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: A Double-Blind, With Recurrent Infections of the Upper Immunostimulation With OM-85 in Children
DOI 10.1378/chest.122.6.2042
Chest 2002;122;2042-2049
Urs B. Schaad, Ralph Mütterlein and Heidi Goffin
Placebo-Controlled Multicenter Study
Respiratory Tract* : A Double-Blind,
With Recurrent Infections of the Upper
Immunostimulation With OM-85 in Children
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Immunostimulation With OM-85 in
Children With Recurrent Infections of
the Upper Respiratory Tract*
A Double-Blind, Placebo-Controlled Multicenter
Study
Urs B. Schaad, MD; Ralph Mu¨ tterlein, MD; and Heidi Goffin, MD; on behalf of
the BV-Child Study Group†
Objective: Recurrent upper respiratory tract infections (URTIs) are common illnesses in young
children. As the immunoactive bacterial extract OM-85 has been shown to prevent these
infections in both adults and children, the aim of the present trial was to investigate further its
efficacy and safety in infection-prone children.
Methods: This is a randomized, double-blind, placebo-controlled, multicenter study with OM-85
in 232 patients aged 36 to 96 months with recurrent URTIs. Treatment was one capsule daily
during month 1 and during 10 days in months 3 to 5. URTI was defined by the presence of at least
two of the following: rhinitis, pharyngitis, cough, hoarseness, temperature > 38.5°C, or URTIrelated
prescription of an antibiotic.
Results: OM-85–treated patients had a lower rate of URTIs (p < 0.05). The cumulated difference
in URTIs between the two groups reached 0.40 URTIs per patient in 6 months, corresponding
to a 16% reduction in the active-treatment group with respect to placebo. The largest difference
was observed in the patients having had three or more URTIs during the study period; odds ratios
for three or more URTIs were 0.51 (95% confidence interval, 0.29 to 0.91) and 0.65 (95%
confidence interval, 0.37 to 1.11) after 5 months and 6 months, respectively. The difference
between OM-85 and placebo was independent of age but was more important in patients
reporting a larger number of URTIs in the previous year. Patients’ global assessment showed
improvement in comparison to the previous season in the majority of the cases (OM-85, 78.4% of
cases; placebo, 75.5%); however, there were more cases reporting worsening with placebo (6.4%
vs 0.9%; p 0.05).
Conclusions: OM-85 treatment significantly reduced the rate of URTIs, particularly in children
with a history of frequent URTIs. Safety and tolerance of test medication were good, comparable
to placebo. (CHEST 2002; 122:2042–2049)
Key words: bacterial extract; child; immunostimulation; OM-85; prevention; recurrence; upper respiratory tract
infection
Abbreviations: ANOVA analysis of variance; URTI upper respiratory tract infection
Pediatric acute infections of the airways continue
to play an important role with regard to morbidity
and mortality and have significant socioeconomic
implications.1–3 They primarily affect children 5
years old. Nearly 50% of the pediatric consultations
in Switzerland are caused by infections of the respiratory
tract.4 The vast majority—80 to 90%—of
these infections are caused by viruses. Uncomplicated
upper respiratory tract infections (URTIs) are
usually self-limiting and do not require antibiotics.
However, several bacterial complications can arise,
such as acute otitis media, sinusitis, and bronchitis.
In a French study, overall incidence of complications
*From the University Children’s Hospital of Basel (Dr. Schaad),
Basel, Switzerland; the Regional Hospital of Parsberg (Dr.
Mu¨ tterlein), Parsberg, Germany; and OM PHARMA (Dr. Goffin),
Meyrin/Geneva, Switzerland.
†Members of the BV-Child Study Group are listed in the
Appendix.
The study was supported by a grant from OM PHARMA,
CH-1217 Meyrin/Geneva, Switzerland.
Dr. Goffin is the project leader of this clinical trial at OM
PHARMA.
Manuscript received November 29, 2001; revision accepted July
12, 2002.
Correspondence to: Urs B. Schaad, MD, Department of Pediatrics,
Universita¨ts-Kinderspital beider Basel, PO Box CH-4005,
Basel, Switzerland; e-mail: urs-b.schaad@unibas.ch
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was 16.8% (10.9% acute otitis media, 4% laryngitis
or bronchitis, 1.9% pulmonary infections).5 Simple
episodes of URTIs generally have a good prognosis,
but recurrence and/or bacterial superinfection may
lead to numerous complications requiring various
medical and surgical treatments, in particular appropriate
antibiotic therapy. Furthermore, duration of
pediatric URTIs is often prolonged: rhinopharyngitis
lasting 14 days in 35% of children vs 20% of
adults.6
From an epidemiologic point of view, it has been
shown that 57% of children with recurrent respiratory
infections (three or more episodes a year during
at least 2 years) were deficient in one of the IgG
subclasses and that 17% were IgA deficient.7 IgG
subclass deficiency is quite prominent in young
children but rare in older children, suggesting a
transient immaturity of the immune system as one of
the possible pathogenic factors. Defects in the immune
system such as common variable immunodeficiency
and the more frequent selective IgA deficiency
are known to be linked with frequent
respiratory infections by bacteria and viruses.8 As
OM-85 stimulates immune defenses and in particular
the production of salivary and bronchoalveolar
serum IgA as well as serum IgA and IgG, it has been
administered since the 1980s to adults and children
in order to prevent recurrences of respiratory tract
infections.
OM-85 is an immunoactive lyophilized extract
from eight pathogenic bacteria of the respiratory
tract. It stimulates the local immune responses, via
activation of the mucosa-associated lymphoid tissue,
and possibly the systemic immune responses, activates
the macrophages and phagocytosis, the natural
killer and cytotoxic activity, as well as increases the
level of serum IgA in saliva and BAL fluid and of IgG
in serum.9–12 Summarizing, Emmerich et al11 defined
OM-85 as having pleiotropic immunomodulating
effects, ie, activating different systems in the
chain of immunologic defense reactions.
The major placebo-controlled adult studies show
that OM-85 diminishes the incidence of respiratory
infections and antibiotic prescriptions in patients
with known immune defects (eg, hemodialysis) or
with a chronic inflammatory and/or obstructive process
of the respiratory tree, making them more
susceptible to bacterial infection (chronic bronchitis,
chronic sinusitis).13–15 OM-85 proved also significantly
superior to placebo with regard to the number
of hospitalizations.16 As regards children, several
double-blind trials have shown its efficacy in reducing
the frequency of respiratory and ear, nose, and
throat infections of both bacterial and viral origin,
accompanied by a reduction in antibiotics and other
concomitant medications.17–22 The rationale for performing
the present study was to investigate further
the therapeutic benefit of OM-85 in children with
recurrent URTIs.
Materials and Methods
This study is a randomized, double-blind, placebo-controlled,
multicenter study with OM-85 (Broncho-Vaxom; OM PHARMA;
Meyrin/Geneva, Switzerland) in patients with acute recurrent
URTIs. Two hundred twenty patients were enrolled in order to
obtain 170 assessable cases (110 patients/85 assessable cases per
treatment group) in 40 centers. The duration of the study was 6
months, with visits planned every 30 days, totaling seven visits
and starting between mid-August and mid-December for all
patients.
Patients
The patients were children of either gender, aged 36 to 96
months, with a history of recurrent URTIs and presenting with
URTI at hospital admission. The definition used for recurrent
URTIs was three or more such episodes during the last 12
months. The current episode required for study eligibility was
defined by the presence of at least two of the following: rhinitis,
pharyngitis, cough, hoarseness, temperature 38.5°C, or prescription
of an antibiotic for a URTI, occurring after an asymptomatic
period of at least 1 week without antibiotics.
Patients meeting any of the following criteria at entry were
excluded: occurrence of otitis media and/or sinusitis and/or
infection of the lower respiratory tract (ie, bronchitis, pneumonia)
and/or proven group A streptococcal angina at the enrollment
visit. Further main exclusion criteria were allergic asthma,
mucoviscidosis, significant systemic disease (eg, hepatic and/or
renal disease, malignancy), immune system disorders, suspected
malabsorption, known allergy to the bacterial extract, major
surgical procedure within 3 months of commencement of the
study, recent immunosuppressive or immunostimulant therapy,
or corticosteroids.
Patients fulfilling the inclusion/exclusion criteria and whose
parents or guardians gave their informed consent were randomly
assigned by blocks of four to OM-85 or placebo at initial visit.
Randomized assignment to masked medication of identical appearance
was accomplished by prepackaging of masked study and
control medications at random sequence. The allocation of the
study treatment to each patient was carried out according to the
next available consecutive patient number printed on the prescription
card and on the label of the box.
Medication
OM-85 contains 3.5 mg per capsule of standardized lyophilized
bacterial fractions of the following: Haemophilus influenzae,
Diplococcus pneumoniae, Klebsiella pneumoniae and Klebsiella
ozaenae, Staphylococcus aureus, Streptococcus pyogenes and
Streptococcus viridans, and Moraxella (Neisseria) catarrhalis.
Patients had to take one capsule per day of OM-85 or placebo on
an empty stomach, as follows: month 1, 1 capsule per day during
30 days; month 2, no therapy; months 3 to 5, 1 capsule per day
during 10 days; and month 6 (follow-up), no treatment.
Assessments
The primary end point of the study was the reduction of URTIs
(as defined above) during treatment and over the entire obserwww.
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vation period. Presence of an URTI was reported at regular or
intermediate visits, and occurrences between scheduled visits
were reported even if they did not imply a supplementary visit.
Secondary end points were the ratings of rhinitis, pharyngitis,
cough, hoarseness, (coded as none, mild, or severe), fever (coded
as 0 absent; 1 38.5 to 39.4°C; 2 39.5°C), number of
days of absence from school, incidence of otitis, sinusitis, or other
related infections.
Prescribed medications were also recorded. Patient (parent or
guardian) and investigator assessments of the efficacy of the
therapy were recorded at the end of the treatment period on a
7-point scale (from 3 marked worsening, to 0 no change,
to 3 marked improvement). No invasive diagnostic procedures
were planned in order to improve study compliance.
Ethics
This study was conducted in accordance with the Declaration
of Helsinki (revised 1996), the specific local laws governing
clinical trials, and in accordance with good clinical practice
guidelines. The study in a participating center was only started
once written approval by the ethics committee and/or regulatory
authorities was obtained.
Statistical Analysis
The sample size was computed to prove that a 15 to 20%
decrease of the rate of URTIs in the OM-85 group compared
with placebo group is statistically significant in a population with
a history of recurrent URTIs. Assuming such a difference and a
URTI rate of approximately 60% in the placebo group, approximately
82 analyzable patients in each group were required, with
0.05 and 0.2, respectively.23
The primary efficacy parameter, the mean rate of URTIs (per
patient, per month) was computed at each visit up to visit 7 and
tested by analysis of variance (ANOVA) for repeated measures.
URTIs in the first 15 days of the trial were discarded, since it was
estimated that they were linked to the infection already present
at the initial visit. A URTI had to be preceded by an asymptomatic
period of at least 7 days in order to be considered a new
URTI.
Secondary efficacy variables were analyzed for descriptive
purposes using adequate standard statistical tests, eg, 2 test resp.
ANOVA for repeated measures for symptom scores, Mann-
Whitney test for global assessments, etc. Analyses and data
management were carried out using software (DataEase v0.4;
DataEase International; Trumbull, CT) for the data management
and SPSSPC release 5.0 resp. (Systat v0.9; SPSS; Chicago, IL;
and NCSS release 2000; NCSS; Kaysville, UT) and TESTIMATE
release 5.2 (IDV, D-82131; Gauting; Munich, Germany) for the
statistical analysis.
Results
Two-hundred thirty-two patients were enrolled in
40 centers (30 in Switzerland and 10 in Germany)
between 1997 and 1999. Of these, 12 patients were
never exposed to the test medication; therefore, 220
patients received treatment and were allotted to the
intent-to-treat sample or the safety sample (OM-85,
120 patients; placebo, 100 patients).
The main demographic data that are summarized
in Table 1 show that the two therapeutic groups were
fairly homogeneous (all variables p 0.3) and therefore
comparable. Distribution by sex was also comparable
(OM-85, 69 male and 51 female patients;
placebo, 61 male and 38 female patients, 1 missing
data). A small percentage of children presented
alterations in other body systems (neurologic, GI,
urogenital, dermatologic, or endocrinologic), slightly
but not significantly higher in the OM-85 group. The
symptom ratings at hospital admission were also
comparable in the two groups, as shown in Table 2
(all variables p 0.11).
URTIs
Table 3 shows the mean rate of URTIs per month
and per patient in the two treatment groups, which
was consistently lower in the patients treated with
OM-85, except in the last month (follow-up).
Table 1—Demographic Characteristics of the Intent-to-Treat Population
Variables
OM-85 Placebo
t Test
No. Mean SD No. Mean SD p Value
Age, yr 120 5.2 1.2 100 5.3 1.4 0.59
Height, cm 120 110.2 9.3 100 111.4 10.3 0.40
Weight, kg 120 20.4 4.0 100 20.5 5.3 0.94
Infections during previous year, No. 119* 5.8 2.4 100 6.1 2.2 0.32
Days since last infection, No. 118* 66.9 67.7 100 74.1 70.1 0.44
Days of absence from school, No. 48 3.2 2.0 52 3.1 1.8 0.77
*Data were missing in one and two patients, respectively.
Table 2—Symptom Score of URTI at Hospital
Admission
Variables
OM-85 Placebo
2 Test
None Mild Severe Normal Mild Severe p Value
Rhinitis* 6 68 45 1 61 38 0.23
Pharyngitis 27 72 21 14 69 17 0.25
Cough† 7 71 41 12 57 30 0.25
Hoarseness‡ 59 56 2 40 54 6 0.11
Fever 75 43 2 57 40 3 0.62
*Data were missing in one OM-85–treated patient.
†Data were missing in one patient in each group.
‡Data were missing in three OM-85–treated patients.
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ANOVA for repeated measures confirmed a significantly
lower rate of URTIs in the OM-85–treated
patients (p 0.05). Calculating the cumulated mean
rate of URTIs, the difference between the two
groups builds up progressively during active therapy
(at end of treatment, the mean cumulated difference
was of 0.42 URTIs per patient in 5 months) and
diminishes very slightly in the month of follow-up, as
can be seen in Figure 1. Thus, over the 6 months of
the study, OM-85 treatment significantly reduced
the mean incidence of URTIs by 16% (ratio of 0.40
on 2.5). In fact, the largest reduction observed in the
OM-85 group is in the number of children with three
or more URTIs in the observation period, as shown in
Figure 2, revealing a difference in favor of OM-85 of
22% at month 4 and of 15% at month 3 and month 5;
the odds ratios for three or more URTIs with OM-85
were 0.51 (95% confidence interval, 0.29 to 0.91)
and 0.65 (95% confidence interval, 0.37 to 1.11) after
5 months and 6 months, respectively.
An explorative analysis by multiple stepwise regression
analysis was performed, with the cumulated
rate of URTIs at month 5 as a dependent variable,
and considering age, treatment, time in study, number
of URTIs in the previous year, sex, year of
participation in trial, and history of allergy as independent
variables. There were higher rates of URTIs
Figure 1. Mean cumulated rate of URTIs. m1 month 1; m2 month 2; m3 month 3;
m4 month 4; m5 month 5; m6 month 6.
Table 3—Mean Monthly URTI Rate and SEM Per
Patient (p < 0.05)
Treatment*
Month
1 2 3 4 5 6
OM-85 (n 118)*
Mean 0.31 0.47 0.43 0.30 0.24 0.31
SEM 0.05 0.05 0.06 0.05 0.04 0.05
Placebo (n 99)*
Mean 0.37 0.54 0.54 0.41 0.31 0.29
SEM 0.05 0.06 0.06 0.06 0.05 0.06
OM-85-PL† 0.06 0.07 0.11 0.11 0.07 0.02
Cumulative OM-85-PL 0.06 0.13 0.24 0.35 0.42 0.40
*Three patients had missing data (two receiving OM-85 and one
receiving placebo).
† OM-85-PL difference of monthly URTI rate between OM-85
and placebo.
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in patients treated with placebo (p 0.06), in
younger children (p 0.006), in those who reported
more URTIs in the previous year (p 0.06), and, as
expected, in those remaining the longer time in the
study (p 0.0001). The difference between OM-85
and placebo was independent of age but was more
important in patients reporting a larger number of
URTIs in the previous year. Stratification by number
of URTIs reported in the previous year (cutoff was
median of 5 URTIs) shows that the cumulated rate
of URTIs was reduced in the OM-85 group by 14%
( 0.28 URTIs) in those reporting 2 to 5 URTIs in
the previous year (not significant), and by 22%
( 0.56 URTIs) in those reporting 6 to 15 URTIs in
the previous year (p 0.05). It may be concluded
that OM-85 treatment significantly reduced the incidence
of URTIs in children with a history of
frequent URTIs.
Secondary Variables
Of the target variables recorded, the main differences
between treatments, favoring OM-85, were
observed in the frequency and severity of rhinitis
(p 0.06) and, to a lesser extent, in the frequency
and severity of pharyngitis (p 0.16) and of fever
(p 0.2). No difference was observed as far as
cough and hoarseness were concerned.
In the first 2 months of treatment, there were
more cases of otitis reported in the OM-85–treated
group (13 episodes vs 4 episodes in the placebo
group), although not reaching the threshold of significance.
In the later visits, the percentage of patients
with otitis was similarly low (2 to 4%) in both
groups. This finding is likely to reflect a difference
between the two groups at baseline. The reported
incidence of sinusitis was very low (mean monthly
percentage 1%) and comparable in both groups.
Anti-infectives
The mean monthly percentage of patients treated
with antibiotics was similar in both groups (OM-85,
15.0%; placebo, 14.2%) and in the large majority of
cases related to lower respiratory tract infection
(OM-85, 11.9%; placebo, 12.2%). However, it has to
be noted that less than half of the URTIs received
antibiotic therapy with no clear-cut pattern of prescription.
This finding contrasts with the prescriptions
of local antiseptic, anti-inflammatory, antitussive,
or mucolytic products, which were significantly
less frequently used in the OM-85–treated group
(mean monthly prescription of 5.2%) than in the
placebo group (9.0%, p 0.05).
Absenteeism
The number of patients with absenteeism from
school diminished from approximately 50% at hospital
admission to 10% during the first month and to
Figure 2. Cumulated percentage of patients reporting three or more URTIs during the study period.
N.S. not significant; see Figure 1 legend for expansion of abbreviations.
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approximately 3% in the last 2 months, without
significant differences between groups. It is not clear
whether this absenteeism is specifically URTI related,
since it was recorded independently of the
occurrence of a URTI at the same visit. The
mean SD duration of an episode of absenteeism
was similar in both groups (approximately 3.5 1.5
days) and did not change significantly over time.
Global Assessment
In comparison to the previous season, the majority
of the patients and/or their parents or guardians
reported some degree of improvement (OM-85,
78.4% of cases; placebo, 75.5% of cases); however,
the distribution of answers was significantly different
(p 0.05) and there were more cases reporting
worsening with placebo (6.4% vs 0.9%; Fisher test,
p 0.05). The investigators also reported an improvement
in the majority of patients, with no
significant differences between OM-85 and placebo.
Influence of Season
Distributing patients on treatment along the year
(ie, mean URTIs of all patients treated in the months
of November, December, etc.) showed in the placebo
group a rapid increase in mean number of
URTIs from September to November, followed by a
plateau until February, and falling off thereafter.
OM-85–treated patients showed a flat pattern, and
the mean number of URTIs was lower. As a consequence,
the benefit of the active treatment was
largest in the period of November to February.
Safety
After active questioning, 164 patients (88 receiving
OM-85 and 76 receiving placebo) complained about
835 adverse events (OM-85, 456 events; placebo,
379 events), of which approximately 40% were manifestations
of the studied respiratory indications. The
events were of different type, duration, and estimated
relationship with the test medication, and
constituted in most cases mild digestive troubles or
respiratory symptoms (the latter already rated as
such in the clinical part). Multiple events in the same
patient were detected with as many as 20 events for
OM-85 and 19 events for placebo. The average
duration of the adverse events was 5.3 9.0 days for
OM-85 and 5.1 6.8 days for placebo. There were a
few reports of serious adverse events (10 events in
nine patients), none of which were estimated to be
related to the study medication, as follows:
OM-85–Treated Group: One case each of operation
for appendicitis, acquired intestinal obstruction
(in same patient), concussion of the brain, adenoidectomy,
diagnostic procedure for epigastric pain (not
specified), accidental burning, and tonsillectomy
(n 6).
Placebo-Treated Group: One case of pneumonia
and otitis media and two cases of tonsillectomy/
adenoidectomy (n 3).
Only seven patients (six patients receiving OM-85,
and one patient receiving placebo) reported nine
adverse reactions (OM-85, eight reactions; placebo,
one reaction) considered to be in possible or probable
relationship to the trial medication. These were
diarrhea (two patients), abdominal pain (two patients),
fatigue, urinary frequency (twice in same the
patient), and exanthem (in the same patient) in the
OM-85 group. In the placebo group, there was an
allergic reaction assessed as in possible relationship.
All these adverse events were minor and transient,
and they did not prompt any treatment discontinuation.
Discussion
This study was aimed at reducing the rate of
URTIs in children with a history of frequent URTIs,
starting from a current episode. Using an algorithm
for diagnosing a URTI, ANOVA for repeated measures
showed that treatment with OM-85 significantly
reduced the incidence of URTIs by 16%,
corresponding to a mean reduction by 0.40 URTIs
per patient in 6 months with respect to placebo in
the intent-to-treat population. It is worthwhile mentioning
that the ANOVA concerning the per protocol
population (excluding protocol violators) confirmed
the main analysis, ie, a significantly lower rate of
URTIs in the OM-85–treated patients (p 0.05).
Rather than increasing the number of patients
without any URTI, OM-85 treatment appeared
to reduce the number of patients with frequent
URTIs (three or more URTIs in 5 months), which
represent almost half the patient population. The
difference between the two treatment groups
builds up during active treatment (months 1 to 5)
and has a tendency to wear off thereafter (although
this trial has a follow-up of only 1 month,
too short to expect a significant detrition curve).
These findings correspond fairly well with those
reported by Collet et al17 if the same criteria are
applied. These authors, who addressed the question
of the efficacy of OM-85 in the primary
prevention of recurrent respiratory infections in
young children in day-care centers, found a 48%
reduction of the relative risk of having three or
more respiratory infections after 3 months of
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treatment. The efficacy of OM-85 in breaking the
cycle of recurrent infections was also demonstrated
by Paupe18 in a double-blind, placebocontrolled
trial including 116 children, aged 6
months to 19 years who had a history of at least
three episodes of respiratory or ear, nose, and
throat infections in the previous 6-month period.
At the end of the prospective study period
(3 months of treatment plus 3 months of followup),
the incidence of all infections in the active
group was 35% (p 0.01) lower than in the
placebo group. This effect was more pronounced
in children 6 years old, a finding that could not
be confirmed in the study reported herein.
Even greater reductions of URTIs—by, respectively,
52% and 38%—have recently been reported
with this bacterial extract in comparison to placebo
during two double-blind studies.21,22 These more
marked findings with respect to those presented
here may be linked to differences in settings. Indeed,
the first trial included only girls aged 6 to 13 years
living in a single fairly crowded center favoring
microbial contamination (an orphanage), located in a
region with high air pollution (Mexico City), and who
were all highly susceptible to respiratory infections (a
median of five infections per child over the previous
6 months, approximately double the value recorded
here).21 Overall, the same comments may address
the other Mexican trial, in particular air pollution
and highly susceptible children aged 1 to 12 years
with a past mean rate of URTIs twice as high as the
one of the present trial, but living at home and
followed up for 1 year with two intermittent treatment
periods of 3 months.22
In one of our previous multicenter studies,24 94
children with frequent URTIs were treated intermittently
with either OM-85 or placebo, under doubleblind
conditions for 3 months followed by 3 months
of observation. The preventive action of OM-85 was
rated as “unequivocal” or “likely” in 77.3% of the
cases vs 57.2% of those treated with placebo without
statistically significant differences.
The findings in the present study contrast somewhat
with those of the above-mentioned studies,
probably conducted in more homogeneous settings18,19,21
or in more air-polluted environments21,22,
but are more favorable for the OM-85 treatment
than our previous results,24 recorded in a heterogeneous
multicentric practice-based setting, similar in
fact to the one herein. Furthermore, explorative
analysis strongly suggests that the efficacy of OM-85
is more evident, both in absolute and relative terms,
in patients reporting frequent URTIs in the previous
year (more than the median of five URTIs in the
previous year), as clearly demonstrated in the abovementioned
two studies conducted in children who
had an average of five acute respiratory tract infections
per 6 months before inclusion.21,22 Patients
reporting “very frequent URTIs” were also likely to
have more URTIs in the study period and constitute
the subgroup that benefited most from the therapy
with OM-85.
However, the findings concerning URTIs were not
fully confirmed for the activity of the test medication
on secondary variables such as the number of patients
with pharyngitis, cough, hoarseness, temperature
38.5°C, or antibiotic consumption. Some
degree of masking of symptoms through prescribed
or self-prescribed medication cannot be excluded.
Nevertheless, intensity of rhinitis over the observation
period was decreased under OM-85 with reference
to placebo (p 0.06), as was the consumption
of local antitussive, anti-inflammatory, systemic antitussive,
or mucolytic agents (p 0.05). As URTIs
tend to improve as children grow older, the global
assessments comparing with the previous year were
positive with both active treatment and placebo;
however, a small but significantly larger proportion
of placebo-treated patients reported a worsening of
the condition.
In conclusion, confirming earlier studies, OM-85
reduced significantly the rate of URTIs in children
with a history of frequent URTIs. This effect was
proportional to the number of URTIs in the history
of the patients. Safety and tolerance of test medication
were good, comparable to placebo.
Appendix
We wish to thank the members of the BV-Child Study Group:
J. F. Babel, J. Ballaman, R. Bardelli, G. Beguin, C. Bernasconi, L.
Bianchetti, U. Bollag, E. Busser-Knusel, R. Christen, G. Ferrazzini,
A. Frank, M. Good, P. Gordon, H. Hafliger, C. Hanggi,
J. Holx, J. P. Kapp, U. Keller, R. Pancaldi, M. Renggli, U. B.
Schaad, T. J. Von Kanel, Ch. Zeller, and A. Zimmerman,
Switzerland; and G. Berzel, U. Brendel, J. Disselhoff, H. Gutzeit,
O. Muller, R. Mu¨ tterlein, F. Panzer, S. Schneider, J. Tessmar,
and F. Thanbichler, Germany.
References
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2 Collet JP, Burtin P, Floret D. Risque infectieux chez l’enfant
en cre` che. Rev Prat 1992; 42:1797–1803
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worldwide distribution of child deaths from acute respiratory
infections. Lancet Infect Dis 2002; 2:25–32
4 Eggenberger K. Les infections des voies respiratoires les plus
fre´quentes chez l’enfant dans la pratique ambulatoire. Ars
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5 Cohen R. Enqueˆ te nationale sur les crite` res de prescription
d’une antibiothe´ rapie dans les rhinopharyngites en pe´ diatrie
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en ville. Ann Pe´ diatr (Paris) 1992; 39:195–201
6 Stickler GB, Smith TF, Broughton DD. The common cold.
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8 David JR, Rosen FS. Deficiencies in immunoglobulins and
cell-mediated immunity [CD-ROM]. Chapter IX. Scientific
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studies. Respiration 1994; 61(suppl 1):8–15
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11 Emmerich B, Emslander HP, Milatovic D, et al. Effects of a
bacterial extract on local immunity of the lung in patients with
chronic bronchitis. Lung 1990; 168:726–731
12 Lusuardi M, Capelli A, Carli S, et al. Local airways immune
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13 Tielemans C, Gastadello K, Husson C, et al. Efficacy of oral
immunotherapy on respiratory infections in hemodialysis
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15 Heintz B, Schlenter WW, Kirsten R, et al. Clinical efficacy of
Broncho-Vaxom in adult patients with chronic purulent sinusitis:
a multicentric, placebo-controlled, double-blind study.
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16 Collet JP, Shapiro P, Ernst P, et al. Effects of an immunostimulating
agent on acute exacerbations and hospitalizations
in patients with chronic obstructive pulmonary disease. Am J
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17 Collet JP, Ducruet T, Kramer MS, et al. Stimulation of
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1742–1748
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www.chestjournal.org CHEST / 122 / 6 / DECEMBER, 2002 2049
© 2002 American College of Chest Physicians
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DOI 10.1378/chest.122.6.2042
Chest 2002;122; 2042-2049
Urs B. Schaad, Ralph Mütterlein and Heidi Goffin
Multicenter Study
of the Upper Respiratory Tract * : A Double-Blind, Placebo-Controlled
Immunostimulation With OM-85 in Children With Recurrent Infections
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Chest 2002;122;2042-2049
Urs B. Schaad, Ralph Mütterlein and Heidi Goffin
Placebo-Controlled Multicenter Study
Respiratory Tract* : A Double-Blind,
With Recurrent Infections of the Upper
Immunostimulation With OM-85 in Children
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Immunostimulation With OM-85 in
Children With Recurrent Infections of
the Upper Respiratory Tract*
A Double-Blind, Placebo-Controlled Multicenter
Study
Urs B. Schaad, MD; Ralph Mu¨ tterlein, MD; and Heidi Goffin, MD; on behalf of
the BV-Child Study Group†
Objective: Recurrent upper respiratory tract infections (URTIs) are common illnesses in young
children. As the immunoactive bacterial extract OM-85 has been shown to prevent these
infections in both adults and children, the aim of the present trial was to investigate further its
efficacy and safety in infection-prone children.
Methods: This is a randomized, double-blind, placebo-controlled, multicenter study with OM-85
in 232 patients aged 36 to 96 months with recurrent URTIs. Treatment was one capsule daily
during month 1 and during 10 days in months 3 to 5. URTI was defined by the presence of at least
two of the following: rhinitis, pharyngitis, cough, hoarseness, temperature > 38.5°C, or URTIrelated
prescription of an antibiotic.
Results: OM-85–treated patients had a lower rate of URTIs (p < 0.05). The cumulated difference
in URTIs between the two groups reached 0.40 URTIs per patient in 6 months, corresponding
to a 16% reduction in the active-treatment group with respect to placebo. The largest difference
was observed in the patients having had three or more URTIs during the study period; odds ratios
for three or more URTIs were 0.51 (95% confidence interval, 0.29 to 0.91) and 0.65 (95%
confidence interval, 0.37 to 1.11) after 5 months and 6 months, respectively. The difference
between OM-85 and placebo was independent of age but was more important in patients
reporting a larger number of URTIs in the previous year. Patients’ global assessment showed
improvement in comparison to the previous season in the majority of the cases (OM-85, 78.4% of
cases; placebo, 75.5%); however, there were more cases reporting worsening with placebo (6.4%
vs 0.9%; p 0.05).
Conclusions: OM-85 treatment significantly reduced the rate of URTIs, particularly in children
with a history of frequent URTIs. Safety and tolerance of test medication were good, comparable
to placebo. (CHEST 2002; 122:2042–2049)
Key words: bacterial extract; child; immunostimulation; OM-85; prevention; recurrence; upper respiratory tract
infection
Abbreviations: ANOVA analysis of variance; URTI upper respiratory tract infection
Pediatric acute infections of the airways continue
to play an important role with regard to morbidity
and mortality and have significant socioeconomic
implications.1–3 They primarily affect children 5
years old. Nearly 50% of the pediatric consultations
in Switzerland are caused by infections of the respiratory
tract.4 The vast majority—80 to 90%—of
these infections are caused by viruses. Uncomplicated
upper respiratory tract infections (URTIs) are
usually self-limiting and do not require antibiotics.
However, several bacterial complications can arise,
such as acute otitis media, sinusitis, and bronchitis.
In a French study, overall incidence of complications
*From the University Children’s Hospital of Basel (Dr. Schaad),
Basel, Switzerland; the Regional Hospital of Parsberg (Dr.
Mu¨ tterlein), Parsberg, Germany; and OM PHARMA (Dr. Goffin),
Meyrin/Geneva, Switzerland.
†Members of the BV-Child Study Group are listed in the
Appendix.
The study was supported by a grant from OM PHARMA,
CH-1217 Meyrin/Geneva, Switzerland.
Dr. Goffin is the project leader of this clinical trial at OM
PHARMA.
Manuscript received November 29, 2001; revision accepted July
12, 2002.
Correspondence to: Urs B. Schaad, MD, Department of Pediatrics,
Universita¨ts-Kinderspital beider Basel, PO Box CH-4005,
Basel, Switzerland; e-mail: urs-b.schaad@unibas.ch
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was 16.8% (10.9% acute otitis media, 4% laryngitis
or bronchitis, 1.9% pulmonary infections).5 Simple
episodes of URTIs generally have a good prognosis,
but recurrence and/or bacterial superinfection may
lead to numerous complications requiring various
medical and surgical treatments, in particular appropriate
antibiotic therapy. Furthermore, duration of
pediatric URTIs is often prolonged: rhinopharyngitis
lasting 14 days in 35% of children vs 20% of
adults.6
From an epidemiologic point of view, it has been
shown that 57% of children with recurrent respiratory
infections (three or more episodes a year during
at least 2 years) were deficient in one of the IgG
subclasses and that 17% were IgA deficient.7 IgG
subclass deficiency is quite prominent in young
children but rare in older children, suggesting a
transient immaturity of the immune system as one of
the possible pathogenic factors. Defects in the immune
system such as common variable immunodeficiency
and the more frequent selective IgA deficiency
are known to be linked with frequent
respiratory infections by bacteria and viruses.8 As
OM-85 stimulates immune defenses and in particular
the production of salivary and bronchoalveolar
serum IgA as well as serum IgA and IgG, it has been
administered since the 1980s to adults and children
in order to prevent recurrences of respiratory tract
infections.
OM-85 is an immunoactive lyophilized extract
from eight pathogenic bacteria of the respiratory
tract. It stimulates the local immune responses, via
activation of the mucosa-associated lymphoid tissue,
and possibly the systemic immune responses, activates
the macrophages and phagocytosis, the natural
killer and cytotoxic activity, as well as increases the
level of serum IgA in saliva and BAL fluid and of IgG
in serum.9–12 Summarizing, Emmerich et al11 defined
OM-85 as having pleiotropic immunomodulating
effects, ie, activating different systems in the
chain of immunologic defense reactions.
The major placebo-controlled adult studies show
that OM-85 diminishes the incidence of respiratory
infections and antibiotic prescriptions in patients
with known immune defects (eg, hemodialysis) or
with a chronic inflammatory and/or obstructive process
of the respiratory tree, making them more
susceptible to bacterial infection (chronic bronchitis,
chronic sinusitis).13–15 OM-85 proved also significantly
superior to placebo with regard to the number
of hospitalizations.16 As regards children, several
double-blind trials have shown its efficacy in reducing
the frequency of respiratory and ear, nose, and
throat infections of both bacterial and viral origin,
accompanied by a reduction in antibiotics and other
concomitant medications.17–22 The rationale for performing
the present study was to investigate further
the therapeutic benefit of OM-85 in children with
recurrent URTIs.
Materials and Methods
This study is a randomized, double-blind, placebo-controlled,
multicenter study with OM-85 (Broncho-Vaxom; OM PHARMA;
Meyrin/Geneva, Switzerland) in patients with acute recurrent
URTIs. Two hundred twenty patients were enrolled in order to
obtain 170 assessable cases (110 patients/85 assessable cases per
treatment group) in 40 centers. The duration of the study was 6
months, with visits planned every 30 days, totaling seven visits
and starting between mid-August and mid-December for all
patients.
Patients
The patients were children of either gender, aged 36 to 96
months, with a history of recurrent URTIs and presenting with
URTI at hospital admission. The definition used for recurrent
URTIs was three or more such episodes during the last 12
months. The current episode required for study eligibility was
defined by the presence of at least two of the following: rhinitis,
pharyngitis, cough, hoarseness, temperature 38.5°C, or prescription
of an antibiotic for a URTI, occurring after an asymptomatic
period of at least 1 week without antibiotics.
Patients meeting any of the following criteria at entry were
excluded: occurrence of otitis media and/or sinusitis and/or
infection of the lower respiratory tract (ie, bronchitis, pneumonia)
and/or proven group A streptococcal angina at the enrollment
visit. Further main exclusion criteria were allergic asthma,
mucoviscidosis, significant systemic disease (eg, hepatic and/or
renal disease, malignancy), immune system disorders, suspected
malabsorption, known allergy to the bacterial extract, major
surgical procedure within 3 months of commencement of the
study, recent immunosuppressive or immunostimulant therapy,
or corticosteroids.
Patients fulfilling the inclusion/exclusion criteria and whose
parents or guardians gave their informed consent were randomly
assigned by blocks of four to OM-85 or placebo at initial visit.
Randomized assignment to masked medication of identical appearance
was accomplished by prepackaging of masked study and
control medications at random sequence. The allocation of the
study treatment to each patient was carried out according to the
next available consecutive patient number printed on the prescription
card and on the label of the box.
Medication
OM-85 contains 3.5 mg per capsule of standardized lyophilized
bacterial fractions of the following: Haemophilus influenzae,
Diplococcus pneumoniae, Klebsiella pneumoniae and Klebsiella
ozaenae, Staphylococcus aureus, Streptococcus pyogenes and
Streptococcus viridans, and Moraxella (Neisseria) catarrhalis.
Patients had to take one capsule per day of OM-85 or placebo on
an empty stomach, as follows: month 1, 1 capsule per day during
30 days; month 2, no therapy; months 3 to 5, 1 capsule per day
during 10 days; and month 6 (follow-up), no treatment.
Assessments
The primary end point of the study was the reduction of URTIs
(as defined above) during treatment and over the entire obserwww.
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© 2002 American College of Chest Physicians
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vation period. Presence of an URTI was reported at regular or
intermediate visits, and occurrences between scheduled visits
were reported even if they did not imply a supplementary visit.
Secondary end points were the ratings of rhinitis, pharyngitis,
cough, hoarseness, (coded as none, mild, or severe), fever (coded
as 0 absent; 1 38.5 to 39.4°C; 2 39.5°C), number of
days of absence from school, incidence of otitis, sinusitis, or other
related infections.
Prescribed medications were also recorded. Patient (parent or
guardian) and investigator assessments of the efficacy of the
therapy were recorded at the end of the treatment period on a
7-point scale (from 3 marked worsening, to 0 no change,
to 3 marked improvement). No invasive diagnostic procedures
were planned in order to improve study compliance.
Ethics
This study was conducted in accordance with the Declaration
of Helsinki (revised 1996), the specific local laws governing
clinical trials, and in accordance with good clinical practice
guidelines. The study in a participating center was only started
once written approval by the ethics committee and/or regulatory
authorities was obtained.
Statistical Analysis
The sample size was computed to prove that a 15 to 20%
decrease of the rate of URTIs in the OM-85 group compared
with placebo group is statistically significant in a population with
a history of recurrent URTIs. Assuming such a difference and a
URTI rate of approximately 60% in the placebo group, approximately
82 analyzable patients in each group were required, with
0.05 and 0.2, respectively.23
The primary efficacy parameter, the mean rate of URTIs (per
patient, per month) was computed at each visit up to visit 7 and
tested by analysis of variance (ANOVA) for repeated measures.
URTIs in the first 15 days of the trial were discarded, since it was
estimated that they were linked to the infection already present
at the initial visit. A URTI had to be preceded by an asymptomatic
period of at least 7 days in order to be considered a new
URTI.
Secondary efficacy variables were analyzed for descriptive
purposes using adequate standard statistical tests, eg, 2 test resp.
ANOVA for repeated measures for symptom scores, Mann-
Whitney test for global assessments, etc. Analyses and data
management were carried out using software (DataEase v0.4;
DataEase International; Trumbull, CT) for the data management
and SPSSPC release 5.0 resp. (Systat v0.9; SPSS; Chicago, IL;
and NCSS release 2000; NCSS; Kaysville, UT) and TESTIMATE
release 5.2 (IDV, D-82131; Gauting; Munich, Germany) for the
statistical analysis.
Results
Two-hundred thirty-two patients were enrolled in
40 centers (30 in Switzerland and 10 in Germany)
between 1997 and 1999. Of these, 12 patients were
never exposed to the test medication; therefore, 220
patients received treatment and were allotted to the
intent-to-treat sample or the safety sample (OM-85,
120 patients; placebo, 100 patients).
The main demographic data that are summarized
in Table 1 show that the two therapeutic groups were
fairly homogeneous (all variables p 0.3) and therefore
comparable. Distribution by sex was also comparable
(OM-85, 69 male and 51 female patients;
placebo, 61 male and 38 female patients, 1 missing
data). A small percentage of children presented
alterations in other body systems (neurologic, GI,
urogenital, dermatologic, or endocrinologic), slightly
but not significantly higher in the OM-85 group. The
symptom ratings at hospital admission were also
comparable in the two groups, as shown in Table 2
(all variables p 0.11).
URTIs
Table 3 shows the mean rate of URTIs per month
and per patient in the two treatment groups, which
was consistently lower in the patients treated with
OM-85, except in the last month (follow-up).
Table 1—Demographic Characteristics of the Intent-to-Treat Population
Variables
OM-85 Placebo
t Test
No. Mean SD No. Mean SD p Value
Age, yr 120 5.2 1.2 100 5.3 1.4 0.59
Height, cm 120 110.2 9.3 100 111.4 10.3 0.40
Weight, kg 120 20.4 4.0 100 20.5 5.3 0.94
Infections during previous year, No. 119* 5.8 2.4 100 6.1 2.2 0.32
Days since last infection, No. 118* 66.9 67.7 100 74.1 70.1 0.44
Days of absence from school, No. 48 3.2 2.0 52 3.1 1.8 0.77
*Data were missing in one and two patients, respectively.
Table 2—Symptom Score of URTI at Hospital
Admission
Variables
OM-85 Placebo
2 Test
None Mild Severe Normal Mild Severe p Value
Rhinitis* 6 68 45 1 61 38 0.23
Pharyngitis 27 72 21 14 69 17 0.25
Cough† 7 71 41 12 57 30 0.25
Hoarseness‡ 59 56 2 40 54 6 0.11
Fever 75 43 2 57 40 3 0.62
*Data were missing in one OM-85–treated patient.
†Data were missing in one patient in each group.
‡Data were missing in three OM-85–treated patients.
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ANOVA for repeated measures confirmed a significantly
lower rate of URTIs in the OM-85–treated
patients (p 0.05). Calculating the cumulated mean
rate of URTIs, the difference between the two
groups builds up progressively during active therapy
(at end of treatment, the mean cumulated difference
was of 0.42 URTIs per patient in 5 months) and
diminishes very slightly in the month of follow-up, as
can be seen in Figure 1. Thus, over the 6 months of
the study, OM-85 treatment significantly reduced
the mean incidence of URTIs by 16% (ratio of 0.40
on 2.5). In fact, the largest reduction observed in the
OM-85 group is in the number of children with three
or more URTIs in the observation period, as shown in
Figure 2, revealing a difference in favor of OM-85 of
22% at month 4 and of 15% at month 3 and month 5;
the odds ratios for three or more URTIs with OM-85
were 0.51 (95% confidence interval, 0.29 to 0.91)
and 0.65 (95% confidence interval, 0.37 to 1.11) after
5 months and 6 months, respectively.
An explorative analysis by multiple stepwise regression
analysis was performed, with the cumulated
rate of URTIs at month 5 as a dependent variable,
and considering age, treatment, time in study, number
of URTIs in the previous year, sex, year of
participation in trial, and history of allergy as independent
variables. There were higher rates of URTIs
Figure 1. Mean cumulated rate of URTIs. m1 month 1; m2 month 2; m3 month 3;
m4 month 4; m5 month 5; m6 month 6.
Table 3—Mean Monthly URTI Rate and SEM Per
Patient (p < 0.05)
Treatment*
Month
1 2 3 4 5 6
OM-85 (n 118)*
Mean 0.31 0.47 0.43 0.30 0.24 0.31
SEM 0.05 0.05 0.06 0.05 0.04 0.05
Placebo (n 99)*
Mean 0.37 0.54 0.54 0.41 0.31 0.29
SEM 0.05 0.06 0.06 0.06 0.05 0.06
OM-85-PL† 0.06 0.07 0.11 0.11 0.07 0.02
Cumulative OM-85-PL 0.06 0.13 0.24 0.35 0.42 0.40
*Three patients had missing data (two receiving OM-85 and one
receiving placebo).
† OM-85-PL difference of monthly URTI rate between OM-85
and placebo.
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in patients treated with placebo (p 0.06), in
younger children (p 0.006), in those who reported
more URTIs in the previous year (p 0.06), and, as
expected, in those remaining the longer time in the
study (p 0.0001). The difference between OM-85
and placebo was independent of age but was more
important in patients reporting a larger number of
URTIs in the previous year. Stratification by number
of URTIs reported in the previous year (cutoff was
median of 5 URTIs) shows that the cumulated rate
of URTIs was reduced in the OM-85 group by 14%
( 0.28 URTIs) in those reporting 2 to 5 URTIs in
the previous year (not significant), and by 22%
( 0.56 URTIs) in those reporting 6 to 15 URTIs in
the previous year (p 0.05). It may be concluded
that OM-85 treatment significantly reduced the incidence
of URTIs in children with a history of
frequent URTIs.
Secondary Variables
Of the target variables recorded, the main differences
between treatments, favoring OM-85, were
observed in the frequency and severity of rhinitis
(p 0.06) and, to a lesser extent, in the frequency
and severity of pharyngitis (p 0.16) and of fever
(p 0.2). No difference was observed as far as
cough and hoarseness were concerned.
In the first 2 months of treatment, there were
more cases of otitis reported in the OM-85–treated
group (13 episodes vs 4 episodes in the placebo
group), although not reaching the threshold of significance.
In the later visits, the percentage of patients
with otitis was similarly low (2 to 4%) in both
groups. This finding is likely to reflect a difference
between the two groups at baseline. The reported
incidence of sinusitis was very low (mean monthly
percentage 1%) and comparable in both groups.
Anti-infectives
The mean monthly percentage of patients treated
with antibiotics was similar in both groups (OM-85,
15.0%; placebo, 14.2%) and in the large majority of
cases related to lower respiratory tract infection
(OM-85, 11.9%; placebo, 12.2%). However, it has to
be noted that less than half of the URTIs received
antibiotic therapy with no clear-cut pattern of prescription.
This finding contrasts with the prescriptions
of local antiseptic, anti-inflammatory, antitussive,
or mucolytic products, which were significantly
less frequently used in the OM-85–treated group
(mean monthly prescription of 5.2%) than in the
placebo group (9.0%, p 0.05).
Absenteeism
The number of patients with absenteeism from
school diminished from approximately 50% at hospital
admission to 10% during the first month and to
Figure 2. Cumulated percentage of patients reporting three or more URTIs during the study period.
N.S. not significant; see Figure 1 legend for expansion of abbreviations.
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approximately 3% in the last 2 months, without
significant differences between groups. It is not clear
whether this absenteeism is specifically URTI related,
since it was recorded independently of the
occurrence of a URTI at the same visit. The
mean SD duration of an episode of absenteeism
was similar in both groups (approximately 3.5 1.5
days) and did not change significantly over time.
Global Assessment
In comparison to the previous season, the majority
of the patients and/or their parents or guardians
reported some degree of improvement (OM-85,
78.4% of cases; placebo, 75.5% of cases); however,
the distribution of answers was significantly different
(p 0.05) and there were more cases reporting
worsening with placebo (6.4% vs 0.9%; Fisher test,
p 0.05). The investigators also reported an improvement
in the majority of patients, with no
significant differences between OM-85 and placebo.
Influence of Season
Distributing patients on treatment along the year
(ie, mean URTIs of all patients treated in the months
of November, December, etc.) showed in the placebo
group a rapid increase in mean number of
URTIs from September to November, followed by a
plateau until February, and falling off thereafter.
OM-85–treated patients showed a flat pattern, and
the mean number of URTIs was lower. As a consequence,
the benefit of the active treatment was
largest in the period of November to February.
Safety
After active questioning, 164 patients (88 receiving
OM-85 and 76 receiving placebo) complained about
835 adverse events (OM-85, 456 events; placebo,
379 events), of which approximately 40% were manifestations
of the studied respiratory indications. The
events were of different type, duration, and estimated
relationship with the test medication, and
constituted in most cases mild digestive troubles or
respiratory symptoms (the latter already rated as
such in the clinical part). Multiple events in the same
patient were detected with as many as 20 events for
OM-85 and 19 events for placebo. The average
duration of the adverse events was 5.3 9.0 days for
OM-85 and 5.1 6.8 days for placebo. There were a
few reports of serious adverse events (10 events in
nine patients), none of which were estimated to be
related to the study medication, as follows:
OM-85–Treated Group: One case each of operation
for appendicitis, acquired intestinal obstruction
(in same patient), concussion of the brain, adenoidectomy,
diagnostic procedure for epigastric pain (not
specified), accidental burning, and tonsillectomy
(n 6).
Placebo-Treated Group: One case of pneumonia
and otitis media and two cases of tonsillectomy/
adenoidectomy (n 3).
Only seven patients (six patients receiving OM-85,
and one patient receiving placebo) reported nine
adverse reactions (OM-85, eight reactions; placebo,
one reaction) considered to be in possible or probable
relationship to the trial medication. These were
diarrhea (two patients), abdominal pain (two patients),
fatigue, urinary frequency (twice in same the
patient), and exanthem (in the same patient) in the
OM-85 group. In the placebo group, there was an
allergic reaction assessed as in possible relationship.
All these adverse events were minor and transient,
and they did not prompt any treatment discontinuation.
Discussion
This study was aimed at reducing the rate of
URTIs in children with a history of frequent URTIs,
starting from a current episode. Using an algorithm
for diagnosing a URTI, ANOVA for repeated measures
showed that treatment with OM-85 significantly
reduced the incidence of URTIs by 16%,
corresponding to a mean reduction by 0.40 URTIs
per patient in 6 months with respect to placebo in
the intent-to-treat population. It is worthwhile mentioning
that the ANOVA concerning the per protocol
population (excluding protocol violators) confirmed
the main analysis, ie, a significantly lower rate of
URTIs in the OM-85–treated patients (p 0.05).
Rather than increasing the number of patients
without any URTI, OM-85 treatment appeared
to reduce the number of patients with frequent
URTIs (three or more URTIs in 5 months), which
represent almost half the patient population. The
difference between the two treatment groups
builds up during active treatment (months 1 to 5)
and has a tendency to wear off thereafter (although
this trial has a follow-up of only 1 month,
too short to expect a significant detrition curve).
These findings correspond fairly well with those
reported by Collet et al17 if the same criteria are
applied. These authors, who addressed the question
of the efficacy of OM-85 in the primary
prevention of recurrent respiratory infections in
young children in day-care centers, found a 48%
reduction of the relative risk of having three or
more respiratory infections after 3 months of
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© 2002 American College of Chest Physicians
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treatment. The efficacy of OM-85 in breaking the
cycle of recurrent infections was also demonstrated
by Paupe18 in a double-blind, placebocontrolled
trial including 116 children, aged 6
months to 19 years who had a history of at least
three episodes of respiratory or ear, nose, and
throat infections in the previous 6-month period.
At the end of the prospective study period
(3 months of treatment plus 3 months of followup),
the incidence of all infections in the active
group was 35% (p 0.01) lower than in the
placebo group. This effect was more pronounced
in children 6 years old, a finding that could not
be confirmed in the study reported herein.
Even greater reductions of URTIs—by, respectively,
52% and 38%—have recently been reported
with this bacterial extract in comparison to placebo
during two double-blind studies.21,22 These more
marked findings with respect to those presented
here may be linked to differences in settings. Indeed,
the first trial included only girls aged 6 to 13 years
living in a single fairly crowded center favoring
microbial contamination (an orphanage), located in a
region with high air pollution (Mexico City), and who
were all highly susceptible to respiratory infections (a
median of five infections per child over the previous
6 months, approximately double the value recorded
here).21 Overall, the same comments may address
the other Mexican trial, in particular air pollution
and highly susceptible children aged 1 to 12 years
with a past mean rate of URTIs twice as high as the
one of the present trial, but living at home and
followed up for 1 year with two intermittent treatment
periods of 3 months.22
In one of our previous multicenter studies,24 94
children with frequent URTIs were treated intermittently
with either OM-85 or placebo, under doubleblind
conditions for 3 months followed by 3 months
of observation. The preventive action of OM-85 was
rated as “unequivocal” or “likely” in 77.3% of the
cases vs 57.2% of those treated with placebo without
statistically significant differences.
The findings in the present study contrast somewhat
with those of the above-mentioned studies,
probably conducted in more homogeneous settings18,19,21
or in more air-polluted environments21,22,
but are more favorable for the OM-85 treatment
than our previous results,24 recorded in a heterogeneous
multicentric practice-based setting, similar in
fact to the one herein. Furthermore, explorative
analysis strongly suggests that the efficacy of OM-85
is more evident, both in absolute and relative terms,
in patients reporting frequent URTIs in the previous
year (more than the median of five URTIs in the
previous year), as clearly demonstrated in the abovementioned
two studies conducted in children who
had an average of five acute respiratory tract infections
per 6 months before inclusion.21,22 Patients
reporting “very frequent URTIs” were also likely to
have more URTIs in the study period and constitute
the subgroup that benefited most from the therapy
with OM-85.
However, the findings concerning URTIs were not
fully confirmed for the activity of the test medication
on secondary variables such as the number of patients
with pharyngitis, cough, hoarseness, temperature
38.5°C, or antibiotic consumption. Some
degree of masking of symptoms through prescribed
or self-prescribed medication cannot be excluded.
Nevertheless, intensity of rhinitis over the observation
period was decreased under OM-85 with reference
to placebo (p 0.06), as was the consumption
of local antitussive, anti-inflammatory, systemic antitussive,
or mucolytic agents (p 0.05). As URTIs
tend to improve as children grow older, the global
assessments comparing with the previous year were
positive with both active treatment and placebo;
however, a small but significantly larger proportion
of placebo-treated patients reported a worsening of
the condition.
In conclusion, confirming earlier studies, OM-85
reduced significantly the rate of URTIs in children
with a history of frequent URTIs. This effect was
proportional to the number of URTIs in the history
of the patients. Safety and tolerance of test medication
were good, comparable to placebo.
Appendix
We wish to thank the members of the BV-Child Study Group:
J. F. Babel, J. Ballaman, R. Bardelli, G. Beguin, C. Bernasconi, L.
Bianchetti, U. Bollag, E. Busser-Knusel, R. Christen, G. Ferrazzini,
A. Frank, M. Good, P. Gordon, H. Hafliger, C. Hanggi,
J. Holx, J. P. Kapp, U. Keller, R. Pancaldi, M. Renggli, U. B.
Schaad, T. J. Von Kanel, Ch. Zeller, and A. Zimmerman,
Switzerland; and G. Berzel, U. Brendel, J. Disselhoff, H. Gutzeit,
O. Muller, R. Mu¨ tterlein, F. Panzer, S. Schneider, J. Tessmar,
and F. Thanbichler, Germany.
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www.chestjournal.org CHEST / 122 / 6 / DECEMBER, 2002 2049
© 2002 American College of Chest Physicians
Downloaded from chestjournal.chestpubs.org by guest on July 18, 2011
DOI 10.1378/chest.122.6.2042
Chest 2002;122; 2042-2049
Urs B. Schaad, Ralph Mütterlein and Heidi Goffin
Multicenter Study
of the Upper Respiratory Tract * : A Double-Blind, Placebo-Controlled
Immunostimulation With OM-85 in Children With Recurrent Infections
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Saturday, 10 September 2011
RADS through ayurveda
The following link will take you to a paper in Ayurveda
http://hmtjournals.com/vol5_1/016.pdf
pls generate one such paper in Siddha
http://hmtjournals.com/vol5_1/016.pdf
pls generate one such paper in Siddha
Monday, 5 September 2011
Milestone of Children
http://centralcouncilforresearchinsiddhasiddhacentralresearch.academia.edu/sathiyarajeswaranParameswaran/Papers/920142/Child_Development_Milestone_Chart
Friday, 2 September 2011
CAM in Pediatrics of Special children
http://pediatrics.aappublications.org/content/111/3/584.full.pdf+html
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