jurnal probiotik

Original Articleped_3325 677..682

Probiotic, zinc and lactose-free formula in children with rotavirusdiarrhea: Are they effective?

Nazan Dalgic,1 Mesut Sancar,3 Banu Bayraktar,2 Mine Pullu1 and Ozlem Hasim1

Divisions of 1Pediatric Infectious Diseases and 2Clinical Microbiology, Sisli Etfal Training and Research Hospital, Sisli and3Division of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Istanbul, Turkey

Abstract Background: The aim of the present study was to evaluate the effectiveness of zinc, probiotic bacteria, and lactose-freeformula and their different combinations in the treatment of rotavirus diarrhea in young children.Methods: Eight different treatment groups were formed: group 1, 60 patients receiving Saccharomyces boulardii; group2, 60 patients receiving zinc; group 3, 60 patients receiving lactose-free formula; group 4, 60 patients receiving S.boulardii plus zinc; group 5, 60 patients receiving S. boulardii plus lactose-free formula; group 6, 60 patients receivingzinc plus lactose-free formula; group 7, 60 patients receiving S. boulardii plus zinc plus lactose-free formula; group 8,60 patients receiving only oral and/or parenteral rehydration solutions.Results: No statistically significant differences were found in the time to resolution of fever after intervention betweenthe treatment groups and the control group. The time to resolution of vomiting was significantly lower in group 4compared with groups 1 and 5. The duration of diarrhea was significantly reduced in groups 2 and 4 compared to control.A statistically significant difference in the duration of hospitalization was observed for the groups 2 and 4 in comparisonto the control group.Conclusions: A different combination of adjunct therapies did not seem to bring additional value to rehydration therapyin children with rotavirus diarrhea except for in those receiving only zinc and zinc plus S. boulardii. Further studies arerequired to determine the optimal protocol of adjunct therapy use in children with rotavirus diarrhea.

Key words children, lactose-free formula, probiotic, rotavirus, zinc.

Since their discovery in the 1970s, the human rotaviruses havebeen recognized as the most common infectious agents associ-ated with diarrhea in the pediatric age group worldwide.1 Virtu-ally all children throughout the world are infected with rotavirusby the time they are 35 years old. Every year, rotavirus causesbetween 352 000 and 592 000 deaths globally among children

Rotavirus causes patchy damage to the small intestinalepithelium, resulting in blunting of the villi. This is associatedwith some reduction in the activity of lactase and other disac-charidases, leading to reduced absorption of carbohydrates.This intestinal morphology and absorptive capacity returns tonormal within 23 weeks.14 Post-gastroenteritis lactose intoler-ance has been reported in 4.318.4% of children in general andin 3050% after rotavirus infection.1518 There is some evidencethat a lactose-free diet may reduce the duration of diarrhea inchildren with acute gastroenteritis. In a systematic review ofstudies comparing lactose-free and lactose-containing dietsfor children with diarrhea and mildmoderate dehydration,lactose-free diets appeared to decrease the duration of diarrheain some subgroups of children.19 Lactose-free diet in thetreatment of rotavirus diarrhea in children, however, has notbeen tested.

Intervention trials have demonstrated that the addition of oralzinc to probiotics can also reduce the duration and severityof acute diarrhea in children.7,20,21 The question as to whetherthe combined administration will result in additional benefit,in synergy with an antagonistic effect, has not been evaluatedbecause there is only one study that has evaluated the combinedeffect of probiotic, prebiotic, and zinc.22 Data are needed on theeffect of the combination of zinc and probiotics. Moreover, noclinical studies have been conducted using different combina-tions of zinc, probiotics and lactose-free formula to treat rotavirusdiarrhea.

Given the current uncertainty as to whether lactose avoidance,and the administration of zinc and probiotic improves outcomesfor young children with acute diarrhea, the aim of the presentstudy was to evaluate the effectiveness of zinc, probiotic, andlactose-free formula and their different combinations in the treat-ment of rotavirus diarrhea in young children.

MethodsPatientsIn this prospective, randomized, single-blind, controlled trial,480 children were enrolled, ranging in age from 1 to 28 monthsand diagnosed with rotavirus diarrhea, and they were hospital-ized between September 2008 and June 2010 at Sisli EtfalTraining and Research Hospital. The inclusion criteria were:time interval between the onset of diarrhea and hospitalization96 h; severe dehydration; exclusively breast-feeding; toxicclinical appearance; immunosuppression; and any known aller-gies to any drugs or foods.

The nutrition status of the patient was classified according toz score and the WHO tables for developing countries. Patientswith a z score of 2-3 were considered to have severe malnutritionand were excluded from the study.

Written informed consent was obtained from parents or guard-ians. The study was approved by the Ethics Committee of SisliEtfal Training and Research Hospital, Istanbul, Turkey (Number:2008-66).Study designThe patients were examined clinically, and the presence of mildmoderate dehydration was established as previously defined.23The first stool obtained from each patient hospitalized wasanalyzed with Immunocard Rotavirus (Meridian Diagnostics,Cincinnati, OH, USA) for rotavirus antigen. All the childrenunderwent routine laboratory testing throughout the trial, includ-ing complete blood count, serum electrolytes, blood urea nitro-gen, creatinine, glucose, aspartate aminotransferase, and alanineaminotransferase.

For rehydration, the patients were offered ORS with a com-position as recommended by the European Society for PediatricGastroenterology, Hepatology and Nutrition.24 If necessary,because of excessive vomiting and clinical signs of dehydration,parenteral rehydration was established. The study preparationwas given right after randomization, and rehydration was notawaited.

The patients were randomly assigned from a computerizedadmissions list to one of the eight different treatment groupsdescribed: group 1, 60 patients receiving S. boulardii; group 2, 60patients receiving zinc; group 3, 60 patients receiving lactose-free formula (Bebelac Lactose Free Formula, 400 g; Nutricia,Istanbul, Turkey); group 4, 60 patients receiving S. boulardii pluszinc; group 5, 60 patients receiving S. boulardii plus lactose-freeformula; group 6, 60 patients receiving zinc plus lactose-freeformula; group 7, 60 patients receiving S. boulardii plus zincplus lactose-free formula; group 8, 60 patients receiving only oraland/or parenteral rehydration solutions. Group 8 was regarded asthe control group.

Zinc acetate suspension was given 10 mg twice daily for theinfants younger than 6 months of age, and 20 mg daily for all theolder infants and children. Saccharomyces boulardii was given250 mg once daily for a minimum of 5 days.

Clinical observationsThe duration of diarrhea, that is, the time from start of treatmentuntil the first normal stool, was chosen as the main outcomecriterion. Body mass (without clothing) was recorded by elec-tronic scales within 50 g on admission and at discharge. Dailyroutine clinical examination and extent of dehydration duringhospital stay were closely monitored. For each child, the numberof vomiting episodes, the number of bowel movements, and therectal temperature were recorded. Diarrhea resolution was estab-lished when stools consistency ceased to be watery, or when thenumber of bowel movements was fewer than three times in 24hours. Due to the ambulatory setting of the study, after diarrhearesolution, the parents were instructed to return to the clinic ifdiarrhea resumed, and daily telephone calls were made to ensurethat there were no relapses. We also investigated safety andtolerability. In addition, the number of hospitalization days foreach patient was recorded.

678 N Dalgic et al.

2011 The AuthorsPediatrics International 2011 Japan Pediatric Society

Statistical analysisThe c2 test was used to evaluate categorical variables, and analy-sis of variance (ANOVA) of Tukey-Kramer multiple compa-rison test for continuous variables, when analyzing differencesbetween group 8 and groups 17. All the analyses were con-ducted using SPSS version 16.0.0 for Windows (SPSS, Chicago,IL, USA). P 2 0.05 was considered statistically significant.

ResultsAll the 480 children completed the study. The patients consistedof 288 boys (60%) and 192 girls (40%) with a mean 1 SD age of13.71 1 6.21 months (range, 128 months). Four hundred andseventy infants (95.8%) were partially breast-fed and 10 (2.1%)were receiving cows milk-based formula only. The mean zscore was 0.66 1 0.26 (z score > -3SD) in all the study groups.Vomiting, dehydration, and fever were common at presentation.Two hundred and eleven (87.9%) suffered from vomiting, andninety-four (39.2%) had fever on admission. No significant dif-ferences regarding duration of illness, fever, vomiting and degreeof dehydration were found among the groups at the time ofhospitalization (Table 1). Four hundred and forty patients(91.6%) received parenteral rehydration (no statistically signifi-cant difference between the treatment groups and control group,P > 0.05).

During the hospitalization period, no significant differencewas found in the time until resolution of fever after interventionbetween the treatment groups and the control group (P > 0.05).There was a statistically significant difference in patient ageamong the treatment groups (P < 0.05; Table 2). No statisticallysignificant difference was found when the treatment groups(groups 17) and the controls (group 8) were compared forpatient age (P > 0.05). We also compared weight between theeight groups, and found a difference among the treatment groupsand between group 1 and controls, and group 4 and controls (P 0.05). When comparison was made withinthe treatment groups, time to resolution of vomiting was sig-nificantly lower in group 4 (10.40 1 8.73 days) compared withgroup 1 (20.31 1 12.94 days) and 5 (17.58 1 13.13 days),respectively.

The duration of diarrhea was significantly reduced in groups 2and 4 compared to the control group (P < 0.05). The medianduration of diarrhea for group 4 (3.11 1 1.81 days) was shorterthan that for the group 2 (3.41 1 1.38 days) but without statisticalsignificance (P > 0.05). We also compared duration of diarrheabetween the groups, and found a significant difference betweengroups 1 and 2; groups 1 and 4; groups 2 and 3; groups 2 and 5;groups 2 and 7; groups 3 and 4; groups 4 and 5; and groups 4 and7 (P < 0.05). The diarrheal phase was the shortest in groups 4 and2 within the total study group. In group 4, the diarrheal phase wasshorter than in group 2 but the difference did not reach signifi-cance (the duration of diarrhea was 3.11 1 1.81 days in group 4vs 3.41 1 1.38 days in group 2). Ta

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Adjunct therapies for rotavirus diarrhea 679


A statistically significant difference in the duration of hospi-talization was observed for groups 2 and 4 in comparison to thecontrol group. In group 4, the duration of hospitalization wasshorter than in group 2 but the difference did not reach signifi-cance (the duration of hospitalization was 4.11 1 1.64 daysin group 4 vs 4.33 1 1.38 days in group 2). We also comparedduration of hospitalization between the groups and found a sig-nificant difference between groups 1 and 4; groups 2 and 7;groups 3 and 4; groups 4 and 5, and groups 4 and 7 (P < 0.05).

No adverse effects were observed in the treatment groups bythe investigators or nursing staff. All the patients who concludedthe study were followed up until after 5 days from dischargewithout signs of recurrence of the diarrhea.

DiscussionDiarrheal diseases are a leading cause of childhood mortality andmorbidity in developing countries and an important cause ofmalnutrition.25 The majority of diarrheal deaths are caused bydehydration that can be treated with ORS or parenteral rehydra-tion. ORS or parenteral rehydration, however, cannot reduce thevolume, frequency, and duration of diarrhea.26 Available anti-peristaltic or anti-secretory drugs to reduce the severity ofdiarrhea can cause serious side-effects in children.5 Various aux-iliary treatments aimed at shortening the diarrheal episodes areoptional.

Probiotics are live microorganisms and, when administered inadequate amounts, confer a beneficial effect on the health of thehost.9 Several studies have shown that probiotic bacteria canshorten the clinical course of acute rotavirus gastroenteritis(RVGE).2729 Five RCT testing S. boulardii in a total of 619patients were included in a recent meta-analysis, and the authorsconcluded that S. boulardii exerts a moderate clinical benefit bysignificantly reducing the duration of diarrhea.30 There is notsufficient evidence to generally recommend continued use ofprobiotics for the prevention of acute diarrhea or RVGE in infantsand young children.31 In the present study we found no significant

differences in the time to resolution of diarrhea, time to resolu-tion of vomiting and duration of hospitalization in those receivingonly S. boulardii compared to the control group. We confirmedthe beneficial effect of probiotic in combination with zinc in thecurrent study. The combination of probiotic and zinc decreasedthe duration of diarrhea and hospitalization in comparison to thecontrol group in the present study. Also, the combined adminis-tration significantly reduced the duration of vomiting comparedto those receiving only S. boulardii and those receiving the com-bination of S. boulardii and lactose-free formula. Interventiontrials have demonstrated that the addition of oral zinc to probi-otics can reduce the duration and severity of acute diarrhea inchildren, similar to the present results.7,20,21 The question as towhether the combined administration will result in additionalbenefit, in synergy with an antagonistic effect, has not beenevaluated because there only one study has been conducted thatevaluated the combined effect of probiotic, prebiotic, and zinctreatment.22 That study demonstrated that the addition of 6 109 c.f.u. of Streptococcus thermophilus, Bifidobacterium lactis,Lactobacillus acidophilus (2 109 c.f.u. of each strain) and10 mg/day of zinc significantly reduced the duration of acutegastroenteritis in children aged 612 months by nearly 15 h, andinduced quicker resumption of normal stool consistency. Incontrast, the addition of probiotics to infant formula in rhesusmonkeys decreased the severity of experimentally induced diar-rhea, but no additional benefit was obtained by adding zinc to theprobiotics.32 Data are needed on the effect of the combination ofzinc and probiotics in children with RVGE to confirm the presentresults.

Zinc supplementation during diarrhea is recommended indeveloping countries by the WHO and the United Nations Chil-drens Fund (UNICEF) based on several trials demonstrating asignificant effect of zinc in reducing the duration, severity, andrecurrence of diarrhea in immunocompetent and in severelymalnourished or immune-deficient children.11,3335 We found apositive effect of zinc on duration of diarrhea and duration ofhospitalization days in the present study when we compared

Table 2 Comparative analysis (mean 1 SD)

Age (months) Weight (kg) Time to resolution ofvomiting (h)

Time to resolution ofdiarrhea (days)

Duration of hospitalization(days)

Group 1 16.95 1 4.87a,b 11.37 1 1.78a,b 20.31 1 12.94a 4.78 1 1.46a 5.30 1 1.73a,b,cGroup 2 15.83 1 5.34b,c 10.33 1 2.32b,c 13.63 1 10.33a,b 3.41 1 1.38b 4.33 1 1.38b,cGroup 3 11.31 1 4.79d 9.43 1 1.94c,d 13.91 1 10.63a,b 4.46 1 1.22a,c 5.23 1 1.54a,bGroup 4 15.39 1 6.38a 10.61 1 2.48b 10.40 1 8.73 b 3.11 1 1.81b,d 4.11 1 1.64c,dGroup 5 11.20 1 5.63d 9.11 1 1.76d 17.58 1 13.13a,c 4.55 1 1.32a,c 5.15 1 1.77a,bGroup 6 11.35 1 5.03d 8.91 1 1.33d 15.46 1 13.97a,b 4.75 1 1.35a,b 4.85 1 1.99a,b,c,dGroup 7 13.15 1 6.87c,d 9.39 1 1.70c,d 16.96 1 14.30a,b 4.36 1 1.85a,c 5.66 1 2.05aControl 13.80 1 6.28a,b,c,d 9.47 1 1.69c,d 16.35 1 11.34a,b 5.35 1 1.80a,c 5.81 1 2.08a

adDifferent superscript letters between groups show significant differences at P < 0.05. Significant differences found between groups: for age,13, 15, 6, 17, 23, 24, 25, 26, 34, 45, 46; for weight, 13, 15, 6, 17, 1control, 25, 26, 34, 45, 46, 47, 4control; for time toresolution of vomiting, 14, 45; for time to resolution of diarrhea, 12, 14, 23, 25, 26, 2control, 34, 45, 47, 4control; for duration ofhospitalization, 27, 2control, 34, 45, 47, 4control.

Group 1, 60 patients receiving Saccharomyces boulardii; group 2, 60 patients receiving zinc; group 3, 60 patients receiving lactose-free formula;group 4, 60 patients receiving S. boulardii plus zinc; group 5, 60 patients receiving S. boulardii plus lactose-free formula; group 6, 60 patientsreceiving zinc plus lactose-free formula; group 7, 60 patients receiving S. boulardii plus zinc plus lactose-free formula; control group, 60 patientsreceiving only oral and/or parenteral rehydration solutions.

680 N Dalgic et al.


the control group with the other treatment groups, except forthose receiving zinc plus S. boulardii and zinc plus lactose-freeformula.

Post-gastroenteritis lactose intolerance has been reported in4.318.4% of children in general and in 3050% after rotavirusinfection.1518 Szajewska et al. designed a study to determine theprevalence of carbohydrate intolerance in Polish children duringan acute episode of diarrhea. They found that the frequency ofcarbohydrate intolerance was significantly higher in childrenwith rotavirus gastroenteritis (13/14, 92.9%) than in childrenwithout (1/14, 7.1%).17 Currently available clinical guidelines(based on detailed literature evaluation and expert consensus)offer conflicting advice on whether lactose avoidance should beadvised for young children with acute diarrhea.3638 A systematicreview published in 1994 found some evidence that lactoseavoidance improved important clinical outcomes for youngchildren with acute diarrhea, especially for children who wereseverely dehydrated because of the acute diarrheal illness.17 Ofthe five subsequent RCT,3943 three found that lactose-free feedssignificantly reduced the duration of diarrhea compared withfeeds containing lactose.39,42,43 The other two RCT found no sig-nificant difference.40,41 In the present study, no significant differ-ences in the time to resolution of fever, time to resolution ofvomiting, time to resolution of diarrhea, and duration of hospi-talization were found between the treatments groups, includingthose receiving only lactose-free formula and combination oflactose-free formula with zinc and/or probiotic. This result maybe due to inclusion of patients with mild/moderate dehydration inthe present study and shorter diarrhea time in the patients prior toenrollment (2.59 1 1.90 days).

No clinical studies have been conducted using different com-binations of zinc, probiotics, and lactose-free formula to treatacute diarrhea. The present study was the first to evaluate differ-ent combinations of zinc, probiotics and lactose-free formulain children with RVGE. In the present study, seven groups ofpatients receiving different combinations of zinc, probiotics andlactose-free formula were compared with the control group andwith each other, and no significant differences were found for thetime to resolution of fever, time to resolution of vomiting, time toresolution of diarrhea, and duration of hospitalization except forthe patients receiving zinc, and zinc plus S. boulardii. In patientsreceiving the combination of zinc and S. boulardii, time to reso-lution of diarrhea and duration of hospitalization were shorterthan in patients receiving only zinc, but the difference did notreach significance. A different combination of adjunct therapiesdid not seem to add value to oral/parenteral rehydration therapyin hospitalized children with RVGE except for in those receivingonly zinc and zinc plus S. boulardii. Further studies, a costeffectanalysis, and large trials are required to determine the optimalprotocol of adjunct therapies (e.g. probiotic, zinc and lactose-freeformula) in children with RVGE.ConclusionProspective randomized studies with a combination of zinc andprobiotics, and that are homogeneous for treatment, dose, meth-odology, definition of diarrhea and outcomes, are still necessary

to better define the duration of supplementation to be recom-mended in each child with RVGE.

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