Probiotics can be defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.”1 They are marketed either as food supplements, typically added to yogurt or to infant formula, or as pharmaceuticals. Components of probiotics consist of single or multiple strains of bacteria (often Lactobacillus or Bifidobacterium species) or fungi (often Saccharomyces boulardii). These strains are usually of human origin1 and are very rarely pathogenic, even in the immunocompromised host. The organisms in probiotics do not always survive storage. Although they would no longer qualify as “probiotics,” some believe that even nonviable microorganisms may still confer benefit.1 The limitation of interpreting and comparing the results of studies of probiotics is that efficacy may vary depending upon the strain(s) present, the quantity of live and dead organism(s), the other ingredients present, the method of manufacture, the lot chosen and the storage conditions. There is a hypothesis that probiotics may decrease the incidence or severity of respiratory tract infections (RTIs) in adults and children.2
MECHANISM OF ACTION OF PROBIOTICS
In gastrointestinal (GI) conditions, probiotics are hypothesized to work by altering the intestinal microbiome and by maintaining gut integrity. The mechanism by which probiotics could modify respiratory tract disease is less intuitive, but enhancement of the innate and adaptive immune response and of mucosal immunity are the postulated mechanisms.2
THERAPY OF RTIs
There appear to be no published trials of probiotics as therapy for RTIs in children or adults, although topical probiotics have been proposed to be worthy of study for chronic rhinosinusitis.3
PREVENTION OF RTIs
A Cochrane Collaboration systematic review of upper respiratory tract infections (URTIs) [12 randomized controlled trials (RCTs), of which 8 were in children] last updated in 2015 reported that the evidence that probiotics prevent URTIs in children is of low or very low quality overall.2 One pediatric study only followed patients during a hospitalization. The duration of the other studies was 3 months (n = 5), 20 weeks (n = 1) or 12 months (n = 1). There was a lower risk of having at least 1 URTI [odds ratio (OR): 0.43; 95% confidence interval (CI): 0.29–0.63; n = 1457) and of having a minimum of 3 URTIs (OR: 0.56; 95% CI: 0.35–0.89; n = 332) in the probiotic group while on study medication. However, the risk ratio for the total number of URTIs was not different at 0.77 (95% CI: 0.57–1.05; n = 1136).
A more recent systematic review used network meta-analysis, which allows for comparison of treatments that have not yet been compared head-to-head in studies. They studied RTI (versus URTI only in the Cochrane review) and found 21 eligible pediatric RCTs.4 The incidence of RTI decreased from 5.72 to 4.81 events/1000 patient days (Relative risk: 0.69; 95% CI: 0.54–0.88; n = 6603) with probiotics. Lactobacillus casei rhamnosus was the only probiotic with greater efficacy than placebo, but the great heterogeneity of the 3 studies that used this probiotic and the small sample size of the studies using the other 9 probiotic regimens precludes definitive conclusions. Six of the 21 studies in the network meta-analysis were excluded from the Cochrane review as the outcome was RTI rather than URTI specifically. Addition of these 6 studies seems logical given that small minority of RTIs are LRTIs. Also, outcomes in the studies that analyzed URTIs were primarily based on parental report, which would not preclude mild LRTIs from being mislabeled as URTIs. Another study was excluded from the Cochrane review as 70% of children had received rotavirus vaccine,5 which is unlikely to have influenced the incidence of RTIs. However, it is more debatable whether results of 5 other studies excluded from the Cochrane review but included in the network meta-analysis inform the research question as to whether probiotics prevent RTIs as they were either not randomized6 or reported outcomes limited to nosocomial pneumonia in preterm infants,7 nosocomial pneumonia in a pediatric intensive care unit,8 or viral detection in middle ear fluid.9,10
Acute otitis media (AOM) is almost always preceded by a URTI so an intervention that prevents URTIs should also prevent AOM. A study from France showed no benefit for AOM incidence in 224 children 7 to 13 months of age given formula supplemented with prebiotics and probiotics versus placebo.11 An open-label trial from Italy reported AOM in 49 of 111 3-year-old children on probiotic tablets (44%) versus 89 of 111 controls (80%) with persistent benefit in the 3 months after probiotics were stopped.12 However, the diagnosis of AOM is not entirely objective so an open-label design is subject to potential bias. In a third study, recurrent AOM occurred in 21 of 53 children on topical probiotics (40%) versus 28 of 55 on placebo (51%); although the authors suggest that this is statistically significant, analysis of those figures with a 2-tailed Fisher exact test indicates this is not the case (P = 0.25).13
Probiotics have also been studied for prevention of ventilator-associated pneumonia (VAP). One proposed mechanisms is that because VAP pathogens often originate from the GI tract, there is utility in altering the GI microbiome to primarily nonpathogenic organisms. A limitation of VAP trials is that colonization of the airways with pathogenic organisms may incorrectly be interpreted as a diagnostic criteria for VAP; probiotics may prevent such colonization without actually preventing VAP.14 A 2014 Cochrane review of adult RCTs suggested that probiotics were protective but only 4 of the 8 included studies had a low risk of bias.15 A large prospective adult trial with a low risk of bias is currently ongoing in Canada and the United States.16 There are 3 pediatric trials of VAP, of which 2 were randomized. Patients in a United States pediatric intensive care unit (including nonventilated patients) were randomized to Lactobacillus rhamnosus versus placebo.8 An interim analysis showed no difference in nosocomial infection rates with 2 of 31 children in the probiotic group having pneumonia versus 0 of 30 controls, and the trial was halted because of a probable lack of efficacy. Preterm infants in Columbia were randomized to Lactobacillus reuteri versus placebo; nosocomial pneumonia occurred in 9 of 372 infants on probiotics and 19 of 378 controls (P = 0.06).7 A pediatric open-label trial from India enrolled children up to age 12 years (n = 150) who were likely to be ventilated for minimum of 48 hours.17 The VAP incidence was 17% in the probiotic group versus 49% in controls (P < 0.001). In this study, the definition of VAP included a “persistent” radiographic infiltrate with fever and leukocytosis, which may have led to overdiagnosis of VAP.14
MODIFICATION OF THE SEVERITY OF RTIs
The Cochrane review of URTIs found no trials studying day-care absenteeism. Only one small trial studied school absenteeism, demonstrating benefit in the probiotic group (OR: 0.10; 95% CI: 0.02–0.47, very-low-quality evidence; n = 80).2 Antibiotic use during URTIs was reported in 3 trials; children in the probiotic group received less antibiotics (OR: 0.65; 95% CI: 0.45–0.94, moderate-quality evidence; n = 1184). The duration of symptoms with each URTI was not compared in any pediatric trials in the Cochrane review. However, another meta-analysis reported no significant difference in 2 pediatric trials that reported this outcome in RTIs in 548 randomized children.18
A novel study performed subsequently randomized 225 children to probiotics versus placebo as prophylaxis after a household contact developed an RTI. Probiotics did not prevent RTIs, but there was a statistically significant decrease in both the severity score and the mean duration of symptoms (from 7 to 5 days).19
SAFETY OF PROBIOTICS
Parents often regard probiotics as “natural” and therefore safe. There were no serious adverse effects in any of the trials mentioned above, but there are case reports of invasive infection with strains proven to be identical to those in ingested probiotics, including a small number of cases in very low birth weight infants20 and immunocompromised hosts. Probiotics are typically regulated as food supplements rather than as pharmaceuticals so there are lower standards for product manufacturing and uniformity, resulting in the potential for contamination with pathogenic organisms.21 Were a patient to develop invasive infection with the contaminant, the link to the probiotic product might only be recognized if there were multiple cases.
Clearly, there is a need for further large high-quality RCTs to demonstrate efficacy and to compare different products before physicians can recommend routine use of probiotics to prevent or decrease the severity of RTIs or VAP. Efficacy of a given product may vary depending upon the prevailing GI microbiome in that part of the world. In searching for the ideal product, it is possible that multiple strains in a probiotic mixture could inhibit each other.17 However, a recent meta-analysis indicated that probiotics with multiple strains were actually more effective than single strains for prevention of necrotizing enterocolitis.22 This may be unique to necrotizing enterocolitis but should also be analyzed in RTI studies.
The cost of probiotics is substantial if they are to be used long term. Even if they prevent or decrease the severity of RTIs, the estimated degree of benefit is a key for determining whether they should be recommended. Analyzing the pediatric studies from the Cochrane review, 9.9 children would need to be treated to prevent a minimum of 1 URTI during the study period (which varied from the duration of a hospitalization to 12 months) and 9.4 children would need to be treated to prevent 3 or more RTIs during the study period (which was 20 weeks and 12 months in the 2 studies that included this outcome).2 One would predict that many parents would desire a more impressive difference between outcomes with probiotics versus placebo to embark on long-term prophylaxis.
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