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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.
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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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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

Milestone of Children

http://centralcouncilforresearchinsiddhasiddhacentralresearch.academia.edu/sathiyarajeswaranParameswaran/Papers/920142/Child_Development_Milestone_Chart

CAM in Pediatrics of Special children

http://pediatrics.aappublications.org/content/111/3/584.full.pdf+html

Focus on infantile colic

Acta Pædiatrica ISSN 0803–5253
VIEWPOINT ARTICLE
Focus on infantile colic
Francesco Savino (francesco.savino@unito.it)
Department of Pediatrics, Regina Margherita Children’s Hospital, University of Turin, Piazza Polonia 94, 10126 Turin, Italy
Keywords
Dietary intervention, Gut microbiota, Infantile colic,
Lactobacillus, Treatment
Correspondence
Francesco Savino, MD PhD, Department of
Pediatrics, Regina Margherita Children’s Hospital,
University of Turin, Piazza Polonia 94, 10126 Turin,
Italy. Tel: +0039-011-3135257 |
Fax: +0039-011-677082 |
Email: francesco.savino@unito.it
Received
26 March 2007; revised 14 May 2007;
accepted 8 June 2007.
DOI:10.1111/j.1651-2227.2007.00428.x
Abstract
Infantile colic is a widespread clinical condition in the first 3 months of life, which is easily recognized,
but incompletely understood and difficult to solve. The available evidence suggests that infantile colic
might have several independent causes. The medical hypotheses include food hypersensitivity or
allergy, immaturity of gut function and dysmotility, and the behavioural hypotheses include
inadequate maternal–infant interaction, anxiety in the mother and difficult infant temperament. Other
recent hypotheses, such as hormone alterations and maternal smoking, still need confirmation,
whereas the new concept of alterations in the gut microflora, have been reported. A number of
interventions, including pharmacological agents, are discussed, but it is probable that infants with colic
require a graded strategy.
Conclusion: Considering the favourable clinical course and the wide range of manifestations, a safe approach
should be adopted, which is proportional to the intensity of the infantile colic. However, further research and
guidelines are still needed.
INTRODUCTION
Infantile colic is a widespread clinical condition in infancy,
which is observed in 10–30% of infants (1), in which a
healthy infant suffers from paroxysms of excessive, highpitched,
inconsolable crying, frequently accompanied by
flushing of the face, meteorism, drawing-up of the legs and
the passing of gas. Even though infantile colic is a common
disturbance, the aetiology is still not fully understood and
the basis of the condition remains elusive. The classical and
most often cited definition of infantile colic is based on the
rule of threes, that is, periods of crying that last for 3 h or
more per day, for 3 or more days per week and for a minimum
of 3 weeks. The condition usually resolves spontaneously by
the age of 3 months. The crying episodes tend to increase at
6 weeks of age and are most frequent in the late afternoon
and evening hours. These characteristics help to differentiate
colic from other more severe conditions (Table 1). Infantile
colic is often described as mild, moderate or severe, but
there are no set definitions for these grades. Further, colic
affects infants of all socioeconomic strata in the same way
without any evidence of family history, and there are no reported
differences in prevalence between either boys and
girls, or nursed and formula-fed infants.
Although there have been some recent progresses in understanding
infantile colic, there has been little practical
change in the clinical approach to these patients, and their
condition continues to frustrate the health care provider
and to produce parental anxiety and lack of confidence in
the infant-caring capability of the parents. Clarification of
the aetiopathogenesis and a better understanding of colic are
needed to allow a more effective and precise management
of the afflicted infant (and his/her exasperated caregiver).
This viewpoint article examines the more recent scientific
evidence supporting the various proposed organic aetiologies
of infantile colic and discusses potential new remedies
(Table 2).
LACTOSE INTOLERANCE
In recent decades, lactose intolerance due to a relative lactase
deficiency has been identified as a possible causative
factor in infant colic. The resulting failure to break down
all the lactose in the food allows significant amounts to enter
the large bowel, where it becomes a substrate for lactobacilli
and bifidobacteria in the colon. Fermentation by
these bacteria leads to production of lactic acid and hydrogen.
The rapid production of hydrogen in the lower bowel
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Infantile colic Savino
Table 1 Differential diagnosis between colic and clinical conditions
Common Infrequent
Feeding disorders Disaccharidase deficiency
Constipation Renal pathology, including
Anal fissures uretero-pelvic obstruction
Gastro-oesophageal Biliary tree pathology, including stones
reflux disease Acute abdomen diseases, including
Infections, including intussusception and volvulus
otitis media Incarcerated hernia
Cow’s milk protein allergy Occult fracture
Urinary tract infection Neurological abnormalities, including
Rashes, including Arnold–Chiari malformation
candidal dermatitis Ocular foreign body or abrasions or
infection
Maternal drug effect (both illicit and
prescription drugs)
Table 2 Infantile colic: aetiopathogenetic features
Lactose intolerance
Dysmotility
Gastro-oesophageal reflux
Gut hormones (motilin, ghrelin)
Gut microflora (Lactobacillus spp.)
Feeding disorders
Food hypersensitivity (cow’s milk allergy)
Psychological factors (infant–parent interaction)
distends the colon, sometimes causing pain, whereas the osmotic
pressures generated by the lactose and lactic acid in
the colon cause an influx of water, leading to further distension
of bowel.
In the first period of life, a large number of infants may display
partial malabsorption of dietary carbohydrate present
in breast milk or formulas and thus a physiological insufficiency
of gut enzyme systems may be one reason for the
development of colic. Studies measuring hydrogen in the
breath of colicky infants have produced inconsistent results,
although increases in breath hydrogen levels have been reported.
Recently, the hypothesis that colic symptoms could
be relieved by reducing the lactose content of the infant’s
feed has been tested once again in a small double-blind study
in which the feed of colicky babies was preincubated with
lactase (2). The interesting results were, however, limited by
the trial size, which prevented any formal proof of effect. In
a similar, more recent study, Kanabar et al. found a significant
difference in both crying time and breath hydrogen in
those infants who used the lactase-treated feed, supporting
the idea that symptoms could be relieved by reducing the
lactose content of a lactose-intolerant infant’s feed, but infants
whose colic is caused by other factors can expect no
relief (3).
MOTILITY
Transient dysregulation of the nervous system during development
may cause intestinal hypermotility in infants with
colic, particularly during the first few weeks of life. Radiological
studies performed many years ago stated that most
cases of infantile colic could be explained by colonic hyperperistalsis
and increased rectal pressure. There may, however,
be some bias in these studies.
Predominance of the parasympathetic as well as the sympathetic
nervous system has also been investigated. The early
literature refers to colic as ‘hypertonia of infancy’, which
was thought to be a consequence of vagotonia. This concept
is supported by the documented beneficial effects of drugs
with antispasmodic effects, such as dicyclomine hydrochloride
(4), and by the relief of high motilin levels in colicky
infants (5,6). However, whether dicyclomine exerts its effect
via the relief of intestinal spasm by a direct relaxant effect
on the colonic smooth muscle or through sedative central
nervous system effects, remains unclear. Today, the use of
this drug is limited in infants due to its known central effects
and the potential to cause respiratory depression (7). Recently,
a double-blind, placebo-controlled clinical trial was
performed to investigate the effectiveness of another drug,
cimetropium bromide (a quaternary ammonium semisynthetic
derivative of the belladonna alkaloid scopolamine), in
the treatment of infants with colic crisis (8). Thus drug acts
through the competitive antagonism of muscatine receptors
of the visceral smooth muscles and a direct myolytic activity.
This trial suggested that cimetropium bromide might significantly
decrease the duration of crying, but not the number of
crises. As far as conventional therapies are concerned, the
anticholinergic and antiadrenergic activity of some herbal
teas or drugs, such as fennel, lemon balm and camomile,
has been also proposed (9).We have already suggested that a
phytotherapeutic agent with Matricariae recrutita, Foeniculum
vulgare andMelissa officinalis improved colic in infants
through its antispasmodic and antimeteoric activity (10).
The findings of Kirjavainen et al. suggest that an imbalance
between the parasympathetic and the sympathetic nervous
system is not associated with infantile colic (11).
GASTRO-OESOPHAGEAL REFLUX (GOR)
It is appealing to explore whether there is a cause-effect relationship
between GOR and infantile colic, especially in
view of the prevalence of GOR during infancy. In my opinion,
GOR and infantile colic are two different clinical conditions.
The confusion arises when GOR does not show its
typical symptoms but is rather only characterized by excessive
crying, similar to colicky infants (12). Thus, particular
care must be taken in the differential diagnosis of these two
conditions.
Few studies have examined the role of gastric emptying
and pathological GOR in colicky infants and the conclusions
are controversial. The results suggest that, in the absence
of regurgitation and vomiting, GOR is not a common
cause of infantile irritability, and pathological GOR is only
implicated in a small subset of young infants with severe colicky
symptoms. Some clinicians suggest a defined antireflux
pharmacotherapy in these selected cases (13), but a recent
review stresses that a direct causal relationship between acid
reflux and infantile colic appears unlikely (14).
1260 C  2007 The Author/Journal Compilation C  2007 Foundation Acta Pædiatrica/Acta Pædiatrica 2007 96, pp. 1259–1264
Savino Infantile colic
GUT HORMONES
The gastrointestinal tract contains a wide variety of hormones
involved in the regulation of intestinal motility, and
these include vasoactive intestinal peptide (VIP), gastrin,
motilin and the newly discovered ghrelin. Lothe et al. (5)
found that VIP and gastrin levels were raised in children with
other gastrointestinal disorders, but not in infantile colic.
Further, formula-fed colicky infants had higher gastrin levels
than breastfed ones. They also reported an increased basal
motilin concentration in colicky infants. Motilin appears to
play an interesting role in the aetiopathogenesis of infantile
colic. It has been hypothesized that motilin enhances gastric
emptying, which increases small-bowel peristalsis and
decreases transit time.
More recently, it has been shown that colicky infants also
have higher serum levels of ghrelin compared to their healthy
counterparts, even though it is not clear whether the high
values observed are a cause or a consequence of infantile
colic. Ghrelin is thus thought to be implicated in promoting
abnormal hyperperistalsis and increased appetite, typical of
colicky patients. It can be considered a mediator between
gut and brain (6).
GUT MICROFLORA
Among the organic hypotheses, the role of intestinal microflora
in the aetiopathogenesis of infantile colic has been
re-proposed recently. In 1994, Lehtonen first suggested that
an aberrant gut microbial composition in the first months of
life, such as inadequate lactobacilli levels, may affect intestinal
fatty acid profiles and could thereby favour the development
of infantile colic (15). Indeed, intestinal colonization
by lactobacilli may be a prerequisite for normal mucosal immune
function.
Lactobacilli are nonpathogenic, anaerobic, Gram-positive
bacteria that play an important role in the development of
local and systemic immune responses (16), and are thus
attractive candidates for exogenous supply to infants. We
found not only lower counts of intestinal lactobacilli in colicky
infants compared to healthy ones (17), but also that
Lactobacillus brevis and L. lactis lactis might even be involved
in the pathogenesis of infantile colic by increasing
meteorism and abdominal distension. Our findings led to
the hypothesis that differences in the composition of intestinal
lactobacilli might influence the aetiopathogenesis of infantile
colic (18). An inadequate balance of lactobacilli in
colicky infants might underlie immaturity in the gut barrier
and lead to aberrant antigen transfer and immune responses,
and increased vulnerability to the breakdown of oral tolerance.
A recently published study examined the hypothesis
that modulating the intestinal microflora of colicky infants
by administering a probiotic would alleviate colic symptoms
(19). In this prospective study, a cohort of 90 breastfed colicky
infants was randomly assigned to treatment with the
probiotic Lactobacillus reuteri or simethicone. Infants in the
L. reuteri-treated-group showed significantly reduced crying
compared to the simethicone group, supporting the hypothesis
that probiotic supplementation could provide health advantages
in colic through intestinal microfloral changes and
thereby alter gut motility and/or immune responses. It has
been demonstrated that luminal endogenous flora can influence
the processes of bacteria-induced innate and adaptive
host responses through the activation of toll-like receptors
and nucleotide oligomerization domain receptors in intestinal
epithelial cells. In experimental models, cytokines can
initiate a hyper-reflex response of the enteric neuromusculature
through neuro-immune and myo-immune interactions.
Inappropriate interactions between the intestinal microflora
and toll-like receptors might affect gut motor function, leading
to abdominal dysmotility and perhaps colic symptoms.
The mechanism that L. reuteri acts through on colic symptoms
in breast-fed infants remains to be clarified.
FEEDING DIFFICULTIES
Infants with colic usually display feeding-related problems,
such as disorganized feeding behaviour, less rhythmic nutritive
and non-nutritive sucking, more discomfort following
feeding and lower responsiveness during feeding interactions.
It is possible that disorganized feeding patterns in
infants with colic are indicative of an underlying disorder in
behavioural regulation. Present knowledge underlines the
impact of these difficulties on parental and infant interactions
and suggests the potential for ongoing regulatory problems
in these infants (20). Evans et al. compared the effect
of two methods of breastfeeding (prolonged emptying of one
breast at each feed vs. both breasts equally drained at each
feed) on breast engorgement, mastitis, infantile colic and duration
of breast feeling. The former group had a lower incidence
of breast engorgement in the first week and of colic
over the first 6 months, but the majority of mothers in this
group felt it necessary to offer the second breast at the end
of a feed to satisfy their infant’s hunger (21).
FOOD HYPERSENSITIVITY
There is increased evidence that infantile colic is related to
food allergy and sometimes it is the first clinical manifestation
of atopic disease. Approximately 25% of infants with
moderate or severe symptoms have cow’s milk-dependent
colic (22,23). The immunological model of colic focuses on
possible allergens, such as cow milk proteins, in breast milk
or infant formula as the cause of the colic (24).
In a recent systematic review, Lucassen et al. confirmed
that hypoallergenic formulas were effective in the treatment
of colic in some formula-fed infants (7). Jakobsson and Lindberg
have previously reported that exclusion of cow’s milk
protein from the diet of mothers of nursed infants with colic
resulted in colic resolution. Similar efficacy was shown in
a trial using casein-hydrolyzed formula as a substitute for
cow’s milk. Lindberg (25) is also of the opinion that infants
with moderate or severe colic respond favourably to
a diet free of cow’s milk protein. More recently, Lucassen
et al. randomized Dutch infants with colic to either a wheyhydrolysate
formula or a standard formula and suggested
that substitution of cow’s milk formula by an extensively hydrolyzed
whey formula could be effective in the treatment of
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Infantile colic Savino
infantile colic. However, considering the favourable clinical
course of infantile colic and the fact that many but not all the
affected infants have symptoms related to cow’s milk allergy,
the majority of the studies on dietary interventions, particularly
in formula-fed infants, concluded that further research
is necessary (26). A recent trial suggests that a new formula
with partially hydrolyzed proteins, a low amount of lactose,
and the addition of a mixture of galacto-oligosaccharides
(GOS) and fructo-oligosaccharides (FOS), led to a significant
improvement in symptoms of the lower gastrointestinal
tract, such as infantile colic (27).
For colicky breastfed infants, research has shown that
simply modifying the mother’s diet could be also effective
(28). Estep et al. has even proposed that a brief intervention
with amino-acid–based formula, coupled with strict maternal
avoidance of milk and dairy products under direct supervision
of a lactation consultant, may be an effective treatment
for colic in some breast-milk-fed infants (29). This kind
of approach can, however, have a negative effect on maternal
anxiety and the duration of breast feeding, and, because
there is no doubt that human milk is superior food for all infants,
I believe that I would never suggest that human milk
be avoided at all in infants with colic (30).
PSYCHOSOCIAL FACTORS
Colic has also been suggested to be a personality disorder
in the child. Colicky infants are often considered irritable
and hypersensitive, with a ‘difficult’ temperament. However,
temperament does not provide an explanation for most of
the features of persistent infant crying, but can only be considered
a contributing factor.
It is a frequently held view that colic results from an unfavourable
climate created by inexperienced and anxious
parents, in particular mothers, and that behavioural problems
could result from a less than optimal parent–infant
interaction. The quality of infant–parent interactions is of
growing interest to those studying excessively crying and irritable
infants. In particular, the relationship between the
mothers and their persistently crying infants appeared mildly
or significantly distressed. Few studies have focused on the
role of the fathers and the whole family unit limiting our
understanding of these factors. Recently, an observational
study showed that excessive crying in infants is clearly associated
with less than optimal parental and father–infant
interaction. However, most of these problems are limited to
the severely colicky group of infants (31).
MANAGEMENT OF INFANTILE COLIC
Over the years, both behavioural to pharmacological remedies
have been studied and proposed as treatments for colic,
although few have been confirmed through rigorous scientific
evaluation in the form of randomized control trials
(RCT). Despite the favourable clinical course of infantile
colic (most infants being free from symptoms by the age of
4–5 months), many parents seek medical help. Moreover,
serious somatic problems are absent in most cases, but still
doctors and nurses believe something has to be done to assist
parents who are experiencing considerable stress.
I think the most effective treatment could be given by first
grading the colic as mild, moderate or severe, but there is no
consensus on the definition of each grade (32). The foregoing
discussion demonstrates that the management of a colicky
infant remains a frustrating problem for both carers and
paediatricians.
Behavioural interventions
The first step in treating a child with infantile colic is to
give general advice and reassurance for the parents. One
should inform them that infantile colic is a self-limiting condition
that is not due to a disease or to anything the parents
have done or omitted to do to their infants. Second, the attentiveness
of the parents should be stimulated by teaching
them to give more appropriate responses to their infants, including
less overstimulation and more effective soothing. At
the same time, the parents should be advised not to exhaust
themselves and, if possible, to leave their infants with others
(7).
Herbal formulation
Herbal teas containing mixtures of vervain, camomile, fennel,
liquorice and lemon balm have been shown to decrease
crying in infants with colic through their antispasmodic activity
(9). Products contain a variety of herbs and herbal
oil and they are thought to provide relief from flatulence
and indigestion. They are not entirely without risk, however,
as they contain sugar and alcohol. Given the multiplicity
of herbal products, the lack of standardization of strength
and dosage and the potential interference with normal feeding,
parents should be cautioned about their use for infantile
colic. A recent study showed that colic in the breastfed
infant could improve within 1 week of treatment with an
extract based on Matricariae recrutita, Foeniculum vulgare
and Melissa officinalis. The phytotherapeutic agent tested
in this study contained a high, standardized concentration
of three herbs with the added advantage of defined dosage
without the need for increased fluid intake (10).
Dietary intervention
1. Breast-fed infants. A strict cow’s milk-free diet for the
mother (with an extra supplement of calcium) may be
suggested. Recently, Hill et al. found a therapeutic benefit
in eliminating dairy products, eggs, wheat and nuts from
the diet of breast-feeding mothers while advising them
to ensure a well-balanced diet and an adequate calcium
intake (28). Dietary interventions in mothers should be
strictly monitored and continued only if they are effective.
2. Formula-fed infants. Hypoallergenic formulas, mainly extensively
hydrolysed formulas based on casein or whey,
are effective in the treatment of infantile colic (see recent
reviews by Lucassen and Garrison (7,26)). It is not
so long ago that even soy-based formulas were used in
the treatment of infantile colic. Recently, the ESPGHAN
Committee on Nutrition has recommended that soy protein
formula should not be used in infants with food al-
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Savino Infantile colic
lergy during the first 6 months of life, stressing that there
is no evidence supporting their use in the management of
infantile colic (33). In view of the wide range of severity
of infantile colic discussed above, and that many infants
without cow’s milk allergy have colic, extensively protein
hydrolyzed formulas might not consider the first dietary
approach. On the other hand, a new formula based on
partially hydrolysed proteins, low amounts of lactose and
supplemented with FOS and GOS was effective (27,34).
Finally, the large number of new formulas containing
functional nutrients for gut well-being indicates the need
for further research to define the best and first dietary
approach for colicky infants.
Hypertonic glucose solution
A randomized clinical trial (RCT) performed by Barr et al.
found that infants with and without colic responded to sucrose
but not to placebo. The response in the colicky infants
lasted on average <3 min whereas the infants with colic
were less effectively calmed by sucrose. In contrast, Akcam
et al. observed that 30% glucose solution might be used as
a safe, effective, easily achievable and well-tolerated alternative
method in the treatment of infantile colic and that
the placebo effect was worthy of note (35). Again, further
research is needed before this remedy can be suggested in
clinical practice.
Pharmaceutical interventions
Simethicone, a defoaming agent, has been promoted as an
effective treatment for colicky infants. It is safe and may reduce
meterorism. However, a recent meta-analysis revealed
that out of three RCTs using simethicone, only one showed
any potential benefit (7,26).
Systematic reviews of anticholinergic drugs in infantile
colic found them to be more effective than placebo. The most
commonly used agent, dicyclomine, has, however, adverse
effects and is now contraindicated in infants <6 months old
(26). Nevertheless, we have shown that cimetropium bromide
is effective in reducing crying during the colic episodes
(8)
Probiotics
Recently, a randomized, controlled study demonstrated that
Lactobacillus reuteri improved colicky symptoms in breastfed
infants more than simethicone, supporting the hypothesis
that probiotic supplementation could lead to health advantages
in colic (1,26). This is the first study performed
to evaluate the efficacy of probiotic agents for colicky infants,
and additional research, from clinical observation to
microbiologic analysis, is needed to confirm the beneficial
effects of L reuteri. Moreover, since specific probiotic strains
have specific properties and targets in the human intestinal
flora, exerting differing health benefits, it remains to be seen
whether other lactobacilli have similar effects. The mechanism
by which L. reuteri reduces colic should be the subject
of future clinical investigation to allow screening for even
more effective probiotics for colic in the future (19).
LONG-TERM OUTCOMES
Infantile colic is characterized by a favourable clinical course
and a self-limiting nature. The majority of colicky infants
completely recover by the age of 4–5 months.
With regard to allergy, an association has been observed
between colic and atopic eczema, food allergy, and respiratory
and ocular allergies (23) although one study did not
obtain such results (36).
Concerning psychological problems, Rautava et al. determined
that families that had colicky infants exhibited more
dissatisfaction with the daily functioning of their family life.
Canivet et al. performed a follow-up study of colicky infants
and controls when they reached 4 years of age and showed
that former colicky children displayed more negative emotions
and more negative moods during meals.
Our recent prospective 10-year study reported that susceptibility
to recurrent abdominal pain, allergic and psychological
disorders in childhood may be significantly increased
in subjects who suffered from infantile colic (37).
Thus, infantile colic might be an early expression of some
of the most common disorders in childhood, although other
long-term follow-up studies are still needed to confirm these
links.
CONCLUDING REMARK
There is no scientifically defined cause for infantile colic,
a behavioural clinical condition, in which an otherwise
healthy infant cries frequently and inconsolably for an extended
period of time for no discernable reason. The selflimiting
nature of colic has precluded the use of invasive investigations
to establish a pathophysiological model in vivo.
Nevertheless, there is a complex relationship between the intestinal
immune system and the commensal flora and motility,
which requires further research. As colic frequently resolves
spontaneously, dietary intervention might be more appropriate
than pharmacological treatment.
Considering the favourable clinical course of infantile
colic, the range of ways in which it manifests itself and the
day-to-day variability of crying time, a safe therapeutic approach
should be adopted and appropriate guidelines could
be useful. However, as ever, there is still a need for further
research and modification of current remedies.
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1264 C  2007 The Author/Journal Compilation C  2007 Foundation Acta Pædiatrica/Acta Pædiatrica 2007 96, pp. 1259–1264

Clinical Studies on Bonnisan in the newborns and Infants

(Probe (1979): (XVIII), 2, 107-109)
Clinical Studies on Bonnisan in the newborns and Infants
Sufi, G.M., M.D., D.C.H., Ramesh Badshah, M.B.B.S., Nazir Ahmed, M.B.,B.S., and
Rafiq Ahmed, M.B.,B.S.
Government Hospital for Women and Medical College, Srinagar, India.
The newborn has to adapt itself from a totally dependent life to an independent existence of its own.
Until birth, it was solely dependent on the mother for its respiratory, assimilative and other
functions. Whereas respiration is established at birth, all other systems are called upon to attain
optimal functioning soon for the growth and development of the newborn. The newborn thus
presents a physiological and clinical problem of metabolic adaptation. Careful studies reveal that
the newborn undergoes a variety of metabolic and hormonal adaptations after birth.
The newborn relies solely on the co-ordinated functioning of all its systems for its metabolic
processes, growth, development and existence. The proper functioning of the digestive system is
very important at this stage, as it helps effectively the processes of anabolism, growth and
development, so essential at this age. The first six months of life are the most important for the
newborn. Utilisation and assimilation of food are important and they depend on the digestive
assimilative processes. Most of the common discomforts in the newborn are caused by indigestion,
flatulence and gripes.
Flatulence in the newborn is caused by aerophagy, trapped wind and indigestion or poor digestion,
apart from low general health, prematurity or immaturity and disturbed hepatic function. It is very
necessary that a newborn thoroughly digests and assimilates all the nutrients it receives. Varied
digestive disturbances often make the mother underfeed the baby or change the brand of milk.
Flatulence alone can be temporarily relieved by the use of carminatives but that would not help the
processes of digestion and assimilation. An ideal drug, in addition to being a carminative, should be
a stomachic, digestive, antispasmodic, hepatic stimulant and metabolic corrective. It should
stimulate the processes of digestion, absorption and assimilation.
Bonnisan (The Himalaya Drug Co.) has been very favourably reported to be useful in improving
appetite and digestive functions and it acts as an anabolic agent. The essential nutrients after
digestion and absorption are converted into metabolites in the liver and utilised for the normal
physiological processes. It probably helps them at different stages. Bonnisan contains some of the
ingredients of Liv.52 which have been well documented and accepted in the relief of anorexia and
digestive and anabolic processes. Athavale, Sharma, Indira Bai et al, Damle and Deshpande,
Saxena, Seshachari, Prasad et al and Dayal et al, have observed very salutary effects on appetite
and growth in cases of malnutrition. Experimental work in animals has shown significant nitrogen
retention and weight gain without other side effects.
MATERIAL AND METHODS
One hundred newborn babies at the Government Hospital for Women, Srinagar (M.C.) were
selected for study with Bonnisan, and its effects on the general health, appetite, digestion,
flatulence, constipation and gain in weight. Babies suffering from acute illnesses were not included
in the study. They belonged to all the sections of the society. All babies up to the age of two months
were given Bonnisan ½ teaspoonful three times a day and those aged 3 to 4 months, one
teaspoonful three times a day. All were followed up regularly at frequent well-defined intervals –
every week up to 1st month and then every month till 4 months. Their initial condition and progress
in respect of appetite, digestion, flatulence, bowel action, weight, general feeling of well-being and
other effects were noted on a previously planned pro forma. Age, sex, birth weight, state of general
health and the type of feeds (breast or artificial) and intervals and quantity of the feeds were also
noted. Most of the children maintained good general health apart from mild icterus neonatorum or
conjunctivitis in a few.
Table I: weight at birth
Birth wt. in grams No. of cases
1500 to 1800 2
2000 to 2500 29
2501 to 3000 33
3001 to 3500 32
3501 to 4000 2
4001 to 5000 2
The appetite continued to remain good and babies took their feeds easily. Most of the babies were
breast-fed and the amount of milk was sufficient. Eighteen babies needed either supplementary
feeds or artificial feeding. There was almost an equal number of males and female babies, 53 males
and 47 females. The birth weight of majority of the babies (94) ranged between 2 to 3.5 kg (Table
1). Initially appetite, digestion were good in most of the babies. Some had flatulence, bloating of the
abdomen, mild gastrointestinal disturbance or constipation and colic. Some had palpable or slightly
enlarged liver which is normal at this age. A few had mild physiological jaundice or conjunctivitis
which did not need any special treatment.
Seventeen babies had constipation and flatulence which were relieved by Bonnisan. Appetite as
judged by vigorous sucking and general satisfaction after the feeds was good in 81%, fair in 19%
cases. Ninety seven babies showed a sense of well-being and in the remaining 3 it was fair. There
were no colics or abdominal uneasiness. Weight gain was observed in almost all the cases. Out of
100 babies 37 showed weight gain from 1.4 to 2 kgs in a period of 4 months. Other 37 showed
weight gain form 2.1 to 2.5 kg, 15 from 2.6 to 3 kg and the rest of the 11 babies 3.1 to 3.5 kg and
the rest of the 11 babies 3.1 to 3.5 kgs. The lowest weight gain was 1.4 kg and the highest 3.5 kg in
a period of four months.
Table 2: Weight gain on Bonnisan in 4 months
Gain in wt. in kg No. of cases %
1.4 to 2 kg 37 37
2.1 to 2.5 kg 37 37
2.6 to 3 kg 15 15
3.1 to 3.5 kg 11 11
The progress in general, the feeling of well-being, appetite, digestion, flatulence, bowel habits and
gain in weight were very satisfactory. There were no untoward side effects or reactions. Most of the
mothers welcomed giving Bonnisan regularly to their babies.
The overall results were good in 81 cases and fair in 19 cases.
SUMMARY
1. One hundred newborns were given Bonnisan for a period of 4 months, ½ to 1 teaspoonful t.i.d.
2. Their progress was observed every week in the first month and thereafter at monthly intervals
for 4 months.
3. Response to digestive functions, appetite, flatulence, bowel activity, general feeling of wellbeing
and gain in weight were recorded at every visit.
4. Result of the study showed a remarkable improvement in flatulence, digestive function, gain in
weight and normal growth and development. Results were good in 81%, fair in 19% and poor in
nil.
5. No toxic or untoward effects of Bonnisan were observed in any case.
ACKNOWLEDGEMENT
Authors acknowledge the help and involvement of the team member of this study, Dr. Rangesh
Paramesh, M.D (Ay), for the successful completion of this trial.

Anti microbial activity of Mathulai odu(Fruit Rind)

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