COMPARATIVE EVALUATION OF EFFICACY OF VARIOUS SYMBITER MULTI PROBIOTIC PREVENTIVE INTAKE REGIMENS IN DOUBLE BLIND PLACEBO-CONTROLLED TRIAL IN CHILDREN
S.A. Kramarev, O.V. Vygovskaya, V.V. Berezhnoy, R.A. Moiseenko, S.V. Ursulenko, N.A. Vlasenko, N.M. Andriyevskaya, V.A. Kobylianskiy, D.S. Yankovskiy
A.A. Bogomolets National Medical University, Kyiv P.L. Shupik National Medical Academy of Postgraduate Education, Kyiv Zhytomyr Regional Children's Home Specialised Regional Children's Home, Boyarka Municipal Children's Home, Rivne Vinnytsia Regional Specialised Children's Home Prolisok O. D. Company
Results of a comparative trial into the efficacy of Symbiter Multi Probiotic on ARVI frequency and duration during autumn and winter seasons in healthy children living in children's houses.
Keywords: acute respiratory viral infections, non_specific ARVI prevention, probiotics, Symbiter.
Respiratory diseases remain the most widespread human pathology; their increased proliferation is registered in many countries worldwide irrespective of climate, geography or social and economic standards.
Acute respiratory viral infections (ARVI) account for the greatest proportion in the structure of children's infectious diseases and make up for up to 90% of the total infection pathologies in children [2, 6]. Treatment and prevention of respiratory infections in children remains in the focus of attention of paediatricians also because of such infections accounting for more than 90% cases of seeking outpatient assistance, particularly in autumn and winter seasons [1, 8].
Frequent ARVI in children pose not just medical but also social issue; recurring and grave ARVIs adversely affect physical and neural-psychic development of children, contribute to lower functional activity of various immunity components and to increased sensitisation of the organism with subsequent development of chronic processes in respiratory organs . They are also a huge economic burden for the state that has to compensate costs of treatment of the infection itself and related complications as well as temporary unfitness for work (parents' sick leaves). The annual economic damage inflicted by flu and other ARVI totals to millions [5, 8].
There are three main methods of flu and ARVI control; these comprise vaccination, chemotherapy and non-specific prevention measures . Flu vaccination does offer a lasting and strong protection but is narrowly aimed; moreover, ever-changing flu virus' antigen characteristics related to its high mutability are a serious hurdle on the way towards fully-fledged vaccinal prevention. Chemotherapy involves synthetized and natural substances affecting virus reproduction. Nevertheless, a rather narrow spectrum of such medications and the ability of the virii to promptly develop high resistance to medicines of the above class further reduce their
administration [1, 5].
The above considerations shape medical, social and economic importance of the problem for the public and the paediatric science and condition the need for upgrading methods of ARVI prevention in children.
Non-specific ARVI prevention with drugs affecting the immune system and enhancing activity of natural infection-protecting mechanisms poses great interest. Probiotics are considered among non-specific antiviral factors [4, 10].
Probiotic microbes are capable of performing important functions, the adaptive, immune, metabolic and fermentative ones included, in the micro-ecological environment, and this conditions their selection for administering for purposes of various diseases treatment and prevention in children [4, 7, 9]
The mechanism of probiotics action is, as follows: synthesis of antibacterial substances, organic acids and proteases inhibiting growth of intestinal flora; competitive struggle for adhesion receptors; immune response stimulation through increased phagocytosis levels and higher concentrations of IgA, killer T-cells and interferon concentrations; correction of anti-inflammatory cytokine production; enhanced cytoprotection through higher mucin production and reduction of permeability of mucous membrane [7, 11]. A number of clinical studies have shown efficacy of probiotics in the prevention and treatment of ARVIs, flu and AIEs, mostly of viral origin, in children [13—16].
Trial objective: evaluation of the effect of Symbiter multi probiotic (OD Prolisok Company, Ukraine) on prevalence and duration of ARVI symptoms in autumn and winter seasons in healthy children residents of children's homes.
Trial tasks: comparison of the effect of two Symbiter multi probiotic administration regimes on ARVI symptoms prevalence and duration.
Research Material and Methods
Trial design: a prospective randomised open double blind comparative placebo-controlled post-registration clinical trial in parallel groups.
The studied children were randomly selected for different Symbiter multi probiotic administration regimens.
The trial included healthy children aged between one month and six years (n=238) who resided in the children's homes: in Zhytomyr Regional Children's Home for orphans and children without parental care (n=60); specialised Regional Children's Home in the town of Boyarka (n=50); Rivne Municipal Children's Home (n=84); and Vinnytsia Regional Specialised Home for Children with CNS and Psychic Disorders
(n=44) and complied with inclusion and exclusion criteria. The children under observation were randomised into three parallel groups. Children in the first group (n=55) received Symbiter multi probiotic once every day (one sachet as the single daily dose in the morning) during three months from the beginning of November till the beginning of February 2010 as an ARVI prevention measure. Children in the second group (n=68) received a double daily dose of Symbiter multi probiotic (one sachet b.i.d., in the morning and in the evening) within 1.5 months from late December/January till mid-February/March 2010.
Children in the third group (n=115) were administered a placebo; of those, 55 took it as a q.d. dose with-in three months, and 60 children, as a b.i.d. dose within 1.5 months. The children enrolled in the trial were insured and passed the ethical commission.
The average age of the children enrolled in the trial made one year and six months (1.63±0.10 year) with the median at 1.2 year. There were 32.8% (78) infants in the first year of age; 28.6% (68) aged between one and two y. o.; 20.6% (49) above two to three years; 15.1% (36) three + to four; and 2.9% (7) children in the range between 4+ to 6 y. o. Gender-wise, there were 132 (55.5%) boys and 106 (44.5%) girls.
The majority (97.5%) of them had burdened premorbidity background characterised with presence of a somatic pathology that pre-existed the trial start; only 2.5% children were free from any somatic pathology (Table 1). All of them exhibited: retardation of psychoverbal development; congenital malformations (CHD), congenital brain malformations, congenital upper lip and hard palate malformations, multiple development defects, congenital inspiratory stridor, dacryocyclitis, bronchopulmonary dysplasia, hydronephrosis, congenital vision malformations; motor skills disorder (MSD); hypoxic-ischemic CNS injury (CNS HII); arrest of statokinetic development (ASKD); developmental speech delay (DSD); fetal alcohol syndrome (FAS); ICP; Down syndrome; minimal cerebral dysfunction (MCD); retarded physical development (RPD); hypertension hydrocephalus syndrome; spastic paresis; Arnold Chiari syndrome; haemangioma; sensorineural deafness, mental deficiency, congenital syphilis, intrauterine infection, hypochondroplasia of connective tissue, and TB infection. Some 68.1% (158) studied children were registered with associated pathology.
As it is seen from Table 1, the groups had no difference in sex, age or intercurrent diseases. All of the children involved in the trial had either of the below somatic pathologies: anaemia; in 9.9% (23 children), open foramen ovale (OFO); in 9.1% (21), protein-energy malnutrition (PEM); in 9.1% (21), atopic dermatitis; in 7.8% (18), umbilical hernia; in 6.5% (15), secondary cardiomyopathy; in 5.6% (13), chord anomaly; in 4.3% (10), functional cardiac murmur; in 3.9% (9), goiter; in 3.9% (9), dysembryogenetic stigmas; in 3.0% (7), prematurity; in 3% (7), recurrent obstruction syndrome; in 3% (7), hypotrophy; in 2.6% (6), rachitism; in 2.6% (6), palatine tonsil hypertrophy; in 2.2% (5), neurosis; in 2.2% (5), EPI syndrome; in 1.7% (4), adenoid vegetations; in 2.6% (6), hip dysplasia; in 1.7% (4), thymomegalia; in 1.3% (3), squinting; in 0.9% (2), chryptorchidism, chronic pyelonephritis, contacts with TB carriers, club foot; in 0.4% (1), nanism, bronchial asthma.
Formula of Symbiter Acidophilous multi probiotic: active substance: a biomass of live cells of the symbiosis of Bifidobacterium, Lactobacilli, Lactococci, propionate-oxidising and acetic acid bacteria, CFU/cm3, at least: Lactobacilli and Lactococci: 1.0х109; Bifidobacterium: 1.0х108; propionate-oxidising bacteria: 3.0х107; acetic acid bacteria: 1.0х105. Additives: skimmed fermented milk .
Symbiter Acidophilous multi probiotic has been registered in Ukraine as a pharmaceutical product (Certificate of Registration No. UA/10146/01/01 if 22.10.2009, No. 763) .
The children were administered the probiotic product under investigation/placebo as per the following two treatment regimens: 1st regimen: one sachet q.d. for three months of the autumn and winter season (from November 2009 till January 2010); 2nd regimen: one sachet b.i.d., in the morning and in the evening for one and a half months of the autumn and winter season (in January — March 2010).
The children were randomised into three parallel groups. Children in all the groups received no flu vaccination, including the one against A/H1N1 California pandemic strain. Also, they were not administered any specific anti-ARVI and flu chemical drugs for the duration of the trial and follow-up observation period. All of the children received nonspecific ARVI and flu prevention measures, including quarantine, room ventilation and wet cleaning, breath mask regime, consumption of phytoncide-containing products (onions, garlic) etc. In the event of ARVI manifestations development, no antiviral therapy was administered with only symptomatic treatment used.
The groups had no meaningful difference by age, sex, pre-morbidity background or stay conditions. Morbidity levels within three and 1.5 months-long periods of Symbiter multi probiotic and placebo intake were taken into account. The total trial duration made three months for children in each group.
Parameters Registered During the Trial
Each child who participated in the trial was subjected to medical examination to determine his/her physical fitness indicators like weight, height, HC at the beginning of the trial and then on a monthly basis for the duration of the trial. The doctors in the trial group in every children's home filled in questionnaires every day noting the health status of the children and ARVI symptoms, if any.
The main clinical ARVI manifestations included: body temperature rise (>37.0°C), rhinorrhoea, hyperaemia of oropharyngeal mucous membrane, and cough. Presence of ARVI complications (sinusitis, acute otitis media, obstructive bronchitis, pneumonia etc.) and frequency of antibacterial medications administration were also registered. When children had to be referred to in-patient clinic, it was mentioned in individual child's card.
Adverse drug reactions possible at Symbiter multi probiotic and placebo administration were also registered. In the event of an acute condition, each such child was examined on a daily basis by a doctor from the trial group. Expression of condition's symptoms and stool characteristics were included in the individual child's card. To express the main ARVI symptoms (rhinorrhoea, hyperaemia of oropharyngeal mucous membrane, cough), a rating scale from «0» to «3» (0 — symptom n/a; 1 — slight expression; 2 — moderate expression; and 3 — strong expression) was used. Temperature response was evaluated using the rating scale of four: 0 for the absence of temperature; 1 for 37–38°С; 2 for 38.1–39°С; 3 for 39.1–40°С; and 4, for temperature above 40.1°С.
The duration of the main ARVI symptoms (temperature response, rhinorrhoea, hyperaemia of oropharyngeal mucous membrane, cough) was registered in the individual child's card. Besides that, each ARVI and diarrhoea episode was also registered.
Before the beginning of the trial, a Clinical Trial Protocol and the individual child's card were developed and approved by the Ethics Commission of A. A. Bogomolets National Medical University. According to the Articles of Incorporation of every children's home and the legislation in force, surgeons general of the children's homes act as official custodians. The custodians of all the trial participants signed their informed consent that was reviewed by the Ethics Commission of A. A. Bogomolets National Medical University before the start of the trials. All the children who took part in the trials were insured.
The results were statistically processed using Epi Info 3.5 statistic software package. For the sake of comparison of quantitative indicators, the t-Student test, and for ordinal and categorical ones, 2 test were used. Differences were deemed significant if at the level р<0.05 .
During the trial, 24 (10.1%) children discontinued their participation due to returning to the family, adoption or breaching the Symbiter multi probiotic and placebo intake regimens. Of these, two children were from 1st group, 10 from 2nd group and 12, from 3rd group. Of the total of 24 children, eight were reunited with their family or adopted and one child was resettled into a pre-school education institution. 15 children were subsequently excluded from the trial for failing to take Symbiter or placebo for the whole required period.
Trial Results and Their Discussion
ARVI morbidity prevalence in 1st group was 46.9% lower than in the 2nd group (р<0.05) and 47.5% lower than in the 3rd group that received placebo (р<0.05). ARVI morbidity prevalence in children in 2nd group had no significant difference from that in 3rd group that received placebo (p>0.05) (Table 2).
ARVI clinical symptoms in sick children members of the trial groups are presented in Table 2. All children in 1st group, 73.9% children in 2nd group and 95.1% in 3rd group had fever on the first day of sickness. 81.8% sick children in 1st group, 82.6% in 2nd group and 87,8% in 3rd group had rhinorrhoea. 90.9% ARVI patients in 1st group, 91.3% them in 2nd group and 92.7% patients in 3rd group developed hyperaemia of oropharyngeal mucous membrane. 90.9% ARVI patients in 1st group, 73.9% in 2nd group and 78.1% in 3rd group had cough.
Besides ARVI morbidity prevalence, prevalence of all other diseases was registered for children in all groups (Table 3). Morbidity prevalence in 1st group was 48.8% lower than that in 2nd group (р<0.05). Prevalence of other morbidity types in children in 1st group was 57.1% than that in 3rd group (р<0.05).
Morbidity prevalence in 2nd group was only 16.3% lower than in 3rd group (р>0.05). Children in 1st group who received one dose of Symbiter acidophilous multi probiotic for three months were 2.2 times less sick (p<0.05), had two times less ARVI prevalence (p<0.05) and in average 2.1 times lesser number of all ARVI episodes (р<0.05) compared to 2nd group that was administered the double dose of Symbiter acidophilous multi probiotic for 1.5 months.
During the trial, one incidence of ARVI was registered in 63.6% (7) children and two ARVI episodes, in 36.4% (4) children from 1st group. In 2nd group, one incidence of ARVI was registered in 65.2% (15) children, two ARVI incidences, in 30.4% (7) children, and three episodes, in 4.4% (1) children. In 3rd group, one ARVI incidence was registered in 63.4% (26) children and two incidences, in 36.6% (15).
The 1st group that received Symbiter acidophilous multi probiotic q.d. for three months had 4.5 times less sick children (р<0.05), 3.7 times less ARVI morbidity (р<0.05) and 4.1 times less average number of ARVI episodes (р<0.05) compared with 3rd group patients who received placebo.
The 2nd group that received Symbiter acidophilous multi probiotic b.i.d. for 1.5 months, had 2.1 times less sick children (р<0.05), 1.8 times less ARVI morbidity (p>0.05) and two times less number of all ARVI episodes (р>0.05) compared with 3rd group patients who received placebo (Table 3).
Prevalence of all ARVI episodes in children in 1st group was 47.2% lower than in 2nd group (р<0.05) and 53.3% lower than in 3rd group (р<0.05) (Table 3).
Prevalence of all ARVI episodes in children in 2nd group was just 11.7% lower than in the group with placebo (р>0.05).
Prevalence of mild ARVI cases in children in 2nd group who received Symbiter multi probiotic b.i.d. for 1.5 months was 62.1% higher than in 1st group administered Symbiter q.d. for 1.5 months (р>0.05); there was no significant difference between mild-tograve cases prevalence in two groups (р>0.05). No grave ARVI cases in 2nd group children were registered. In the second group, the prevalence of grave ARVI cases made 0.02 (р>0.05). The prevalence of mild cases in 1st group had no significant difference from that in the placebo group (р>0.05); for mild-tograve cases, the prevalence was 65.2% lower (р<0.05) and for grave cases, 75% lower than in the placebo group (р>0.05).
Incidence of mild forms development in children in 2nd group was 31% lower, (р<0.05) and for mild-tograve forms, 56,5% lower, than in the placebo group (р<0.05). No grave forms were registered in 2nd group.
There was no significant difference in the number of ARVI complications developed in children in 1st group who received Symbiter acidophilous multi probiotic q.d. for three months compared with those in 2nd group administered Symbiter acidophilous multi probiotic b.i.d. for 1.5 months (р>0.05). The prevalence of ARVI complications in 1st group was 74.7% lower compared with 3rd group that received placebo (р<0.05). The prevalence of ARVI complications in 2nd group was 77.3% lower than in the placebo group (р<0.05). No significant difference by nature of complications between 1st and 2nd group was noted. ARVI morbidity in children in 1st group was complicated with obstructive bronchitis (prevalence=0.038) and in 2nd group, with obstructive bronchitis (prevalence=0.017) and pneumonia (prevalence=0.017). In 3rd group that received placebo, the prevalence of purulent complications (sinusitis, pneumonia, otopyosis) was 100% higher than in 1st group (р<0.05) and 82.5% higher than in 2nd group (р=0.05) (Table 3).
For 1st group, antibacterial medications were administered in 13.2% cases for the whole group. In 2nd group, antibiotics were used in 24.1% cases and in 3rd group, in 28.2% cases. The number of patients who received antibiotics in 1st group was two times less than that in 2nd group (р>0.05). Antibiotics were administered to 1st group patients 4.1 times less frequently than to those in 3rd group (р<0.05). For 2nd group, the indicator was 2.1 times less than for 3rd group (р>0.05) (Table 3).
Hospital admission was needed for just 5.7% children from 1st group and 1.7% children from 2nd group. In 3rd group, 10.7% children were admitted. In-patient hospital admission prevalence for children from 1st and 2nd groups showed no significant difference (р>0.05); in 1st group, it was 3.7 times less frequent (р>0.05) and in 2nd group, 11 times less frequent (р<0.05) than in the 3rd (placebo) group (Table 3).
The duration of main ARVI symptoms is shown in Table 4.
The duration of the main ARVI symptoms in children who received one dose of Symbiter multi probiotic daily for three months with prevention purposes (1st group) compared with the placebo group was less, as follows: fever — one day (р<0.05); rhinorrhoea — 1.1 days (р<0.05); hyperaemia of orthopharyngeal mucous membrane — 0.3 day (р>0.05); cough — 1.2 days (р>0.05) less. They also had shorter duration of ARVI (by 0.9 day (р<0.05)), antibiotic intake (by 1.1 days (р>0.05)) and hospital stay (by 3.7 days (р>0.05)).
The duration of the main ARVI symptoms in children from 2nd group who received Symbiter multi probiotic two times a day for 1.5 months was considerably shorter than in the placebo group (р<0.05): by 1.6 days (р<0.05) for fever; by 1.9 days (р<0.05) for rhinorrhoea; by 2 days (р<0.05) hyperaemia of orthopharyngeal mucous membrane; by 1.3 days (р>0.05) for cough. The duration of ARVI in 2nd group was 3.4 days shorter than that in 3rd group (р<0.05) and the duration of antibiotic intake, 2.1 days (р<0.05) shorter. The period of stay in hospital for them was 6.7 days shorter (the results remain uncertain though as only one child from 2nd group was hospitalised).
The duration of the main ARVI symptoms in children from 2nd group compared to 1st was shorter: by 0.6 day (р<0.05) for fever; by 0.8 day (р>0.05) for rhinorrhoea; by 1.7 days (р<0.05) for hyperaemia of orthopharyngeal mucous membrane; and by 2.5 day (р<0.05) for cough. Besides, compared with the children from 1st group, the children from 2nd group showed 2.5 times shorter ARVI duration, one less day of antibiotic intake (р>0.05), and their in-patient hospital stay time was three days shorter (the results remain uncertain though as only one child from 2nd group was hospitalised).
No incidents of diarrhoea in children were registered during the trial. No adverse effects throughout the time of Symbiter acidophilous multi probiotic administration both q.d. for three months and b.i.d. for 1.5 months or placebo intake were registered.
1. Symbiter multi probiotic has anti-ARVI and anti-stomatitis prevention potential in children.
2. Symbiter multi probiotic reduces ARVI severity and duration of ARVI symptoms (fever, rhinorrhoea, hyperaemia of oropharyngeal mucous membrane) and reduces chances of complications or required administration of antibiotics.
3. The three-months preventive regimen of Symbiter multi probiotic is more efficient than the 1.5 months-long one.
4. Symbiter multi probiotic is a safe product that can be used in practical paediatrics.
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