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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 5  |  Page : 234-242

Probiotics in critically ill children: An updated review


1 Department of Pediatrics, Division of Pediatric Critical Care, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pediatric Intensive Care, Zydus Hospitals, Ahmedabad, Gujarat, India

Date of Submission15-Aug-2021
Date of Decision29-Aug-2021
Date of Acceptance04-Sep-2021
Date of Web Publication28-Sep-2021

Correspondence Address:
Dr. Suresh Kumar Angurana
Department of Pediatrics, Division of Pediatric Critical Care, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcc.jpcc_73_21

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  Abstract 


Gut microbiome is a complex ecosystem where good microbes outnumber pathogenic bacteria. Gut microbiome plays important role in host biology, function, physiology, and immune response by performing nutritive and immune functions and by providing physical barriers against pathogenic microorganisms. Critical illness leads to disruption of the gut microbiome, colonization with and overgrowth of pathogenic microorganisms, translocation of pathogens and their toxins, systemic inflammatory response syndrome, and sepsis. Probiotics restore gut microbiome, improve the barrier function of gastrointestinal tract, and prevent bacterial translocation. Commonly used probiotics are Lactobacillus, Bifidobacterium, and Saccharomyces. Enteral administration of probiotics has been shown to reduce the rate of necrotizing enterocolitis, candida colonization, candidiasis, sepsis, feed intolerance, mortality, and duration of hospital stay among preterm infants; and ventilator-associated pneumonia and antibiotic-associated diarrhea in critically ill children. Few studies suggested that probiotics supplementation among critically ill children resulted in reduction in the rate of candida colonization and candidiasis; and modulation of inflammation. However, there are safety concerns with probiotics as there are few reports of bacteremia/sepsis and fungemia in immunocompromised cases. Further, well-designed multicentric studies are needed to give clear answers on the dose and duration of treatment, the effectiveness of a single or multiple strain of probiotics, risk-benefit potential, and cost-effectiveness in critically ill children.

Keywords: Gut, pediatric intensive care unit, probiotics


How to cite this article:
Angurana SK, Mehta A. Probiotics in critically ill children: An updated review. J Pediatr Crit Care 2021;8:234-42

How to cite this URL:
Angurana SK, Mehta A. Probiotics in critically ill children: An updated review. J Pediatr Crit Care [serial online] 2021 [cited 2021 Oct 26];8:234-42. Available from: http://www.jpcc.org.in/text.asp?2021/8/5/234/326870




  Introduction Top


Children admitted to pediatric intensive care units (PICUs) are at high risk to develop changes in gut microbiome leading to various infectious complications and adverse clinical outcomes.[1],[2],[3] Based on their actions and benefits, probiotics have the potential and capability to restore the gut microbiome and confer a health benefit to the host. In the recent past, the use of probiotics among critically ill adults and neonates has been shown to prevent several infectious complications. Recently, the role of probiotics has been demonstrated among children admitted to PICU in the prevention of candida infection, ventilator-associated pneumonia (VAP), and modulation of inflammation.[3],[4],[5],[6],[7],[8],[9] In this paper, we discuss the role of probiotics in children admitted to PICU in the light of accumulated evidence and areas for future research identified.


  Composition and Role of Gut Microbiome Top


Gut microbiome is community of microorganisms which reside in our gastrointestinal tract (GIT) and with whom we have developed a symbiotic relationship over the course of millions of years. The gut microbiome is an ecologically complex and diverse ecosystem wherein a delicate and fine balance between the intestinal microflora and the human host is essential for health. Under physiological conditions, the good or beneficial microorganisms outnumber potentially pathogenic microorganisms. These microorganisms live in symbiosis with the host and perform many beneficial functions. There are >10,000 species of microorganisms in the GIT with the estimated total number being more than 10 times the total number of eukaryotic cells in the human body.[3],[10] A normal gut microbiome of humans predominantly consists of obligate anaerobes (95%, consisting of Bifidobacterium, Fusobacterium, Clostridium, Peptostreptococcus, Eubacterium, and Bacteriodes) as well as facultative anaerobes (1%–10%, consisting of Lactobacillus, Streptococcus, Staphylococcus, Klebsiella,  Escherichia More Details coli, and Bacillus). The predominant microorganisms are Bifidobacterium and Lactobacillus. However, each individual has his own unique microbiome composition based on geographical location, dietary pattern, age, underlying disease conditions, stress, medications/antibiotic usage, and critical illness.[3] In healthy state, gut microbiome performs several beneficial and health-promoting functions. In addition, there is crosstalk between the gut and other organs (gut-organ axis including gut-lung axis, gut-kidney axis, and gut-brain axis). The functioning of the gut-organ axis is bidirectional and important for homeostasis. The gut microbiome is important contributor to the gut-organ axis.[11],[12] Various beneficial functions performed by the gut microbiome are enumerated in [Table 1].
Table 1: The beneficial actions exhibited by the gut microbiome

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  Critical Illness and Effect on Gut Microbiome Top


The critical illness as well as its treatment creates a hostile environment in the gut leading to alterations in the gut microbiome and overgrowth of pathogenic microorganisms. The usage of broad-spectrum antibiotics, invasive catheters and lines, steroids, endotracheal intubation and invasive mechanical ventilation, H2 blockers, and immunosuppressants alter the gut microbiome and lead to a hostile environment in the gut. This is further compounded by multiple organ dysfunction syndrome (MODS), altered gut motility, malnutrition, burns, acid-base imbalance, osmolality, and outpouring of stress hormones.[2],[3]

During critical illness, there are disturbances in the composition and function of the gut microbiome (gut dysbiosis), alteration in the mucosal defense mechanisms, and overgrowth of potentially pathogenic microorganisms. Further, cell apoptosis, neutrophil activation, cytokine release, and disruption in epithelial tight junctions lead to loss of local colonization resistance, translocation of pathogenic microorganisms and their toxins across the gut mucosa into the bloodstream, and finally, systemic inflammatory response syndrome, sepsis, MODS, and mortality.[1],[2] Therefore, the GIT is labeled as the origin and promoter of healthcare-associated infections (HCAIs) and MODS (gut-derived sepsis or gut as motor of MODS).[1],[19],[20] Restoring the healthy gut microbiome with the extraneous supply of beneficial microorganisms (probiotics) is an attractive and effective option.


  Probiotics in Clinical Setting Top


Probiotics are defined by the joint working group of FAO/WHO as “live microbes which when administered in adequate amount confer health benefit to the host.”[21] Lactobacillus and Bifidobacterium are commonly used probiotics[22] [Table 2]. The commercially available probiotics preparations contain either single or multiple strains. The multiple strain probiotics may be having more benefits and are more effective than single strain as they may have synergistic functions of individual probiotic strains. Daily supplementation of >106–109 colony-forming units (CFUs) of probiotics is suggested to be the minimum therapeutic dose.[22],[23]
Table 2: Commonly used microorganisms as probiotics

Click here to view


The pre-requisites for probiotic strains include that they should be nonpathogenic; demonstrated to have several beneficial effects without any adverse effects or safety issues; retain adequate viability during storage, transport, and use; stable in gastric acid, and bile; and should be able to adhere to and colonize the gut mucosa.[3],[4],[22],[24]


  How Probiotics Act? Top


Probiotics exert beneficial clinical effects by restoring the composition of the gut microbiome, imparting colonization resistance, modulating the immune response, and preventing bacterial translocation.[4],[5],[25] Probiotics activate gut mucosal immunity, stimulate secretion of immunoglobulin A, promote phagocytosis, produce inhibitory substances (bacteriocins, organic acids, hydrogen peroxide), provide competition for nutrients and adhesion sites to pathogenic bacteria, inhibit the action of various toxins produced by pathogens; modulate immune response (innate and adaptive), exert trophic effect on GIT mucosa, stimulate proliferation and differentiation of normal mucosal epithelium, maintain mucosal barrier defenses, and ultimately, prevent bacterial translocation.[3],[4],[5],[22],[24]


  Probiotic Use in Critically Ill Children Top


Among critically ill children, probiotics have been evaluated for prevention and treatment of antibiotic associated diarrhea (AAD), necrotising enterocolitis (NEC), HCAIs, VAP, candida colonization, candiduria, candidiasis, and modulation of inflammation.


  Probiotics and Prevention of Nec Top


Hoyos et al.[26] demonstrated that oral supplementation with probiotics (L. acidophilus and B. infantis) lead to reduction in the rate of NEC among preterm neonates. Later on, it was demonstrated that supplementation with L. rhamnosus GG among preterm infants (for 7 days) was not effective in decreasing urinary tract infection, sepsis, and NEC.[27] Subsequently, many randomized controlled trials (RCTs) demonstrated that probiotic supplementation among preterm neonates resulted in reduction in rates of NEC.[28],[29] In a meta-analysis (24 trials) involving preterm neonates, Al Faleh et al.[30] demonstrated that administration of probiotics (containing Lactobacillus ± Bifidobacterium) prevented severe NEC and mortality. Recently, Morgan et al.[31] in a meta-analysis (63 trials with 15,712 preterm neonates) demonstrated that a combination of 1 Lactobacillus species and ≥1 Bifidobacterium species lead to a significant reduction in severe NEC, time to reach full enteral feeds, duration of hospitalization, and mortality (moderate-to-high-quality evidence).


  Probiotic and Prevention of AAD Top


The osmotic and invasive AAD is common complication noted in critically ill children admitted to PICU receiving broad-spectrum antibiotics. It occurs because of decrease in the population of beneficial microorganisms, overgrowth of pathogens, and disruption of the mucosal barrier.[32] Several meta-analyses have shown that probiotics were effective in reducing the rate of AAD in children.[33],[34],[35],[36],[37],[38] The commonly used probiotics were S. boulardii and Lactobacilli (alone or in combination). Guo et al.[39] in a recent Cochrane systematic review (33 studies, 6352 participants) demonstrated that administration of probiotics (Lactobacillus, Bifidobacterium, Bacillus, Lactococcus, Saccharomyces, or Streptococcus, alone or in combination) lead to reduction in the AAD incidence [probiotics 8% (259/3232) vs. control 19% (598/3120), moderate certainty evidence]. The authors also noted that high dose of probiotics (≥5 billion CFUs/day) was more efficacious than low dose (<5 billion CFUs/day) in reduction of the incidence of AAD. Furthermore, probiotics reduced the duration of diarrhea by almost one day (low certainty evidence).


  Probiotics and Prevention of Healthcare Associated Infections Top


Various studies evaluated probiotics for the prevention of HCAIs among critically ill adults and yielded mixed results. A meta-analysis (12 RCTs, n = 1546) involving critically ill adults demonstrated that administration of probiotics resulted in significant reduction in healthcare-associated pneumonia but no significant effect on the duration of ICU and hospital stay, and ICU and hospital mortality.[40] Another systematic review (8 RCTs; n = 999) demonstrated that probiotic supplementation in critically ill adults leads to no beneficial effect on the duration of ICU stay, rate of HCAIs, and ICU mortality.[41] Petrof et al.[42] conducted a systematic review (23 RCTs) and noted that probiotics supplementation leads to reduction in infectious complications among critically ill adults, VAP rates, and ICU mortality. However, there was no effect on hospital mortality, and duration of ICU and hospital stay. Manzanares et al.[43] in a meta-analysis (30 RCTs, n = 2972) demonstrated that probiotics supplementation resulted in significant reduction in the incidence of HCAIs and VAP; but no effect on mortality or duration of hospital stay. In a recent meta-analysis (14 studies, n = 1975), Su et al.[44] demonstrated that supplementation with probiotics leads to reduction in the incidence of VAP and shorter length of antibiotic usage for VAP but no effect on ICU mortality, duration of mechanical ventilation, duration of stay in ICU, or occurrence of diarrhea.

Among critically ill children, there are limited studies on this topic. Honeycutt et al.[45] in a RCT (n = 61), demonstrated that supplementation with L. rhamnosus to critically ill children did not result in reduction in the incidence of HCAIs. However, there was a statistically non-significant trend toward increase in the rate of HCAIs in the probiotics group (11 vs. 4) (P = 0.31). However, further studies did not substantiate these findings. Wang et al.[46] conducted an RCT involving critically ill full-term infants (n-100) and demonstrated that the administration of a multiple strain probiotic (Lacticaseibacillus casei, Lactobacillus acidophilus, Bacillus subtilis, and Enterococcus faecalis) for 8 days resulted in increased immune activity, lesser incidence of healthcare-associated pneumonia and MODS, and shorter duration of hospital stay. In another RCT, Banupriya et al.[9] enrolled children ≤12 years of age (n = 150) receiving mechanical ventilation and demonstrated that supplementation with a multi-strain probiotic preparation (L. acidophilus, L. rhamnosus, L. casei, L. plantaris, L. bulgaricus, B. longum, B. breve, B. infantis, and S. thermophilus) for 7 days resulted in decrease in VAP rate; and duration of PICU stay, hospital stay, and mechanical ventilation.


  Probiotics and Prevention of Candida Infection Top


Many RCTs have evaluated the effect of probiotic supplementation on the prevention of GIT candida colonization as well as invasive candidiasis among neonates. In an RCT conducted by Manzoni et al.[47] including 80 VLBW neonates, authors demonstrated that administration of L. rhamnosus resulted in reduction in the rate as well as the intensity of gut Candida colonization. Similarly, Romeo et al.[48] in an RCT (n = 249) demonstrated that supplementation with either L. reuteri or L. rhamnosus resulted in significant reduction in GIT Candida colonization, late-onset neonatal sepsis, and abnormal neurological state among preterm neonates. Demirel et al.[49] conducted an RCT including VLBW infants and demonstrated that the prophylactic administration of S. boulardii was effective in reducing fungal colonization as well as invasive fungal infections (similar to nystatin); and was more effective (compared to nystatin) in reducing the rates of sepsis and better feed tolerance. Roy et al.[50] conducted an RCT involving preterm neonates and noted that the probiotics supplementation (L. acidophilus, B. longum, B. bifidum and B. lactis) resulted in reduction in fungal colonization in gut, invasive fungal infection, early achievement of full enteral feeds, and reduction in length of hospital stay. In another RCT by Oncel et al.[51] involving preterm infants, it was demonstrated that administration of L. reuteri led to reduction in fungal colonization, invasive candidiasis, the incidence of sepsis, feeding intolerance, and duration of hospital stay. These effects were similar to that noted with nystatin. Recently, Hu et al.[52] in a meta-analysis (7 RCTs, n = 1371 preterm neonates) demonstrated that probiotic supplementation resulted in decrease in the rate of candida colonization and invasive fungal infections.

In critically ill children, few trials evaluated the role of multiple strains of probiotics in the reduction of Candida colonization and invasive Candidiasis. Our group conducted an RCT involving critically ill children on broad-spectrum antibiotics admitted in PICU and demonstrated that the administration of multiple strains of probiotics (L. acidophilus, L. rhamnosus, B. longum, B. bifidum, S. boulardi, and S. thermophilus) for 7 days resulted in significant decrease in GIT Candida colonization and candiduria; and nonsignificant decrease in the rates of Candidiasis.[8] Further, in a before-after study, we demonstrated that probiotic supplementation among children on broad-spectrum antibiotics in PICU resulted in significant decrease in the incidence of candiduria and invasive candidiasis.[7] To summarize, there is some evidence that probiotic supplementation could be a potential strategy in decreasing the rates of Candida colonization and candidiasis among critically ill children in PICU.


  Probiotics and Modulation of Inflammation Top


Various clinical studies and trials involving adults and children in health and disease states evaluated the potential role of probiotic supplementation on inflammation and other clinically important outcomes.[6],[53],[54],[55],[56],[57],[58],[59],[60] In a meta-analysis, Kazemi et al.[56] (167 clinical trials) included studies that evaluated the effect of probiotic or synbiotic supplementation (for a duration of >7 days) among healthy people and those with several disease conditions on inflammatory markers. Authors demonstrated that some of the probiotics resulted in reduction in C-reactive protein (CRP) among healthy individuals, in those with metabolic disorders, arthritis, and in critically ill; decrease in tumor necrosis factor (TNF)-α levels among healthy individuals, those with fatty liver, hepatic cirrhosis, and IBD; increased in interleukin-6 (IL-6) in renal failure and cirrhosis; and increased IL-10 in arthritis. Another meta-analysis (8 clinical trials, 1337 patients with diabetes) demonstrated that supplementation with probiotics resulted in significant decrease in CRP and TNF-α.[57] These meta-analyses suggested that probiotic supplementation in health and several disease states resulted in modulation of inflammation.[56],[57],[58]

In an RCT involving critically ill children with severe sepsis (n = 100), we demonstrated that supplementation of a probiotics mix for 7 days resulted in a significant reduction in the levels of pro-inflammatory (IL-6, IL-12p70, IL-17, and TNF-α) and increase in anti-inflammatory cytokines (IL-10 and TGF-β1).[6] Few other studies also noted that supplementation with probiotics was effective in the modulation of inflammation among critically ill.[59],[60]


  Probiotics and Coronavirus Disease 2019 Top


In COVID-19, the gut microbiome and bidirectional gut-lung interaction are important pathways that may be playing an important role. The higher severity of COVID-19 among young children and elderly and those with underlying co-morbid medical conditions is possibly due to less diversity of gut microbiome and gut dysbiosis in these cohorts of cases.[61],[62],[63],[64],[65],[66] In cases with COVID-19, it has been shown that there is the alteration in the gut microbiome, reduction in diversity and number of beneficial microorganisms, and increase in number and diversity of potentially pathogenic opportunistic microorganisms.[67],[68],[69] These changes in gut microbiome ultimately result in gut dysbiosis, mucosal barrier disruption, translocation of potentially pathogenic microorganisms across the gut mucosa, sepsis and bacterial infections, hyper-inflammatory response, and MODS, and increased mortality. The severe COVID-19 is perse characterized by hyper-inflammation, immune dysregulation, and cytokine storm. The levels of several cytokines are reported to be higher in cases with severe COVID-19 and among nonsurvivors.[69],[70],[71],[72],[73],[74],[75] Therefore, gut dysbiosis and the heightened or dysregulated inflammation are major pathways in cases with COVID-19 leading to increased severity of disease and poor outcomes.

By virtue of their actions, probiotics have the potential to have an impact at multiple steps in the cascade of COVID-19. Probiotics have antiviral actions,[76],[77],[78],[79],[80],[81],[82] they restore gut microbiome,[5],[6],[53],[54],[55],[83],[84],[85],[86],[87],[88] modulate inflammation/cytokine storm (anti-inflammatory),[6],[53],[54],[55],[56],[57],[58],[59],[60] and prevent secondary bacterial and fungal infections.[4],[7],[8],[43],[44],[89],[90],[91],[92],[93] In comparison to antiviral medications, immunomodulators, and other treatment strategies tested or used in COVID-19 patients, probiotics are easily available and easy to use (oral administration). Furthermore, they are safe and economical.[94] Therefore, probiotics by virtue of their beneficial effects maybe a useful strategy in the prevention of complications due to COVID-19.[95] The role of probiotics in moderate-to-severe COVID-19 needs to be tested. There are few ongoing studies that were designed to evaluate the effect of probiotics supplementation in cases with COVID-19 (NCT04368351, NCT04366180, and NCT04366089). In a recently published retrospective, observational cohort study, Ceccarelli et al.[96] enrolled adults (n = 200) with severe COVID-19 pneumonia. Authors compared the group that received the best available therapy (BAT) (n = 122) (low molecular-weight heparin plus ≥1 between azithromycin, hydroxychloroquine, antivirals, and Tocilizumab) with the group that received oral bacteriotherapy (n = 88) (Sivomixx® composed of S. thermophilus DSM 32245, B. lactis DSM 32246, B. lactis DSM 32247, L. acidophilus DSM 32241, L. helveticus DSM 32242, L. paracasei DSM 32243, L. plantarum DSM 32244, and L. brevis DSM 27961) in addition to BAT. The authors demonstrated that the mortality was lower in BAT plus oral bacteriotherapy group as compared to the BAT group (11% vs. 30%, P < 0.001). Further, oral bacteriotherapy was demonstrated to be an independent predictor for reduced risk for death.


  Probiotics and Safety Profile Top


Most of the available probiotic strains are usually safe in various settings, different age groups, and in critically ill. However, there are few concerning reports of lactobacillemia, liver abscess, and infective endocarditis, especially in immunosuppressed or severely debilitated patients.[3],[97],[98],[99],[100],[101],[102],[103] Although the risk of infection and sepsis due to Lactobacillus is very rare (0.05%–0.4%),[104] few reports of sepsis due to Lactobacillus (directly linked with the ingested probiotics), especially among immune-compromised cases raise safety concerns.[97] Rare reports of septicemia and fungemia due to S. boulardii in immunocompromised patients and critically ill are also documented.[105],[106],[107] B. longum bacteremia has been noted in preterm infants receiving probiotics.[108],[109] Despite these rare reports of adverse effects, probiotics are generally safe in wide range of settings including preterm neonates and critically ill children.[110],[111],[112] Other serious concerns are the genetic transfer of antibiotic resistance from probiotics strains to pathogenic microorganisms,[113],[114] immune stimulation, and harmful metabolic activities.[3],[4]


  Future Directions Top


Several studies demonstrated that probiotics have promising role in the prevention of various infectious complications in critically ill children in PICU. However, these studies have several limitations as most of these were single-center studies, had small sample sizes, involved different populations, and included children with variable disease conditions. The probiotics used, their dose and duration were different. Large multicentric well-designed trials are required to understand the efficacy and safety of probiotics in critically ill children in PICU. More information is needed on their mechanisms of action, optimal dose and duration, adverse events, risk-benefit potential, and whether single or multiple strain (combination) are more beneficial.


  Conclusions Top


Among critically ill children, the gut microbiome is altered which predisposes them to bacterial translocation, sepsis, MODS, and increased mortality. Probiotics have the potential to restore the balance of the intestinal microbiome. In critically ill children, probiotics supplementation has shown to reduce NEC, HCAIs, AAD, VAP, Candida colonization, candidiasis, and inflammation. The rare reports of bacteremia, fungemia, and sepsis due to probiotics in critically ill fragile patients raise safety concerns. Further, well-designed studies are needed before the routine use of probiotic supplementation could be recommended in critically ill children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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