Severe and recurrent infections of the respiratory tract in early childhood constitute major risk factors for the development of bronchial hyper-responsiveness and obstructive respiratory diseases in later life. In the first years of life, the vast majority of respiratory tract infections (RTI) leading to wheezing and asthma are of a viral origin and severity and recurrence are the consequence of a greater exposure to infectious agents in a period when the immune system is still relatively immature. Therefore, boosting the efficiency of the host immune response against viral infections seems to be a rational preventative approach. In the last decades it has been demonstrated that living in farm environments, i.e. early-life exposure to microbes, may reduce the risk of allergic and infectious disorders, increasing the immune response efficacy. These findings have suggested that treatment with bacterial lysates could promote a nonspecific immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. Experimental and clinical studies showing the reduction of RTI frequency and severity in childhood and elucidating the involved mechanisms can support this hypothesis.

Department of Pediatric Pulmonology and Allergy The Medical University of Warsaw Warsaw Poland

Department of Pediatrics Pulmonary and Allergy Disease Unit and Cystic Fibrosis Center G Gaslini University Hospital Largo G Gaslini 4 16148 Genoa Italy

Dept of Paediatrics 2nd Faculty of Medicine Charles University Prague Czech Republic

Division of Pediatric Pulmonology Miller School of Medicine University of Miami Miami FL USA

Medical Affairs Lead Infectious Diseases OM Pharma a Vifor Pharma Company Meyrin Geneva Switzerland

See more in PubMed

Griffin MR, Walker FJ, Iwane MK, Weinberg GA, Staat MA, Erdman DD. Epidemiology of respiratory infections in young children. Pediatr Infect Dis J. 2004;23:188–192. PubMed

Nair H, Simoes EA, Rudan I, Dherani M, Madhi SA, Singleton RJ, et al. Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis. Lancet. 2013;381:1380–1390. PubMed PMC

Brealey JC, Sly PD, Young PR, Chappell KJ. Viral bacterial co-infection of the respiratory tract during early childhood. FEMS Microbiol Lett. 2015 doi: 10.1093/femsle/fnv062. PubMed DOI

Tregoning JS, Schwarze J. Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology. Clin Microbiol Rev. 2010;23:74–98. PubMed PMC

Murphy T, Bakaletz L, Smeesters P. Microbial interactions in the respiratory tract. Pediatr Infect Dis J. 2009;28(Suppl 10):S121–S126. PubMed

Cohen R, Just J, Koskas M, Bingen E, Boucherat M, Bourrillon A, François P, et al. Recurrent respiratory tract infections: how should we investigate and treat. Arch Pediatr. 2005;12:183–190. PubMed

de Martino M, Ballotti S. The child with recurrent respiratory infections: normal or not? Pediatr Allergy Immunol. 2007;18(Suppl. 18):13–18. PubMed

Townsi N, Laing IA, Hall GL, Simpson SJ. The impact of respiratory viruses on lung health after preterm birth. Eur Clin Respir J. 2018;5:1487214. PubMed PMC

Martinez FD. The origins of asthma and chronic obstructive pulmonary disease in early life. Proc Am Thorac Soc. 2009;6:272–277. PubMed PMC

Brand PL, Caudri D, Eber E, Gaillard EA, Garcia-Marcos L, Hedlin G, et al. Classification and pharmacological treatment of preschool wheezing: changes since 2008. Eur Respir J. 2014;43:1172–1177. PubMed

Ruszczyński M, Ambrożej D, Adamiec A, Ruszczynski M, Elenius V, Cavkaytar O, et al. Management of preschool wheezing and asthma in children: systematic review of guidelines and quality appraisal with the Agree II Instrument. Pediatr Allergy Immunol. 2020;31:206–209. PubMed

Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354:1985–1997. PubMed

Fuchs O, Genuneit J, Latzin P, Büchele G, Horak E, Loss G, Sozanska B, et al. Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide. J Allergy Clin Immunol. 2012;130(382–8):e6. PubMed

Esposito S, Soto-Martinez ME, Feleszko W, Jones MH, Shen KL, Schaad UB. Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence. Curr Opin Allergy Clin Immunol. 2018;18:198–209. PubMed PMC

Le Souëf P. Viral infections in wheezing disorders. Eur Respir Rev. 2018;27:170133. PubMed PMC

Man WH, de Steenhuijsen Piters WA, Bogaert D. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat Rev Microbiol. 2017;15:259–270. PubMed PMC

Jackson DJ, Hartert TV, Martinez FD, Weiss ST, Fahy JV. Asthma, NHLBI Workshop on the primary prevention of chronic lung diseases. Ann Am Thorac Soc. 2014;11(Suppl 3):139–145. PubMed PMC

Jartti T, Gern JE. Role of viral infections in the development and exacerbation of asthma in children. J Allergy Clin Immunol. 2017;140:895–906. PubMed PMC

Jartti T, Smits HH, Bønnelykke K, Bircan O, Elenius V, Konradsen JR, et al. EAACI Task Force on Clinical Practice Recommendations on Preschool Wheeze.. Bronchiolitis needs a revisit: distinguishing between virus entities and their treatments. Allergy. 2019;74:40–52. PubMed PMC

Rossi GA, Colin AA. Infantile respiratory syncytial virus and human rhinovirus infections: respective role in inception and persistence of wheezing. Eur Respir J. 2015;45:774–789. PubMed

Makris Spyridon, Johnston Sebastian. Recent advances in understanding rhinovirus immunity. F1000Research. 2018;7:1537. PubMed PMC

Coverstone AM, Wang L, Sumino K. Beyond respiratory syncytial virus and rhinovirus in the pathogenesis and exacerbation of asthma: the role of metapneumovirus, bocavirus and influenza virus. Immunol Allergy Clin N Am. 2019;39:391–401. PubMed PMC

Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 infection in children [published online ahead of print, 2020 Mar 18] N Engl J Med. 2020 doi: 10.1056/nejmc2005073. PubMed DOI PMC

Yeganeh B, Xia C, Movassagh H, Koziol-White C, Chang Y, Al-Alwan L, et al. Emerging mediators of airway smooth muscle dysfunction in asthma. Pulm Pharmacol Ther. 2013;26:105–111. PubMed

Rossi GA, Colin AA. Respiratory syncytial virus-host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life. Pediatr Allergy Immunol. 2017;28:320–331. PubMed

Holt PG, Mok D, Panda D, Renn L, Fabozzi G, deKlerk NH, et al. Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development. J Allergy Clin Immunol. 2019;143:1176–1182. PubMed

Chiu C, Openshaw PJ. Antiviral B cell and T cell immunity in the lungs. Nat Immunol. 2015;16:18–26. PubMed PMC

Yoo JK, Kim TS, Hufford MM, Braciale TJ. Viral infection of the lung: host response and sequelae. J Allergy Clin Immunol. 2013;132:1263–1276. PubMed PMC

Wegrzyn AS, Jakiela B, Rückert B, Jutel M, Akdis M, Sanak M. T-cell regulation during viral and nonviral asthma exacerbations. J Allergy Clin Immunol. 2015;136:194–197. PubMed

Pociask DA, Scheller EV, Mandalapu S, McHugh KJ, Enelow RI, Fattman CL, et al. IL-22 is essential for lung epithelial repair following influenza infection. Am J Pathol. 2013;182:1286–1296. PubMed PMC

Bianco A, Sethi SK, Allen JT, Knight RA, Spiteri MA. Th2 cytokines exert a dominant influence on epithelial cell expression of the major group human rhinovirus receptor, ICAM-1. Eur Respir J. 1998;12:619–626. PubMed

Stenberg Hammar K, Niespodziana K, van Hage M, Kere J, Valenta R, Hedlin G, et al. Reduced CDHR3 expression in children wheezing with rhinovirus. Pediatr Allergy Immunol. 2018;29:200–206. PubMed

Bochkov YA, Gern JE. Rhinoviruses and their receptors: implications for allergic disease. Curr Allergy Asthma Rep. 2016;16:30. PubMed PMC

Thomas AO, Lemanske RF, Jr, Jackson DJ. Infections and their role in childhood asthma inception. Pediatr Allergy Immunol. 2014;25:122–128. PubMed PMC

Lan F, Zhang N, Gevaert E, Zhang L, Bachert C. Viruses and bacteria in Th2-biased allergic airway disease. Allergy. 2016;71:1381–1392. PubMed

Sly PD, Holt PG. Role of innate immunity in the development of allergy and asthma. Curr Opin Allergy Clin Immunol. 2011;11:127–131. PubMed

Renz H, Holt PG, Inouye MI, Logan AC, Prescott SL, Sly PD. An exposome perspective: early life events and immune development in a changing world. J Allergy Clin Immunol. 2017;140:24–40. PubMed

Gahr M, Schulze M, Scheffczyk D, Speer CP, Peters JH. Diminished release of lactoferrin from polymorphonuclear leukocytes of human neonates. Acta Haematol. 1987;77:90–94. PubMed

Basha S, Surendran N, Pichichero M. Immune responses in neonates. Expert Rev Clin Immunol. 2014;10:1171–1184. PubMed PMC

Sundström Y, Nilsson C, Lilja G, Kärre K, Troye-Blomberg M, Berg L. The expression of human natural killer cell receptors in early life. Scand J Immunol. 2007;66:335–344. PubMed

Remot A, Descamps D, Jouneau L, Laubreton D, Dubuquoy C, Bouet S, et al. Flt3 ligand improves the innate response to respiratory syncytial virus and limits lung disease upon RSV reexposure in neonate mice. Eur J Immunol. 2016;46:874–884. PubMed

Holt PG, Upham JW, Sly PD. Contemporaneous maturation of immunologic and respiratory functions during early childhood: implications for development of asthma prevention strategies. J Allergy Clin Immunol. 2005;116:16–24. PubMed

Langrish CL, Buddle JC, Thrasher AJ, Goldblatt D. Neonatal dendritic cells are intrinsically biased against Th-1 immune responses. Clin Exp Immunol. 2002;128:118–123. PubMed PMC

Tucci A, Mouzaki A, James H, Bonnefoy JY, Zubler RH. Are cord blood B cells functionally mature? Clin Exp Immunol. 1991;84:389–394. PubMed PMC

Diesner SC, Förster-Waldl E, Olivera A, Pollak A, Jensen-Jarolim E, Untersmayr E. Perspectives on immunomodulation early in life. Pediatr Allergy Immunol. 2012;23:210–223. PubMed

Bacchetta R, Gambineri E, Roncarolo MG. Role of regulatory T cells and FOXP3 in human diseases. J Allergy Clin Immunol. 2007;120:227–235. PubMed

Fulton RB, Meyerholz DK, Varga SM. Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. J Immunol. 2010;185:2382–2392. PubMed PMC

Christiaansen AF, Syed MA, Ten Eyck PP, Hartwig SM, Durairaj L, Kamath SS, et al. Altered Treg and cytokine responses in RSV-infected infants. Pediatr Res. 2016;80:702–709. PubMed PMC

Minnicozzi M, Sawyer RT, Fenton MJ. Innate immunity in allergic disease. Immunol Rev. 2011;242:106–127. PubMed

Martinez FD. Childhood asthma inception and progression: role of microbial exposures, susceptibility to viruses and early allergic sensitization. Immunol Allergy Clin N Am. 2019;39:141–150. PubMed PMC

Kunisawa J, Fukuyama S, Kiyono H. Mucosa-associated lymphoid tissues in the aerodigestive tract: their shared and divergent traits and their importance to the orchestration of the mucosal immune system. Curr Mol Med. 2005;5:557–572. PubMed

Jackson DJ, Gern JE, Lemanske RF., Jr Lessons learned from birth cohort studies conducted in diverse environments. J Allergy Clin Immunol. 2017;139:379–386. PubMed PMC

Stokholm J, Blaser MJ, Thorsen J, Rasmussen MA, Waage J, Vinding RK, et al. Maturation of the gut microbiome and risk of asthma in childhood. Nat Commun. 2018;9:141. PubMed PMC

Di Cicco M, Pistello M, Jacinto T, Ragazzo V, Piras M, Freer G, et al. Does lung microbiome play a causal or casual role in asthma? Pediatr Pulmonol. 2018;53:1340–1345. PubMed

Fouhy F, Guinane CM, Hussey R, Ryan CA, Dempsey EM, et al. High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Antimicrob Agents Chemother. 2012;56:5811–5820. PubMed PMC

Ni J, Friedman H, Boyd BC, McGurn A, Babinski P, Markossian T, et al. Early antibiotic exposure and development of asthma and allergic rhinitis in childhood. BMC Pediatr. 2019;19:225. PubMed PMC

Korpela K, Salonen A, Virta LJ, Kekkonen RA, Forslund K, Bork P, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun. 2016;7:10410. PubMed PMC

Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. Pharm Ther. 2015;40:277–283. PubMed PMC

Pavot V, Rochereau N, Genin C, Verrier B, Paul S. New insights in mucosal vaccine development. Vaccine. 2012;30:142. PubMed

Kearney SC, Dziekiewicz M, Feleszko W. Immunoregulatory and immunostimulatory responses of bacterial lysates in respiratory infections and asthma. Ann Allergy Asthma Immunol. 2015;114:364–369. PubMed

Cerutti A, Rescigno M. The biology of intestinal immunoglobulin A responses. Immunity. 2008;28:740–750. PubMed PMC

Parola C, Salogni L, Vaira X, Scutera S, Somma P, Salvi V, et al. Selective activation of human dendritic cells by OM-85 through a NF-kB and MAPK dependent pathway. PLoS ONE. 2013;8:e82867. PubMed PMC

Spisek R, Brazova J, Rozkova D, Zapletalova K, Sediva A, Bartunkova J. Maturation of dendritic cells by bacterial immunomodulators. Vaccine. 2004;22:2761–2768. PubMed

Planelles L, Thomas MC, Marañón C, Morell M, López MC. Differential CD86 and CD40 co-stimulatory molecules and cytokine expression pattern induced by Trypanosoma cruzi in APCs from resistant or susceptible mice. Clin Exp Immunol. 2003;131:41–47. PubMed PMC

Pasquali C, Salami O, Taneja M, Gollwitzer ES, Trompette A, Pattaroni C, et al. Enhanced mucosal antibody production and protection against respiratory infections following an orally administered bacterial extract. Front Med. 2014;1:41. PubMed PMC

Huber M, Mossmann H, Bessler WG. Th1-orientated immunological properties of the bacterial extract OM-85-BV. Eur J Med Res. 2005;10:209–217. PubMed

Bowman LM, Holt PG. Selective enhancement of systemic Th1 immunity in immunologically immature rats with an orally administered bacterial extract. Infect Immun. 2001;69:3719–3727. PubMed PMC

Sozzani S, D’Alessandro F, Capsoni F, Luini W, Barcellini W, Guidi G, et al. In vitro modulation of human monocytes functions by RU 41740. Int J Immunopharmacol. 1988;10:93–102. PubMed

Baladi S, Kantengwa S, Donati YR, Polla BS. Effects of the bacterial extract OM-85 on phagocyte functions and the stress response. Mediators Inflamm. 1994;3:143–148. PubMed PMC

Mauël J. Stimulation of immunoprotective mechanisms by OM-85 BV. A review of results from in vivo and in vitro studies. Respiration. 1994;61(Suppl 1):8–15. PubMed

Marchant A, Goldman M. OM-85 BV upregulates the expression of adhesion molecules on phagocytes through a CD 14-independent pathway. Int J Immunopharmacol. 1996;18:259–262. PubMed

Broug-Holub E, Persoons JH, Schornagel K, Kraal G. Changes in cytokine and nitric oxide secretion by rat alveolar macrophages after oral administration of bacterial extracts. Clin Exp Immunol. 1995;101:302–307. PubMed PMC

Ruedl C, Albini B, Böck G, Wick G, Wolf H. Oral administration of a bacterial immunomodulator enhances murine intestinal lamina propria and Peyer’s patch lymphocyte traffic to the lung: possible implications for infectious disease prophylaxis and therapy. Int Immunol. 1993;5:29–36. PubMed

Rouse BT, Sarangi PP, Suvas S. Regulatory T cells in virus infections. Immunol Rev. 2006;212:272–286. PubMed

Hawrylowicz Catherine M. Regulatory T cells and IL-10 in allergic inflammation. J Exp Med. 2005;202:1459–1463. PubMed PMC

Strickland DH, Judd S, Thomas JA, Larcombe AN, Sly PD, Holt PG. Boosting airway T-regulatory cells by gastrointestinal stimulation as a strategy for asthma control. Mucosal Immunol. 2011;4:43–52. PubMed

Jiang J, Wang Y, Tang X, Yao Y, Zhou J. Regulation of viral infection-induced airway remodeling cytokine production by the TLR3-EGFR signaling pathway in human bronchial epithelial cells. COPD. 2016;13:750–755. PubMed

Fu R, Li J, Zhong H, Zeng X, Deng M, Sun Y, et al. Broncho-Vaxom attenuates allergic airway inflammation by restoring GSK3b-related T regulatory cell insufficiency. PLoS ONE. 2014;9:e92912. PubMed PMC

Gao W, Li L, Wang Y, Zhang S, Adcock IM, Barnes PJ, et al. Bronchial epithelial cells: the key effector cells in the pathogenesis of chronic obstructive pulmonary disease? Respirology. 2015;20:722–729. PubMed

Roth M, Pasquali C, Stolz D, Tamm M. Broncho Vaxom (OM-85) modulates rhinovirus docking proteins on human airway epithelial cells via Erk1/2 mitogen activated protein kinase and cAMP. PLoS ONE. 2017;12:e0188010. PubMed PMC

Aloui R, Gormand F, Guibert B, Corallo F, Perrin Fayolle M, et al. RU 41740 (Biostim) stimulates the production of granulocyte macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro. Gen Pharmacol. 1996;27:1351–1353. PubMed

Rossi GA, Bessler W, Ballarini S, Pasquali C. Evidence that a primary anti-viral stimulation of the immune response by OM-85 reduces susceptibility to a secondary respiratory bacterial infection in mice. Ital J Pediatr. 2018;44:112. PubMed PMC

Liu C, Huang R, Yao R, Yang A. The immunotherapeutic role of bacterial lysates in a mouse model of asthma. Lung. 2017;195:563–569. PubMed

Navarro S, Cossalter G, Chiavaroli C, Kanda A, Fleury S, Lazzari A, et al. The oral administration of bacterial extracts prevents asthma via the recruitment of regulatory T cells to the airways. Mucosal Immunol. 2011;4:53–65. PubMed

Del-Rio-Navarro BE, Espinosa Rosales F, Flenady V, Sienra-Monge JJ. Immunostimulants for preventing respiratory tract infection in children. Cochrane Database Syst Rev. 2006;4:CD004974. PubMed

Steurer-Stey C, Lagler L, Straub DA, Steurer J, Bachmann LM. Oral purified bacterial extracts in acute respiratory tract infections in childhood: a systematic quantitative review. Eur J Pediatr. 2007;166:365–376. PubMed

Jurkiewicz D, Zielnik-Jurkiewicz B. Bacterial lysates in the prevention of respiratory tract infections. Otolaryngol Pol. 2018;72:1–8. PubMed

Yin J, Xu B, Zeng X, Shen K. Broncho-Vaxom in pediatric recurrent respiratory tract infections: a systematic review and meta-analysis. Int Immunopharmacol. 2018;54:198–209. PubMed

Rozy A, Chorostowska-Wynimko J. Bacterial immunostimulants-mechanism of action and clinical application in respiratory diseases. Pneumonol Alergol Pol. 2008;76:353–359. PubMed

Bonfils P. Prevention of infections of the respiratory tract in children with RU 41740. Presse Med. 1988;17:1450–1452. PubMed

Paupe J, Paupe G. Biostim prevention of recurrent respiratory infections in children. A double-blind versus placebo study. Ann Pediatr. 1986;33:843–845. PubMed

Rutishauser M, Pitzke P, Grevers G, van Aubel A, Elsasser U, Kämmereit A. Use of a polyvalent bacterial lysate in patients with recurrent respiratory tract infections: results of a prospective, placebo-controlled, randomized, double-blind study. Adv Ther. 1998;15:330–341. PubMed

Esposito S, Marchisio P, Prada E, Daleno C, Porretti L, Carsetti R, et al. Impact of a mixed bacterial lysate (OM-85 BV) on the immunogenicity, safety and tolerability of inactivated influenza vaccine in children with recurrent respiratory tract infection. Vaccine. 2014;32:2546–2552. PubMed

Razi CH, Harmancı K, Abacı A, Özdemir O, Hızlı S, Renda R, et al. The immunostimulant OM-85 BV prevents wheezing attacks in preschool children. J Allergy Clin Immunol. 2010;126:763–769. PubMed

Liao JY, Zhang T. Influence of OM-85 BV on hBD-1 and immunoglobulin in children with asthma and recurrent respiratory tract infection. Zhongguo Dang Dai Er Ke Za Zhi. 2014;16:508–512. PubMed

Lu Y, Li Y, Xu L, Xia M, Cao L. Bacterial lysate increases the percentage of natural killer T cells in peripheral blood and alleviates asthma in children. Pharmacology. 2015;95:139–144. PubMed

Han RF, Li HY, Wang JW, Cong XJ. Study on clinical effect and immunologic mechanism of infants capillary bronchitis secondary bronchial asthma treated with bacterial lysates Broncho-Vaxom. Eur Rev Med Pharmacol Sci. 2016;20:2151–2155. PubMed

Sly PD, Galbraith S, Islam Z, Holt B, Troy N, Holt PG. Primary prevention of severe lower respiratory illnesses in at-risk infants using the immunomodulator OM-85. J Allergy Clin Immunol. 2019;144:870–872. PubMed

ORal Bacterial EXtracts for the prevention of wheezing lower respiratory-tract illness (ORBEX) trial (NCT02148796).