{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:03:25Z","timestamp":1792206205190,"version":"4.4.0"},"reference-count":31,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Upper respiratory tract infections (URTIs) are prevalent in children, prompting frequent health care consultations, especially among those with fever. Probiotics show potential as an adjuvant treatment for URTIs, but evidence in children is limited.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To evaluate the efficacy of a probiotic mixture containing\n Bifidobacterium breve<\/jats:italic>\n M-16V,\n Bifidobacterium lactis<\/jats:italic>\n HN019, and\n Lactobacillus rhamnosus<\/jats:italic>\n HN001 in shortening fever duration among children with URTIs.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This randomized clinical trial was conducted between November 19, 2021, and June 20, 2023, at the pediatric emergency department of the Ca\u2019 Granda Ospedale Maggiore Policlinico in Milan, Italy. Patients between 28 days and 4 years of age with a fever (\u226538.5 \u00b0C) and URTI were eligible. Exclusion criteria included recent probiotic use, chronic autoimmune diseases, immunosuppressive treatment, and requirement for hospitalization. Randomization was computer generated and assigned participants to either the intervention (probiotics) or control (placebo) group. Participants, parents or caregivers, and investigators were masked to the group assignments. The primary analysis followed the intention-to-treat approach.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n \n The probiotic group received daily single dose of 0.5 mL probiotic mixture containing\n Bifidobacterium breve<\/jats:italic>\n M-16V,\n Bifidobacterium lactis<\/jats:italic>\n HN019, and\n Lactobacillus rhamnosus<\/jats:italic>\n HN001 for 14 days. The placebo group received daily single dose of 0.5 mL placebo for 14 days.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was fever duration, defined as the number of days between the first and the last days with fever.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of the 128 patients enrolled (69 males [54%]; mean [SD] age 2.5 [1.3] years), 65 (51%) were randomly assigned to receive placebo and 63 (49%) to receive probiotics. The median (IQR) fever duration was shorter in the probiotic group than the placebo group (median [IQR], 3 [2-4] days vs 5 [4-6] days; adjusted risk ratio, 0.64; 95% CI, 0.51-0.80). Few mild adverse events were reported and did not significantly differ between the probiotic and placebo groups, including constipation (6 [16%] and\u20096 [12%];\n P<\/jats:italic>\n \u2009=\u2009.80) and abdominal pain (3 [8%] and 2 [4%];\n P<\/jats:italic>\n \u2009=\u2009.65).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this randomized clinical trial, administering a probiotic mixture reduced fever duration by 2 days compared with placebo, with no meaningful safety concerns. The probiotic mixture under investigation could be an effective adjuvant for shortening fever duration in children with URTIs.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT06052540<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.0669","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T11:31:34Z","timestamp":1741951894000},"page":"e250669","source":"Crossref","is-referenced-by-count":23,"title":["Probiotics and Fever Duration in Children With Upper Respiratory Tract Infections"],"prefix":"10.1001","volume":"8","author":[{"given":"Silvia","family":"Bettocchi","sequence":"first","affiliation":[{"name":"Pediatric Unit, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Comotti","sequence":"additional","affiliation":[{"name":"Occupational Health Unit, Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Elli","sequence":"additional","affiliation":[{"name":"Company AAT\u2013Advanced Analytical Technologies Srl, Fiorenzuola d\u2019Arda, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"De Cosmi","sequence":"additional","affiliation":[{"name":"Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanit\u00e0, Rome, Italy"},{"name":"Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiana","family":"Berti","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Alberti","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Mazzocchi","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Rosazza","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Agostoni","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"},{"name":"Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregorio Paolo","family":"Milani","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"},{"name":"Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"issue":"5","key":"zoi250055r1","doi-asserted-by":"crossref","first-page":"431","DOI":"10.3920\/BM2020.0185","article-title":"Probiotics with vitamin C for the prevention of upper respiratory tract symptoms in children aged 3-10 years: randomised controlled trial.","volume":"12","author":"Garaiova","year":"2021","journal-title":"Benef Microbes"},{"issue":"1","key":"zoi250055r2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1517\/14712598.2015.980233","article-title":"Probiotics for the prevention of pediatric upper respiratory tract infections: a systematic review.","volume":"15","author":"Ozen","year":"2015","journal-title":"Expert Opin Biol Ther"},{"issue":"4","key":"zoi250055r3","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1179\/acb.2006.027","article-title":"Spectrum and frequency of illness presenting to a pediatric emergency department.","volume":"61","author":"Massin","year":"2006","journal-title":"Acta Clin Belg"},{"issue":"22","key":"zoi250055r4","first-page":"8034","article-title":"Oral probiotics influence oral and respiratory tract infections in pediatric population: a randomized double-blinded placebo-controlled pilot study.","volume":"22","author":"Campanella","year":"2018","journal-title":"Eur Rev Med Pharmacol Sci"},{"issue":"11","key":"zoi250055r5","doi-asserted-by":"crossref","first-page":"S188","DOI":"10.1097\/01.inf.0000144660.53024.64","article-title":"Epidemiology of respiratory infections in young children: insights from the new vaccine surveillance network.","volume":"23","author":"Griffin","year":"2004","journal-title":"Pediatr Infect Dis J"},{"issue":"4","key":"zoi250055r6","doi-asserted-by":"crossref","first-page":"642","DOI":"10.12669\/pjms.36.4.1420","article-title":"Outcome of upper respiratory tract infections in healthy children: antibiotic stewardship in treatment of acute upper respiratory tract infections.","volume":"36","author":"Khan","year":"2020","journal-title":"Pak J Med Sci"},{"key":"zoi250055r7","first-page":"241","article-title":"Infectious diseases of children.","author":"Musmar","year":"2016","journal-title":"Fam Med"},{"issue":"6","key":"zoi250055r8","doi-asserted-by":"crossref","first-page":"518","DOI":"10.3390\/antibiotics13060518","article-title":"Exploring the impact of antibiotics on fever recovery time and hospital stays in children with viral infections: insights from advanced data analysis.","volume":"13","author":"Al Qahtani","year":"2024","journal-title":"Antibiotics (Basel)"},{"issue":"5","key":"zoi250055r9","article-title":"Does the use of antipyretics prolong illness? A systematic review of the literature and meta-analysis on the effects of antipyretics in acute upper and lower respiratory tract infections.","volume":"53","author":"Nicolas","year":"2023","journal-title":"Infect Dis Now"},{"issue":"4","key":"zoi250055r10","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/coa.13335","article-title":"Immunity-targeted approaches to the management of chronic and recurrent upper respiratory tract disorders in children.","volume":"44","author":"Feleszko","year":"2019","journal-title":"Clin Otolaryngol"},{"issue":"2","key":"zoi250055r11","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1097\/MPG.0000000000003633","article-title":"Probiotics for the management of pediatric gastrointestinal disorders: position paper of the ESPGHAN special interest group on gut microbiota and modifications.","volume":"76","author":"Szajewska","year":"2023","journal-title":"J Pediatr Gastroenterol Nutr"},{"issue":"19","key":"zoi250055r12","doi-asserted-by":"crossref","first-page":"6076","DOI":"10.3390\/molecules26196076","article-title":"Probiotics regulate gut microbiota: an effective method to improve immunity.","volume":"26","author":"Wang","year":"2021","journal-title":"Molecules"},{"issue":"1","key":"zoi250055r13","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1186\/s12879-024-09259-3","article-title":"Role of probiotic as adjuvant in treating various infections: a systematic review and meta-analysis.","volume":"24","author":"Nelwan","year":"2024","journal-title":"BMC Infect Dis"},{"issue":"20","key":"zoi250055r14","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1001\/jama.2013.281053","article-title":"World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.","volume":"310","author":"World Medical Association","year":"2013","journal-title":"JAMA"},{"key":"zoi250055r15","doi-asserted-by":"crossref","first-page":"f7027","DOI":"10.1136\/bmj.f7027","article-title":"Duration of symptoms of respiratory tract infections in children: systematic review.","volume":"347","author":"Thompson","year":"2013","journal-title":"BMJ"},{"issue":"3","key":"zoi250055r16","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3920\/BM2019.0119","article-title":"The effect of probiotics on prevention of upper respiratory tract infections in the paediatric community - a systematic review.","volume":"11","author":"Emre","year":"2020","journal-title":"Benef Microbes"},{"issue":"3","key":"zoi250055r17","first-page":"222","article-title":"Use of a probiotic mixture containing Bifidobacterium animalis subsp. lactis BB-12 and Enterococcus faecium L3 as prophylaxis to reduce the incidence of acute gastroenteritis and upper respiratory tract infections in children.","volume":"73","author":"DI Pierro","year":"2021","journal-title":"Minerva Pediatr (Torino)"},{"issue":"7298","key":"zoi250055r18","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1136\/bmj.322.7298.1327","article-title":"Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial.","volume":"322","author":"Hatakka","year":"2001","journal-title":"BMJ"},{"issue":"1","key":"zoi250055r19","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3920\/BM2021.0065","article-title":"Lacticaseibacillus rhamnosus GG DSM 33156 effects on pathogen defence in the upper respiratory tract: a randomised, double-blind, placebo-controlled paediatric trial.","volume":"13","author":"Damholt","year":"2022","journal-title":"Benef Microbes"},{"issue":"7","key":"zoi250055r20","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1111\/all.15997","article-title":"A systematic review and meta-analysis on nutritional and dietary interventions for the treatment of acute respiratory infection in pediatric patients: an EAACI taskforce.","volume":"79","author":"Milani","year":"2024","journal-title":"Allergy"},{"issue":"2","key":"zoi250055r21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3920\/BM2020.0171","article-title":"Limosilactobacillus reuteri ATCC PTA 5289 and DSM 17938 as adjuvants to improve evolution of pharyngitis\/tonsillitis in children: randomised controlled trial.","volume":"12","author":"Maya-Barrios","year":"2021","journal-title":"Benef Microbes"},{"issue":"3","key":"zoi250055r22","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1007\/s00394-021-02689-8","article-title":"Probiotic Bifidobacterium lactis Probio-M8 treated and prevented acute RTI, reduced antibiotic use and hospital stay in hospitalized young children: a randomized, double-blind, placebo-controlled study.","volume":"61","author":"Mageswary","year":"2022","journal-title":"Eur J Nutr"},{"issue":"12","key":"zoi250055r23","first-page":"15029","article-title":"Synbiotic or Zinc supplementation in the treatment of children with bacterial pneumonia, a double-blinded randomized clinical trial.","volume":"9","author":"Binesh","year":"2021","journal-title":"Int J Pediatr"},{"issue":"8","key":"zoi250055r24","article-title":"Probiotics for preventing acute upper respiratory tract infections.","volume":"8","author":"Zhao","year":"2022","journal-title":"Cochrane Database Syst Rev"},{"key":"zoi250055r25","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ijid.2021.02.011","article-title":"The effect of probiotics on respiratory tract infection with special emphasis on COVID-19: systemic review 2010-20.","volume":"105","author":"Darbandi","year":"2021","journal-title":"Int J Infect Dis"},{"issue":"11","key":"zoi250055r26","doi-asserted-by":"crossref","first-page":"3386","DOI":"10.1007\/s10620-015-3769-7","article-title":"Administration of Bifidobacterium breve decreases the production of TNF-a in children with celiac disease.","volume":"60","author":"Klemenak","year":"2015","journal-title":"Dig Dis Sci"},{"issue":"6","key":"zoi250055r27","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1017\/S0007114518001861","article-title":"Effect of Bifidobacterium lactis HN019 on inflammatory markers and oxidative stress in subjects with and without the metabolic syndrome.","volume":"120","author":"Bernini","year":"2018","journal-title":"Br J Nutr"},{"key":"zoi250055r28","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.rvsc.2021.04.011","article-title":"Probiotics Lactobacillus rhamnosus GG ATCC53103 and Lactobacillus plantarum JL01 induce cytokine alterations by the production of TCDA, DHA, and succinic and palmitic acids, and enhance immunity of weaned piglets.","volume":"137","author":"Geng","year":"2021","journal-title":"Res Vet Sci"},{"issue":"1","key":"zoi250055r29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/jir.2020.0213","article-title":"Cytokines in febrile diseases.","volume":"41","author":"Lai","year":"2021","journal-title":"J Interferon Cytokine Res"},{"issue":"9","key":"zoi250055r30","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1001\/jamapediatrics.2022.1973","article-title":"Multispecies probiotic for the prevention of antibiotic-associated diarrhea in children: a randomized clinical trial.","volume":"176","author":"Lukasik","year":"2022","journal-title":"JAMA Pediatr"},{"issue":"6","key":"zoi250055r31","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1111\/apa.14270","article-title":"Guidance on the use of probiotics in clinical practice in children with selected clinical conditions and in specific vulnerable groups.","volume":"107","author":"Hojsak","year":"2018","journal-title":"Acta Paediatr"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2831509\/bettocchi_2025_oi_250055_1746030012.40078.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T11:01:17Z","timestamp":1746529277000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2831509"}},"subtitle":["A Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2025,3,14]]},"references-count":31,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3,3]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2025.0669","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,14]]}}}