Scenario: 5 yo patient presents to you with a cough, runny nose, and fever. Based on physical exam findings and normal lab results, you make the diagnosis of upper respiratory infection. The mother tells you the child has had multiple URI’s in the past, and she has heard that probiotics are a good preventative measure. She wants to get your opinion on the use of probiotics for her child before she starts using them.
Clinical Question: Does probiotic consumption in pediatric patients decrease the incidence of respiratory tract infections?
PICO Question:
P🡪 Pediatric patients
I🡪 Probiotic consumption
C🡪 No intervention
O🡪 Rate of respiratory tract infections
What type of scenario is this?
□ Therapy/ Intervention □ Diagnosis □ Etiology □ Prognosis □ Screening □ Prevalence
□ Harms
Type of study best to answer this question: (think about the level of evidence)
□ Meta-analysis □ Systematic Review □ Randomized Controlled Trial □ Cohort Study
□ Case Control Study □ Case Series/Report
Search Strategy:
PICO Search Terms
| P | I | C | O |
| Pediatric patients | Probiotics | NO probiotics | Decreased incidence of respiratory tract infections |
| Patients < 18 years | Probiotic supplementation | NO treatment | Reduced number of respiratory tract infections |
| Young patients | Lactobacillus acidophilus | NO probiotic intervention | Reduced duration of respiratory tract infections |
Filters Applied:
- Recent publications within the past 5 years
- Recent publications within the past 10 years
- Review
- Full Article
- Journal
Databases Used:
- PubMed
- ScienceDirect
- Wiley Online Library
- Google Scholar
Results:
| Database | Filter | Articles Returned | |
| PubMed | English/Last 5 years/Full Text/Full Article/ | Probiotics for prevention of respiratory tract infection in pediatric patients | 1,503 |
| ScienceDirect | English/ 2010-2021/ Research Articles | prevention of respiratory tract infections with probiotics in pediatric | 1202Since 2015 → 504 |
| Wiley Online Library | English/ 2015-2020/ Journals | prophylactic probiotic use in respiratory tract infections in pediatrics | 955 |
| Google Scholar | 2010-2020/Include patents/Include Citations | probiotics in pediatric patient reduce respiratory tract infection | 17,400 |
I narrowed down these results by applying the filters above, and then looking for studies that focused on pediatric patients. I wanted to make sure that the age was appropriate for my clinical scenario. I looked for studies that were meta analyses or systematic reviews, specifically of cohort studies or RCTs. I used cohort studies as those would follow patients over a longer period of time, and randomized controlled trials because they would compare the use of preventative probiotics to a control, in order to best assess the outcomes. I also focused on studies whose outcome was related to incidence and duration of respiratory tract infections, as these outcomes are most likely to show a correlation or causation. I looked for studies that had multiple strong outcomes being assessed, and that used strong methodology to limit confounding variables and any other sources of bias.
Articles Chosen for Inclusion:
| Citation | Laursen, R. P., & Hojsak, I. (2018). Probiotics for respiratory tract infections in children attending day care centers—a systematic review. European Journal of Pediatrics, 177(7), 979–994. doi:10.1007/s00431-018-3167-1 https://link.springer.com/article/10.1007/s00431-018-3167-1#citeas |
| Abstract | Probiotics have been suggested to have a preventive effect on respiratory tract infections (RTIs), but limited evidence exist on strain-specific effects. The main aim of this systematic review and meta-analysis was to evaluate strain-specific probiotic effects on RTIs in children attending day care. We included 15 RCTs with 5121 children in day care settings (aged 3 months to 7 years), but due to high diversity in reported outcomes, different number of RCTs were available for evaluated outcomes. Twelve RCTs (n = 4527) reported results which could be compared in at least one outcome of the meta-analysis. Compared to placebo, Lactobacillus rhamnosus GG (LGG) significantly reduced duration of RTIs (three RCTs, n = 1295, mean difference − 0.78 days, 95% confidence interval (CI) − 1.46; − 0.09), whereas no effect was found on other evaluated outcomes. Based on the results from two studies (n = 343), Bifidobacterium animalis subsp. lactis BB-12 showed no effect on duration of RTIs or on absence from day care. Meta-analyses on other strains or their combination were not possible due to limited data and different outcome measures. Conclusion: LGG is modestly effective in decreasing the duration of RTIs. More RCTs investigating specific probiotic strains or their combinations in prevention of RTIs are needed. |
| PDF Link | |
| Reason for Inclusion | I selected this article because it was a recent systematic review focused on the use of probiotics for respiratory tract infections (RTI) in children attending day care centers. It included 15 RCTs with 5121 children aged 3 months to 7 years, which matches the age range I was looking for. The results compared various strains of probiotics to placebo to evaluate outcomes. Because there is some question of the use of meta-analysis for probiotics considering the various strains, this study looked at each of the strains in comparison. It measured the primary outcome of the number of children with RTIs with secondary outcomes of the number of children with acute otitis media, antibiotic use, duration of respiratory tract infections, and days missed from daycare. |
| Citation | Amaral, M. A., Guedes, G. H. B. F., Epifanio, M., Wagner, M. B., Jones, M. H., & Mattiello, R. (2017). Network meta-analysis of probiotics to prevent respiratory infections in children and adolescents. Pediatric Pulmonology, 52(6), 833–843. doi:10.1002/ppul.23643 https://doi.org/10.1002/ppul.23643 |
| Abstract | Probiotics have emerged as a promising intervention for the prevention of respiratory tract infections (RTIs) in children. Assess the effect of probiotics on prevention of RTIs in children and adolescents. MEDLINE, EMBASE, LILACS, SCIELO, CINAHL, SCOPUS, and Web of Science. Key words: “respiratory tract infections” AND probiotics. Randomized controlled trials RCT assessing the effect of probiotics on RTIs in children and adolescents were included. Two reviewers, working independently, to identify studies that met the eligibility criteria. Main and secondary outcomes were RTIs and adverse effects, respectively. Twenty-one trials with 6.603 participants were included. Pairwise meta-analysis suggested that Lactobacillus casei rhamnosus (LCA) was the only effective probiotic to the rate of RTIs compared to placebo (RR0.38; Crl 0.19–0.45). Network analysis showed that the LCA exhibited 54.7% probability of being classified in first, while the probability of Lactobacillus fermentum CECT5716 (LFC) being last in the ranking was 15.3%. LCA showed no better effect compared to other probiotic strains by indirect analysis. This systematic review found a lack of evidence to support the effect of probiotic on the incidence rate of respiratory infections in children and adolescents. |
| PDF Link | |
| Reason for Inclusion | I selected this article because it was a meta-analysis of probiotics looking at the prevention of acute respiratory infections. The aim was to evaluate the effect of probiotics on prevention of respiratory tract infections. It looked at the primary outcome of respiratory tract infections – pneumonia, pharyngitis, laryngitis, epiglottitis, sinusitis, otitis, tracheobronchitis, or bronchitis/bronchiolitis. The secondary outcome was the analysis of adverse effects. It included 21 RCTs with 6,603 participants of both sexes, aged 0-18 years. LGG was the probiotic of highest prevalence, and the routes of administration varied. |
| Citation | Ozen, M., Kocabas Sandal, G., & Dinleyici, E. C. (2014). Probiotics for the prevention of pediatric upper respiratory tract infections: a systematic review. Expert Opinion on Biological Therapy, 15(1), 9–20. doi:10.1517/14712598.2015.980233 |
| Abstract | Background: Acute upper respiratory tract infections (URTIs) contribute substantially to pediatric morbidity and mortality worldwide. Prevention of these infections in childhood is a very important public health challenge. Previous systematic reviews, including both adult and childhood populations, have reported that probiotics seem promising, but with modest evidence. This study aimed to focus on prophylactic probiotic use in the prevention of URTIs in childhood. Methods: Relevant trials on two databases were identified in a systematic review, from inception to June 2014. Study selection, data extraction and quality assessment were carried out by two reviewers. In this review, the effects of probiotics, particularly the Lactobacillus and Bifidobacterium strains, on the incidence and symptom scores of URTI in otherwise healthy children were evaluated for the first time. This review comprises 14 randomized controlled trials (RCTs) applied to a pediatric population with high-quality methodology. Results: This systematic review suggests that probiotics in immunocompetent children have a modest effect both in diminishing the incidence of URTIs and the severity of the infection symptoms. Conclusions: At least one beneficial effect of prophylactic probiotic was observed in the majority of RCTs. Even a minimal reduction of 5 – 10% in the incidence of URTIs would have an important clinical and economic impact on societies. Furthermore, the long-term administration of probiotics appeared to have a good safety profile in childhood and none of the studies reported any serious adverse events related to the probiotic strain. |
| PDF Link | |
| Reason for Inclusion | I selected this article because it is a systematic review that selected 14 RCTs. It included RCTs that were double-blind, placebo-controlled, randomized design, and the participants included were healthy children totaling 5857 participants, and included a large proportion of studies that specifically looked at daycare. It focused specifically on the lactobacillus and bifidobacterium strains. It looked at both single strain probiotics and combination strain probiotics, with the duration of treatment up to 12 months. It looked at the incidence and symptom scores of URTIs in otherwise healthy children. It focused solely on the prevention of acute URTIs in childhood. |
| Citation | Wang Y, Li X, Ge T, et al. Probiotics for prevention and treatment of respiratory tract infections in children: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2016;95(31):e4509. doi:10.1097/MD.0000000000004509https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979858/ |
| Abstract | Background: Respiratory tract infections (RTIs) represent one of the main health problems in children. Probiotics are viable bacteria that colonize the intestine and affect the host intestinal microbial balance. Accumulating evidence suggests that probiotic consumption may decrease the incidence of or modify RTIs. The authors systematically reviewed data from randomized controlled trials (RCTs) to investigate the effect of probiotic consumption on RTIs in children. Methods: MEDLINE/PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for RCTs regarding the effect of probiotics on RTIs in children. The outcomes included the number of children experienced with at least 1 RTI episode, duration of illness episodes, days of illness per subject, and school/day care absenteeism due to infection. A random-effects model was used to calculate pooled relative risks, or mean difference (MD) with the corresponding 95% confidence interval (CI). Results: A total of 23 trials involving 6269 children were eligible for inclusion in the systematic review. None of the trials showed a high risk of bias. The quality of the evidence of outcomes was moderate. The age range of subjects was from newborn to 18 years. The results of meta-analysis showed that probiotic consumption significantly decreased the number of subjects having at least 1 RTI episode (17 RCTs, 4513 children, relative risk 0.89, 95% CI 0.82–0.96, P = 0.004). Children supplemented with probiotics had fewer numbers of days of RTIs per person compared with children who had taken a placebo (6 RCTs, 2067 children, MD −0.16, 95% CI −0.29 to 0.02, P = 0.03), and had fewer numbers of days absent from day care/school (8 RCTs, 1499 children, MD −0.94, 95% CI −1.72 to −0.15, P = 0.02). However, there was no statistically significant difference of illness episode duration between probiotic intervention group and placebo group (9 RCTs, 2817 children, MD −0.60, 95% CI −1.49 to 0.30, P = 0.19). Conclusion: Based on the available data and taking into account the safety profile of RCTs, probiotic consumption appears to be a feasible way to decrease the incidence of RTIs in children. |
| PDF Link | |
| Reason for Inclusion | I selected this article because it looked at the data on the effect of probiotic consumption on RTIs in children. It is a systematic review and meta-analysis that pooled RCTs. It included 23 trials that involved 6269 children that did not have a high risk of bias. Subjects were newborn to 18 years. It focused on the outcomes of RTI incidence, duration of RTIs, days absent from daycare/school. The duration of the treatment ranged from 5 days to 12 months but most trials included were carried out for > 3 months over winter months. All RCTs were double blind with appropriate methodology for randomization and procedures. |
| Citation | Sarah King, Daniel Tancredi, Irene Lenoir-Wijnkoop, Kelsie Gould, Hailey Vann, Grant Connors, Mary Ellen Sanders, Jeffrey A Linder, Andi L Shane, Dan Merenstein, Does probiotic consumption reduce antibiotic utilization for common acute infections? A systematic review and meta-analysis, European Journal of Public Health, Volume 29, Issue 3, June 2019, Pages 494–499, https://doi.org/10.1093/eurpub/cky185 |
| Abstract | Background: Overall reduction of antibiotic use is a widely adopted public health goal. Given evidence that consuming probiotics reduce the incidence, duration and/or severity of certain types of common acute infections, we hypothesized that probiotics are associated with reduced antibiotic use. This systematic review of randomized controlled trials (RCTs) assessed the impact of probiotic supplementation (any strain, dose or duration), compared to placebo, on antibiotic utilization for common, acute infections in otherwise healthy people of all ages. Methods: We searched 13 electronic databases including MEDLINE, Embase and CENTRAL from inception to 17th January 2017. Backward and forward citation searches were also conducted. Two reviewers independently selected studies for inclusion and extracted study data. We assessed risk of bias for individual studies using criteria adapted from the Centre for Reviews and Dissemination, and the quality of evidence for each outcome was assessed using the GRADE system. Studies that evaluated similar outcomes were pooled statistically in meta-analyses using a random-effects model. Results: We screened 1533 citations, and of these, 17 RCTs met our predefined inclusion criteria. All 17 were conducted in infants and/or children with a primary aim of preventing acute respiratory tract infections, acute lower digestive tract infections or acute otitis media. Included studies used 13 probiotic formulations, all comprising single or combination Lactobacillus and Bifidobacterium delivered in a range of food or supplement products. Mean duration of probiotic supplementation ranged from 4 days to 9 months. Trial quality was variable. Meta-analysis demonstrated that infants and children who received probiotics to prevent acute illnesses had a lower risk of being prescribed antibiotics, relative to those who received placebo (Pooled Relative Risk = 0.71, 95% CI: 0.54–0.94). When restricted to five studies with a low risk of bias, the pooled relative risk was 0.46 (95% CI: 0.23–0.97). Significant statistical heterogeneity was present in effect size estimates, which appeared to be due to one trial which could partly be considered as an outlier. Conclusions: Probiotics, provided to reduce the risk for common acute infections, may be associated with reduced antibiotic use in infants and children. Additional well-designed studies are needed to substantiate these findings in children and explore similar findings in other population groups. |
| PDF Link | |
| Reason for Inclusion | I selected this article because it was a systematic review and meta-analysis focused on probiotic consumption and the reduction of antibiotic utilization in acute infections. It reviewed randomized controlled trials to assess the impact of probiotic supplementation (any strain) compared to placebo. While it initially sought to include all ages, the RCTs utilized were conducted on infants and children.Many of the studies included children in day care or public school settings as well. It focused on the impact of probiotics on respiratory and gastrointestinal tract infections. Overall it was 17 RCTs with many different countries and trial locations. |
Summary of the Evidence:
| Author (Date) | Level of Evidence | Sample/Setting(# of subjects/ studies, cohort definition etc. ) | Outcome(s) studied | Key Findings | Limitations and Biases |
| Laursen et al, 2018Probiotics for respiratory tract infections in children attending day care centers—a systematic review. | Systematic Review and Meta-Analysis | 15 RCTs from various countries including a total of 5121 children aged 3 months-7 years in a daycare settingComparison of various probiotic strains with placebo | Number of children with respiratory tract infectionsSecondary Outcomes:Number of children with acute otitis media, number of children with antibiotic use, duration of respiratory tract infections, and days missed from daycare due to infections | Treatment with probiotics as compared with placebo reduced the risk of at least one respiratory tract infection Probiotic lactobacillus rhamnosus (LGG) significantly reduced duration of RTIs in multiple RCTs by at least 1 day Bifidobacterium animalis (BB-12) had no effect on duration of RTIsTreatment with probiotics reduced the risk of antibiotic use Probiotics had no effect on the risk of development of acute otitis media | Potential risk of bias due to unclear or no description of allocation, unclear binding, unclear intention-to-treat analysesStudies were often industry fundedVariation in study duration and methodology |
| Amaral et al, 2017 Network meta-analysis of probiotics to prevent respiratory infections in children and adolescents | Meta-Analysis and Systematic Review | 10 RCTs involving 3451 participants Participants were children and adolescents of both sexes aged 0-18 years at risk or suffering from respiratory infectionsStudies that used only one or various probiotic strains | Primary Outcome:Respiratory tract infections (pneumonia or upper respiratory infections–pharyngitis, laryngitis, epiglottitis, sinusitis, otitis, OR lower respiratory infections –tracheobronchitis or bronchitis and bronchiolitis Secondary Outcome:Analysis of adverse effects | Overall incidence of respiratory tract infections was 4.81 per 1000 person-days in the intervention group and 5.72 per 1,000 person-days in the placebo group for the 6,603 participants included LCA was the only probiotic that significantly reduced the incidence rate of respiratory infections compared to other probioticsRanked first in effectiveness among all strains evaluated in meta-analysisHad positive effects associated with treatmentNo adverse effects were seen with the use of any probiotics There appears to be insufficient evidence overall to recommend general use of both isolated and mixtures of probiotics in prevention and treatment of respiratory tract infection | Risk of bias or vested interest bias, potential for publication biasPossible variation in adequacy of randomization, allocation concealment, blinding participants, blinding outcomes, selective reportingLoss of participant follow up |
| Ozen et al, 2014Probiotics for the prevention of pediatric upper respiratory tract infections: a systematic review | Systematic Review | 14 RCTs that had double-blinded, placebo controlled, randomized designPopulation of 5857 healthy children or infants and the use of probiotics as treatment, both single and combination strain up to 12 months duration | Incidence of respiratory tract infections between probiotic and placebo groups Secondary Outcomes:Severity of symptoms related to respiratory tract infections, missed days of school because of illness, incidence of antibiotic use, and adverse events with probiotic use | Probiotics are better than placebo in reducing the incidence of acute URTIs and antibiotic use in childhood Probiotics in otherwise healthy children have a modest effect on the prevention of URTIs and diminish the severity of infection symptomsSeem more promising than other interventions At least one beneficial effect of prophylactic antibiotic use on the incidence of RTIs and antibiotic prescription and/or severity of episode was observed in majority of RCTsEven reduction of 5-10% in URTIs has significant clinical significance A significant reduction in severity of symptoms was found in 7 out of 11 RCTsThere was lower incidence of URTIs in 7 out of 11 RCTsNo serious adverse events were reported in any of the groups | Some studies report on probiotic effect on incidence/recurrence of RTIs and/or antibiotic use, whereas other report on total days of single/total episodes of common infectious disease → primary and secondary outcomes need to better unified for a better meta-analysisDifferences in administration of probiotics including dose, route, time, duration could affect outcomes |
| Wang et al, 2016Probiotics for prevention and treatment of respiratory tract infections in children: A systematic review and meta-analysis of randomized controlled trials. | Systematic Review and Meta-Analysis | 23 trials involving 6269 children aged from newborn to 18 yearsStudies were double blinded, randomized, and placebo-controlled in many countriesDuration of treatment ranged from 5 days to 12 months and most trials were carried out for > 3 months in winter months | Effects of probiotics on rates of respiratory tract infections including URTIs and LRTIsSecondary Outcomes:Effects of probiotics on subjects having at least 1 RTI episodeEffect of probiotic on duration of RTI illness episodeEffect of probiotic on the days absent from daycare/school | Probiotic consumption appears to be a feasible way to decrease incidence of RTIs in children Seventeen trials including 4513 children reported a significant effect on the reduction of respiratory symptoms and episodes9 trials and 2817 subjects showed no statistically significant difference on illness episode duration Children supplemented with probiotics had fewer number of days of symptomatic RTIs per person compared to placebo Children supplemented with probiotics had fewer days absent from daycare/ school compared to placebo | Variation in probiotic strains, duration of regimens, administration forms, doses, and follow up timesChildren < 5 years are more likely to get RTIs, so trials ranging up to 18 years that don’t report outcomes based on different age groups can cause statistical bias of the overall effect |
| King et al, 2019Does probiotic consumption reduce antibiotic utilization for common acute infections? A systematic review and meta-analysis | Systematic Review and Meta-Analysis | 17 RCTs conducted in infants and children with 13 different probiotic formulations comprising single or combination Lactobacillus and BifidobacteriumMean duration of 4-9 months | Impact of probiotic supplementation compared to placebo on antibiotic utilization for common acute infectionsReduction of risk of infection with probiotic supplement | Infants and children who are given probiotics to reduce risk for acute respiratory tract infections have a 29% relative risk reduction for being prescribed antibiotics in patients who consumed probioticsProbiotic consumption may be associated with reduced antibiotic prescribingProbiotic consumption has been shown to reduce duration of symptoms with common illnesses | Not all the infants or children who were randomized into each trial were included in the study as they would be with a strict intention-to-treat analysisLack of reporting methods or randomization sequence could create unclear risk of biasMajority of trials did not state whether or not antibiotics were for acute infections evaluated within study or other reasons, also no assessment of compliance |
Conclusion(s):
Laursen et al. – LGG is modestly effective in decreasing the duration of RTIs. More RCTs investigating specific probiotic strains or their combination in prevention of RTIs are needed.
Amaral et al. – LCA probiotics showed positive effects associated with the treatment of respiratory tract infections but there is insufficient evidence to support the general use of both isolated and mixtures of probiotics in prevention and treatment of respiratory tract infections. Larger and more rigorously designed RCTs are needed.
Ozen et al. – Probiotics have a modest effect in both diminishing the incidence of URTIs and the severity of infection symptoms. At least one beneficial effect of prophylactic probiotic was observed in the majority of RCTs.
Wang et al. – Probiotic consumption may decrease the incidence and illness duration of RTI episodes. The optimal strains, dosing, administration, and time of intervention should be considered in future clinical trials.
King et al. – Probiotics provided to reduce the risk for common acute infections in infants and children may be associated with reduced antibiotic use, and probiotic consumption has been shown to reduce the duration of respiratory tract infections.
Overall, all studies showed that probiotics had positive effects on the incidence and duration of RTIs. All studies recommended further research to determine the exact effects and the best dosing, timing, and length of treatment with probiotics.
Clinical Bottom Line:
The clinical bottom line I found from these articles is that in children with RTIs, probiotics have beneficial effects.Various strains have shown benefit in reducing the severity of symptoms associated with RTIs in addition to a decreased duration of the RTI itself. All had a beneficial effect on RTIs with probiotic use in comparison with placebo. Use of probiotics also reduced the incidence and use of antibiotics in these patients. However, there is currently not enough data to make a definitive recommendation regarding its regular use. Much more research needs to be done to determine the strains of probiotics, either single or combination that should be used, in addition to the dosage, timing, method, etc. More research will be able to provide a clear recommendation for patients. However, there were limited adverse effects associated with probiotic use, so if patients are interested in using them, there is no harm in it.
If patients are interested in using a probiotic and are seeking a recommendation, most studies included lactobacillus and bifidobacterium strains of probiotics in their studies. In the study by Laursen et al, the Lactobacillus rhamnosus (LGG) strain of probiotic significantly reduced the duration of RTIs. Other strains were monitored and there was no effect on duration of RTIs or lack of data to support any definitive conclusion. In the meta-analysis by Amaral et al, they found that Lactobacillus casei rhamnosus (LCA) was the only effective probiotic to the rate of RTIs compared to placebo. Almost all the studies I included looked at lactobacillus and found relatively promising outcomes. Because this strain appears to be the most studied, I would recommend patients try a lactobacillus strain first if they’re considering trying a probiotic. Bifidobacterium strains were also studied, but with less available data to draw a conclusion from.
Weight of Evidence:
1- Laursen et al. Probiotics for Respiratory Tract Infections in Children Attending Daycare Centers – A Systematic Review. (2018)
I weighted this article third because it was a recent systematic review focused on the use of probiotics for respiratory tract infections (RTI) in children attending day care centers.I weighted it lower because it focused specifically on daycare, which I felt was a little specific and less generally applicable to all patients that might present to a pediatric office. It included 15 RCTs with 5121 children aged 3 months to 7 years, which matches the age range I was looking for. The results compared various strains of probiotics to placebo to evaluate outcomes. It looked at each strain in comparison, which I found to be strong. It measured the primary outcome of the number of children with RTIs with secondary outcomes of the number of children with acute otitis media, antibiotic use, duration of respiratory tract infections, and days missed from daycare.
2- Amaral et al., Network Meta-Analysis of Probiotics to Prevent Respiratory Infections in Children and Adolescents. (2017)
I weighted this article the highest because it’s a very large meta-analysis of probiotics. Its outcome looked at the prevention of acute respiratory infections which was directly related to my PICO question. The aim was to evaluate the effect of probiotics on prevention of respiratory tract infections. It looked at the primary outcome of respiratory tract infections – pneumonia, pharyngitis, laryngitis, epiglottitis, sinusitis, otitis, tracheobronchitis, or bronchitis/bronchiolitis. I thought it was strong that it included many different RTIs as part of the study. It included 21 RCTs with 6,603 participants of both sexes, aged 0-18 years. There is some variability in the probiotics, but overall they did assess the difference strains and found that LGG was the probiotic of highest prevalence.
3- Ozen et al., Probiotics for the Prevention of Pediatric Upper Respiratory Tract Infections: A Systematic Review. (2014)
I weighted this article second because it is a systematic review that selected 14 RCTs. It included RCTs that were double-blind, placebo-controlled, randomized design, and the participants included were healthy children totaling 5857 participants, and included a large proportion of studies that specifically looked at daycare. It focused specifically on the lactobacillus and bifidobacterium strains, which I think the focus on the strains makes it a stronger weight, as it allows for a more specific comparison. Additionally, it looked at both single strain probiotics and combination strain probiotics, with the duration of treatment up to 12 months. It looked at the incidence and symptom scores of URTIs in otherwise healthy children. It focused solely on the prevention of acute URTIs in childhood.
4- Wang et al. Probiotics for Prevention and Treatment of Respiratory Tract Infections in Children. (2016).
I weighted this article fourth because it looked at the data on the effect of probiotic consumption on RTIs in children, which is my outcome. I think it’s positive that it is a systematic review and meta-analysis of RCTs. It included 23 trials that involved 6269 children that did not have a high risk of bias. Subjects were newborn to 18 years, which the timespan up to 18 years did introduce some heterogeneity, which makes it ranked lower in my opinion. It focused on the outcomes of RTI incidence, duration of RTIs, days absent from daycare/school. The duration of the treatment ranged from 5 days to 12 months but most trials included were carried out for > 3 months over winter months. All RCTs were double blind with appropriate methodology for randomization and procedures.
5- King et al. Does probiotic consumption reduce antibiotic utilization for common acute infections? A systematic review and meta-analysis. (2019)
I weight this article fifth because it was a systematic review and meta-analysis focused on probiotic consumption and the reduction of antibiotic utilization in acute infections. Antibiotic use for RTIs wasn’t my direct outcome, so that made the article less strong in my opinion. However, it included other outcomes that made it still worth considering and utilizing for my research. It reviewed randomized controlled trials to assess the impact of probiotic supplementation (any strain) compared to placebo. While it initially sought to include all ages, the RCTs utilized were conducted on infants and children.Many of the studies included children in day care or public school settings as well. It focused on the impact of probiotics on respiratory and gastrointestinal tract infections. Overall it was 17 RCTs with many different countries and trial locations.
Overall, the evidence presented in the above studies is strong, considering the studies were all RCTs and meta-analyses that specifically looked at the comparison between probiotic use and placebo for treatment of RTIs. The data used included large enough sample sizes for the data to be reasonably extrapolated across many demographics and applicable to all patients. All the studies had strong methodology that worked to eliminate bias and lurking variables where possible. These studies looked at the comparison and outcomes in question specifically, thus strongly answering the proposed question. Some weaknesses of the articles are the heterogeneity in probiotic strains as well as dosing, administration, timing, and duration. However, there were enough total studies and participants assessed throughout all the trials that I think the evidence remains very strong.
Magnitude of Effects:
Wang et al. Probiotics for Prevention and Treatment of Respiratory Tract Infections in Children. (2016). A total of 23 trials involving 6269 children were eligible for inclusion in the systematic review. None of the trials showed a high risk of bias. The quality of the evidence of outcomes was moderate. The age range of subjects was from newborn to 18 years. The results of meta-analysis showed that probiotic consumption significantly decreased the number of subjects having at least 1 RTI episode (17 RCTs, 4513 children, relative risk 0.89, 95% CI 0.82–0.96, P=0.004). Children supplemented with probiotics had fewer numbers of days of RTIs per person compared with children who had taken a placebo (6 RCTs, 2067 children, MD 0.16, 95% CI 0.29 to 0.02, P=0.03), and had fewer numbers of days absent from day care/school (8 RCTs, 1499 children, MD 0.94, 95% CI 1.72 to 0.15, P=0.02). However, there was no statistically significant difference of illness episode duration between probiotic intervention group and placebo group (9 RCTs, 2817 children, MD 0.60, 95% CI 1.49 to 0.30, P=0.19).
Laursen et al. Probiotics for Respiratory Tract Infections in Children Attending Daycare Centers – A Systematic Review. (2018)
Number of children with respiratory tract infections as defined by the investigators (Fig. 3) This outcome was available for five RCTs [4, 6, 10, 11, 16]. Treatment with probiotics (as a group) compared with placebo reduced the risk of at least one respiratory tract infection (five RCTs, n = 1841, RR 0.78, 95% CI 0.63 to 0.98, random effect model). High level of heterogeneity was found (Chi2 = 25.09, P < 0.0001, I 2 = 84%). The overall quality of evidence based on GRADE system is presented in Supplement Table 1. Number of children with upper respiratory tract infections as defined by the investigators (Fig. 4) This outcome was available for five RCTs [4, 10, 11, 17, 25]. Treatment with probiotics (as a group) compared with placebo had no effect on the risk of at least one upper respiratory tract infection (five RCTs, n = 1711, RR 0.81, 95% CI 0.62 to 1.05, random effect model). High level of heterogeneity was found (Chi2 = 25.00, P < 0.00001, I 2 = 84%). The overall quality of evidence based on GRADE system is presented in Supplement Table 2. Number of children with AOM as defined by the investigators (Fig. 5) This outcome was available for four RCTs [6, 10, 11, 17]. Treatment with probiotics (as a group) compared with placebo had no effect on the risk of at least one episode of AOM (four RCTs, n = 1289, RR 0.85, 95% CI 0.67 to 1.06, random effect model). Low level of heterogeneity was found (Chi2 = 3.81, P = 0.28, I 2 = 21%). The overall quality of evidence based on GRADE system is presented in Supplement Table 3. Number of children with antibiotic use (Fig. 6) This outcome was available for seven RCTs [6, 10, 11, 16–18, 20]. Treatment with probiotics (as a group) compared with placebo reduced the risk of antibiotic use (seven RCTs, n = 2858, RR 0.69, 95% CI 0.49 to 0.95, random effect model). High level of heterogeneity was found (Chi2 = 57.74, P < 0.00001, I 2 = 88%). The overall quality of evidence based on GRADE system is presented in Supplement Table. Duration of respiratory tract infection (Fig. 7) This outcome was available for nine RCTs [2, 4, 6, 10, 11, 16, 18, 25, 37]. Treatment with probiotics (as a group) compared with placebo had no effect on the duration of respiratory tract infections (nine RCTs, n = 3529, MD − 0.81 days, 95% CI − 1.88 to 0.25, random effect model). High level of heterogeneity was found (Chi2 = 247.27, P < 0.00001, I 2 = 96%). The overall quality of evidence based on GRADE system is presented in Supplement Table.
Amaral et al., Network Meta-Analysis of Probiotics to Prevent Respiratory Infections in Children and Adolescents. (2017). Conventional pairwise meta-analysis of twenty-one studies was included in the systematic review. Figure 2 shows the relative risk and probability-based ranking with the corresponding 95% credible intervals for each intervention compared to placebo. The LCA the only probiotic is that significantly reduced the incidence rate of respiratory infections compared to PLA (RR 0.38; CrI 0.19–0.45). Other probiotic strains showed no effect on the incidence rate of respiratory infections as compared to placebo. Statistical heterogeneity was explored and quantified using the I2 test. The value was I2 ¼ 49%. Three trials with a total of 1.731 participants examined the effect of the probiotic LCA.14,21,26 The age of participants in these studies ranged from 3 to 7 years,14 1 to 6 years,21 and 3 to 12 years.26 The follow-up time was similar: 7 months,14 6 months,21 and 5 months.26 The dose of probiotic administered in the intervention group was 1.2 108 cfu/day14 and 5.108 cfu/day,21 with one trial failing to specify the dose26 (Table 1). Although this outcome indicates that the number of participants who experienced episodes of respiratory tract infections was lower in the probiotic group than the placebo group, the substantial heterogeneity must be considered when using this outcome in the future.
Ozen et al., Probiotics for the Prevention of Pediatric Upper Respiratory Tract Infections: A Systematic Review. (2014). Compared with the placebo group, the pooled data in the LGG group had a significantly reduced risk of AOM (four RCTs, n = 1805, RR 0.76, 95% CI 0.64 — 0.91, fixed effects model, number need to treat 17, 95% CI 11 — 46) and a reduced risk of URTIs (one RCT, n = 281, RR 0.62, 95% CI 0.50 — 0.78, number need to treat 4, 95% CI 3 — 8). However, there was no effect on lower respiratory infections, perhaps due to the small number of infections affecting the lower respiratory tract [53]. Current data suggests that consumption of LGG appears to be an effective strategy for reducing the risk of AOM and URTIs in basically healthy children. Another strain, L. casei DN-114 001, which has been studied extensively in humans, is a reminder of the necessity to study a strain at different ages before recommending it for all age group immunity. Double-blind RCTs (DBRCTs) of this strain reported beneficial effects both in children (638 children, 3 — 6 years old in daycare/schools, the incidence rate for CIDs in probiotic group [0.0782] was 19% lower than the control group [0.0986], [incidence rate ratio = 0.81, 95% CI: 0.65, 099] p = 0.046) and in adults (1072 elderly, reduced the mean duration of CID episode to 6.5 versus 8 days, p = 0.008) [54]. The latter author published another study in adults, reporting that daily consumption of a fermented dairy product containing L. casei DN-114 001 could reduce the risk of common infections in stressed individuals such as shift workers (OR = 0.75, 95% CI 0.59 — 0.95, p = 0.017). The reduction in the incidence and duration of CID episodes at different ages suggested that this strain is effective throughout the lifetime, which might not be the case with other strains and different probiotics, since it is well known that human microbiota change with age, diet and chronic disease.
King et al. Does probiotic consumption reduce antibiotic utilization for common acute infections? A systematic review and meta-analysis. (2019)
There was a high level of statistical heterogeneity among the studies (Tau2=0.15, Chi2P values=P < 0.001, I2=79%). When we omitted one statistical outlier (Leyer et al. 2009)16 from the analysis, the amount of statistical heterogeneity became negligible (Tau2 = 0.00; Chi2P values = 0.51; I2=0%) and the pooled RR of antibiotic use was 0.87 (95% CI: 0.78–0.97; n = 3627; P = 0.01). In a sensitivity analysis, we removed studies considered to have a high risk of bias from the meta-analysis leaving five studies. In this analysis, children who took probiotics were less likely to receive antibiotics (RR 0.47 [95% CI: 0.23–0.97], n = 2067, P = 0.04), but again there was a high level of statistical heterogeneity among the studies (Tau2=0.48; Chi2P values=P < 0.001; I2=86%), which could be eliminated by the exclusion of one statistical outlier (Leyer et al., 2009)16 from the analysis. After this exclusion, the protective effect of probiotic supplementation on antibiotic receipt in these four-remaining low risk-of-bias studies is similar as that for the primary meta-analysis but becomes statistically non-significant (RR 0.78 [95% CI: 0.60–1.01], n = 1711, P = 0.06, Tau2=0.00; Chi2P values = 0.49; I2=0%).
Clinical Significance:
The significance of this research is that there is benefit to the use of probiotics in treating RTIs specifically in children. Various studies have shown there is a reduction in symptom severity, duration of RTIs, reduction in antibiotic use, and decreased incidence of RTIs with antibiotic use. However, because there is too much heterogeneity in the nature of probiotics and the research done, there is no definitive recommendation for best use. With that being said, if patients choose to use probiotics on their own, it is safe to encourage them to do so. If patients are interested in choosing to use probiotics, I would recommend one of the lactobacillus strains as those have been studied the most in depth at this point which provides the most significant data.
Other Considerations:
A consideration for the future is comparing different probiotic strains and their effects on these outcomes. So many studies had various strains or dosing or timeframes of the doses that it makes it hard to draw a definitive conclusion regarding the general use of probiotics for RTIs in children. More specific testing would help provide better evidence-based recommendations.
One additional thing to consider is the adverse effects or risk of probiotics. This is especially important considering the population this will be used on is young children. In most studies overall, the adverse effects were mild and no severe adverse effects were seen. For example, in the study done by Laursen et al, there were no serious adverse events and no difference in the incidence of adverse events between active and placebo groups. The most common side effects seen were mild gastrointestinal symptoms. In the study done by Amaral et al, they found adverse effects were minor and probiotics were safe overall. Additionally, Ozen et al showed adverse effects were minor clinical severity – mainly vomiting, diarrhea, and rash, with no serious adverse events. In the study by Wang et al, they found that adverse events included diarrhea, vomiting, lack of appetite, constipation, hives, rash, dry skin, and abdominal pain. It’s definitely something to inform patients of if they choose to use probiotics, but nothing that should defer patients who are interested from using them.
