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Schaad_OM Pharma_A4_2011 02/11/2012 11:18 Page 111
Respiratory Tract Infections
The Management of Recurrent Respiratory Tract Infections in Children
Urs B Schaad1 and Nicola Principi2
1. Professor Emeritus in Paediatrics and Paediatric Infectious Diseases, University of Basel, Basel, Switzerland; 2. Chair of Paediatrics, Universita degli Studi di
Milano, Fondazione IRCCS Ospedale Maggiore Policinico, Mangiagalli e Regina Elena, Milan, Italy
Abstract
Respiratory tract infections (RTIs) constitute a major healthcare burden in children throughout the world. They tend to be recurrent, often
causing multiple episodes of illness within a single year. Immature immune system, the presence of genetic and environmental factors and
exposure to pathogens make young children highly susceptible to RTIs. These infections are still treated with antibiotics but the rise in
resistant bacterial strains has prompted investigation of novel preventative strategies. One such approach to prevent recurrent RTIs (RRTIs)
is the immunostimulant OM-85 that is an extract of eight pathogenic bacteria which has proven safe and effective as prophylaxis of recurrent
respiratory infections in children at risk. Increased awareness and use of preventative approaches, including OM-85, are likely to help avoid
the complications and co-morbidities of RTIs; and have the potential to significantly reduce the burden of disease and bacterial resistance.
Keywords
Recurrent respiratory tract infections, bacterial infection, virus, lung damage, immune response, immunostimulant, OM-85
Disclosure: Urs B Schaad serves as Consultant in Paediatrics for OM Pharma SA, Geneva, Switzerland. Urs B Schaad and Nicola Principi are Members of the Scientific
Advisory Board for OM-85.
Received: 12 September 2012 Accepted: 1 October 2012 Citation: European Infectious Disease, 2012;6(2):111–5
Correspondence: Urs B Schaad, University Children’s Hospital Basel UKBB, PO Box, CH-4031 Basel, Switzerland. E: [email protected]
Support: The publication of this article was funded by OM Pharma SA.
Burden of Respiratory Tract Infections
in Children
Paediatric respiratory tract infections (RTIs) are associated with
significant morbidity and mortality worldwide.1 In industrialised
countries, approximately half of the medical consultations concerning
children involve RTIs.2 Moreover, these are often recurrent infections,
occurring numerous times a year.
The epidemiology data of RTIs are variable depending on the specific
year and setting studied. In general, mortality rates in children within
developed countries are relatively low.3 In contrast, RTIs in developing
countries are not only more prevalent but also more severe, resulting
in over 2 million deaths per year.4,5 A recent report from the United
Nations International Children's Emergency Fund (UNICEF) concluded
that over 2 million child deaths could be prevented in the 75 countries
with the highest mortality burden if the entire population of children
aged less than five years in each of these countries received the same
coverage already available to the wealthiest 20 % of people in those
countries.6 From other studies, it was estimated that approximately
6 % of children under the age of six years present with recurrent RTI.7
In developed countries, up to 25 % of children less than one year and
18 % of those aged 1–4 years experience recurrent RTIs.8
The vast majority (80–90 %) of RTIs are caused by viruses including
rhinovirus, respiratory syncytial virus (RSV) and influenza. RSV is a
common cause of both upper and lower RTIs. The same has been
demonstrated for rhinovirus. However, whereas RSV is more common
in younger children, rhinovirus strains A and B have been found as a
© TOUCH MEDICAL MEDIA 2012
cause of RTIs in both younger and older children.9 Recent studies have
highlighted the burden of influenza in young children.10,11 While
recurrent RTIs often begin as viral infections, bacterial infection is
observed in 60 % of patients with symptoms of an upper RTI lasting at
least 10 days.12,13 Bacteria commonly involved in recurrent RTIs include
Haemophilus influenzae, Streptococcus pneumoniae, Moraxella
catarrhalis, Klebsiella pneumoniae and Streptococcus pyogenes.8,14,15
Bacterial infections of the lung have also been found to play a role in
preschool children with recurrent wheeze.16 In particular, Mycoplasma
pneumoniae, H. influenzae, S. pneumoniae and M. catarrhalis were
the most commonly isolated species in these individuals.
The burden of RTIs extends beyond their incidence and epidemiology
data. The diagnosis of recurrent RTIs can be particularly challenging for
paediatricians. While many infections involving the upper respiratory
tract are easily managed, others are indicative of a more serious
underlying pathology such as bronchiectasis or immune dysfunction.7
Further, differential diagnosis requires the appropriate use of
diagnostic tools by physicians. Additional burdens include subsequent
morbidity and complications in the child, resultant overuse and misuse
of antibiotics, and all associated healthcare as well as indirect societal
costs. These will be discussed in greater detail below.
The Child Immune System
The high incidence of respiratory infections in children relative to
older adolescent and adult populations can be partially explained by
the apparent limitations of their young immune systems. In fact,
defects in immune responses are known to correlate with multiple
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Respiratory Tract Infections
Table 1: Summary of Environmental and Genetic Risk
Factors for the Development of Recurrent Respiratory
Tract Infections
Environmental risk factors
Day care attendance
Early socialisation
Large family size and overcrowding
School-aged siblings
Reduced breastfeeding
Passive smoking, excessive exposure to pollutants, contact with
infectious agents and the absence of breastfeeding have all been
reported to increase the risk of infection.7,29 Indeed, breast milk
contains important nutrients that help enhance the child’s immune
response.30 Furthermore, attendance at crowded day care centres or
preschools as well as interactions with siblings and other family
members may add to the likelihood of RTIs.25 Missed or lack of
vaccinations and malnutrition are other risk factors for RTIs that are
especially prevalent in developing countries.31
Exposure to pollutants (indoor and outdoor)
Home dampness and pets
Genetic Risk Factors
Parental smoking and smoking during pregnancy
Certain children have a familial predisposition for recurrent and
severe respiratory infections.32 This is often linked to the anatomical,
physiological and/or immunological features of the individual.33 RTIs
have been attributed to anatomic or functional alterations of the
upper and/or lower airways as well as reduced immunity in the child.
A family history of atopic diseases, low bodyweight and male gender
have also been reported to contribute to a higher risk of RTIs.7
Malnutrition and missed vaccination
Intense training and physical stress
Genetic risk factors
Positive family history of atopic diseases
Prematurity and low bodyweight infants
Anatomic or functional alterations of the airways
Allergy/atopy
Male gender
Source: Jesenak et al., 2011.7
RTIs.17,18 It is, however, rare for a child with recurrent RTIs to present
with a true immunodeficiency, rather there is likely an immaturity in
their immune system due to their young age leading to increased
infections;19 humoral and phagocytic immunity do not reach their
optimal protective state until the fifth or sixth year of life.20,21 As such,
it is important for paediatricians to be able to differentiate between
deficiency and immaturity. For the most part, the child has normal
immune functions – albeit young and immature – and therefore any
symptoms or complications from RTIs will be transient and of limited
duration. On the other hand, if a child presents with excessive
amounts of infections (e.g. eight or more occurrences of otitis media
in 12 months, two or more serious sinus infections within 12 months
or several community-acquired pneumonia), there is likely to be
an underlying primary immunodeficiency that requires attention.22,23
Careful history-taking and examination along with prompt
immunologic testing are needed to make an accurate diagnosis and
treat these patients appropriately.
Although most affected children do not have immunodeficiencies,
some may exhibit lower levels of haematological or immunological
parameters such as deficiencies in specific immunoglobulin (Ig)
isotypes or, much more rarely, decreased phagocytosis.7 Other
aspects of the immune system that are immature in newborn and
young children include T cells, cytotoxic activity, neutrophil production
and function, and complement levels.24
It is also important to note the possibility that the observed immune
defects are the consequences rather than the cause of recurrent RTIs.
In particular, viral infections are known to influence immune
responses.7 As such, repeated infections and viral penetration could
result in ever deeper virus-induced immune dysfunction, which would
in turn favour further respiratory infections, leading to a vicious cycle
of recurrent RTIs.25,26
Patient Profile and Risk Factors
Environmental Risk Factors
A number of environmental factors have a well-established effect of
increasing the susceptibility of a child to recurrent lung infections.27, 28
112
Table 1 lists the key environmental and genetic risk factors associated
with the development of recurrent RTIs. Strategies to prevent recurrent
RTIs must take into consideration all these patient characteristics and
factors that potentially increase the risk for disease. Research has
suggested that patients with the greatest risk of recurrent RTIs benefit
the most from therapeutic intervention and prevention.17
Definition
RTIs include all viral and bacterial infections of the upper or lower
airways. These could be relatively benign and easily controlled or
potentially more serious diseases such as pneumonia or bronchitis that
can cause permanent lung damage. Recurrent RTIs can be defined as
at least three RTI episodes per year or fall/winter season for at least two
years.17,32 However, in terms of more specific definitions of individual
types of infections (e.g. otitis media, infectious rhinitis, etc.), there is no
clear consensus on a definition of ‘recurrent’, although standard
references exist.7 For otitis media, three episodes within six months or
four within 12 months is considered recurrent. In contrast, recurrent
infectious rhinitis is frequently defined as greater than five episodes
per year. Finally, recurrent pharyngitis or tonsillitis is more than three
episodes within 12 months.8,34,35 For the most part, however, definitions
tend to be arbitrary and may not necessarily help physicians determine
the optimal therapeutic option for individual patients.
Morbidity and Complications
Direct complications from recurrent RTIs include bacterial
manifestations such as acute otitis media, sinusitis and bronchitis.32
Infections of the ear, nose and throat constitute the most common
pathologies in children aged six months to six years.34,36 Other
important consequences include mastoiditis, pneumonia and sepsis.
Paediatricians therefore need to diagnose and monitor patients
carefully to limit these potentially life-threatening events and manage
them appropriately.
In some severe cases, the RTI may be fatal for the child. This risk is
especially prevalent in developing countries where child mortality
rates are generally higher.32 In the long-term, recurrent RTIs can cause
damage to the lungs and lead to further respiratory problems as well
as increased risk of disease in the future.37 Moreover, RTIs can at
times lead to exacerbations of cough and wheeze in children.38 An
association between recurrent RTIs in early life and asthma has been
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The Management of Recurrent Respiratory Tract Infections in Children
reported39 and for some children, repeated respiratory infections are
the first manifestations of asthma.7
These strategies look to prevent the development of recurrent RTIs in
children by reducing the risks of infection.
Socioeconomic Burden
Parent Education
Recurrent RTIs are responsible for much socioeconomic burden in the
world, causing absenteeism from school for the child and from work
for the parent(s).8,40,41 Healthcare and medical costs as well as learning
delays from missed school days also add to the socioeconomic
burden of recurrent RTIs.31
A key aspect of initiatives to prevent recurrent infections in children is
the education of their parents. They need to know what factors
increase a child’s risk of recurrent RTIs and work to minimise them.
For example, the absence of breastfeeding is a risk factor for
infection, suggesting a protective role of mothers’ milk in the infant.
Breast milk is rich in nucleotides that have immunomodulatory activity
thus enhancing a child’s immune defence. Similarly, nucleotide
supplementations to infant formulas augment natural killer cell
activity and humoral response.30 By increasing their knowledge of the
disease and risk factors, parents can better care for their children and
potentially reduce the frequency of RTIs.
A study of 600 Australian families showed a mean 2.2 respiratory
episodes per person per year, the frequency and severity being higher
in young children (<2 years).42 The mean episode duration was 6.3
days; 28.7 % of these events required a visit to the physician and there
was a 23 % rate of absenteeism. Another study with healthy children
aged 12–71 months during a winter season in Australia demonstrated
an average of 0.53 respiratory infectious episodes per child per
month.43 The mean duration per episode was 10.4 days and for every
100 episodes there were 46.7 general practitioner visits, 19.7 courses
of antibacterial therapies prescribed and 2.2 hospital admissions, all
increasing the cost and burden of disease. The average cost of a
community-managed acute respiratory episode was found to be
AU$241 and approximately 70 % of this cost was the carer’s time
away from their normal activities in order to care for the child.
Non-prescription medications and general practice visits made up only
a small proportion of the costs at 5.4 and 5.0 %, respectively.44
Other risk factors must also be limited; a child’s exposure to air
pollution, passive smoke and overcrowded day care centres should
be reduced as much as possible, and parents can play a major role in
avoiding such adverse environments.7 Parents must also remember
that children with recurrent infections are still ‘normal’ with regard to
their immune response and so any major interferences to their
developing immune system, such as surgery (e.g. adenoidectomy and
tonsillectomy) or prophylactic antibiotic treatment, may actually be
harmful and counter-productive.7
Immunisation
Antibiotic Overuse and Misuse
Antibacterial resistance in the bacteria that commonly cause or
complicate RTIs is a major healthcare concern.45 If it is not adequately
addressed, children will continue to encounter stronger, more resistant
pathogens in the future. Overuse and misuse of antibiotics are the main
factors that perpetuate this issue of resistance. Overuse refers to using
antibiotic treatment when it is not necessary or indicated (i.e. for viral
infections and non-infectious diseases). Conversely, antibiotic misuse
occurs when the therapy is used incorrectly, either the wrong antibiotic
is chosen or the dosage and/or duration are not appropriate.
The use of antibiotics is common for the treatment of infections
including RTIs. However, as these are often viral infections,
antibacterials will likely not be effective in these situations.46,47 When a
bacterial infection has been properly diagnosed as the cause of
disease, antibiotics are the favoured treatment option. However, even
with such infections, multiple courses of antibacterial therapies do
not cure nor do they prevent subsequent recurrences. Importantly,
application of these therapies contributes to the development of
antibiotic-resistant strains of bacteria.48–50 Other drivers of resistance
include the type of antibiotic used and the high rate of clonal spread.
Considering the prevalence and effects of antibiotic resistance, it
becomes important for paediatricians to take care when prescribing
and ensure appropriate and responsible use of antibiotics.51 Improved
diagnostic techniques that can provide more rapid and reliable
identification of causal pathogens in RTI would allow antibiotics to be
avoided whenever possible thereby limiting the number of unnecessary
courses administered prior to a definitive diagnosis.
Many vaccines are currently available to prevent various childhood
diseases. As such, effective vaccination programmes for children to
protect against viruses and bacteria known to cause RTIs will be the
ultimate goal. At present, there are vaccines against influenza,
measles, S. pneumoniae, B. pertussis and H. influenzae type b, which
are relevant to the prevention of the infections due to these infectious
agents. However, the availability of these vaccines is low in some
areas of the world therefore limiting the effect of this strategy.
Large-scale take-up of vaccination within any population is vital to
establish herd immunity and limit exposure of vulnerable children
to pathogens. Parents therefore need to understand the importance
of immunisations for their children. While these vaccines should be
administered wherever available, their role in preventing some
recurrent viral infections is limited. In fact, only influenza vaccination
can have a direct impact in this setting. As RTIs are mainly due to
viruses the roles of bacterial vaccines (pertussis, pneumococcus and
H. influenzae b) are limited in avoiding initial episodes even if they can
play a relevant role in reducing bacterial complications.
Immunostimulation
As a result of the strong association between recurrent RTIs and
inadequacies of the immune system, bacterial immunostimulants have
been developed to non-specifically boost the body’s own defences
against any invasive pathogens.31 Bacterial immunostimulants were first
introduced in the 1980s and there are now several licensed formulas
that are marketed around the world for the prevention and treatment
of bacterial infections of the upper and lower respiratory tract. These
include BioStim®, Luivac®, IRS 19®, Ribomunyl® and Broncho-Vaxom®
(Broncho-Munal®, Ommunal®, Paxoral® and Vaxoral®).40
Preventive Measures
As a result of the risks and negative impact antibiotic use can have in
society, other forms of infection management have been explored.
EUROPEAN INFECTIOUS DISEASE
Some immunostimulant preparations are bacterial lysates while others
contain cellular structures such as ribosomes. The constituents of each
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Respiratory Tract Infections
Figure 1: Proportion of Children with Recurrent
Respiratory Tract Infections Following OM-85 or Placebo
Percentage of patients in each group with ≥3 respiratory tract infections per six months
70 %
58.20 %
60 %
50 %
p<0.001
40 %
32 %
bacteria strains coming from eight bacteria species (Haemophilus
influenzae, Streptococcus pneumonia, Streptococcus viridans,
Streptococcus pyogenes, Klebsiella pneumoniae ssp. pneumonia,
Klebsiella pneumoniae ssp. ozaenae, Staphylococcus aureus, Moraxella
catarrhalis) often associated with respiratory infections. Taken orally, it
is capable of inducing non-specific innate and adaptive immune
responses in an individual. Following intestinal absorption, OM-85
stimulates immune cells in the intestinal mucosa. As a result,
OM-85 can raise the overall body defences against infections by
shaping the dendritic cell activation into a ‘pre-alert’ phenotype.53
30 %
Efficacy
20 %
10 %
0%
OM-85
Placebo
Source: Schaad, 2010.17
Figure 2: Relationship Between Efficacy of OM-85 and
Number of Respiratory Tract Infections in the 12
Months Prior to Treatment
Favours OM-85
4.5
4.0
Mean differences & 2 SEM
3.5
The efficacy of OM-85 in children was supported in a recent meta-analysis
of eight randomised controlled trials.17 Mean age and number of RTIs
were comparable between the OM-85 (n=435) and placebo (n=416)
groups at admission. Following treatment, there was a significant
decrease in the percentage of children with recurrent RTIs (defined
as at least three RTIs in six months) in the OM-85 treatment
group relative to the placebo group (32 versus 58.2 %, p<0.001)
(see Figure 1). There is also an association between OM-85 efficacy
and the number of RTIs in the year prior to treatment indicating that
patients with the highest frequency of RTIs benefit the most from
treatment (see Figure 2). OM-85 was also shown to significantly
reduce the duration of acute RTI, the number of infections, the use of
antibiotics and conventional drugs, and the time on treatment
compared with placebo.54
3.0
2.5
2.0
Ref 2
Ref 6
1.5
Ref 5
Ref 4
1.0
0.5
0.0
-0.5
-1.0
Ref 3
2
4
6
8
10
12
Ref 1
Number of recurrent RTIs during previous 12 months
Favours placebo
RTIs = Respiratory tract infections; SEM = Standard error of the mean.
References 1: Schaad et al., 1986,58 2: Jara-Pérez et al., 2000,59 3: Schaad et al., 2002.60
4: Zagar et al., 1988,61 5: Del-Rio-Navarro et al., 2003.62 6: Gutiérrez-Tarango et al., 2001.63
Mean differences are shown with error bars representing the standard error of the mean.
Source: Schaad, 2010.17
formulation were chosen according to their highly immunogenic
properties. In RTI immunostimulants enhance the immune system,
eliciting immune responses both in the respiratory tract and
systemically, thereby inducing better protection against infections. This
reduces both the frequency and severity of RTIs which in turn decreases
the need for antibiotics and any subsequent resistance.31
Bacterial immunostimulants have shown positive safety data in trials while
decreasing the number of RTIs as well as the use of antibiotics and other
concomitant medications. Other immunostimulants in the form of herbal
extracts and synthetic compounds also exist – such as pidotimod – that
may be effective in decreasing the number of recurrent RTIs.52 However,
compared with bacterial extracts, there is substantially less data available
for these treatment options and further research is required.
OM-85 in the Prevention of Recurrent
Respiratory Tract Infection in Children
OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral® and
Vaxoral®) is a standardised immunoactive lyophilised extract of 21
114
Another recent study looked at the effect of OM-85 on wheezing attacks
associated with acute RTIs in children over the course of 12 months.55
Wheezing attacks are also a large healthcare concern, responsible for
many hospital admissions in young children. OM-85 significantly
reduced the number of wheezing attacks (37.9 % cumulative reduction,
p<0.001) and the number of RTIs (31.4 % cumulative reduction, p<0.001)
relative to placebo in the children studied (n=75).
OM-85 was also shown to improve Ig levels and reduce infections in
children with recurrent RTIs and hypogammaglobulinemia.56 This
therapy significantly increased IgG and IgA levels post-treatment
versus pre-treatment as well as versus placebo, with many reaching
normal serum levels for their age.
Safety
The safety profile of OM-85 has been evaluated during more than 30
years of post-marketing experience. Adverse events are mostly
non-serious and transitory. The most common side effects are
headache and nausea, and OM-85 has shown a similar safety profile
as placebo. Furthermore, no signs of autoimmunity have been
observed in any subjects. A recent study on the effect of OM-85
prophylaxis on autoimmunity in IgA-deficient children found no
significant difference between receivers and non-receivers of OM-85
in terms of clinical or laboratory markers for autoimmunity during four
years of follow-up.57
Parent education and practical prophylaxis are important in managing
recurrent RTIs in children. Parents need to be aware of the options
available and how best to use them to benefit their offspring. At
present, for preventive treatment, OM-85 is indicated for children as
follows: one capsule/sachet (3.5 mg) or 10 drops (11 mg/ml) per day
on an empty stomach for 10 consecutive days per month for three
consecutive months, ideally before the beginning of the autumn.
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The Management of Recurrent Respiratory Tract Infections in Children
Improved understanding by parents will ensure optimal compliance
and improved clinical outcomes.
essential alternative for the management of this disease and help reduce
the risk of developing respiratory infections. At present, many practitioners
still fail to employ prevention strategies in children with recurrent RTIs.
Conclusions
Paediatric recurrent RTIs represent a huge global health burden, resulting
in much morbidity and mortality in children. Moreover, they contribute
greatly to socioeconomic costs in the form of absenteeism from work of
parents as well as visits to the general practitioner. Antibacterial
treatments are often prescribed in this population; however, they have
limited efficacy and, more importantly, increase the level of antibiotic
resistance around the world. Preventive measures are therefore an
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