infections
informahealthcare.com
Medical prevention of rAOM Review
have mainly examined patients with gastrointestinal diseases
and clearly demonstrated that administering some of these bac-
teria can significantly reduce the risk of developing antibiotic-
associated diarrhea [51]. However, with a few exceptions [52],
respiratory infection data, particularly AOM data, are scarce
and often controversial. In general, any reduction in respiratory
infection incidence observed in children receiving probiotics
was marginal at best [50–57].
One study found that the recurrence of AOM in children
receiving a daily probiotic capsule (which contained Lactobacil-
lus rhamnosus GG and LC705, Bifidobacterium breve 99 and
Propionibacterium freudenreichii JS) was similar to that of chil-
dren receiving placebo [55]. Administering probiotics did not
modify the nasopharyngeal carriage of Sp or Haemophilus influ-
enzae and actually increased the carriage of Moraxella catarrhalis
(odds ratio = 1.79). Similar conclusions were obtained in a
double-blind, placebo-controlled trial where healthy infants
(aged 7–13 months) were randomly assigned to a follow-up
formula supplemented with probiotics (Streptococcus thermophi-
lus NCC 2496, Streptococcus salivarius DSM 13084 and
L. rhamnosus LPR CGMCC 1.3724) and prebiotics (Raftilose/
Raftiline) or follow-up formula alone [57]. During the 12-month
study period, the treated and control groups did not experience
different incidences in AOM occurrence (incidence rate ratio
[IRR]: 1.0; 95% CI: 0.8–1.2), in lower respiratory tract infec-
tions (IRR: 0.9; 95% CI: 0.7–1.2) or in the number of antibiotic
treatment courses (IRR: 1.0; 95% CI: 0.8–1.2) which were
mainly prescribed for AOM. Furthermore, nasopharyngeal flora
composition did not differ between the two groups any time
during follow-up.
These data clearly indicate that, at the moment, probiotic
administration cannot be considered a rAOM prophylactic
method, and further studies are needed. In particular, the role
of a single organism and the importance of simultaneous
administration of more than one probiotic organism should
be investigated.
Topical probiotics
Topical probiotic administration via a nasal spray has also been
considered as a method for reducing the risk of rAOM in chil-
dren. The most studied microorganism is a-hemolytic Strepto-
coccus (AHS), an infectious agent with low infectivity and that
could interfere with the survival and multiplication of patho-
gens carried in the nasopharynx and more frequently associated
with AOM [58].
However, despite initially positive results [59], rAOM prophy-
laxis via topical AHS administration has been rapidly aban-
doned due to the fear that AHS could cause infection as well
as findings from a well-conducted study [59]. One study ran-
domized 43 children to 4 months of a daily nasal spray (10%
skim milk and 0.9% NaCl) with or without five AHS
strains [60]. The proportion of children with rAOM episodes
was similar between the two groups (AHS: 44%; placebo:
40%), and no significant changes in otopathogen nasopharyn-
geal colonization were detected.
613
 Review Marchisio, Nazzari, Torretta, Esposito & Principi
More recently, attention has focused on Streptococcus salivar-
ius, an AHS isolated from healthy individuals that has never
been demonstrated to cause infection. S. salivarius is a potential
nasopharyngeal probiotic because of its immunomodulatory
and anti-inflammatory properties, its production of plasmin-
encoded bacteriocins and its good safety profile [61]. Studies
regarding the topical use of S. salivarius are ongoing. Prelimi-
nary results are promising, but no definite conclusions can be
drawn at this time [61,62].
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14
Xylitol
Xylitol is a pentitol (i.e., a 5-carbon polyol sugar alcohol) that
can be found in fruits such as plums, strawberries, raspberries
and rowan berries. It is a sweetener that does not cause teeth
caries and is widely used in chewing gums, confectionery,
toothpaste and medicines. Previous studies have shown that
1 and 5% xylitol could markedly reduce the in vitro growth [63]
and respiratory-cell adhesion [64] of several otopathogens. Thus,
xylitol was also considered as an agent for AOM prevention
administered as chewing gum or as a solution containing
mucosal adherence agents intended to prolong xylitol contact
with the pharyngeal mucosa. However, data in both healthy
children and children with a history of rAOM are scant and
conflicting [65–68]. Different xylitol dosages, administrations and
For personal use only.
preparations have made the results of these various studies diffi-
cult to compare. However, the most recent study of xylitol use
(viscous solution of 5-mg xylitol with adherence agents) in
otitis-prone children observed no difference in AOM incidence
children (xylitol: 0.53 episodes; placebo: 0.59 episodes per
90 days) or antibiotic use (xylitol: 6.8 days; placebo: 6.4 days
per 90 days) between treated and untreated nor did the total
antibiotic use [69].
Vitamin D
In the last 10 years, vitamin D (VD) has been found to play a
crucial role in immune system regulation by governing macro-
phage and dendritic cell activities and various Toll-like recep-
tor-mediated events in neutrophils [70,71]. VD also induces the
expression of antimicrobial peptides such as cathelicidin and
b-defensins. Finally, VD shifts cytokine expression from
Th1 to Th2. Thus, several studies have evaluated whether VD
deficiency is associated with an increased risk for infection and
whether VD supplementation could reduce the number of
infections in children, particularly those with recurrent infec-
tious episodes [72].
Children with rAOM have significantly lower serum 25
(OH)D levels than healthy controls, and administering VD can
significantly reduce the incidence of new AOM episodes [73]. In
a double-blind, placebo-controlled trial, the number of children
with rAOM who experienced more than one AOM episode
was significantly lower among the group who received 1000 IU
of VD than among untreated controls (26 vs 38; p = 0.03) [73].
In addition, there was a marked difference in the number of
children who developed uncomplicated AOM (p < 0.001), but
no difference in the number of children with more than one
614
episode of spontaneous otorrhea. These results were similar to
observations of children with rAOM who received a virosomal-
adjuvanted influenza vaccine [48]; children who did not respond
to VD prophylaxis also had a history of repeated tympanic
membrane perforation. This again suggests that not all rAOM
factors are clearly defined and that several subgroups exist
among children with rAOM [73]. Further studies are needed to
confirm that serum 25(OH)VD levels are associated with
AOM risk and to determine the optimal dosage of VD that
can significantly reduce the occurrence of AOM episodes.
Complementary & alternative medicine
Complementary and alternative medicine (CAM) is comprised
of practices with purported healing effects but with no scien-
tific basis. It encompasses a wide range of healthcare practices,
products and therapies and uses alternative medical diagnoses
and treatments that are not typically taught by medical schools
or used in conventional medicine [74]. Examples of alternative
medicine include homeopathy, naturopathy, chiropractic and
acupuncture. CAM use has dramatically grown in recent years;
approximately 20–40% of healthy children in outpatient clinics
and more than 50% of children with chronic, recurrent or
incurable conditions are treated by CAM, often in conjunction
with mainstream medicine [75].
Several studies on the efficacy and safety of CAM for AOM
prevention have been conducted but with conflicting results.
One study found that Echinacea purpurea did not decrease the
risk of AOM in otitis-prone children aged 12–60 months, but
it might actually increase the risk of recurrences [76]. In con-
trast, Echinacea combined with propolis and ascorbic acid
(Chizukit) was found able to decrease the occurrence of AOM
in children aged 1–5 years (treated: 19.4%; placebo: 43.5%;
p < 0.001) [77]. Moreover, propolis and zinc solution combined
with eliminating environmental risk factors has been reported
to prevent AOM in children (aged 1–5 years) with a history of
rAOM [78]. In this study, AOM diagnoses were significantly
lower among children receiving the propolis and zinc suspen-
sion compared with children where only environmental risk
factors were eliminated (treated: 50.8%; untreated: 70.5%;
p = 0.04). However, the benefits of this propolis and zinc solu-
tion have not been demonstrated for any respiratory infections
besides AOM.
Finally, studies in which homeopathy were used as treatment
for AOM yielded inconclusive results, and no data are available
for rAOM [79].
Thus, further studies are needed to clarify whether some
forms of CAM prophylaxis are effective for reducing the occur-
rence of AOM and which treatments should be recommended.
Antibiotic prophylaxis
For decades, antibiotics have been considered the primary
option for AOM prevention. Both the administration of inter-
mittent prophylactic antibiotics beginning at the first sign of an
upper respiratory tract infection and discontinued after the
upper respiratory tract infection has resolved and the use of
Expert Rev. Anti infect. Ther. 12(5), (2014)

continuous prophylaxis during the winter season have been
used. In both cases, antibiotic prophylaxis reduces the nasopha-
ryngeal bacterial load and consequently is effective for reducing
the number of new AOM episodes. Moreover, particularly
when administration of antibiotics is intermittent, it is easily
practiced. A recent review found that antibiotic prophylaxis
prevents an average of 1.5 AOM episodes per year of treat-
ment [80]. Even more recently, antibiotic prophylaxis has also
been shown to be the best method for reducing rAOM among
children [11]. The number of prevented AOM episodes is likely
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14
even higher among children who tend to experience more
AOM recurrences per year.
Despite these favorable results, the use of antibiotic prophy-
laxis of rAOM is today considered an emergency treatment.
Antibiotic prophylaxis of AOM is unique and differs from anti-
biotic prophylaxis of most other diseases. When prophylaxis is
given for rheumatic fever, neonatal gonococcal ophthalmia,
tuberculosis, pertussis and H. influenzae type b, it is targeted at
a single organism, whereas AOM is caused by several different
organisms, each one with quite different antibiotic susceptibili-
ties. As such, broader spectrum drugs are recommended, and
this is associated with an increased risk of side effects, such as
diarrhea or allergic reactions, as well as increased antibiotic
resistance by selecting resistant bacterial otopathogens [81].
For personal use only.
Starting from these premises, antibiotic prophylaxis should
be considered on a case by case basis for children younger than
2 years of age who have highly rAOM and when all other
options, including reducing possible risk factors and adminis-
tering influenza vaccine, have not worked. In these selected
cases, on the basis of the antimicrobial profile, amoxicillin rep-
resents the drug of choice [7].
Conclusion
Medical prevention of rAOM remains far from optimal since no
current methods are completely satisfactory. Several factors that
are clearly associated with increased rAOM risk cannot be modi-
fied, and reducing factors that can be modified is not always
easy. Bottle-feeding and poor daycare attendance are frequently
the result of the mother’s inability to produce breast milk and
family problems, respectively. Consequently, while such factors
are theoretically modifiable, it is not always the case.
Both PCVs and influenza vaccines are effective for reducing
AOM incidence in the general pediatric population and are
strongly recommended. However, their effectiveness in children
with rAOM is lower than expected, which is primarily due
to a subgroup of these children who have reduced vaccination
immune responses.
Oral and topical probiotics as well as xylitol and VD are
intriguing options for AOM prevention. However, the current
data are insufficient for recommending their use in AOM pro-
phylaxis, and the same is true for CAM. Antibiotics remain a
good solution for rAOM prevention, but the risk of microbial
selection and resistance means they must be used with caution.
In a child with a documented history of rAOM, the best solution
is to try reducing all modifiable factors, administer pneumococcal
informahealthcare.com
Medical prevention of rAOM Review
and influenza vaccines, and then only if AOM recurrence has not
declined, consider antibiotic prophylaxis. Surgical approaches for
preventing AOM are also available and could be recommended
when medical interventions do not work.
Expert commentary
AOM recurrence is common and can cause problems for the
child, family and health systems. Thus, attempts to reduce the
risk for new AOM episodes in children with a history of
rAOM are needed worldwide, and several options exist.
Medical and surgical interventions, such as inserting tympanos-
tomy tubes, are recommended. Reducing AOM incidence in
otitis-prone children has medical, social and economic effects.
Unfortunately, accurate AOM diagnosis is challenging, and
overdiagnosing often contributes to classifying a child as otitis-
prone. Several reports have shown that medical education of
AOM and the use of official AOM diagnosis and treatment
guidelines are poor among pediatricians [82–84]. Pneumatic oto-
scopy, the best method for diagnosing AOM, is not systemati-
cally performed, and tympanometry and acoustic reflectometry
are not considered useful for detecting AOM [85,86]. In contrast,
otoscopy is frequently performed by primary care pediatricians
who have not received intensive otoscopy training and, conse-
quently, are not valid [82–84]. Several cases of inappropriate anti-
biotic therapy for AOM treatment have also been documented
as the cause of treatment failures and recurrences, thereby
increasing the number of AOM episodes and resulting in the
classification of a child as otitis-prone. Antibiotic therapy is
almost always empirically prescribed without evaluating AOM
etiology and without taking otopathogen sensitivity to antibiot-
ics in the child’s geographic area into account; in addition,
tympanocentisis is not routinely performed [38]. When AOM
treatment and prevention is individualized and official AOM
recommendations are followed, the number of children diag-
nosed as otitis-prone significantly declines [38], reducing the
need for prophylaxis.
When AOM prophylaxis is considered necessary, eliminating
or reducing modifiable environmental or personal risk factors is
recommended in conjunction with PCV and influenza vaccines.
In industrialized countries, a pneumococcal vaccine is included
in infant immunization schedules, resulting in high coverage
and herd immunity for children not protected against the
pneumococcal serotypes included in vaccine. Considerable
efforts must be made for implementing pneumococcal vaccina-
tion in children living in the developing world. In contrast to
pneumococcal vaccines, the influenza vaccine has a different set
of problems. Despite the support of health authorities on
administering influenza vaccines to all children or at least those
in the first years of life, most European countries only officially
recommend influenza vaccinations for children at risk of com-
plications due to chronic underlying conditions, which do not
include rAOM [87–89]. Consequently, pediatricians usually do
not prescribe influenza vaccines to otitis-prone children.
Further studies confirming the relationship between influenza
vaccination and AOM recurrence could address this problem.
615
 Review Marchisio, Nazzari, Torretta, Esposito & Principi

However, if interventions to reduce modifiable factors, vaccine
prophylaxis and even antibiotic prophylaxis do not work, surgi-
cal intervention should be considered. At the moment, no
other medical interventions can be considered effective as
AOM prophylaxis due to a lack of data.
Five-year view
In the next few years, data on the prophylactic role of oral and
topical probiotics, xylitol and VD will likely emerge. This could
increase AOM prophylactic possibilities for children with a his-
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14
The same could be true for an NTHi vaccine and for vac-
cines against respiratory syncytial virus and human metapneu-
movirus. Unfortunately, the real protective role of the NTHi
protein included as carrier in PCV10 is not defined [91,92], and
other NTHi vaccines are only in the early stages of develop-
ment [93,94]. However, the most advanced solution for prevent-
ing rAOM seems to be linked to identifying subjects who are
genetically predisposed to this problem. Several rAOM studies
have tried to evaluate whether genetics can explain why some
children have rAOM; this would allow for the early identifica-

tory of rAOM. However, a substantial modification in the
actual incidence of rAOM will only be possible in later years
when new vaccines against Sp and nontypeable H. influenzae
(NTHi) will become available. A subset of children with rAOM
do not respond adequately to vaccines and, consequently,
remain susceptible to infection by the pathogens included in
these vaccines; however, the availability of new vaccine prepara-
tions for all pneumococcal serotypes and/or other otopathogens
will still significantly increase rAOM prevention. Conjugated
polysaccharide vaccines have greatly reduced the burden of
pneumococcal disease, but differences in the global distribution
of pneumococcal serotypes and increasing disease due to
replacement serotypes suggest that even a vaccine with 13 sero-
types will not provide long-term, sustainable protection against
For personal use only.
tion of AOM-predisposed individuals, which means preventive
measures could be implemented as soon as possible before the
first infection even begins [95,96]. Unfortunately, studies analyz-
ing single-nucleotide polymorphisms (SNPs) of genes encoding
factors involved in innate or adaptive immunity have reported
debatable results due to their small sample sizes and relatively
few genes examined [95]. A recent study of genetic susceptibility
using genome-wide associations was able to evaluate 324,748
SNPs in 602 subjects [96]. These results seem significantly more
reliable but require further confirmation. In this study, the
SNP rs10497394 on chromosome 2 in the 537 kb intergenic
region between CDCA7 and SP3 was significantly associated
with rAOM. When the role of this and similar variants in
AOM predisposition is confirmed, children at risk for rAOM

pneumococcal AOM. Vaccines comprised of broadly conserved
protein antigens, such as those currently in development, would
provide serotype-independent coverage and theoretically would
not be associated with serotype replacement. Moreover, such
vaccines would be cheaper to produce than conjugate vaccines,
guaranteeing protection in even resource-poor settings where the
need is greatest. Furthermore, these new vaccines could signifi-
cantly reduce rAOM in subjects with impaired immunity due
to the reduced circulation of all pneumococcal serotypes; thus,
individuals could be independently protected by the vaccination
status and immune system efficiency of others [90].
could be identified earlier, and effective preventive methods
could be immediately implemented to greatly reduce their
clinical problems.
Financial & competing interests disclosure
This review was supported by a grant from the Italian Ministry of Health
(Bando Giovani Ricercatori 2009). The authors have no other relevant
affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Acute otitis media (AOM) is one of the most common pediatric diseases; by the age of 3, almost all children have experienced at least
one episode of AOM and a third have experienced two or more episodes.
• Recurrent AOM (rAOM) has significant medical, social and economic effects.
• Medical interventions for rAOM prevention are still far from optimal since no current medical methods can completely reduce the risk
for rAOM.
• Reducing child-specific factors that are associated with rAOM and can be modified (i.e., daycare attendance, bottle-feeding,
secondhand smoke and pacifier use) is the first step in rAOM prevention.
• Both pneumococcal conjugate vaccines and influenza vaccines are effective for reducing AOM incidence in the general pediatric
population and are strongly recommended; however, their effectiveness in children with rAOM is lower than expected due to a subset
of children with rAOM who have a reduced vaccination immune response.
• Oral and topical probiotics, xylitol, vitamin D and complementary and alternative medicine remain intriguing options for rAOM
prophylaxis, but current data are insufficient for recommending their use.
• Antibiotics remain a good method for rAOM prevention; however, the risk of microbial selection means they should be used with caution.
• Several rAOM studies have tried to evaluate genetic characteristics associated with rAOM; these studies could identify genetic markers
that allow the early identification of AOM-predisposed individuals, allowing preventative measures to be implemented as soon as possible.

616 Expert Rev. Anti infect. Ther. 12(5), (2014)


References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1. Rovers MM, Schilder AG, Zielhuis GA,
Rosenfeld RM. Otitis media. Lancet
2004;363:465-73
2. Teele DW, Klein JO, Rosner B.
Epidemiology of otitis media during the
first seven years of life in children in greater
Boston: a prospective, cohort study. J Infect
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14
Dis 1989;160:83-94
3. Arguedas A, Kvaerner K, Liese K, et al.
Otitis media across nine countries: disease
burden and management. Int J Pediatr
Otorhinolaryngol 2010;74:1419-24
4. Dubé E, De Wals P, Gilca V, et al. Burden
of acute otitis media on Canadian families.
Can Fam Physician 2011;57:60-5
5. Bardach A, Ciapponi A, Garcia-Marti S,
et al. Epidemiology of acute otitis media in
children of Latin America and the
Caribbean: a systematic review and
meta-analysis. Int J Pediatr
Otorhinolaryngol 2011;75:1062-70
For personal use only.
6. Greenberg D, Bilenko N, Liss Z. The
burden of acute otitis media on the patient
and the family. Eur J Pediatr 2003;162:
576-81
7. Marchisio P, Bellussi L, Di Mauro G, et al.
Acute otitis media: from diagnosis to
prevention. Summary of the Italian
guideline. Int J Pediatr Otorhinolaryngol
2010;74:1209-16
8. Vergison A, Dagan R, Arguedas A, et al.
Otitis media and its consequences: beyond
the earache. Lancet Infect Dis 2010;10:
195-203
9. Lieberthal AS, Carroll AE, Chonmaitree T,
et al. The diagnosis and management of
acute otitis media. Pediatrics 2013;131:
e964-99
•• This evidence-based clinical practice
guideline is a revision of the 2004 acute
otitis media (AOM) guideline from the
American Academy of Pediatrics
and American Academy of Family
Physicians.
10. Poehling KA, Szilagyi PG, Grijalva CG,
et al. Reduction of frequent otitis media
and pressure-equalizing tube insertions in
children after introduction of pneumococcal
conjugate vaccine. Pediatrics 2007;119:
707-15
11. Cheong KH, Hussain SS. Management of
recurrent acute otitis media in children:
systematic review of the effect of different
interventions on otitis media recurrence,
informahealthcare.com
Medical prevention of rAOM
recurrence frequency and total recurrence
time. J Laryngol Otol 2012;126:874-85
• A study showing that prophylactic
antibiotics are effective in reducing otitis
media recurrence, recurrence frequency
and total recurrence time, whereas
tympanostomy tube insertion failed to
reduce the prevalence of otitis media
recurrence but reduced the recurrence
frequency and total recurrence time.
12. Uhari M, Mantysaari K, Niemela M.
A meta-analytic review of the risk factors for
acute otitis media. Clin Infect Dis 1996;22:
1079-83
13. Lubianca Neto JF, Hemb L, Silva DB.
Systematic literature review of modifiable
risk factors for recurrent acute otitis media
in childhood. J Pediatr (Rio J) 2006;82:
87-96
14. Salah M, Abdel-Aziz M, Al-Farok A,
Jebrini A. Recurrent acute otitis media in
infants: analysis of risk factors. Int J Pediatr
Otorhinolaryngol 2013;77:1665-9
• A study showing that factors which may
cause recurrence of the disease in infant
population are use of pacifiers, short
duration of breastfeeding, older infantile
age, winter season, upper respiratory tract
infections and adenoid hypertrophy; also,
treatment failure may be caused by
adenoid hypertrophy and short duration
of breastfeeding.
15. Alho OP, Laara E, Oja H. Public health
impact of various risk factors for acute otitis
media in northern Finland. Am J Epidemiol
1996;143:1149-56
16. Uhari M, Möttönen M. An open
randomized controlled trial of infection
prevention in child day-care centers. Pediatr
Infect Dis J 1999;18:672-7
17. Saarinen UM. Prolonged breast feeding as
prophylaxis for recurrent otitis media. Acta
Paediatr Scand 1982;71:567-671
18. Duffy LC, Faden H, Wasielewski R, et al.
Exclusive breastfeeding protects against
bacterial colonization and day care exposure
to otitis media. Pediatrics 1997;100:E7
19. Collet JP, Larson CP, Boivin JF, et al.
Parental smoking and risk of otitis media in
pre-school children. Can J Public Health
1995;86:269-73
20. Csákányi Z, Czinner A, Spangler J, et al.
Relationship of environmental tobacco
smoke to otitis media (OM) in children.
Int J Pediatr Otorhinolaryngol 2012;76:
989-93
21. Håberg SE, Bentdal YE, London SJ, et al.
Prenatal and postnatal parental smoking and
Review
acute otitis media in early childhood. Acta
Paediatr 2010;99:99-105
22. Klerman L. Protecting children: reducing
their environmental tobacco smoke
exposure. Nicotine Tob Res 2004;
6(Suppl 2):S239-53
23. Abrahams SW, Labbok MH. Breastfeeding
and otitis media. a review of recent
evidence. Curr Allergy Asthma Rep
2011;11:508-12
24. Rovers MM, Numans ME, Langenbach E,
et al. Is pacifier use a risk factor for acute
otitis media? A dynamic cohort study. Fam
Pract 2008;25:233-6
25. Niemela M, Pihakari O, Pokka T, Uhari M.
Pacifier as a risk factor for acute otitis
media: a randomized, controlled trial of
parental counseling. Pediatrics 2000;106:
483-8
26. Torretta S, Marchisio P, Cappadona M,
et al. Habitual use of push and pull plastic
bottle caps is more prevalent among
children with recurrent acute otitis media.
Int J Pediatr Otorhinolaryngol 2013;77:
1179-82
• A preliminary study showing a
significantly increased prevalence of
push-and-pull plastic cap bottle habitual
users among children with a history or
recurrent AOM (rAOM) and supporting
the need for larger studies to confirm the
role of using push-and-pull plastic bottles
as risk factor of rAOM and to identify
the age groups at higher risk.
27. Eskola J, Kilpi T. Potential of bacterial
vaccines in the prevention of acute otitis
media. Pediatr Infect Dis J 2000;
19(5 Suppl):S72-8
28. Haggard M. Otitis media: prospects for
prevention. Vaccine 2008;265:G20-4
29. Pelton SI, Leibovitz E. Recent advances in
otitis media. Pediatr Infect Dis J 2009;28:
S133-7
30. Principi N, Baggi E, Esposito S. Prevention
of acute otitis media using currently
available vaccines. Future Microbiol 2012;7:
457-65
31. Fletcher MA, Fritzell B. Pneumococcal
conjugate vaccines and otitis media:
an appraisal of clinical trials. Int
J Otolaryngol 2012;2012:590206
32. Sarasoja I, Jokinen J, Lahdenkari M, et al.
Long-term effect of pneumococcal conjugate
vaccines on tympanostomy tube placements.
Pediatr Infect Dis J 2013;32:517-20
•• A study showing that the PCV7 reduces
the tympanostomy tube placements up to
5 years of age; no impact on new surgical
617
 Review Marchisio, Nazzari, Torretta, Esposito & Principi
procedures could be demonstrated after
that but the benefit achieved is sustained.
33. Veenhoven R, Bogaert D, Ulterwaal C,
et al. Effect of conjugate pneumococcal
vaccine followed by polysaccharide
pneumococcal vaccine on recurrent acute
otitis media: a randomised study. Lancet
2003;361:2189-95
34. van Kempen MJ, Vermeiren JS,
Vaneechoutte M, et al. Pneumococcal
conjugate vaccination in children with
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14
recurrent acute otitis media: a therapeutic
alternative? Int J Pediatr Otorhinolaryngol
2006;70:275-85
35. Pichichero ME, Casey JR, Almudevar A.
Nonprotective responses to pediatric
vaccines occur in children who are otitis
prone. Pediatr Infect Dis J 2013;32:1163-8
36. Sharma SK, Pichichero ME. Cellular
immune response in young children
accounts for recurrent acute otitis media.
Curr Allergy Asthma Rep 2013;13:
495-500
• This review focuses on the studies
performed to define immunologic
dysfunction in stringently defined
For personal use only.
otitis-prone children.
37. Sharma SK, Casey JR, Pichichero ME.
Reduced serum IgG responses to
pneumococcal antigens in otitis-prone
children may be due to poor memory B-cell
generation. J Infect Dis 2012;205:1225-9
• A study showing significantly lower
percentages of memory B cells to
3 pneumococcal protein antigens (PhtD,
PhtE and Ply) and reduced
antigen-specific immunoglobulin G
concentrations in otitis-prone children,
compared with non-otitis-prone children.
38. Pichichero ME, Casey JR, Almudevar A.
Reducing the frequency of acute otitis
media by individualized care. Pediatr Infect
Dis J 2013;32:473-8
• A study showing that individualized care
of AOM significantly reduces the
frequency of AOM and tympanostomy
tube surgery. Use of strict diagnostic
criteria for AOM and empiric antibiotic
treatment using evidence-based
knowledge of circulating otopathogens
and their antimicrobial susceptibility
profile also produces improved outcomes.
39. Principi N, Esposito S. Use of the 13-valent
pneumococcal conjugate vaccine in infants
and young children. Expert Opin Biol Ther
2012;12:641-8
• A review showing that a pneumococcal
conjugate vaccine with the composition
618
of pneumococcal conjugate vaccine
13 has significantly increased the
possibility of preventing pneumococcal
disease: its immunogenicity, safety and
tolerability seem to be optimal, as does its
cost–effectiveness. However, despite these
favorable premises, it cannot be
considered the final preparation for the
prevention of pneumococcal disease, and
it is likely that a new vaccine capable of
covering all pneumococcal serotypes will
be needed in the future.
40. Giannakopoulos P, Chrysovergis A,
Xirogianni A, et al. Microbiology of acute
mastoiditis and complicated or refractory
acute otitis media among hospitalized
children in the postvaccination era. Pediatr
Infect Dis J 2014;33:111-13
•• In the post-heptavalent pneumococcal
conjugate vaccine era, Streptococcus
pneumoniae remains the leading cause of
acute mastoiditis and other complicated
or refractory AOM among hospitalized
children; serotype 19A is predominant,
invasive and multidrug resistant causing
more than half of all mastoiditis cases,
two-thirds of cases with subperiosteal
abscess and all those requiring
mastoidectomy. Continuous surveillance
is required.
41. Hau I, Levy C, Caeymaex L, Cohen R.
Impact of pneumococcal conjugate vaccines
on microbial epidemiology and clinical
outcomes of acute otitis media. Paediatr
Drugs 2014;16(1):1-12
42. Shea KM, Weycker D, Stevenson AE, et al.
Modeling the decline in pneumococcal
acute otitis media following the
introduction of pneumococcal conjugate
vaccines in the US. Vaccine 2011;29:
8042-8
43. Principi N, Esposito S. Prevention or
control of influenza in the pediatric
population. Emerg Infect Dis 2004;10:
574-80
44. Marchetti M, Kùhnel U, Colombo G, et al.
Cost-effectiveness of adjuvanted influenza
vaccination of healthy children 6 to
60 months of age. Hum Vaccines 2007;3:
14-22
45. Manzoli L, Schioppa F, Boccia A, Villari P.
The efficacy of influenza vaccine for healthy
children: a meta-analysis evaluating potential
sources of variation in efficacy estimates
including study quality. Pediatr Infect Dis J
2007;26:97-106
46. Heikkinen T, Block SL, Toback SL, et al.
Effectiveness of intranasal live attenuated
influenza vaccine against all-cause acute
otitis media in children. Pediatr Infect Dis J
2013;32:669-74
• A study showing that intranasal live
attenuated influenza vaccine reduced the
incidence of all-cause AOM compared
with placebo in children: The estimated
12-month effectiveness of live attenuated
influenza vaccine was comparable with
7-valent pneumococcal conjugate vaccine.
47. Marchisio P, Cavagna R, Maspes B, et al.
Efficacy of intranasal virosomal influenza
vaccine in the prevention of recurrent acute
otitis media in children. A randomized
single-blind clinical trial. Clin Infect Dis
2002;35:168-74
48. Marchisio P, Esposito S, Bianchini S, et al.
Efficacy of injectable trivalent
virosomal-adjuvated inactivated influenza
vaccine in preventing acute otitis media in
children with recurrent non-complicated or
complicated acute otitis media. Pediatr
Infect Dis J 2009;28:855-9
49. Iannitti T, Palmieri B. Therapeutical us of
probiotic formulations in clinical pratice.
Clin Nutr 2010;29:701-25
50. Principi N, Tagliabue C, Tenconi R,
Esposito S. Probiotics and prevention of
pediatric upper respiratory tract infections.
Eur J Inflamm 2013;11:581-9
• An update on the effect of probiotics in
prevention of pediatric upper respiratory
tract infections.
51. Szajewska H, Ruszczyński M,
Radzikowski A. Probiotics in the prevention
of antibiotic-associated diarrhea in children:
a meta-analysis of randomized controlled
trials. J Pediatr 2006;149:367-72
52. Niittynen L, Pitkäranta A, Korpela R.
Probiotics and otitis media in children. Int
J Pediatr Otorhinolaryngol 2012;76:465-70
53. John M, Dunne EM, Licciardi PV, et al.
Otitis media among high-risk populations:
can probiotics inhibit Streptococcus
pneumoniae colonisation and the risk of
disease? Eur J Clin Microbiol Infect Dis
2013;32:1101-10
54. Hatakka K, Savilahti E, Pönkä A, et al.
Effect of long term consumption of
probiotic milk on infections in children
attending day care centres: double blind,
randomised trial. BMJ 2001;322:1327
55. Hatakka K, Blomgren K, Pohjavuori S,
et al. Treatment of acute otitis media with
probiotics in otitis-prone children-a
double-blind, placebo-controlled randomised
study. Clin Nutr 2007;26:314-21
56. Rautava S, Salminen S, Isolauri E. Specific
probiotics in reducing the risk of acute
Expert Rev. Anti infect. Ther. 12(5), (2014)

infections in infancy - a randomised,
double-blind, placebo-controlled study. Br
J Nutr 2009;101:1722-6
57. Cohen R, Martin E, de La Rocque F, et al.
Probiotics and prebiotics in preventing
episodes of acute otitis media in high-risk
children: a randomized, double-blind,
placebo-controlled study. Pediatr Infect Dis
J 2013;32:810-14
• A study showing that the probiotics and
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14
prebiotics included in follow-up formula
given to children at 7 to 13 months of
age did not reduce the risk of AOM,
rAOM, antibiotic use or lower respiratory
tract infections at 1 year.
58. Santagati M, Scillato M, Patanè F, et al.
Bacteriocin-producing oral streptococci
and inhibition of respiratory pathogens.
FEMS Immunol Med Microbiol 2012;65:
23-31
59. Roos K, Håkansson EG, Holm S. Effect of
recolonisation with “interfering” alpha
streptococci on recurrences of acute and
secretory otitis media in children:
randomised placebo controlled trial. BMJ
2001;322:210-12
For personal use only.
60. Tano K, Grahn Håkansson E, Holm SE,
Hellström S. A nasal spray with
alpha-haemolytic streptococci as long term
prophylaxis against recurrent otitis media.
Int J Pediatr Otorhinolaryngol 2002;62:
17-23
61. Power DA, Burton JP, Chilcott CN, et al.
Preliminary investigations of the
colonisation of upper respiratory tract tissues
of infants using a paediatric formulation of
the oral probiotic Streptococcus salivarius
K12. Eur J Clin Microbiol Infect Dis
2008;27:1261-3
62. Di Pierro F, Donato G, Fomia F, et al.
Preliminary pediatric clinical evaluation of
the oral probiotic Streptococcus salivarius
K12 in preventing recurrent pharyngitis
and/or tonsillitis caused by Streptococcus
pyogenes and recurrent acute otitis media.
Int J Gen Med 2012;5:991-7
63. Kontiokari T, Uhari M, Koskela M. Effect
of xylitol on growth of nasopharyngeal
bacteria in vitro. Antimicrob Agents
Chemother 1995;39:1820-3
64. Kontiokari T, Uhari M, Koskela M.
Antiadhesive effects of xylitol on
otopathogenic bacteria. Antimicrob Agents
Chemother 1998;41:563-5
65. Uhari M, Kontiokari T, Koskela M,
Niemela M. Xylitol chewing gum in
prevention of acute otitis media: double
blind randomised trial. BMJ 1996;313:
1180-4
informahealthcare.com
Medical prevention of rAOM
66. Uhari M, Kontiokari T, Niemela M, et al.
A novel use of xylitol sugar in preventing
acute otitis media. Pediatrics 1998;
102(4 pt 1):879-84
67. Tapiainen T, Luotonen L, Kontiokari T,
et al. Xylitol administered only during
respiratory infections failed to prevent acute
otitis media. Pediatrics 2002;109:E19
68. Hautalahti O, Renko M, Tapiainen T, et al.
Failure of xylitol given three times a day for
preventing acute otitis media. Pediatr Infect
Dis J 2007;26:423-7
69. Vernacchio L, Corwin MJ, Vezina RM,
et al. Xylitol syrup for the prevention of
acute otitis media. Pediatrics 2014;133(2):
289-95
70. Shaw NJ, Mughal Z. Vitamin D and child
health (skeletal aspects). Arch Dis Child
2013;98:363-7
71. Shaw NJ, Mughal Z. Vitamin D and child
health (extra skeletal aspects). Arch Dis
Child 2013;98:368-72
72. Esposito S, Baggi E, Bianchini S, et al. Role
of vitamin D in children with respiratory
tract infections. Int J Immunopathol
Pharmacol 2013;26:1-13
• A review showing that vitamin D (VD)
seems to be very important because of its
part in the complexity of the immune
system; however, there are few pediatric
studies and most have various limitations.
73. Marchisio P, Consonni D, Zampiero A,
et al. Vitamin D supplementation reduces
the risk of acute otitis media in otitis-prone
children. Pediatr Infect Dis J 2013;32:
1055-60
• A study showing that VD
hypovitaminosis is common in children
with rAOM and associated with an
increase in the occurrence of AOM when
serum 25(OH)D levels are <30 ng/ml.
The administration of VD in a dosage of
1000 IU/d restores serum values of
$30 ng/ml in most cases and is
associated with a significant reduction in
the risk of uncomplicated AOM.
74. Ernst E. Complementary medicine
scrutinizing the alternatives. Lancet
1993;341:1626
75. Marchisio P, Bianchini S, Galeone C, et al.
Use of complementary and alternative
medicine in children with recurrent acute
otitis media in Italy. Int J Immunopathol
Pharmacol 2011;24:441-9
76. Wahl RA, Aldous MB, Worden KA,
Grant KL. Echinacea purpurea and
osteopathic manipulative treatment in
children with recurrent otitis media:
Review
a randomized controlled trial. BMC
Complement Altern Med 2008;8:56
77. Cohen HA, Varsano I, Kahan E, et al.
Effectiveness of an herbal preparation
containing echinacea, propolis, and vitamin
C in preventing respiratory tract infections
in children: a randomized, double-blind,
placebo-controlled, multicenter study. Arch
Pediatr Adolesc Med 2004;158:217-21
78. Marchisio P, Esposito S, Bianchini S, et al.
Effectiveness of a propolis and zinc solution
in preventing acute otitis media in children
with a history of recurrent acute otitis
media. Int J Immunopathol Pharmacol
2010;23:567-75
79. Levi JR, Brody RM, McKee-Cole K, et al.
Complementary and alternative medicine
for pediatric otitis media. Int J Pediatr
Otorhinolaryngol 2013;77:926-31
80. Leach AJ, Morris PS. Antibiotics for the
prevention of acute and chronic suppurative
otitis media in children. Cochrane Database
Syst Rev 2006;4:CD004401
81. Marchisio P, Bellussi L, Di Mauro G, et al.
Acute otitis media: from diagnosis to
prevention. Summary of the Italian
guideline. Int J Pediatr Otorhinolaryngol
2010;74:1209-16
82. Pichichero ME, Poole MD. Assessing
diagnostic accuracy and tympanocentesis
skills in the management of otitis media.
Arch Pediatr Adolesc Med 2001;155:
1137-42
83. Pichichero ME. Diagnostic accuracy,
tympanocentesis training performance and
antibiotic selection by pediatric residents in
management of otitis media. Pediatrics
2002;110:1-7
84. Marchisio P, Mira E, Klersy C, et al.
Medical education and attitudes about acute
otitis media guidelines: a survey of Italian
pediatricians and otolaryngologists. Pediatr
Infect Dis J 2009;28:1-4
85. Helenius KK, Laine MK, Tähtinen PA,
et al. Tympanometry in discrimination of
otoscopic diagnoses in young ambulatory
children. Pediatr Infect Dis J 2012;31:
1003-6
86. Laine MK, Tähtinen PA, Helenius KK,
et al. Acoustic reflectometry in
discrimination of otoscopic diagnoses in
young ambulatory children. Pediatr Infect
Dis J 2012;31:1007-11
87. Committee on Infectious Diseases.
Recommendations for prevention and
control of influenza in children.
2013Pediatrics 2013;132:e1089-104
88. Antonova EN, Rycroft CE, Ambrose CS,
et al. Burden of paediatric influenza in
619
 Review Marchisio, Nazzari, Torretta, Esposito & Principi
Western Europe: a systematic review. BMC
Public Health 2012;12:968
89. Esposito S, Principi N. The rational use of
influenza vaccines in healthy children and
children with underlying conditions. Curr
Opin Infect Dis 2009;22:244-9
90. Pelton SI, Pettigrew MM, Barenkamp SJ,
et al. Panel 6: vaccines. Otolaryngol Head
Neck Surg 2013;148(4 Suppl):E90-E101
91. Weigl JA. RSV –a substantial slice of the
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by University of Queensland on 05/28/14
airway disease burden and the way to a
vaccine. Paediatr Int Child Health 2012;
32(Suppl 2):S9-15
92. Le Bayon JC, Lina B, Rosa-Calatrava M,
Boivin G. Recent developments with
live-attenuated recombinant paramyxovirus
vaccines. Rev Med Virol 2013;23:15-34
93. van den Bergh MR, Spijkerman J,
Swinnen KM, et al. Effects of the 10-valent
pneumococcal nontypeable Haemophilus
influenzae protein D-conjugate vaccine on
For personal use only.
620
nasopharyngeal bacterial colonization in
young children: a randomized controlled
trial. Clin Infect Dis 2013;56:e30-9
• A study showing that the 10-valent
pneumococcal nontypeable Haemophilus
influenzae (NTHi) protein D-conjugate
vaccine had no differential effect on
nasopharyngeal NTHi colonization or H.
influenzae density in healthy Dutch
children up to 2 years of age, implying
that herd effects for NTHi are not to be
expected. Other bacterial colonization
patterns were also similar.
Barenkamp SJ. Rationale and prospects for
94.
a nontypeable Haemophilus influenzae
vaccine. Pediatr Infect Dis J 2004;23:461-2
95. Sale MM, Chen WM, Weeks DE, et al.
Evaluation of 15 functional candidate genes
for association with chronic otitis media
with effusion and/or recurrent otitis media
(COME/ROM). PLoS One 2011;6:e22297
96. Allen EK, Chen WM, Weeks DE, et al.
A genome-wide association study of chronic
otitis media with effusion and recurrent
otitis media identifies a novel susceptibility
locus on chromosome 2. J Assoc Res
Otolaryngol 2013;14:791-800
• A study showing that the
single-nucleotide polymorphism
rs10497394 on chromosome 2 is
significantly associated with rAOM
susceptibility. This single-nucleotide
polymorphism is within a 537 kb
intergenic region, bordered by
CDCA7 and SP3. The genomic and
functional significance of this newly
identified locus in rAOM pathogenesis
requires additional investigation.
Expert Rev. Anti infect. Ther. 12(5), (2014)