TABLE 2.

Effect of synbiotics on respiratory tract infections in participants of all ages¹

Author, Year (Country)	Design/Level of evidence	Quality2	Participants, age, n	Intervention, daily dose	Control, daily dose	Duration	Effect of synbiotic on respiratory tract infections
Infants
Cohen et al., 2013(France) (40)	RCT/II	+	Healthy infants, 7–13 mo, n = 166	NAN 3 follow-up formula with:Probiotic—Streptococcus thermophiles, 1 × 107 CFU/g; S. salivarius, 2.5 × 107 CFU/g; Lactobacillus rhamnosus, 1 × 107 CFU/gPrebiotic - Inulin-like fructans, n/a	NAN 3 follow-up formula	12 mo	↔ number of subjects with ≥1 URTI3 episode
							↔ total LRTI4 episodes
Kukkonen et al., 2008(Finland) (12)	RCT/II	+	Infants at high risk of atopy, gestational age ≥37 wk, n = 939	Synbiotic capsule containing:Probiotic—L. rhamnosus, 9 × 109 CFU; Bifidobacterium breve, 9 × 109 CFU; Propionibacterium freudenreichii subsp. shermanii, 9 × 109 CFUPrebiotic—GOS, 0.8 g	Placebo capsule	6 mo	↔ number of subject with ≥1 RTI5 episode
Luoto et al., 2014(Finland) (48)	RCT/II	+	Infants with birthweight >1500 g, gestational age 32–36 wk, n = 47	Probiotic—L. rhamnosus, 1 × 109 CFU (d 1–30) then 2 × 109 CFU (d 31–60)Prebiotic—PDX/GOS, 0.6 g (d 1–30) then 1.2 g (d 31–60)	Cellulose/dextrose anhydrate	60 d	↓ number of children with >3 viral RTI6 episodes
Panigrahi et al., 2017(India) (67)	RCT/II	+	Infants with suspected sepsis or possible severe bacterial infection, gestational age ≥35 wk, n = 4556	Probiotic—Lactobacillus plantarum ATCC strain 202195, 1 × 109 CFUPrebiotic—FOS, 150 mg	MDX, 250 mg	60 d	↓ number of subjects with ≥1 LRTI7 requiring abx treatment
Picaud et al., 2010(France) (53)	RCT/II	+	Infants, 4–6 mo, n = 771	Synbiotic formula enriched with:Probiotic— Bifidobacterium longum 1 × 107 CFU/g; S. thermophilus 1 × 106 CFU/gPrebiotic—FOS, 28 mg/g(mean ± SD, 748 ± 180 mL prescribed formula)	Standard formula (mean ± SD, 752 ± 176 mL prescribed formula)	3 mo	↔ number of subjects with ≥1 URTI8 episode
							↔ number of subjects with ≥1 LRTI9 episode
Children
Ahanchian et al., 2016(Iran) (10)	RCT/II	Ø	Children with mild persistent asthma, 6–12 y, n = 72	Probiotic—Lactobacillus casei, L. rhamnosus, S. thermophiles, B. breve, Lactobacillus acidophilus, Bifidobacterium infantis, Lactobacillus bulgaricus, 1×109 CFU/capsulePrebiotic—FOS, n/a	Placebo capsule, n/a	8 wk	↓ total viral RTI10 episodes
Cazzola et al., 2010(Italy) (39)	RCT/II	+	Children, 3–7 y, n = 135	Probiotic—Lactobacillus helveticus, B. longum subsp. infantis, Bifidobacterium bifidum, 5 × 109 CFU/capsulePrebiotic—FOS, 750 mg	Placebo capsule, n/a	3 mo	↔ total RTI9 episodes
Fox et al., 2019 (Multiple) (44)	RCT/II	Ø	Children with a clinical history or suspicion of non-IgE-mediated CMA, >13 mo, n = 35	Formula containing:Probiotic—B. breve, 1.47 × 108 CFU/LPrebiotic - FOS/inulin, 6.3 g/L (0–6 mo, 500 mL; 6–8 mo, 450 mL; and >9 mo, 350 mL)	Control formula	8 wk	↔ number of subjects with ≥1 URTI11 episode
Gerasimov et al., 2016(Ukraine) (11)	RCT/II	+	Healthy children with household expressed symptoms of ARI, 3–12 y, n = 225	Probiotic—L. acidophilus, 5 × 109 CFU; Bifidobacterium lactis, 5 × 109 CFUPrebiotic—FOS powder, 50 mg	MDX powder, 1 g	2 wk	↔ number of subjects with ≥1 RTI12 episode
							↓ RTI12 duration
Gerasimov et al., 2010(Ukraine) (45)	RCT/II	+	Children with atopic dermatitis, 12–36 mo, n = 90	Probiotic—L. acidophilus 1 × 1010 CFU; B. lactis, 1 × 1010 CFUPrebiotic—FOS powder, 50 mg	MDX powder, 1g	8 wk	↔ number of subjects with ≥1 URTI9 episode
							↔ number of subjects with ≥1 LRTI9 episode
Ringel-Kulka et al., 2015(USA) (73)	RCT/II	+	Healthy children attending childcare ≥5 d/wk for >4 h, 12–48 mo, n = 149	Synbiotic yogurt drink containing:Probiotic - S. thermophiles, 1 × 108 CFU/g; L. bulgaricus, 1 × 108 CFU/g; B. lactis, 5 × 109 CFU/g (97 g/serve)Prebiotic — Inulin, 1g	Acidified, flavored milk drink	16 wk	↔ URTI13 duration
Sazawal et al., 2010(India) (68)	RCT/II	+	Children from permanent resident families, 1–3 y, n = 624	Milk powder fortified with:Probiotic—B. lactis, 1.9 × 109 CFUPrebiotic—Oligosaccharide, 2.4g	Unfortified milk powder	12 mo	↓ number of subjects with ≥1 severe LRTI14 episode
							↓ number of subjects with ≥1 pneumonia episode
Adults
Childs et al., 2014 (UK) (27)	RCT/II, x-over	+	Healthy adults, 25–70 y, n = 41	Probiotic—B. lactis, 1 × 109 CFUPrebiotic—XOS powder, 8 g	MDX powder, n/a	3 wk/arm4 wk w/o	↔ number of subjects with ≥1 URTI15 episode
Coman et al., 2017 (Italy) (41)	RCT/II	Ø	Healthy adults in an intense gym-training program, 20–45 y, n = 10	Fermented milk enriched with:Probiotic—L. rhamnosus, 1 × 109 CFU; L. paracasei, 1 × 109 CFUPrebiotic—Oat bran fiber, n/a	Fermented milk	28 d	↔ total URTI16 symptoms
Pregliasco et al., 2008(Italy) (13)Stage 1	RCT/II	+	Healthy adults with a lifestyle favoring the development of respiratory infection, ≥18 y, n = 219	Synbiotic powder containing:Probiotic—L. plantarum, 1 × 1010 CFU; L. rhamnosus, 1 × 1010 CFU; B. lactis, 1 × 1010 CFUPrebiotic—FOS, 3 g	MDX powder, 5 g	90 d	↓ URTI17 episodes
							↓ URTI17 severity
							↓ URTI17 duration
Pregliasco et al., 2008(Italy) (13)Stage 2	RCT/II	+	Healthy adults with a lifestyle favoring the development of respiratory infection, ≥18 y, n = 212	Synbiotic powder containing:Probiotic—L. plantarum, 1 × 1010 CFU; L. rhamnosus, 1 × 1010 CFU; B. lactis, 1 × 1010 CFUPrebiotic—FOS, 3 g; Lactoferrin, 0.3 g	MDX powder, 5 g	90 d	↓ URTI17 episodes
							↓ URTI17 severity
							↓ URTI17 duration
Pregliasco et al., 2008(Italy) (13)Stage 3	RCT/II	+	Healthy adults with a lifestyle favoring the development of respiratory infection, ≥18 y, n = 250	Synbiotic powder containing:Probiotic—L. plantarum, 5 × 109 CFU; L. rhamnosus, 5 × 109 CFU; B. lactis, 5 × 109 CFUPrebiotic—GOS, 2.5 g	MDX powder, 3.5 g	90 d	↓ URTI17 episodes
							↓ URTI17 severity
							↓ URTI17 duration

¹Abbreviations: abx, antibiotics; ARI, acute respiratory infection; ATCC, American Type Culture Collection; CMA, cow's milk allergy; FOS, fructooligosaccharide; GOS, galactooligosaccharide; LRTI, lower respiratory tract infection; MDX, maltodextrin; n/a, not available; PDX, polydextrose; RCT, randomized controlled trial; RTI, respiratory tract infection; URTI, upper respiratory tract infection; w/o, washout; XOS, xylooligosaccharide; x-over, crossover study; Ø, neutral study quality; +, positive study quality; ↓ indicates decrease; ↔ indicates no change.

²Methodological study quality was determined using the American Dietetic Association critical appraisal checklist.

³Doctor diagnosis of acute otitis media, common cold, pharyngitis, or sinusitis.

⁴Doctor diagnosis of bronchiolitis, bronchitis, pneumonia, or laryngitis.

⁵RTI requiring hospitalization.

⁶One or more parent-reported symptoms of fever, rhinitis, or cough along with nasal swab positive for viral RNA.

⁷Supported diagnosis by chest X-ray or strong auscultatory findings.

⁸Doctor diagnosis of URTIs including pharyngitis, laryngitis, and tracheitis.

⁹Diagnosis method not described.

¹⁰Doctor-diagnosed viral URTI, including acute nasopharyngitis or common cold.

¹¹Parent-reported symptoms of blocked nose, cough, and wheeze.

¹²Parent-reported Canadian Acute Respiratory Illness and Flu Scale symptoms.

¹³Doctor diagnosis of URTI.

¹⁴Defined as respiratory rate ≥50/min.

¹⁵Self-reported cold or flu-like symptoms.

¹⁶Wisconsin Upper Respiratory Symptom Survey (self-reported), where 0 indicates no symptoms, 3 indicates mild symptoms, 5 indicates moderate symptoms, and 7 indicates severe symptoms, including throat soreness, sneeze, blocked or runny nose, and cough.

¹⁷Self-reported symptoms of influenza-like illness, bronchitis, laryngitis, tracheitis, or common cold with a severity score where 1 indicates no symptoms; 2 indicates mild, non-persistent symptoms; 3 indicates mild, persistent symptoms; 4 indicates moderate symptoms; and 5 indicates severe symptoms.