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L’immunoterapia specifica per il bambino asmatico “Ma me la può prescrivere anche il mio pediatra?

L’immunoterapia specifica per il bambino asmatico “Ma me la può prescrivere anche il mio pediatra? SLIT nel bambino: una terapia sottovalutata? Fabio Agostinis Unità Strutturale Complessa di Pediatria Ospedali Riuniti di Bergamo.

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L’immunoterapia specifica per il bambino asmatico “Ma me la può prescrivere anche il mio pediatra?

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  1. L’immunoterapia specifica per il bambino asmatico “Ma me la può prescrivere anche il mio pediatra? SLIT nel bambino: una terapia sottovalutata? Fabio Agostinis Unità Strutturale Complessa di Pediatria Ospedali Riuniti di Bergamo

  2. Changes in Prevalence of Asthma and Allergies Among Children and Adolescents in Italy: 1994–2002 PEDIATRICS Volume 117, Number 1, January 2006 Galassi Claudia et al.

  3. Variazione della prevalenza della rinite stagionale in Italia Galassi C. .Changes in prevalence of asthma and allergies among children and adolescents in Italy: 1994-2002. Pediatrics 2006; 117:34-42 * % (95% CI) ….. nel 2020 50% degli adolescenti con rinite allergica

  4. Popolazione allergica in ITS= 0,9%

  5. L’immunoterapia allergene-specifica Alessandro Fiocchi, Sergio Arrigoni, Giorgio Bonvini, Fabio Agostinis, Daniele G. Ghiglioni Pediatria Ospedale Macedonio Melloni di Milano, Azienda Ospedaliera Fatebenefratelli di Milano N. 9 Anno 8- Novembre 2007

  6. Popolazione in terapia ITS rispetto alla popolazione allergica anno 2003 1,19% 1,24%* 1,13% 1,05% 0,74% 0,46% 1,24%* 0,52% 58.000.00014.500.000 128.000 0,91% Viene distribuita una media di 325.000 terapie/anno negli ultimi 5 anni.

  7. Presently, subcutaneous immunotherapy (SCIT) is the only form of specific allergen immunotherapy that has an FDA-approved formulation, but SLIT is currently under investigation in the United States. However, only a small percentage (less than 5 percent) of allergic individuals receive SCIT,which, unlike medications, has the potential to modify the allergic disease and produce sustained clinical remission of allergic symptoms after discontinuation.

  8. Inconvenience due to the time involved in receiving allergen IT injections in a medically supervised setting is likely the reason for the low utilization of SCIT. SLIT appears to have a more favorable safety profile, allowing for home administration, and this may expand the population of allergic patients who receive SIT (e.g., young children, adults who find it difficult to comply with the weekly visits during a SCIT build-up).

  9. The Official Journal of the British Society for Allergy & Clinical Immunology

  10. L. B. Bacharier, A. Boner, et al (16)…, The European Pediatric Asthma Group Review articleAllergy 2008: 63: 5–34 Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report Asthma is the leading chronic disease among children in most industrialized countries. However, the evidence base on specific aspects of pediatric asthma, including therapeutic strategies, is limited and no recent international guideline shave focused exclusively on pediatric asthma. the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams to find a consensus to serve as a guideline for clinical practice in Europe as well as in North America.

  11. L. B. Bacharier, A. Boner, et al (16)…, The European Pediatric Asthma Group Review articleAllergy 2008: 63: 5–34 Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report IMMUNOTHERAPY: is the only way of permanently redirecting the disease process of allergic (atopic) asthma. Pajno GB. Clin Exp Allergy 2005;35:551–553 Preventive effect • Can prevent sensitization to other allergens, Des Roches A, et al. J Allergy Clin Immunol 1997;99:450–453. • can improve asthma, prevent progression from allergic rhinitis to asthma Niggemann B, et al. Allergy 2006;61:855–859. • reduce the development of asthma in children with seasonal allergies Novembre E, et al. J Allergy Clin Immunol 2004;114:851–857, (the PATstudy) J Allergy Clin Immunol 2002;109. • The effect appears to continue after treatment has stopped Durham et al. N Engl J Med 1999;341:468–475.

  12. L. B. Bacharier, A. Boner, et al…, The European Pediatric Asthma Group Review article Allergy 2008: 63: 5–34 Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report Sublingual immunotherapy (SLIT) • SLIT may be a safe and effective alternative to subcutaneous injections in children Olaguibel JM. J Investig Allergol Clin Immunol 2005;15:9–16. • A systematic review concluded that SLIT has only low-to moderate clinical efficacy in children with mild-to-moderate persistent asthma who are at least 4 years old and sensitized only to house-dust mites Sopo SM, et al. Arch Dis Child 2004;89:620–624. • some studies have compared injection and SLIT in children and reported similar efficacy Khinchi MS. Allergy 2004;59:45–53.; Mungan D, Ann Allergy Asthma Immunol 1999;82:485–490. • …. definitive evidence of the efficacy of SLIT is lacking.

  13. L. B. Bacharier, A. Boner, et al…, The European Pediatric Asthma Group Review article Allergy 2008: 63: 5–34 Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report Patient selection • The treatment of allergic disease should be based on allergen avoidance, pharmacotherapy, allergen IT, and patient education. • The combination of IT with other therapies allows a broad therapeutic approach ……. with the aim of making patients as symptom free as possible Bousquet J, et al. J Allergy Clin Immunol 2001;108:S147–S334. • Early institution of IT may be recommended not only as a therapeutic measure, but also as a prophylactic measure to prevent rather than reduce bronchial inflammation.

  14. L. B. Bacharier, A. Boner, et al…, The European Pediatric Asthma Group Review article Allergy 2008: 63: 5–34 Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report Recommendations • Consider IT for allergic asthma …. only when the allergenic component is well documented and reliable allergen extracts are available • IT is not recommended when asthma is unstable; on the day of treatment, patients should have few, if any, symptoms and pulmonary function (FEV1) of at least 80% of the predicted value

  15. L. B. Bacharier, A. Boner, et al…, The European Pediatric Asthma Group Review article Allergy 2008: 63: 5–34 Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report Recommendations • Sensitization to more than one allergen is not a contraindication for immunotherapy but can reduce its efficacy due to the need to limit the allergen dose when several allergens are being administered concurrently • Age is not an absolute contraindication – such therapy can be used from 3 years of age, although with caution and only by well-trained staff in specialist centers as this is well below the current licensed age limit • Patients should be able to comply with regular treatment

  16. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Recent findings: long-term follow-up on IT studies demonstrates that: • SIT for 3 years shows persistent long-term effectson clinical symptoms after termination of treatment and preventive effects on later development of asthma in children with seasonal rhinoconjunctivitis. • IT seems to reduce the development of new allergic sensitivities

  17. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 • What is the the scientific evidence ? • Should immunotherapy be recognized as the first-line therapeutic treatment for allergic rhinoconjunctivitis?

  18. Grado di evidenza sperimentale per immunoterapia Sottocutanea (scit) e sublinguale (slit) SCIT SLIT Ia Ia Ib Ib Ib Ib* Ib Ia Ia Ia Ib IIa Ib* IIa Efficacia clinica (rinite) Efficacia clinica (asma) Efficacia clinica bambini (rinite) Efficacia clinica bambini (asma) Prevenzione sensibilizzazioni Prevenzione asma Effetto a lungo termine * Un solo studio randomizzato in aperto. Passalacqua e Durham, JACI 2007, modificata

  19. ITS: come viene prescritta? • I vaccini sono preparati industrialmente su richiesta scritta del medico, il quale si impegna ad utilizzarli • su quel determinato paziente, nella struttura pubblica o privata in cui opera, • sotto la sua diretta e personale responsabilità. Decreto Legislativo n. 219 del 24 aprile 2006 (Titolo II, Art. 5) Gazzetta Ufficiale n. 142 del 21 giugno 2006 – Supplemento Ordinario n. 153

  20. ITS: come vengono prescritti? • La richiesta deve riportare: • nome e cognome del paziente • data e firma del medico • forma farmaceutica e posologia Legge 8 aprile 1998, n. 94 (art. 5, c. 1 e 2)

  21. ITS: come viene erogata? L’ITS per via sottocutanea, anche per i suoi possibili effetti collaterali indesiderati, dovrebbe essere riservata allo specialista allergologo. Le vie non iniettive (sublinguale e topica nasale) si prestano all’auto-somministrazione, che deve essere praticata dal paziente seguendo scrupolosamente le istruzioni. Linee guida sull’immunoterapia specifica delle allergopatie respiratorie Giorn. It. Allergol. Immunol. Clin. (2002), 12: 167-189

  22. Sublingual-swallow immunotherapy Treatment schedules and dose modification • It is advisable to adjust the dose when systemic adverse effects appear. • The administration of SLIT must be postponed in the following circumstances: – In the presence of oro-pharyngeal infection. – In the case of major dental surgery. – Acute gastroenteritis. – Exacerbation of the asthma. – PEFR <80% of personal best value. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR, Malling H-J, Valovirta E. Standards for practical allergen-specific Immunotherapy. Allergy 2006;61(suppl 82):1-20.

  23. Sublingual-swallow immunotherapy Discontinuation of sublingual immunotherapy • • After a minimum of 3–5 years of administration, the patient is asymptomatic or has mild symptoms for two consecutive years • • Poor compliance with treatment by the patient. • • Appearance of any type of contraindication to immunotherapy. • • Persistent troublesome local side effects. • • Repeated systemic reactions. • • Absence of a clinical response to treatment after 2 years. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR, Malling H-J, Valovirta E. Standards for practical allergen-specific Immunotherapy. Allergy 2006;61(suppl 82):1-20.

  24. Children's compliance with allergen immunotherapy according to administration routes. G. Pajno, et al. Journal of Allergy and Clinical Immunology, 2005 Volume 116, Issue 6, Pages 1380-1381 • Percentage of noncompliant: (82 pts) LNIT, 73.2% • (806 pts) SLIT, 21.5% • (1886 pts) SCIT, 10.9%; • In groups SCIT and SLIT only 6.4% of patients withdrew immunotherapy very early (first 12 months), in group LNIT 43.9% Data on the dropout rate among 2774 children aged 6 to 15 years

  25. Quantitative assessment of the compliance with once-daily sublingual immunotherapy in children (EASY Project: Evaluation of A novel SLIT formulation during a Year) Passalacqua G, et al. Pediatr Allergy Immunol 2007 18: 58–62. in real-life the compliance is good, despite the therapy managed at home.

  26. Sublingual immunotherapy: update 2006.Current Opinion in Allergy & Clinical Immunology. 6(6):449-454, December 2006.Passalacqua, Giovanni; Canonica, Giorgio Walter • The good safety profile is one of the major advantages of • SLIT. • Looking at the literature, no severe or life-threatening • event has ever been described or reported in • approximately 20 years of trials and clinical use.

  27. Anaphylaxis to multiple pollen allergen sublingual immunotherapy. Eifan AO, et.al Allergy 2007;62:567–568. .. multiple allergen SLIT should not be recommended; ….special attention on children receiving co-seasonal pollen SLIT especially when mixture of multiple extracts is concerned • Anaphylaxis due to sublingual immunotherapy. • Dunsky E , et al. Allergy 2006; 61: 1235 • non standardized extracts in an extemporaneous mixture were used

  28. SINGLE ALLERGEN 162 N (%) MULTIPLE ALLERGENS 253 N (%) Grass 140 (86) 36 pre-coseasonal Grass + Trees 228 (90) 64 pre-coseasonal Birch 14 (9) 4 pre-coseasonal Grass + Olive 18 (7) 6 pre-coseasonal Parietaria 4 (2.5) Grass + Parietaria 6 (2.5) Alternaria 4 (2.5) Grass+Mugwort 1 (0.5) TOTAL 162 253 THE SAFETY OF SUBLINGUAL IMMUNOTHERAPY WITH ONE OR MULTIPLE ALLERGENS IN CHILDRENSubmitted Fabio Agostinis1, Carlo Foglia1, Marcello Cottini2, Giorgio Walter Canonica3, Giovanni Passalacqua3 Table 1. Prescribed SLIT

  29. Single allergen 16,744 doses Multiple allergens 22,666 doses Oral itching/burning 36 mild 4 moderate 48 mild 5 moderate Oral/tongue swelling 8 mild 11 mild 1 moderate Rhinitis/ear itching 3 mild 2 mild Troath irritation 12 mild 1 moderate 22 mild 2 moderate Nausea/abdominal pain 3 mild 4 mild Vomiting/diarrhea - - Cough 5 mild 7 mild Asthma - - Generalized urticaria - - Anaphylaxis - - TOTAL 72 episodes 44,44% patients 4,3/1000 doses 102 episodes 40,32% patients 4,5/1000 doses THE SAFETY OF SUBLINGUAL IMMUNOTHERAPY WITH ONE OR MULTIPLE ALLERGENS IN CHILDREN Fabio Agostinis1, Carlo Foglia1, Marcello Cottini2, Giorgio Walter Canonica3, Giovanni Passalacqua3 Table 2. Summary of the reported side effects.

  30. L’immunoterapia allergene-specifica Alessandro Fiocchi, Sergio Arrigoni, Giorgio Bonvini, Fabio Agostinis, Daniele G. Ghiglioni Pediatria Ospedale Macedonio Melloni di Milano, Azienda Ospedaliera Fatebenefratelli di Milano N. 9 Anno 8- Novembre 2007 • La via sublinguale si è rivelata di una sicurezza tale che non solo ha liberato la ITS dalla limitazione ad ambienti ultraspecialistici, ma la rende oggi proponibile e praticabile anche nella pediatria del territorio. • .. oggi possono avere accesso a questa possibilità terapeutica non solo i bambini affetti da allergie gravi ma anche quelli con forme più lievi: un fatto importante, considerata la dimensione delle allergie e la possibilità di modificarne il decorso.

  31. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for prevention of asthma • Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in children – a 14-year study. Pediatrics 1968; 42:793–802. • 14-year follow-up study in children • 22% of the placebo-treated children free of asthma compared with 72% of the SCIT-treated children. • Bauer CP. Study of preventing the development of asthma during specific immunotherapy in children Allergologie 1993; 11:468. • children with allergy to grass and allergic rhinitis • reduced development of seasonal BHR to histamine after 2 years

  32. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for prevention of asthma • Moller C, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002; 109:251-256. • SCIT for 3 years; 208 children, 6-14 years; grass and/or birch pollen allergy • the group treated with SIT had significantly less asthma as evaluated by clinical symptoms (OR = 2.52; P<0.001) • Novembre E, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 2004; 114:851-857. • children (5-14 years) treated with SLIT for 3 consecutive years (4 months every year) • 8/45 treated vs 18/44 controls developed asthma; OR 3.80

  33. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for the prevention of new allergies • Johnstone DE, Crump L. Value of hyposensitization therapy for perennial bronchial asthma in children. Pediatrics 1961; 61:39–44. • 4-year course of high-dose SCIT; • new IgE sensitivities: 0 treated vs 25% in the control group. • Des Roches A, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99:450–453. • children with allergy to HDM; monosensitized; 3 years SIT • New sensitivity 55% (IT-treated group) vs 100% (control group)

  34. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for the prevention of new allergies • Pajno GB, Barberio G, De Luca F, et al. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin Exp Allergy 2001; 31: 1392–1397. • 134 children (75 treated/63 controls); IT for 3 years • After 3 years: new sensitivities 66% control vs 25% SIT group Marogna M, Spadolini I, Massolo A, et al. Randomized controlled open study of sublingualimmunotherapy for respiratory allergy in real-life: clinical efficacy and more. Allergy 2004; 59:1205–1210. • 5.9% patients of the SLIT group vs 38% patients of the control group (P<0.001) after 3 years

  35. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for long-term prevention • Moller C, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002; 109:251–256. • 205 children aged 6 to 14 years; SIT for 3 years • Niggemann B, Jacobsen L, Dreborg S, et al. Five-year follow up on the PAT study: specific immunotherapy and long-termprevention of asthma in children. Allergy 2006; 61:855–859. • Significant improvement in hay fever • Treated children had less asthma (OR = 2.68; P<0.01)

  36. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for long-term prevention • Jacobsen L, Niggemann B, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow up on the PAT study. Allergy 2007; 62:943–948. • 147 pts (16-25 years) • Significant improvements in rhinoconjunctivitis persisted • Less treated subjects had developed asthma [odds ratio 2.5]

  37. Categorie di prova sperimentale Shekelle et al, BMJ 1999 Ia—evidence for meta-analysis of randomised controlled trials Ib—evidence from at least 1 randomised controlled trial IIa—evidence from at least 1 controlled study without randomisation IIb—evidence from at least one other type of quasi-experimental study III—evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies IV—evidence from expert committee reports or opinions or clinical experience of respected authorities, or both

  38. ISAAC Programma di ricerca epidemiologica iniziato nel 1991 • Fase 1: 700.000 bambini di 156 centri in 56 Paesi; è stata condotta tra il 1992-98 (per lo più 1995-96) • Fase 2: acquisizione di informazioni più approfondite in 30 centri di 22 Paesi • Fase 3: 300.000 bambini di 106 centri in 56 Paesi; è stata condotta tra il 1999-2004 (per lo più 2002-03)

  39. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for prevention of asthma • The experimental evidence for prevention of asthma in patients with allergic rhinitis.. is Ib for allergen SIT and SLIT • Together with the long-term clinical experience available, we regard SIT as an important treatment for the prevention of asthma in patients with allergic rhinitis. Ib—evidence from at least 1 randomised controlled trial

  40. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for the prevention of new allergies • The level of evidence for allergen SIT according to these studies is Ib for SCIT and IIA for SLIT • the exact mechanism is not clear; • the potential for the long-term prognosis of the disease should be taken into consideration. Ib—evidence from at least 1 randomised controlled trial IIa—evidence from at least 1 controlled study without randomisation

  41. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for long-term prevention • Moller C, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002; 109:251–256. • 205 children aged 6 to 14 years; SIT for 3 years • Niggemann B, Jacobsen L, Dreborg S, et al. Five-year follow up on the PAT study: specific immunotherapy and long-termprevention of asthma in children. Allergy 2006; 61:855–859. • Jacobsen L, Niggemann B, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow up on the PAT study. Allergy 2007; 62:943–948. • Significant improvements in rhinoconjunctivitis persisted • Less treated subjects had developed asthma [odds ratio 2.5]

  42. How strong is the evidence that immunotherapy in children prevents the progression of allergy and asthma? Lars Jacobsen and Erkka Valovirta Current Opinion in Allergy and Clinical Immunology 2007, 7:556–560 Evidence for long-term prevention • The category of evidence for the long-term effect of SIT is Ib for SCIT • Since BHR in children with seasonal allergic rhinitis is significantly related to an increased risk for later development of asthma it could be considered to include evaluation of BHR in the indication of immunotherapy. Ib—evidence from at least 1 randomised controlled trial

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