. 2021 Nov 8;13(1):167–192. doi: 10.1093/advances/nmab114

TABLE 1.

Effect of prebiotics 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 intervention on respiratory tract infections
Infants
Arslanoglu et al., 2007(Germany) (37)	RCT/II	+	Healthy term infants, gestational age 37–42 wk, n = 206	Infant formula supplemented with scGOS/lcFOS, 8 g/L	Infant formula supplemented with MDX, 8 g/L	6 mo	↓ number of subjects with ≥1 URTI³ episode
Arslanoglu et al., 2008(Germany) (6)	RCT/II	+	Healthy term infants with parental history of atopy,⁴ gestational age 37–42 wk, n = 134	Infant formula supplemented with scGOS/lcFOS, 8 g/L	Infant formula supplemented with MDX, 8 g/L	6 mo	↓ number of URTI³ episodes
							↔ number LRTI³ episodes
Bruzzese et al., 2009(Italy) (38)	RCT/II	+	Infants with birthweight >2500 g, gestational age 37–42 wk, n = 342	Infant formula supplemented with GOS/FOS, 4 g/L	Standard infant formula	12 mo	↔ number of subjects with ≥1 URTI⁵ episode
							↔ number of subjects with ≥1 LRTI³ episode
Moore et al., 2003(USA) (50)	RCT/II	+	Healthy term infants, 4–12 mo, n = 56	Infant cereal supplemented with FOS, 0.75 g/25 g serve (mean ± SD, 35 ± 22.5 g/d cereal intake)	Infant cereal supplemented with MDX, 0.75 g/25 g serve (mean ± SD, 35 ± 27.5g/d cereal intake)	4 wk	↔ number of subjects with ≥1 URTI⁶ episode
Niele et al., 2013(The Netherlands) (51)	RCT/II	+	Infants with gestational age <32 wk and/or birthweight <1500 g admitted to NICU, n = 94	Enteral supplementation with scGOS/lcFOS/pAOS, 1.5 g/kg (mean ± SD, 1.4 ± 0.4 kg birthweight)	Enteral supplementation with MDX, 1.5 g/kg (mean ± SD, 1.3 ± 0.3 kg birthweight)	6 mo	↔ number of subjects with ≥1 URTI⁷ episode
							↔ number of subjects with ≥1 LRTI⁸ episode
Paganini et al., 2017(Kenya) (78)	RCT/II	+	Infants, 6.5–9.5 mo, n = 96	GOS powder, 7.5 g	MDX powder, 7.5 g	4 mo	↓ number of subjects with ≥1 RTI³ episode
Puccio et al., 2017(Italy) (54)	RCT/II	+	Healthy infants with gestational age 37–42 wk and birthweight 2500–4500 g, ≤2 wk, n = 175	Infant formula containing 2′FL, 1 g/Llacto-N-neotetratose, 0.5 g/L (908 mL, mean formula intake)	Standard infant formula (929 mL, mean formula intake)	6 mo	↔ number of subjects with ≥1 LRTI³ episode
Ranucci et al., 2018(Italy) (56)	RCT/II	+	Infants with gestational age 37–42 wk and birthweight >2500 g, n = 222	Formula containing GOS/PDX, 4 g/L	Standard formula	48 wk	↔ number of subjects with ≥1 RTI³ episode
							↔ number of subjects with ≥1 LRTI³ episode
Sierra et al., 2015(Spain) (58)	RCT/II	+	Healthy term infants, <2 y, n = 264	Formula supplemented with GOS, 5 g/L	Standard formula	12 mo	↔ number of subjects with ≥3 URTI³ episode
							↔ total URTI³ episodes
Shahramian et al., 2018(Iran) (69)	RCT/II	Ø	Infants with gestational age 38–42 wk with birthweight >2500 g, n = 120	Formula supplemented with scGOS/lcFOS, n/a	Standard formula	12 mo	↓ total URTI⁹ episodes
Westerbeek et al., 2010(The Netherlands) (61)	RCT/II	+	Infants with gestational age <32 wk and birthweight <1500 g admitted to NICU, n = 113	Enteral preterm formula with scGOS/lcFOS/pAOS, max 1.5 g/kg (mean ± SD, 0.48 ± 0.31g/kg)	Enteral preterm formula with MDX, 1.5g/kg	27 d	↔ number of subjects with ≥1 LRTI¹⁰ episode
Children
Anaya-Loyola et al., 2020(Mexico) (76)	RCT/II	+	Children, 6–8 y, n = 65	Mango juice extract containing soluble dietary fiber, 285 mg	Flavored water	2 mo	↓ Patient reported URTI symptoms¹¹
Chatchatee et al. 2014(Multiple) (80)	RCT/II	Ø	Children attending daycare ≥2 d/wk, 11–29 mo, n = 767	GUM supplemented with scGOS/lcFOS, 12 g/L; Omega-3 lcPUFAs, 192 mg/L	GUM	12 mo	↓ number of subjects with ≥1 URTI¹² episode
Leung et al., 2020(Hong Kong) (71)	RCT/II	+	Healthy children of Chinese ethnicity, 1–2.5 y, n = 456	Control formula with added 100 mg Ig, 170 mg lactoferrin, 1.5 g TGF-β, 1.7 g milk fat, 281 mg linoleic acid, 300 mg 2′FL per 100 mL, 400 mL	Formula containing 2.7 g protein, 2.5 g fat (337 mg linoleic acid), 10 g carbohydrates (400 mg GOS) per 100 mL, 400 mL	6 mo	↔ URTI¹³ episodes
							↔ URTI¹³ duration
							↔ number of subjects with ≥1 URTI¹³ episode
				Control formula with added 300 mg 2′FL per 100 mL, 400 mL			↔ URTI¹³ episodes
							↑ URTI¹³ duration
							↔ number of subjects with ≥1 URTI¹³ episode
Li et al., 2014 (China) (9)	RCT/II	+	Children attending childcare for up to 3 mo, 3–4 y, n = 310	Follow-up formula PDX/GOS, 3.6 gB-glucan, 26.1 mg	Standard follow-up formula	28 wk	↓ number of subjects with ≥1 URTI¹⁴ episode
							↓ URTI¹⁴ duration
Lohner et al., 2018(Hungary) (46)	RCT/II	+	Children attending kindergarten, 3–7 y, n = 219	Inulin-type fructan, 6 g	MDX, 6 g	24 wk	↔ total URTI¹⁵ episodes
							↔ total LRTI¹⁶ episodes
Pontes et al., 2016(Brazil) (75)	RCT/II	Ø	Children attending childcare, 1–4 y,n = 97	Follow-up formula GOS, 1.8gβ-glucan, 26.1 mg	Standard follow-up formula	28 wk	↔ number of subjects with ≥1 RTI¹⁷ episode
Adults
Childs et al., 2014 (UK) (27)	RCT/II, x-over	+	Healthy adults, 25–65 y, n = 42	XOS powder, 8 g	MDX powder, 8 g	3 wk/arm 4 wk w/o	↔ number of subjects with ≥1 URTI⁷ episode
Choi et al., 2014 (Japan) (65)	RCT/II	+	Healthy individuals with WBC 4000–8000 cells/μL, 25–70 y, n = 77	RBEP capsule, 18 g	Corn starch capsule, 18 g	8 wk	↔ number of subjects with ≥1 URTI¹⁸ episode
Hughes et al., 2011(USA) (7)	RCT/II	+	Healthy full-time university students, ≥18 y, n = 419	GOS powder, 2.5 g or 5.0 g	Baker's sugar, 5 g	8 wk	↓ URTI¹⁷ duration¹⁹
Kitagawa et al., 2020(Japan) (70)	RCT/II	+	Volunteers with BMI between 23–30 kg/m², 20–65 y, n = 138	Tea beverage containing resistant MDX, 5 g	Control tea beverage	12 wk	↔ number of subjects with ≥1 episode of cold symptoms²⁰
Langkamp-Henken et al.,2004 (USA) (8)	RCT/II	+	Individuals in assisted- and independent-living facilities, ≥65 y, n = 34	Formula containing FOS, 4.41 g	Control formula	6 mo	↔ number of subjects with ≥1 URTI²¹ episode
							↓ URTI²¹ duration
Takahashi and Kozawa,2021 (Japan) (72)	RCS/III-2	+	Patients consuming food orally who were hospitalized in the convalescent rehabilitation ward, n = 492	PHGG, 5.2 g	Nonsupplemented	2 mo	↓ number of subjects with ≥1 influenza²² episode
			Patients consuming food orally who were hospitalized in the long-term care ward, n = 30				↓ number of subjects with ≥1 influenza²² episode

Abbreviations: 2′FL, 2′fucosyl lactose; FOS, fructooligosaccharide; GOS, galactooligosaccharide; GUM, growing up milk formulated milk drink; lc, long chain; LRTI, lower respiratory tract infection; MDX, maltodextrin; n/a, not available; NICU, neonatal intensive care unit; pAOS, pectin-derived acidic oligosaccharide; PDX, polydextrose; PHGG, partially hydrolyzed guar gum; RBEP, rice bran exo-polymer; RCS, retrospective cohort study; RCT, randomized controlled trial; RTI, respiratory tract infection; sc, short chain; TGF, transforming growth factor; URTI, upper respiratory tract infection; WBC, white blood cell count; w/o, washout; XOS, xylooligosaccharide; x-over, crossover study; Ø, neutral study quality; +, positive study quality; ↓ indicates decrease; ↑ indicates increase; ↔ indicates no change.

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

Doctor diagnosis.

⁴

Parental history of atopy includes: atopic eczema, allergic rhinitis, or asthma.

⁵

Doctor-diagnosed otitis, pharyngitis, laryngitis, tracheitis, and bronchitis were considered as URTIs.

⁶

Parent-reported adverse event.

⁷

URTIs included at least 1 doctor-diagnosed episode of severe rhinitis, pharyngitis, or otitis media.

⁸

LRTIs included at least 1 physician-diagnosed episode of bronchitis, bronchiolitis, or pneumonia.

⁹

Doctor-diagnosed in the presence of symptoms of common cold, wheezing, watery nose, cough, rhinitis, and pharyngitis.

¹⁰

Doctor-diagnosed pneumonia with a positive bacterial culture.

¹¹

Reduction in URTI symptoms of runny nose, crystalline mucus, itchy nose, itchy throat, sore nose, and sneezing. No change in congested nose, yellow mucus, bloody mucus, hoarseness, dry cough, and cough with phlegm.

¹²

Parent-reported diary of respiratory symptoms, including cough, fever, blocked or runny nose, sore throat, wheeze, and/or ear discharge.

¹³

Parent-reported episodes verified by investigators and nurses from study diary.

¹⁴

ARI was defined as upper respiratory infections, including common cold, pharyngitis, tonsillitis, otitis media, infectious sinusitis and rhinitis, and lower respiratory infections, including pneumonia, bronchiolitis, and bronchitis.

¹⁵

Acute URTIs included doctor-diagnosed common cold (rhinitis acuta, rhinosinusitis acuta), sinusitis maxillaris (acute bacterial sinusitis), pharyngitis acuta/tonsillitis acuta/tonsillopharyngitis acuta, croup (laryngotracheobronchitis/laryngotracheitis), and acute infectious laryngitis.

¹⁶

Acute LRTIs included doctor-diagnosed acute bronchitis/acute tracheobronchitis and pneumonia.

¹⁷

Acute respiratory infections comprised doctor-diagnosed URTIs, including common cold, pharyngitis, tonsillitis, otitis media, infectious sinusitis and rhinitis; and LRTIs, including pneumonia, bronchiolitis, and bronchitis.

¹⁸

Self-reported episodes of cold or flu-like symptoms.

¹⁹

Healthy weight (BMI, 18.5–24.9 kg/m²) group only.

²⁰

Cold symptoms included.

²¹

Self-reported symptoms of cough, running or congested nose, sore throat, stiffness or chills, fever, achiness, and headache. Combinations of 2 or more symptoms, including 1 or more of the first 3 listed symptoms, were defined as a day of URTI symptoms. A URTI episode was defined as symptoms lasting 2 or more consecutive days, while a new URTI was defined as an initial infection separated from a new URTI episode by 5 or more symptom-free days.

²²

Positive influenza test result using a rapid diagnostic kit.