Efficacy and safety of immunomodulators in pediatric age - Slideset by Professor Susanna Esposito
•Als PPTX, PDF herunterladen•
1 gefällt mir•642 views
«The first cause of recurrent infections in children is... childhood itself.» (J. Gary Wheeler) Is it possibe to treat and prevent recurrent respiratory infections (RTIs) in pediatric age? Some studies have shown that immunostimulants/immunomodulators can reduce and prevent RTIs in children. To learn more please visit www.waidid.org
Empfohlen
Weitere ähnliche Inhalte
Was ist angesagt?
Was ist angesagt? (20)
Ähnlich wie Efficacy and safety of immunomodulators in pediatric age - Slideset by Professor Susanna Esposito
Ähnlich wie Efficacy and safety of immunomodulators in pediatric age - Slideset by Professor Susanna Esposito (20)
Mehr von WAidid
Mehr von WAidid (20)
Kürzlich hochgeladen
Kürzlich hochgeladen (20)
Efficacy and safety of immunomodulators in pediatric age - Slideset by Professor Susanna Esposito
- 1. EFFICACY AND SAFETY OF IMMUNOMODULATORS IN PEDIATRIC AGE Susanna Esposito Pediatric Clinic & Pediatric Section Università degli Studi di Perugia Perugia
- 2. DEFINITION OF RECURENT RESPIRATORY TRACT INFECTIONS (RTIs) «THE FIRST CAUSE OF RECURRENT INFECTIONS IN CHILDREN IS...CHILDHOOD ITSELF»2 Absence of any pathological underlying condition that may justify that may justify the recurrence of infections1 1. Gruppo di studio di immunologia della società Italiana di pediatria. Le infezioni ricorrenti nel bambino: definizione ed approccio diagnostico. Riv Immunol Allergol Pediatrica 1988; 2: 127–34. 2. J. Gary Wheeler Evaluating the child with recurrent infections - includes patient information sheet. Nov 15, 1996.
- 3. Savitha MR, Nandeeshwara SB, Pradeep Kumar MJ, ul-Haque F, Raju CK. Modifiable risk factors for acute lower respiratory tract infections. Indian J Pediatr. 2007 May;74(5):477-82.
- 4. RISK FACTORS FOR RRTI IN 286 CHILDREN 3 TO 6 YEARS DE MARTINO M, GALLI L, VIERUCCI A. THE CHILD WITH RECURRENT RESPIRATORY INFECTIONS. IN: “PATHOGENESIS AND CONTROL OF VIRAL INFECTIONS”, RAVEN PRESS: NEW YORK 1989
- 5. EPIDEMIOLOGY AND ETIOLOGY OF RRTIs • RRTIs affect up to 25% of children aged <1 year and 18% of children aged 1-4 years in developed countries1 • Bacteria such as Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae and Streptococcus pyogenes may play a role3 • Viruses (mainly respiratory syncytial virus, rhinovirus and influenza viruses) are the main etiological agents of RRTIs2 1. Bellanti et al. Drugs 1997 2. Esposito et al. Eur J Clin Microbiol Infect Dis 2012 3. Purushothama V. Et al. Chapter 93. Infections of the Respiratory System. Medical Microbiology. 4th edition. Baron S, editor. Galveston (TX): University of Texas Medical Branch at Galveston; 1996.
- 6. 6 • Treatment limited role of antibiotics role of symptomatic measures • PREVENTION Firstly, based on risk factors Secondly, based on past history What can be done?
- 7. RRTIs
- 8. THE FIRST CAUSE OF RECURRENT RESPIRATORY INFECTIONS IN CHILDREN IS... CHILDHOOD ITSELF (J.G. Wheeler 1996)
- 9. New complexities in CD4+ T cell differentiation Z. Chen et al, Immunol Res, 2007
- 10. Dominguez-Bello MG et al. Gastroenterology 2011;140:1713–1719 Initial gut bacteria (founder species) depends upon delivery mode Vaginal delivery: -Lactobacillus, Prevotella spp -Vertical inheritance from mother C-section: Staphylococcus Corynebaterium Propionibacterium spp -Higher susceptibility to certain pathogens -Higher risk of atopic disease New strains (less certain in origin) outcompete old ones -Rapid increase in diversity -Early microbiota in development=high instability -Shifts in response to diet, illness -Highly distinct, differentiate microbiota -Microbial community may continue to change, but at a slower rate than in childhood Substantially different gut communities than in younger adults
- 11. De Martino, Pediatr Allergy Immunol 2007:18: 3 Infezioni virali Immunodeficit transitorio secondario Aumentata suscettibilità Fattori di rischio OMA CAP 2 settimane
- 12. SGCC small group child care LGCC large group child care
- 13. Suckling on a pacifier increases the reflux of nasopharyngeal secretions into the middle ear Changes in the dental structure can cause dysfunction of the Eustachian Tube
- 14. EFFECTIVENESS FOR INFLUENZA VACCINATED AND UNVACCINATED CHILDREN WITH RECURRENT RESPIRATORY TRACT INFECTIONS STUDY CHILDREN VACCINATED (N=64) CONTROLS (N=63) P VALUE NO. OF URTI 1.68 + 1.62 4.52 + 2.43 <0.0001 NO. OF LRTI 0.68 + 0.88 1.24 + 1.32 0.0042 NO. OF FEBRILE RESPIRATORY ILLNESSES 1.59 + 1.49 3.87 + 2.74 <0.0001 NO. OF HOSPITALIZATIONS 0.05 + 0.23 0.10 + 0.25 0.417 NO. OF ANTIBIOTIC PRESCRIPTIONS 1.32 + 1.28 2.35 + 1.59 <0.0001 NO. OF ANTIPYRETIC PRESCRIPTIONS 2.21 + 2.03 3.98 + 2.37 <0.0001 MISSED SCHOOL DAYS 3.10 + 6.23 13.83 + 12.50 <0.0001 Esposito S et al., Vaccine 2003.
- 15. 0.000.250.500.751.00 0 30 60 90 120 150 180 Time (days after randomisation) Controls Treated with vitamin D complicated with othorrea AOM episodes 0.000.250.500.751.00 0 30 60 90 120 150 180Time (days after randomisation) Controls Treated with vitamin D 0.000.250.500.751.00 0 30 60 90 120 150 180 Time (days after randomisation) Controls Treated with vitamin D uncomplicated AOM episodes Efficacy of vitamin D3 1,000 U/day in children 1 – 5 yrs with a history of rAOM ALL episodes Marchisio P et al. PIDJ 2013
- 16. THE FIRST CAUSE OF RECURRENT RESPIRATORY INFECTIONS IN CHILDREN IS... CHILDHOOD ITSELF (J.G. Wheeler 1996) WAIT : lets age do its job REDUCTION OF RISK FACTORS USE OF IMMUNOSTIMULANTS/ IMMUNOMODULANTS
- 17. Cochrane Library 2011, issue 6
- 18. 18 Cochrane Review 2011 Immuno- stimulant n n analysis data Duration <6 months Duration 6 months Duration >6 months Quality A Quality B Quality C D53 18 11 7 11 – – 18 – IRS19 1 0 – 1 – – – 1 Lantigen B 2 0 – 2 – – 2 – LW50020 2 0 2 – – – 2 – OM-85 12 9 – 10 2 4 8 – RU41740 5 5 – 3 2 – 5 – Pidotimod 6 2 6 - - - 6 - Herbal (echinacea / garlic) 4 2 2 1 1 2 2 - Thymic extract 5 3 4 - 1 - 5 - Levamisole 4 3 2 2 - - 4 - Synthetic interferon 1 0 1 - - - 1 - Total 61 35 24 31 6 6 54 1 Del-Rio-Navarro BE et al, Evid-Bas Child Health (Cochrane Review) 2012 (6):5-12
- 19. 19 -100 -50 0 50 Study or Subgroup Mean difference (IV, Random, 95% CI) Favours OM-85 Favours placebo 100 Ahrens, 1984 Del-Rio-Navarro, 2003 Gutiérrez-Barreto, 1998 Gómez-Barreto, 1998 Jara-Pérez, 2000 Maestroni, 1984 Schaad, 1986 Schaad, 2002 Zagar, 1988 Total (95% CI) Percentage difference and 95% CI between OM-85 and placebo OM-85 reduce total number of ARTIs in children by 35.9% -35.9% reduction [95% CI: –49.5%, 22.4%] Del-Rio-Navarro et al. Cochrane Database Syst Rev 2012
- 20. 20 OM-85 in children with recurrence of upper RTIs* Schaad UB et al. Chest 2002 Upper RTI was defined as the presence of at least 2 of the following: • rhinitis, pharyngitis, cough, hoarseness, temperature ≥38.5°C or upper RTI-related prescription of antibiotic
- 21. 21 • Double-blind, randomised, placebo-controlled trial • 220 patients with recurrent upper RTIs* (aged 3–6 years) – prone to infections • Study duration: 6 months • Primary endpoint: incidence of upper RTIs • Other endpoints: symptoms, other infections, prescribed medication, school absence, subjective assessment of efficacy, safety • Dosage regimen: OM-85 (3.5mg) or placebo, 1 capsule/day Study design * Upper RRTI: ≥3 episodes of URTIs in the last 12 months. URTI: rhinitis, pharyngitis, cough, hoarseness, temperature ≥38.5°C or upper RTI-related prescription of an antibiotic. Schaad UB et al. Chest 2002
- 22. 22 Significant reduction in cumulative mean rate (-0.40; -16%) of upper RTIs was seen in patients receiving OM-85 vs placebo Cumulativemeanrate Time (months) 1 632 OM-85 (n=118) Placebo (n=99) 54 3 2 1 0 p<0.05 OM-85 reduces cumulative mean rate of upper RTIs in children Schaad UB et al. Chest 2002
- 23. 23 Higher the risk, higher the benefit This beneficial effect is proportional to the number of RTIs in the previous 12 months and is larger in younger children a a= data not shownSchaad UB et al. World J Pediatr 2010;6(1):5-12
- 24. 24 OM-85 effects on type and incidence of RTIs* over 12 months Gutiérrez-Tarango MD et al. Chest 2001 * Both upper RTIs (URTIs) and lower RTIs (LRTIs)
- 25. 25 • Double-blind, randomised, placebo-controlled trial • 54 children with recurrent acute RTIs* (aged 1–12 years) living in metropolitan polluted area of Mexico • Study duration: 1 year • Primary endpoints: incidence of acute RTIs • Other endpoints: type of RTI, school absenteeism, antibiotic/other therapy, safety • Dosage regimen: OM-85 (3.5mg) or placebo, 1 capsule/day Study design *RRTIs: ≥ 3 in the previous 6 months; of note: mean ARTIs rate in the previous year: 12 Gutiérrez-Tarango MD et al. Chest 2001
- 26. 26 %ofpatientswith<6RTI Time (months) 40 20 0 126 60 100 OM-85 Placebo 3 9 80 p<0.001 Higher % of patients with <6 ARTI in 12-month period with OM-85 • Higher percentage of patients with no recurrence • RR for ≥6 ARTIs : 0.37 in favor of OM-85 (95% CI, 0.20-0.68) Gutiérrez-Tarango MD et al. Chest 2001
- 27. 27 Meanno.ofAbcourses Antibiotic courses Drug courses (including antibiotics) p<0.001 p<0.001 12 8 4 0 OM-85 Placebo Significant reduction in antibiotic consumption in OM-85 group • Mean 2.46 courses in OM-85 vs 4.46 in placebo (p<0.001) • Total duration of acute RTIs was significantly lower in OM-85 (median 30.5 vs 55.0; p<0.01) Gutiérrez-Tarango MD et al. Chest 2001
- 28. 28 Prevention of acute otitis media in children Gutiérrez-Tarango MD et al. Chest 2001 Jara-Perez JV and Berber A, Clinical Therapeutics, 2000, 22, 6, 748-759 -68% p<0.001 0 5 10 15 20 25 30 Jara Perez Gutierrez Placebo OM-85p< 0.01 -75% Over 6 months Over 12 months TotalnumberofAOM
- 29. 29 OM-85 in recurrence of acute tonsillitis in children Bitar MA et al. Int J Pediatr Otorhinolaryngol 2013;77:670-673
- 30. 30 • A retrospective 5-year observational study • From 1 Jan 2006 – 31 Dec 2010 • 177 children with recurrent acute tonsillitis (≥3 episodes previous year) - aged 1–15 yrs • Typical dosing regimen: OM-85, 1 capsule (3.5mg) /day • Study duration: 3 months of treatment plus up to 45 months of follow-up (median 9 months) • Primary outcome: response to therapy after 3 months (reduction in tonsillitis - >50% or ≤ compared to same period previous year) • Secondary long-term outcome for responders: no tonsillectomy (<3 RTIs/year) Study design Bitar MA et al. Int J Pediatr Otorhinolaryngol 2013;77:670-673
- 31. 31 75.6 51.2 24.4 24.4 Any response (99/131) Total response (67/131) Partial response (32/131) No response (32/131) Percentageofpatients(%) 100 0 20 40 60 80 Total response: >50% decrease in acute tonsillitis episodes at the end of treatment (3 months) Partial response: ≤50% OM-85 reduced the frequency of acute tonsillitis in children 75,6% patients responders Bitar MA et al. Int J Pediatr Otorhinolaryngol 2013;77:670-673 No tonsillectomy required Median 9 months up to 45 months Only 11% patients required tonsillectomy
- 32. OM-85 in children with wheezing Razi C et al. J Allergy Clin Immunol 2010;126:763-9
- 33. 33 Study design • Randomized, double-blind, placebo-controlled, parallel-group study • 75 children (aged 1–6 years) with recurrent wheezing (≥3 in 6 months) • Duration of study: 1 year • Primary endpoint: number of wheezing attacks • Other endpoints: acute RTI incidence, acute nasopharyngitis incidence, wheezing attacks duration, hospitalization rate, safety • Dosage regimen: OM-85 (3.5mg) or placebo, 1 capsule/day Razi C et al. J Allergy Clin Immunol 2010;126:763-9
- 34. 34 Cumulativenumberof wheezingattacksperpatient 37.9% p<0.001 36% p=0.001 34.3% p=0.003 30.4% p=0.013 6 4 2 0 3 6 9 12 OM-85 Placebo Months after start of study OM-85 prevented wheezing attacks in pre-school children The cumulative difference in wheezing attacks between the 2 groups was 2.18 wheezing attacks per patient in 12 months; there was a 37.9% reduction in the group given OM-85 compared with the group given placebo (P < 0.001)
- 35. 35 OM-85 reduced the number of RTIs 0 3 6 9 12 31.4% p<0.001 29.4% p<0.001 27.9% p<0.001 21.6% p=0.009 8 6 4 2 0 OM-85 Placebo Cumulativenumberof RTIsperpatient Months after start of study The main difference in RTIs between the 2 groups was 2.5 per patient in 12 months (7.8 vs 5.3); there was a 31.4% cumulative reduction in the group given OM-85 compared with the group given placebo (p< 0.001)
- 36. 36 OM-85 reduced the number of nasopharyngitis 37.5% p<0.001 35.5% p<0.001 32.9% p<0.001 26.4% p=0.032 0 3 6 9 12 8 6 4 2 0 Cumulativenumberof nasopharyngitiscasesperpatient OM-85 Placebo Months after start of study The main difference in nasopharyngitis between the 2 groups was 2.11 per patient in 12 months (5.62 vs to 3.51); there was a cumulative 37.5% reduction in the group given OM-85 compared with the group given placebo (p < 0.001)
- 37. 37 OM-85 in prevention of RTIs* in combination with IIV • Assess the immune response towards a combined prevention (IIV and OM-85) and IIV only • Evaluate efficacy and tolerability of combined preventative strategies Esposito S et al. Vaccine 2014;32:2546-2552 *Both URTIs and LRTIs
- 38. 38 Study design • Prospective randomized single blind study (1 October 2012 and 31 March 2013) • 68 children included (36-59 months) • ≥6 practitioner-attended episodes in 1 years • At least 1 previous IIV • Single-blind: the patients and their parents were asked not to mention the treatment assignment to their pediatricians Esposito S et al. Vaccine 2014;32:2546-2552
- 39. 39 Higher reduction in RTIs and Ab use in OM-85 and IIV group Significant reduction versus IIV only arm: • number of patients with ≥ URTI* (-35%) • number of patients with ≥ LRTI* (-67%) • mean number of antibiotics courses (-72%) • mean number of days lost from school (-52%) Esposito S et al. Vaccine 2014;32:2546-2552
- 40. 40 Humoral and cellular immune response to IIV was not affected • No between-group differences in the humoral (antibodies against each of the three influenza strains) and cellular (dendritic and memory B cells in peripheral blood) immune responses • Low dose of administration compared to that used in the mouse model • Measurement in blood (i.e. BAL measurements more relevant but limited in young children) Administration of IIV about 15 days after the start of the first course of OM-85 does not affect humoral or cell- mediated immunity to the vaccine Esposito S et al. Vaccine 2014;32:2546-2552
- 41. 41 OM-85 administered with flu vaccine was well tolerated in the short-term Esposito S et al. Vaccine 2014;32:2546-2552
- 42. 42 Signal detection and pharmacovigilance • 35 years of marketing experience • > 79 million patients treated, including 34 million children since 1996 • Mean 3.6 million treated patients/year worldwide Well-tolerated therapy with known and manageable risks Data on file – PSUR 2015
- 43. 43 Cost effectiveness of OM-85 in RRTIs prevention in children • URTI are mainly viral but secondary bacterial infections are frequent • ARTI: acute respiratory infections defined as bacterial infections – Otitis media, bacterial sinusitis, tonsillitis, bronchitis/pneumonia • Cost-Consequence Analysis (CCA) – Assess costs and effectiveness of therapeutic choices (including prophylaxis with OM-85) – Perspectives: 1. patient 2. Health System 3. Society – in Italy Ravasio R. Global & Regional Health Technology Assessment 2015 ; 0 (0): 00--00I: 10.5301/GRHTA.5000200
- 44. 44 Main assumptions • Number of ARTI with OM-85: – -35.9% versus PB (Cochrane) • Probability of 1 ARTI in children is: – 31% in not treated (Zaniolo) – 19.9 % in OM-85 (based on -35.9%, Cochrane) • Probability of 1 URTI (that is not ARTIs): – 69% in not treated [(100-31)%] – 80.1% in OM-85 [(100-19.9)%] • Mean 2,4 RTIs in OM-85 and 3,6 in case of no prophylaxis – -1,20 [95% CI -1,75 – -0,66]) in 6 months (Cochrane) Ravasio R. Global & Regional Health Technology Assessment 2015 ; 0 (0): 00--00I: 10.5301/GRHTA.5000200
- 45. 45 Results on costs based on therapeutic options and probabilities € 0.00 € 100.00 € 200.00 € 300.00 € 400.00 € 500.00 € 600.00 € 700.00 Community NHS Patient OM-85 Placebo Difference: €182.99 (-31.4%) Cost Stakeholder Difference: €40.30 (-43.0%) Difference: €7.73 (+20.6%) Ravasio R. Global & Regional Health Technology Assessment 2015 ; 0 (0): 00—00 DOI: 10.5301/GRHTA.5000200 • Cost of OM-85 for one cycle: Euro 20.99 Euro • This is largely compensated by the societal cost saving • Saving for HCS will be sufficient to cover also OM-85 price +1.29 €/month OM-85 is cost effective for Society… and for HCS
- 46. 46 Curr Opin Allergol Clin Immunol 2018
- 47. 47 Esposito S et al., unpublished data A Randomized, Placebo-Controlled, Double-Blinded, Single Centre, Phase IV trial to assess the efficacy and safety of OM-85 in children with RRTIs - I • Phase IV, randomized (3:3:1), double-blind, placebo- controlled, single-centre trial • Population of otherwise healthy children 1-6 yrs old with a history of RRTIs • Treatment administered per os as either 3.5 mg OM-85 (active, n=100) or placebo (n=109), once a day for the first 10 days of the first 3 months of the 6-month study or once a day for the first 10 days of the 6-months (n=37)
- 48. 48 Esposito S et al., unpublished data A Randomized, Placebo-Controlled, Double-Blinded, Single Centre, Phase IV trial to assess the efficacy and safety of OM-85 in children with RRTIs - II • Reduction of 33% in ARTIs • Reduction of 21% of AOM • Reduction of 25% of antibiotic prescriptions • Decrease of 22% of the days of absence from day-care • Decrease of 18% of the working days lost by parents • No difference in efficacy between 3 vs 6 months of treatment • Good safety profile in the treated population
- 49. 49 Esposito S et al., unpublished data REtrospective controlled study of Broncho-Vaxom® (OM-85) use in PEdiatric patients with recurrent Respiratory Tract Infections - I • Phase IV, retrospective, controlled study in pediatric patients 1-6 yrs old receiving (n=203), or not receiving (n=201) preventive treatment with OM-85 for the management of RRTIs during the study period • Treatment received for at least 2 consecutive years • The aim was to review and describe the effectiveness and safety of OM-85 in children in the prevention of RRTIs
- 50. 50 Esposito S et al., unpublished data REtrospective controlled study of Broncho-Vaxom® (OM-85) use in PEdiatric patients with recurrent Respiratory Tract Infections - II • Reduction of 28% of RTIs • Reduction of 24% URTIs • Reduction of 21% of antibiotic prescriptions • Reduction of 31% of outpatient medical visits (visits to ERs or to a physician/health care provider) • Good safety profile in the treated population • No difference between the impact in year 1 and year 2
- 51. 5151 Concept of the "ideal" time window with the largest absolute efficacy of OM-85 in pediatric RTIs
Hinweis der Redaktion
- L’impossibilità a contenere completamente i fattori di rischio fa perpetuare il processo, con innesco di nuove infezioni virali che conducono ad un immunodeficit transitorio secondario, con può perdurare per 2- 4 settimane. In questo periodo è inevitabile la possibilità di nuove infezioni. Il ciclo continua
- The primary outcome examined in the Cochrane review conducted by Del-Rio-Navarro et al was the number of acute RTIs experienced during the study period1. Studies of bacterial extracts, including OM-85, were included in the Cochrane review together with synthetic immunostimulants, thymic extracts and plant extracts. A total of 61 placebo-controlled randomised trials were included in the review, of which 40 investigated bacterial extracts and 12 were studies of OM-85. The overall quality of the studies included in the meta-analysis was deemed poor. Of 40 studies of bacterial extracts, only 4 were of sufficient standard to be graded ‘A’ according to Cochrane criteria. All 4 of the ‘A’ graded studies of bacterial immunostimulants2–5 were clinical trials of OM-85; 2 studies of herbal remedies (echinacea) were also graded ‘A’. The following domains were assessed when rating the quality of the studies: random sequence generation; allocation concealment; blinding design; blinding of participants and personnel; blinding of outcome assessment; data completeness; selective reporting. References Del-Rio-Navarro BE et al. Immunostimulants to prevent acute respiratory tract infections in children. Cochrane Database Syst Rev 2006; 18: CD004974/ Del-Rio-Navarro BE et al, Evid-Bas Child Health (Cochrane Review) 2012 (6):5-12 Collet JP et al. Stimulation of nonspecific immunity to reduce the risk of recurrent infections in children attending day-care centers. The Epicreche Research Group. Ped Infect Dis J 1993; 12: 648–52. Del-Rio-Navarro BE et al. Use of OM-85 in children suffering from recurrent respiratory tract infections. Allergologia et Immunopathologia 2003; 31: 7–13. Gutiérrez-Tarango MD et al. Safety and efficacy of two courses of OM-85 in the prevention of respiratory tract infections in children during 12 months. Chest 2001; 119: 1742–8. Jara-Pèrez JV et al. Primary prevention of acute respiratory tract infections in children using a bacterial immunostimulant: a double-masked, placebo-controlled clinical trial. Clin Ther 2000; 22: 748–59.
- Across the 9 studies, there was a significant reduction in total number of acute RTIs with OM-85 vs placebo of –1.20 (95% CI: –1.75, –0.66). This translates to a percentage reduction of –35.9% (95% CI: –49.5%, –22.4%). References Del-Rio-Navarro BE et al. Immunostimulants to prevent acute respiratory tract infections in children. Cochrane Database Syst Rev 2006; 18: CD004974. Del-Rio-Navarro BE et al, Evid-Bas Child Health (Cochrane Review) 2012 (6):5-12
- No notes for this slide
- This study, which was published by Schaad et al in Chest in 2002, was conducted at multiple centres in Switzerland (10) and Germany (30) in paediatric patients with recurrent upper RTIs who had presented at hospital with an upper RTI. Patients received study treatment (3.5 mg OM-85 or placebo) every day for 1 month, then no treatment for 1 month. They then received study treatment on each of the first 10 consecutive days of Months 3, 4 and 5. Primary endpoint: rate of upper RTIs during treatment and over the study period. Upper RTI was defined as the presence of at least 2 of the following: rhinitis, pharyngitis, cough, hoarseness, temperature ≥38.5°C or upper RTI-related prescription of an antibiotic. Other endpoints: symptoms (rhinitis, pharyngitis, cough and hoarseness) were graded as none, mild or severe; fever was coded based on temperature (0= <38.5°; 1=38.5°-39.4°; 2= ≥39.5°); school absence was reported as number of days; other infections comprised otitis, sinusitis or other related infections; prescribed medication included use of antibiotics, antiseptics, anti-inflammatories, antitussives or mucolytic agents; subjective assessments were determined by investigators and parent/guardian on a scale of -3 (marked worsening) to +3 (marked improvement); safety was assessed throughout, including at regular and intermittent visits. Reference Schaad UB et al. Immunostimulation with OM-85 in children with recurrent infections of the upper respiratory tract. Chest 2002; 122: 2042–9.
- OM-85 significantly (p<0.05 by ANOVA) decreased the cumulative rate of upper RTIs in children over 6 months. OM-85 significantly reduced the incidence of upper RTI over 6 months by 16% vs placebo. A greater effect of OM-85 vs placebo was observed in those with a greater number of recurrent upper RTIs at baseline: 22% reduction in upper RTI incidence at Month 4 for those with ≥3 recurrent upper RTIs at baseline 22% reduction in cumulative upper RTI rate over 6 months for those with 6−15 recurrent upper RTIs at baseline (exploratory analysis). Reference Schaad UB et al. Immunostimulation with OM-85 in children with recurrent infections of the upper respiratory tract. Chest 2002; 122: 2042–9.
- The highest benefit was observed in children at highest risk (more infectious episodes in the previous year). Thus our recommendation to use the product in the overall children population in case of 6 RTIs per year.
- No notes for this slide
- This study, which was published by Gutierrez-Tarango et al in Chest in 2001, was conducted in Chihuahua City, Mexico. The aim was to investigate the efficacy of OM-85 in reducing the recurrence of RTIs in children ≤12 years of age. All of the children who participated in the study had a history of three acute RTIs in the six months prior to study start. They also all lived in an environment of high outdoor air pollution, an important contributing factor to vulnerability to RTIs1, particularly in the developing world. Study treatment (OM-85 or placebo, once daily) was given according to the 10-10-10 dosing regimen (1 capsule per day for each of 10 consecutive days) in the first 3 months of the study, then again in months 7, 8 and 92. Primary endpoint: type and incidence of acute RTI with OM-85 compared with placebo. Upper acute RTI was defined as ≥1 of: rhinorrhea, or sore throat/cough without signs of lower acute RTI for ≥2 days. Lower acute RTI was defined as ≥1 of: rales or crepitations, wheezing, stridor, respiratory rate >50/min, cyanosis or chest indrawing for ≥2 days. Otitis was defined as acute onset of earache with erythema. Other endpoints: absenteeism was defined as days out of school due to acute RTI. Antibiotic therapy was recorded as the number and duration of treatments, other therapies comprised a drug course that included antibiotics. Safety was assessed throughout. References Cohen AJ et al. The global burden of disease due to outdoor air pollution. J Toxicol Environ Health 2005; 68: 1301–7. Gutiérrez-Tarango MD et al. Safety and efficacy of two courses of OM-85 in the prevention of respiratory tract infections in children during 12 months. Chest 2001; 119: 1742–8.
- At 12 months, the majority of patients receiving OM-85 had experienced <6 acute RTIs whereas most patients receiving placebo had experienced 6 or more acute RTIs. The difference was significant (p<0.001) indicating OM-85 exhibited a marked effect in reducing the frequency of acute RTIs. In a separate analysis, OM-85 therapy was associated with a significantly lower risk of patients experiencing ≥6, ≥7 or ≥8 acute RTIs vs placebo. Reference Gutiérrez-Tarango MD et al. Safety and efficacy of two courses of OM-85 in the prevention of respiratory tract infections in children during 12 months. Chest 2001; 119: 1742–8.
- Other endpoints that were examined in this study included number of antibiotic courses, total courses of drug treatment, total duration of illness and of treatment, and school or daycare absenteeism. As shown in the figure, a significant reduction in the number of antibiotic courses and in total drug courses was seen among the children who received OM-85 over the 12 months of study. The mean number of antibiotic courses was reduced to 2.5 in the OM-85 versus 4.5 in the placebo group, and the mean number of drug courses was 5.0 in the OM-85 versus 8.0 in the placebo group. Mean total duration of illness in the OM-85 group (35 days) was just over half that observed among children receiving placebo (61 days) and represented a significant reduction (p<0.001). The data for mean total duration of drug treatment were similar and a significant treatment difference was also seen. A numerical reduction in RTI-associated school or daycare absenteeism was observed in the OM-85 group (mean 3.6 days vs 5.8 days in the placebo group); however, this treatment difference did not reach the threshold of statistical significance. Reference Gutiérrez-Tarango MD et al. Safety and efficacy of two courses of OM-85 in the prevention of respiratory tract infections in children during 12 months. Chest 2001; 119: 1742–8.
- Bitar and colleagues, in a study published in 20131, were the first to investigate the efficacy of OM-85 in preventing recurrent acute tonsillitis. Occasional bouts of tonsillitis in childhood are very common and in most cases resolved without treatment or with a single course of antibiotics2. In a minority of patients, frequent recurrent episodes has a severe impact on quality of life and schooling3. Historically, surgery has often been indicated for patients so affected, but tonsillectomy is associated with considerable morbidity, risk and cost4. Hence, a preventive approach that could help reduce the number of patients requiring surgery could be of great interest in the management of patients suffering from recurrent tonsillitis. Based upon the findings of Bitar et al, the use of OM-85 shows promise in this patient population1. References Bitar MA et al. The role of OM-85 (OM-85) in preventing recurrent acute tonsillitis in children. Int J Pediatr Otorhinolaryngol 2013; 77: 670–3. Del Mar CB et al. Antibiotics for sore throat. Cochrane Database Syst Rev 2006; 4: CD000023. Georgalas CC et al. Tonsillitis. Clin Evid 2009; Oct 26: 0503. Baugh RF et al. Clinical practice guideline: tonsillectomy in children. Otolaryngol Head Neck Surg 2011; 144: S1–30.
- This cohort study was conducted over 4 years in Beirut, Lebanon. The study population comprised children aged 1 to 15 years presenting to the clinic with a diagnosis of recurrent acute tonsillitis (defined as a history of ≥3 episodes in the year prior to study start). Treatment comprised OM-85, tonsillectomy or antibiotics. OM-85 therapy was given according to the 10-10-10 dosing regimen over 3 months. Primary endpoint: response to therapy was assessed in terms of change in frequency of acute tonsillitis episodes over 3 months. Other endpoints: baseline demographic and laboratory variables were assessed in bivariate and multivariate analyses to identify factors associated with response to OM-85 therapy. Reference Bitar MA et al. The role of OM-85 (OM-85) in preventing recurrent acute tonsillitis in children. Int J Pediatr Otorhinolaryngol 2013; 77: 670–3.
- Patients who experienced a decrease in tonsillitis episodes of >50% were classed as total responders; those who experienced a decrease of ≤50% as partial responders; all others were classed as no response. In total responders, long-term outcome of recurrent infection (≥3 times/year) necessitating tonsillectomy was also assessed. Of a total of 177 participating children, 131 (74%) received OM-85. Of the 131 children who received OM-85, 99 (76%) showed a decrease in the frequency of acute tonsillitis episodes 6 months after start of treatment. The majority of responders were total responders so, overall, 51% of the patients who received OM-85 had a decrease of more than 50% in the frequency of their tonsillitis episodes. Of the 51% of patients achieving total response, none required tonsillectomy in the subsequent long-term follow-up period. Reference Bitar MA et al. The role of OM-85 (OM-85) in preventing recurrent acute tonsillitis in children. Int J Pediatr Otorhinolaryngol 2013; 77: 670–3.
- This study was conducted in Ankara, Turkey, in a population of children with recurrent wheezing induced by respiratory tract illness (≥3 events in prior 6 months). Study treatment (OM-85 BV or placebo, once daily) was given according to the registered 10-10-10 dosing regimen in the first 3 months of the study. Primary endpoint: number of acute wheezing attacks, defined as episodes of progressively increasing shortness of breath, cough, wheezing, chest retraction or tightness (or any combination thereof) lasting for >6 hours in the presence of a normal chest x-ray. Other endpoints: number of acute RTIs, defined as presence of diagnostic symptoms (acute nasopharyngitis, sinusitis, acute otitis, tonsillitis, viral croup or pneumonia) for >48 hours; number of acute nasopharyngitis events; duration of wheezing attack from diagnosis to assessment of clinical cure by investigator; number/duration of hospitalisations. Safety was recorded throughout. As with most clinical studies of OM-85 BV, double-blind treatment was administered according to the registered 10-10-10 dosing regimen. Reference Razi et al. The immunostimulant OM-85 BV prevents wheezing attacks in preschool children. J Allergy Clin Immunol 2010; 126: 763-769.
- Benefit on wheezing attacks in children with more the 6 episodes of respiratory infections in the previous year There was a significant difference in the cumulative number of wheezing attacks from 0−6, 0−9 and 0−12 months for OM-85 vs placebo. The difference at 0−3 months cannot be considered significant because the p-value (p=0.013) exceeded the significance threshold (p=0.0125) required to account for multiplicity of testing (Bonferroni correction). Over the 12-month period, the mean number of wheezing attacks was 2.18 events lower in the OM-85 arm (3.57 events) vs the placebo arm (5.75 events). In regression analysis, the difference between OM-85 and placebo was independent of age, wheezing attacks in the prior year, sex, atopy, history of allergy and history of smoking at home; adding acute RTIs and acute nasopharyngitis into the model showed that reduction in wheezing attacks was significantly associated with reduction in acute RTIs. Reference Razi et al. The immunostimulant OM-85 prevents wheezing attacks in preschool children. J Allergy Clin Immunol 2010; 126: 763-769.
- This correlated with the reduction in URTIs mainly rhinopharingitis. A reduction in overall number of acute RTIs was observed that paralleled the difference between the treatment groups for the primary outcome; it is likely that these effects are correlated, as a majority of acute RTIs are, like the wheezing attacks, caused by viruses rather than bacteria. The 31% decrease in cumulative number of RTIs in patients receiving OM-85 compared with placebo after 12 months is equivalent to a reduction of 2.5 episodes per patient per year. Significant treatment effects were observed at all timepoints. Reference Razi et al. The immunostimulant OM-85 prevents wheezing attacks in preschool children. J Allergy Clin Immunol 2010; 126: 763-769.
- There was a significant difference in the cumulative number of nasopharyngitis cases. A 37.5% decrease in cumulative number of acute nasopharyngitis (a viral infection most commonly caused by rhinoviruses) in patients receiving OM-85 compared with placebo after 12 months. The main causative agents of wheezing attacks are viruses, rather than bacteria. These findings, which show that OM-85 safely and effectively reduces wheezing attacks in children1, indicate that OM-85 is effective in enhancing the immune response to viral, as well as bacterial, infections. OM-85’s mode of action, stimulating the innate immune system, means that it has a broad effect that goes beyond the bacteria from which the lysate is produced. This study shows that the broad-ranging efficacy suggested by OM-85’s mode of action2,3 is reflected in clinical data. References Razi et al. The immunostimulant OM-85 prevents wheezing attacks in preschool children. J Allergy Clin Immunol 2010; 126: 763-769. Bessler WG, et al. The bacterial extract Broncho-Vaxom protects against respiratory infections – in vivo and in vitro studies. Microbial pathogens and strategies for combating them: science, technology and education vol. 3 2013 (A. Méndez –Vilas, Ed.). Parola C et al. Selective activation of human dendritic cells by OM-85 through a NF-kB and MAPK dependent pathway PLoS One 2013; 8: e82867. doi: 10.1371/journal.pone.0082867.
- Although virosomal adjuvant preparations are effective for reducing influenza and RTIs as a whole, the immunogenicity and efficacy of conventional IIVs are not completely satisfactory in young children. • OM-85 is usually given in the beginning of autumn in children with recurrent RTIs. IIV is administered some weeks after the first course of OM-85. • According to previous mouse studies, the immune stimulation induced by OM-85 could potentially strengthen the influenza antibodies response evoked by IIV.
- These results may be explained by several factors, among them: The low dose of administration compared to that used in the mouse model The timing of administration Measurement in blood (i.e. BAL measurements more relevant but limited in young children)