key: cord-0700801-wzlsgvg6
authors: Rozga, Mary; Cheng, Feon W.; Handu, Deepa
title: Effects of Probiotics in Conditions or Infections Similar to COVID-19 on Health Outcomes: An Evidence Analysis Center Scoping Review
date: 2020-07-20
journal: J Acad Nutr Diet
DOI: 10.1016/j.jand.2020.07.016
sha: e7c95bd923aaedceca9ad83f6a472299d1dde35d
doc_id: 700801
cord_uid: wzlsgvg6

Abstract Probiotics have been suggested as a potential intervention for improving outcomes, particularly ventilatory-associated pneumonia, in patients infected with COVID-19. However, with the rapid development of the COVID-19 pandemic, there is little direct evidence available in infected patients. The objective of this scoping review is to examine the availability and nature of literature describing the effect of probiotics in adults with conditions or infections similar to COVID-19 infection, on related health outcomes. MEDLINE, CINAHL and Cochrane Databases were searched for studies, published from 1999 to May 1, 2020, examining the effect of probiotics in conditions applicable to individuals infected with COVID-19, including, but not limited to, other forms of coronavirus, critical illness, and mechanical ventilation. The databases search identified 1,925 unique articles, 77 full-text articles were reviewed, and 48 studies were included in this scoping review, including 31 primary studies and 17 systematic reviews. Primary studies examined a range of interventions that varied by probiotic diversity and types, including eight studies which focused on synbiotics, which include both pre- and probiotics. Several systematic reviews examined the effect of probiotics on ventilator-associated pneumonia and other infections. While most systematic reviews concluded probiotics may improve these outcomes, most systematic review authors concluded that the evidence was low in quality and high in heterogeneity. In the absence of direct evidence with COVID-19 infected patients, studies in comparable populations are currently the best resource to guide probiotics interventions in conjunction with clinical expertise and multidisciplinary healthcare planning.

As the COVID-19 pandemic unfolds, dietitians are moving quickly to determine best 25 methods for preventing and treating the effects of COVID-19 infection. 1 Probiotics are living 26 microorganisms that are consumed or applied for health benefits, 2 and have been suggested as a 27 potential intervention to improve outcomes in patients infected with COVID-19. Probiotics may 28 be delivered with in the form of a symbiotic, which also includes prebiotics to stimulate the 29 growth or activity of probiotic microorganisms. 2 Specific to COVID-19, probiotics have been 30 suggested as a possible method of: addressing the "cytokine storm" and inflammation caused by The research question was formulated using the Population-Concept-Context approach. 15 57 A full description of the eligibility criteria can be found in Table 1 . Studies were included if they 58 included adults with conditions that were applicable to individuals with COVID-19 infection, 59 including but not limited to, adults with other forms of coronavirus, ARDS, critical illness, 60 and/or on mechanical ventilation. Use of probiotics to prevent viral infections, such as rhinovirus 61 or influenza, in healthy individuals were not included in this scoping review. The major concept 62 explored was the intervention of probiotics. Interventions with synbiotics, which contain both 63 pre-and probiotics, were included. Though the primary focus of this scoping review was to 64 report studies targeting individuals in the ICU, the context was left open to also include free-whether the intervention was delivered in the context of a synbiotic, and mode of delivery; 90 comparison treatment; and outcomes reported. Eligibility and data extraction were confirmed by 91 a second reviewer, with questions and discrepancies determined by consensus or a third 92 reviewer. As is customary for scoping reviews, eligibility criteria were clarified during the full-93 text review, and the authors determined that trauma, burn and acute pancreatitis were conditions 94 or infections not applicable to the COVID-19 population. The search and selection process was 95 documented on a PRISMA flowchart. 21 Results were synthesized narratively and were mapped 96 using a heat map, pie chart and bar graph. 

Of the 48 included articles, twenty-three articles [23] [24] [25] [26] 30, 31, 36, 37, 40, [43] [44] [45] [46] [47] 49, 50, 52, 53, 55, 58, 60, 64, 69 The most commonly reported outcomes were mortality, followed by development of RCTs with critically ill and mechanically ventilated patients, 28, 39, 41, 42, 49, 51, 59, 61, 62 eight of them 119 reported development of ventilator-associated pneumonia as an outcome. 28, 39, 41, 42, 49, 51, 59, 61 120 121

Of the 31 primary research studies included, sample sizes ranged from 15 to 259 123 participants and intervention durations ranged from two to 60 days. However, intervention 124 durations were often variable even within a study depending on how long the participant was in 125 the ICU or on mechanical ventilation. Eight of the included primary studies examined probiotics 126 in the context of synbiotics (pre-and probiotics combined). [59] [60] [61] [62] [63] [64] 67, 69 The number of probiotic 127 strains varied between studies, with 42% of studies intervening with one probiotic strain and 128 16% intervening with 7-10 probiotic strains (Figure 3) . The probiotic genus most frequently 129 utilized in interventions was lactobacillus (90.3% of interventions), followed by bifidobacterium 130 (32.2% of interventions) and streptococcus (19.4% of interventions) (Figure 4) ; several species 131 of these genera was included across study interventions. Interventions were delivered enterally 132 through a feeding tube due to the critical condition of nearly all participants in included studies, 133 except in two studies each in which probiotics were ingested orally 56,57 or applied topically. 48, 49 In four studies, authors indicated multiple routes of probiotics delivery. Patients were given Table 2 . In these systematic reviews, authors' conclusions are heterogeneous, 143 though there were no systematic reviews describing high-quality evidence examining the effect 144 of probiotics in the populations of interest. Most of the systematic reviews describe that 145 probiotics decreased incidence of VAP, 26-28,34-36 though other systematic reviews that specifically 146 focused on VAP incidence concluded no beneficial effect from probiotics. 22, 29, 32 Several authors 147 describe that intervention heterogeneity 22, 25, 26, 29, 32, 34, 36 and/or risk of bias [24] [25] [26] 29, 34, 36 were a 148 concern. While most systematic reviews did include an analysis of the risk of bias of included 149 studies, 22, [24] [25] [26] [28] [29] [30] [33] [34] [35] 37, 38 few reported on the certainty of evidence for outcomes. 30, 34 The conclusions describing the effect of probiotics on other outcomes. Authors concluded that 153 probiotics may decrease infections but had no effect on mortality. One systematic review focused 154 specifically on the outcome of adverse events and found no increased risk for critically ill 155 patients administered probiotics. 30

This scoping review elucidated that there was considerable research, including recent 159 systematic reviews, on the use of probiotics to treat ventilator-associated pneumonia in critically 160 ill patients on mechanical ventilation, which may be applicable to patients infected with COVID-161 19. There were also systematic reviews available describing the effect of probiotics on length of 

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and 

International Scientific Association for Probiotics and Prebiotics. How some probiotic scientists 444 are working to address COVID-19. https://isappscience.org/how-some-probiotic-and-prebiotic-445 scientists-are-working-to-address-covid-19/. Published 2020 . Updated May 4, 2020 

Academy of Nutrition and Dietetics. ANDHII Academy of Nutrition and Dietetics Health 453

Intervention and observational primary studies Systematic review and meta-analyses Narrative reviews, commentary, editorials, letters to the editorYear Range January 1999 to May 1, 2020Articles published before 1999 or after the search on May 1, 2020 Critical Illness "The present meta-analysis suggests that the administration of probiotics did not significantly reduce ICU or hospital mortality rates but did reduce the incidence of ICU-acquired pneumonia and ICU length of stay." Critical Illness "The use of pre-pro-or synbiotics in adult critically ill patients confers no statistically significant benefit [for nosocomial infections, length of ICU stay, hospital mortality and specifically pneumonia]. There is currently a lack of evidence to support the use of pre-pro-or synbiotics in patients admitted to adult ICUs, and a large well-designed trial is needed in this area."