Primary prevention of severe lower respiratory illnesses in at-risk infants using the immunomodulator OM-85
2019; Elsevier BV; Volume: 144; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2019.05.032
ISSN1097-6825
AutoresPeter D. Sly, Sally Galbraith, Mohammad Zahirul Islam, Barbara J. Holt, Niamh Troy, Patrick G. Holt,
Tópico(s)Respiratory and Cough-Related Research
ResumoSevere lower respiratory illnesses (sLRIs) during infancy (ie, those associated with fever [>38°C], wheeze, or both) increase the likelihood of subsequent asthma in at-risk subjects.1Jackson D.J. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. Pappas T.E. et al.Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.Am J Respir Crit Care Med. 2008; 178: 667-672Crossref PubMed Scopus (986) Google Scholar, 2Jackson D.J. Gern J.E. Lemanske R.F. The contributions of allergic sensitization and respiratory pathogens to asthma inception.J Allergy Clin Immunol. 2016; 137: 659-665Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 3Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 4Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (60) Google Scholar, 5Teo S.M. Mok D. Pham K. Kusel M. Serralha M. Troy N. et al.The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.Cell Host Microbe. 2015; 17: 704-715Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar Moreover, time to first sLRI after birth appears to be significantly reduced in children with persistent wheeze,5Teo S.M. Mok D. Pham K. Kusel M. Serralha M. Troy N. et al.The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.Cell Host Microbe. 2015; 17: 704-715Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar suggesting that early infancy might be a period of particularly high vulnerability to the "asthmatogenic" effects of these infections. Significant interest exists in primary prevention of asthma, and we have previously postulated that this might be achievable through protection against sLRIs during infancy.6Holt P.G. Sly P.D. Infections and atopy in asthma pathogenesis: the hygiene hypothesis and beyond.Nat Med. 2012; 18: 726-735Crossref PubMed Scopus (201) Google Scholar However, progress in testing this hypothesis has been limited by the availability of appropriate therapeutics approved for use in this age group. In this regard the immunomodulator OM-85 (Broncho-Vaxom; Vifor Pharma, St Gallen, Switzerland) has been used in Europe to prevent recurrent upper respiratory tract infections (URIs) in children7Schaad U.B. Mutterlein R. Goffin H. Immunostimulation with OM-85 in children with recurrent infections of the upper respiratory tract: a double-blind, placebo-controlled multicenter study.Chest. 2002; 122: 2042-2049Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar and to reduce the frequency and severity of wheeze episodes in asthmatic children.8Razi C.H. Harmanci K. Abaci A. Ozdemir O. Hizli S. Resida R. et al.The immunostimulant OM-85 BV prevents wheezing attacks in preschool children.J Allergy Clin Immunol. 2010; 126: 763-769Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar OM-85 is a lyophilized extract derived from a mixture of bacterial respiratory pathogens containing multiple Toll-like receptor–like ligands with a long history of safe use in children. However, it has not been tested previously in the specific context of sLRI prevention in at-risk infants. Accordingly, we conducted a randomized clinical trial (BV2012/15, ACTRN12612000518864) in which at-risk infants, by virtue of a parental history of asthma and allergies, were randomized to OM-85 (3.5 mg) or identical placebo for the first 10 days of April through August, 1 month before and during the months of the winter viral seasons in Brisbane, Australia. Infants were 3 to 9 months of age when recruited, treated for their first 2 winter seasons, and followed off treatment for a third year. The primary outcome variable was the frequency of sLRIs over the first 2 winters of the child's life (see the Methods section in this article's Online Repository at www.jacionline.org for clinical definitions). An a priori decision was taken to complete all secondary analyses for which data were available. All analyses were performed as intention-to-treat analyses. All children who received at least 1 dose of study treatment were included in the safety analyses. Because no previous study had used OM-85 in primary prevention of sLRIs, we used the data published by Razi et al,8Razi C.H. Harmanci K. Abaci A. Ozdemir O. Hizli S. Resida R. et al.The immunostimulant OM-85 BV prevents wheezing attacks in preschool children.J Allergy Clin Immunol. 2010; 126: 763-769Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar showing a 30% to 40% reduction in wheeze episodes (OM-85, 3.57 ± 1.61; placebo, 5.75 ± 2.71) in asthmatic children to determine sample size, which showed that 26 children per group would be required to produce 80% power (α = 0.05) to detect a 38% difference in sLRIs between the groups. Therefore we aimed to recruit 30 children per group. Those who withdrew or dropped out were not replaced, primarily because of resource limitations. Fifty-nine children aged 5.8 ± 1.9 months were recruited and randomized, 29 to OM-85 and 30 to placebo. There were no differences in demographic characteristics (see Table E1 in this article's Online Repository at www.jacionline.org). One child from each group withdrew before taking any study medication. Twenty-five children randomized to OM-85 had evaluable data at the end of the first winter, 24 had evaluable data at the end of the second winter, and 23 completed the study. More children in the placebo group were lost to follow-up. Evaluable data were available at the end of the first winter for 27 children and for 22 children at the end of the second winter, and 18 children finished the study. There was no significant difference in the frequency of sLRIs over the first 2 winters between the groups. Within the OM-85 group, 17 (70.8%) of 24 recorded 37 sLRIs (median, 1.0 [25% to 75%, 0.0-2.0]) and 14 (63.6%) of 22 recorded 47 sLRIs (median, 1.0 [25% to 75%, 0.0-4.0]) in the placebo group (P = .84, Mann-Whitney test). The time to the first sLRI was significantly longer for children receiving OM-85 than for those receiving placebo (median, 442.0 days [25% to 75%, >853.0-124.0 days] vs 85.0 days [25% to 75%, 386.0-54.0 days]; P = .006, Kaplan-Meier survival analysis with the Gehan-Breslow test; Fig 1, A). In this analysis children who did not experience an sLRI during the study were censored on the date when they left the study (withdrew or competed). Although there was a tendency for a reduction in the number of children who had any LRIs, the number of LRIs per child, and the time to first LRI, there were no statistically significant differences between groups (see the Methods section and Tables E2 and E3 in this article's Online Repository at www.jacionline.org). OM-85 appeared to be more effective at preventing sLRIs in the first winter. Fewer children in the OM-85 group had an sLRI than those in the placebo group (6/25 [24.0%] vs 14/27 [51.9%]; P = .05, Fisher exact test). Similarly, children receiving OM-85 had fewer sLRIs (7 infections; median, 0.0 [25% to 75%, 0.0-0.75]) than those in the placebo group (18 infections; median, 1.0 [25% to 75%, 0.0-1.0]), but this did not reach statistical significance (P = .052). For those children who did have sLRIs, there was no difference in duration for those in the active and control groups (10.3 days [25% to 75%, 8.3-25.8] vs 20.0 days [25% to 75%, 7.0-23.3 days], P = .61). There did not appear to be any carryover protection for the rest of the first year of the study once children stopped taking OM-85 (on OM-85, 6/25 [24.0%]; off OM-85, 11/25 [44.4%]; on placebo, 12/27 [44.4%]; and off placebo, 4/27 [14.8%]; P = .046, χ2 test). A similar pattern was seen for the number of sLRIs during the first study year (median: on OM-85, 0.00 [25% to 75%, 0.00-0.75]; off OM-85, 0.50 [25% to 75%, 0.00-1.00]; on placebo, 0.00 [25% to 75%, 0.00-1.00]; and off placebo, 0.00 [25% to 75%, 0.00-0.00], P = .062). By definition, sLRIs are LRIs accompanied by fever (febrile lower respiratory illnesses [fLRIs]) and/or wheezing (wheeze-associated LRIs). Examining the individual components showed similar effects of OM-85 at decreasing the number of fLRIs and wheezing LRIs and the proportion of children experiencing them. However, lack of study power for these secondary analyses meant that most comparisons did not reach statistical significance (see Tables E4 and E5 in this article's Online Repository at www.jacionline.org). Fewer children receiving OM-85 had a URI in the first winter season than in the placebo group (45.8% vs 88.5%, P = .002). The number of URIs was also lower in those receiving OM-85 than placebo (median, 0.00 [255 to 75%, 0.00-1.00] vs 2.00 [25% to 75%, 1.00-3.00]; P = .002). There was no difference in the time to first URI (41.3 [9.4] vs 50.7 [18.9] days, P = .69). The cumulative frequency of sLRIs was greater in the placebo group (total, 75; median, 1.00 [25% to 75%, 1.00-5.00]) than in those receiving OM-85 (total, 58; median, 2.00 [25% to 75%, 0.00-3.00]; Fig 1, B, and see Tables E6 and E7 in this article's Online Repository at www.jacionline.org; P < .001). Throughout the study period, children in the placebo group had more days of sLRIs (total, 838 days; median, 589 days [25% to 75%, 428-749 days]) than those randomized to OM-85 (total, 656 days; median, 439 days [25% to 75%, 212-545 days]; Fig 1, C, and see Tables E8 and E9 in this article's Online Repository at www.jacionline.org; P < .001), and these group differences were greatest in early infancy. Giving OM-85 to infants 3 to 9 months of age was safe and tolerable. Parents opened the capsule and dissolved the contents in a small amount of liquid (water, breast milk, or formula). The most commonly reported adverse events were gastrointestinal disorders, skin conditions, ear infections, and general disorders, with no significant differences between groups (see Table E10 in this article's Online Repository at www.jacionline.org). The study did not achieve its primary outcome, in that the overall frequency of sLRIs over the first 2 winters in children receiving OM-85 and those receiving placebo did not differ significantly. However, the time to first sLRI was significantly longer for those receiving OM-85 than those receiving placebo. This is encouraging because early sLRIs3Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 4Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (60) Google Scholar and in particular reduced time to first sLRI after birth5Teo S.M. Mok D. Pham K. Kusel M. Serralha M. Troy N. et al.The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.Cell Host Microbe. 2015; 17: 704-715Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar increases the risk of persistent asthma in at-risk children. Moreover, the cumulative frequency of sLRIs and the number of days with sLRI symptoms were also significantly lower in those receiving OM-85, suggesting a reduction in the overall inflammatory burden in the lower airways during this crucial period of early lung growth. We acknowledge that this proposed mechanism for OM-85 is speculative and requires mechanistic studies. In contrast, although there was a tendency for reduced overall LRI frequency in the group receiving OM-85, this did not reach statistical significance during any study period. The implication of these data is that OM-85 was more effective at preventing sLRIs than milder LRIs. The effects of OM-85 were strongest in the first winter season, with a trend for fewer children in the OM-85 group to have sLRIs and URIs. There was no evidence of a carryover protective effect after treatment had stopped in the first study year. This suggests that infants and young children might require treatment year round to maintain the early benefit of OM-85. This lack of a carryover effect differs from the findings of Razi et al.8Razi C.H. Harmanci K. Abaci A. Ozdemir O. Hizli S. Resida R. et al.The immunostimulant OM-85 BV prevents wheezing attacks in preschool children.J Allergy Clin Immunol. 2010; 126: 763-769Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar However, they studied older children but not infants, and the differences in the maturational stage of immune development between respective study populations might have an influence here. In this context we have recently shown that susceptibility to fLRIs in infancy is greatest in infants at the lower end of the innate immune development spectrum.6Holt P.G. Sly P.D. Infections and atopy in asthma pathogenesis: the hygiene hypothesis and beyond.Nat Med. 2012; 18: 726-735Crossref PubMed Scopus (201) Google Scholar Despite the study being underpowered, some important lessons have been learned. First, OM-85 appears to be safe and can be given to infants as young as 3 months of age. Second, OM-85 can be used for primary prevention of sLRIs in the high-vulnerability period of infancy but might not be effective in preventing milder LRIs. Third, the treatment regimen of giving OM-85 for the first 10 days of the winter months might not be adequate to provide sufficient protection to at-risk infants against sLRIs occurring while off treatment. In this regard animal studies9Scott N.M. Lauzon-Joset J.F. Jones A.C. Minchin K.T. Troy N.M. Leffler J. et al.Protection against maternal infection-associated fetal growth restriction: proof-of-concept with a microbial-derived immunomodulator.Mucosal Immunol. 2017; 10: 789-801Crossref Scopus (17) Google Scholar with OM-85 suggest that protection against viral respiratory tract infection is maximal if treatment is ongoing during the infection period. Further studies with greater power and possibly using alternative treatment regimens are warranted to determine whether OM-85 can prevent asthma in at-risk infants and young children. The distinctions between upper and lower respiratory tract infections were based on symptoms reported by parents on a diary card kept during symptomatic periods, as used in our previous studies.E1Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy & atopy are risk factors for persistent asthma & wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (85) Google Scholar Temperature was measured by the parents at home and recorded on the diary card. Fever was defined as a temperature of greater than 38°C. Upper respiratory symptoms include mild-to-moderate cough; sneezing; blocked or runny nose; and sore throat. Lower respiratory symptoms include moist or rattling cough, wheeze, or noisy breathing and breathlessness. Fever was used as part of the distinction between URIs and LRIs. sLRIs are LRIs were associated with fever, wheeze, or both.E1Kusel M.M. Kebadze T. Johnston S.L. Holt P.G. Sly P.D. Febrile respiratory illnesses in infancy & atopy are risk factors for persistent asthma & wheeze.Eur Respir J. 2012; 39: 876-882Crossref PubMed Scopus (85) Google Scholar, E2Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar There were no data in the literature on use of OM-85 for the primary prevention of sLRIs, especially in infants. Previous studies in children have demonstrated a reduction in the frequency of wheezing attacks in preschool-aged children, a reduction in respiratory tract infections in children with previous recurrent infections, and a reduction in recurrent otitis media in older children. Razi et alE3Razi C.H. Harmanci K. Abaci A. Ozdemir O. Hizli S. Resida R. et al.The immunostimulant OM-85 BV prevents wheezing attacks in preschool children.J Allergy Clin Immunol. 2010; 126: 763-769Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar demonstrated a group mean reduction of 30% to 40% in wheezing episodes in preschool children with intermittent treatment with OM-85 (OM-85: 3.57 ± 1.61 vs placebo: 5.75 ± 2.71). Using this reduction in cumulative wheezing frequency over 12 months (−2.18) and the SD of the placebo group (2.71), 26 children per group completing the trial will produce 80% power to detect a 38% difference in sLRI frequency between the groups. Thirty children per group (ie, 60 in total) will be recruited to allow for dropouts (12% to 15%). The following groups of participants were predefined for end point analysis:•Intention-to-treat sample: All participants were randomized and had evaluable data for the end point under investigation. Participants were analyzed in the group to which they were randomized, regardless of compliance with their allocated treatment. The number of participants who had evaluable data differed for each end point being investigated. Parametric or nonparametric tests were used depending on the data distribution.•Safety sample: All participants who took at least 1 dose of the investigational product were included in the safety analyses. All adverse events reported during the study were included. Frequencies and incidence rates were calculated on a per-patient basis. Comparisons of proportions between groups were undertaken by using Fisher exact or χ2 tests for multiple groups. Grouped data were tested for normality by using the Shapiro-Wilk test. Group comparisons were undertaken by using t tests, Mann-Whitney rank sum tests, Kruskal-Wallis 1-way ANOVA on ranks, or Friedman repeated-measures ANOVA on ranks, as appropriate. Analyses of time to first event were performed by using Kaplan-Meier survival analysis with the Gehan-Breslow test.Table E1Demographic characteristics of participants randomized to receive OM-85 or placeboOM-85 (n = 29)Placebo (n = 30)P valueAge at visit 1 (mo), mean ± SD5.8 ± 2.05.9 ± 1.9.68∗t Test.Sex (male/female)12/1717/13.30†Fisher exact test.Height at visit 1 (cm), mean ± SD66.1 ± 4.4166.6 ± 3.86.61∗t Test.Weight at visit 1 (kg), mean ± SD7.3 ± 1.527.7 ± 1.35.36∗t Test.Prior URI, no. (%)2 (6.8)4 (13.3).67†Fisher exact test.Prior LRI, no. (%)3 (10.3)3 (10.0)1.00†Fisher exact test.Prior sLRI, no. (%)2 (6.8)0.27†Fisher exact test.First-born child, no. (%)14 (48.3)19 (63.3).30†Fisher exact test.Tobacco smoke exposure, no. (%)4 (13.8)3 (10.0).71†Fisher exact test.Any pets, no. (%)19 (65.5)20 (66.7)1.00†Fisher exact test.Furry pets, no. (%)16 (55.2)19 (63.3).50†Fisher exact test.∗ t Test.† Fisher exact test. Open table in a new tab Table E2Proportion of children with any LRI during the study periodPeriodOM-85PlaceboP value∗Fisher exact test.First winter40.0% (10/25)53.4% (14/25).40First study year60.0% (15/25)69.2% (18/26).54Second winter45.8% (11/24)52.4% (11/21).77Second study year70.8% (17/24)62.9% (13/21).55Third winter39.1% (9/23)61.1% (11/18).22Third study year65.2% (15/23)77.8% (14/18).50Entire study period68.0% (17/25)62.1% (18/26)1.00Although there was a trend toward a longer time to first LRI in those receiving OM-85, this did not reach statistical significance (median: OM-85, 144.0 days [25% to 75%, 578.0-93.0 days] vs placebo, 87.0 days [25% to 75%, 420.0-54.0 days], P = .33).∗ Fisher exact test. Open table in a new tab Table E3Number of any LRIs during the study periodPeriodOM-85, no. of infections; group median (25% to 75%)Placebo, no. of infections; group median (25% to 75%)P value∗Mann-Whitney rank sum test.First winter14; 0.00 (0.00-1.00)20; 0.00 (0.00-1.25).29First study year26; 1.00 (0.00-1.50)32; 1.00 (0.00-2.00).54Second winter13; 0.00 (0.00-1.00)20; 1.00 (0.00-3.00).033Second study year29; 1.00 (0.00-2.00)39; 1.00 (0.00-3.00).56Third winter18; 0.00 (0.00-1.00)11; 0.50 (0.00-1.00).91Third study year34; 0.00 (0.00-3.00)26; 1.00 (0.75-2.00).53Entire study period89; 3.00 (1.50-5.00)97; 2.00 (1.00-6.00).57∗ Mann-Whitney rank sum test. Open table in a new tab Table E4fLRIs and wheeze-associated LRIs occurring in the first winterOM-85, no. of infections; group median (25% to 75%)Placebo, no. of infections; group median (25%-75%)P value∗Mann-Whitney test.fLRI5; 0.00 (0.00-0.00)9; 0.00 (0.00-1.00).31wLRI3; 0.00 (0.00-0.00)11; 0.00 (0.00-1.00).045wLRI, Wheeze-associated lower respiratory illness.∗ Mann-Whitney test. Open table in a new tab Table E5Number of fLRIs and wheeze-associated LRIs occurring during the first year of the study on and off study treatmentOn treatment, no. of infections; group median (25% to 75%)Off treatment, no. of infections; group median (25% to 75%)P value∗Kruskal-Wallis 1-way ANOVA on ranks.fLRI OM-854; 0.00 (0.00-0.00)7; 0.00 (0.00-0.00).37 Placebo6; 0.00 (0.00-0.25)3; 0.00 (0.00,0.00)wLRI OM-852; 0.00 (0.00-0.00)7; 0.00 (0.00-0.00).035 Placebo11; 0.00 (000-1.00)6; 0.00 (0.00-0.00)wLRI, Wheeze-associated lower respiratory illness.∗ Kruskal-Wallis 1-way ANOVA on ranks. Open table in a new tab Table E6Cumulative frequency of sLRIs: Placebo group individual and grouped dataIDDays on study0-9091-180181-270271-360361-450451-540541-630631-720721-810811-900>900211111111111300000000000611111111111711122333344911111111111122478101314141616161314000011112331820222222222222212233444445231112344445526000000000112711133333455300000000000032330000000001136011122222223700000001111391111111111141000233577774400000000000461111111111148000000000005112223444455521111111111154560000111111157023467781010105800000000011Sum1522263545535660667475Mean0.580.851.001.351.732.042.152.152.312.852.80SD0.640.971.471.772.222.843.043.043.193.633.65Median0.051.001.001.001.001.001.001.001.001.001.0025%0.000.000.000.000.000.000.000.000.001.001.0075%1.001.001.002.002.003.003.253.253.254.255.00 Open table in a new tab Table E7Cumulative frequency of sLRIs: OM-85 group individual and grouped dataIDDays on study0-9091-180181-270271-360361-450451-540541-630631-720721-810811-900901-990100001111144401112222333502233333444801111111333100112222222211000000000001501122222222161222222222217000000011121921240000000001125011112222332829000000000003100000002233341368101010101317173501122222222380000000000040000000000004200012222222430000000000045000011111134711223334444490000000000050000111111115355000000000005900000000000Sum314182633343438455558Mean0.120.560.721.041.321.361.361.361.522.202.30SD0.330.821.311.722.082.082.082.082.083.393.39Median0.00.0000.000.001.001.001.001.001.002.002.0025%0.000.000.000.000.000.000.000.000.000.000.0075%1.001.001.002.002.002.002.002.002.003.003.00 Open table in a new tab Table E8Cumulative days with sLRIs: OM-85 group individual and grouped dataIDDays on study0-9091-180181-270271-360361-450451-540541-630631-720721-810811-900>900100002121212121575740111117171729292950111129292929293838388011111119991002323525252525252525211000000000001506612121212121212121661313131313131313131317000000003131351921240000000009925070707070898989891121122829000000000003100000000141515341127487010610610610613114915535016162121212121212121380000000000040000000000004200014141414141414144300000000000450000131313131313274791623373737373744444449000000000005000014141414141414145355000000000005900000000000Sum26184212234404439439439545632656Mean1.07.48.413.416.217.617.617.621.825.326.2SD3.015.317.121.826.027.727.727.731.036.337.1Median0.000.000.000.001.0012.0012.0012.0013.0013.0014.0025%0.000.000.000.000.000.000.000.000.000.000.0075%0.0012.0012.0017.5021.0021.0021.0021.0031.0034.5036.30 Open table in a new tab Table E9Cumulative days with sLRIs: Placebo group individual and grouped dataIDDays on study0-9091-180181-270371-360361-450541-540541-630631-720721-810811-900>90022929292929292929292929362121212121212121213636746464656565656567171719212121212121212121212112156060606060606767676713140001212121260107114114182038383838414141414141412232828283535350062352424373737373743495026000000003662777777771317212130000000000003233000000000232336364343535353616161616137000000000003944444444444410000617545454545444000000000004600000000000480000000000051273838488787878787106106521111111111154560003333333357000011111115806727384108108114122122122Sum253362428487554589634666749826838Mean10.115.117.820.323.124.526.429.031.234.434.7SD14.518.822.023.627.730.131.033.132.438.738.6Median1.003.504.009.509.5014.5016.5021.0019.0022.0022.0025%0.000.000.000.000.000.000.000.000.000.251.0075%21.0028.7535.7537.7540.0040.0050.2556.0059.2559.2559.25 Open table in a new tab Table E10Adverse events in categoriesCategoryActive (n = 28)Control (n = 29)P valueEvents (no.)Subjects, no. (%)Events (no.)Subjects, no. (%)Skin and subcutaneous disorders (total)12319 (67.9)11714 (48.3).22 Eczema415 (17.9)374 (13.8).73 Diaper dermatitis131 (3.6)62 (6.9)1.00 Hand-foot-mouth disease107 (25.0)403 (10.3).18 Viral rash131 (3.6)001.00Injury, poisoning, and procedural complications (total)349 (32.1)159 (31.0)1.00Infection and infestation (total)288 (28.6)349 (31.0).77 Viral infection42 (7.1)133 (10.3)1.00Immune system disorders (total)187 (25.0)2510 (34.4).57 Hypersensitivity62 (7.1)84 (13.8).67 Urticaria67 (25.0)103 (10.3).18General disorders and administration-site conditions (total)28523 (82.1)24424 (82.8)1.00 Irritability81 (3.6)001.00 Pyrexia26924 (85.7)24423 (79.3)1.00Eye disorders (total)229 (32.1)3512 (41.4).59 Conjunctivitis218 (28.6)3512 (41.4).41Ear and labyrinth disorders (total)7213 (46.4)7916 (55.2).60 Ear infection428 (28.6)5812 (41.4).41 Otitis media102 (7.1)91 (3.4)1.00 Tympanic membrane perforation31 (3.36)72 (6.9)1.00Gastrointestinal disorders (total)13321 (75.0)14221 (72.4)1.00 Constipation51 (3.6)152 (6.9)1.00 Diarrhea102 (7.1)162 (6.9)1.00 Gastroenteritis00162 (6.9)1.00 Teething7814 (50.0)9013 (44.8).80 Vomiting416 (21.4)245 (17.2).75Note: Adverse events affecting less than 1% of participants have not been listed. Open table in a new tab Although there was a trend toward a longer time to first LRI in those receiving OM-85, this did not reach statistical significance (median: OM-85, 144.0 days [25% to 75%, 578.0-93.0 days] vs placebo, 87.0 days [25% to 75%, 420.0-54.0 days], P = .33). wLRI, Wheeze-associated lower respiratory illness. wLRI, Wheeze-associated lower respiratory illness. Note: Adverse events affecting less than 1% of participants have not been listed.
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