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

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

                         

Sintomi di rinite negli ultimi 12 mesi 1994-95* 2001-02* Variazione %*

Bambini di 6-7 anni 13.8% 18.9% +5.2 (4.0-6.4)

Adolescenti di 13-14 anni 31.6% 35.1% +4.1 (1.9-6.3)

* % (95% CI)

Pollinosi nella vita 1994-95* 2001-02* Variazione %*

Bambini di 6-7 anni 6.3% 9.0% +2.7 (1.9-3.6)

Adolescenti di 13-14 anni 14.4% 17.2% +2.8 (1.5-4.1)

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

….. nel 2020 50% degli adolescenti con rinite allergica

Popolazione

allergica in

ITS =

0,9%0,9%

L’immunoterapia allergene-specificaAlessandro 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

1,19%

58.000.000 14.500.000 128.000 0,91%0,91%

1,13%

1,05%

0,74%

0,46%

1,24%*

0,52%

Popolazione in terapia ITS rispetto alla popolazione allergica anno 2003

1,24%*

Viene distribuita una media di 325.000 terapie/anno negli ultimi 5 anni.

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 only a small percentage (less than 5 percent) of allergic individuals receive SCIT,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.

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).

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

L. B. Bacharier, A. Boner, et al (16)…, The European Pediatric Asthma Group

Review article Allergy 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.

L. B. Bacharier, A. Boner, et al (16)…, The European Pediatric Asthma Group

Review article Allergy 2008: 63: 5–34

Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report

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.

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

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.

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.

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

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

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 effects on

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

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 What is the the scientific evidence ?evidence ?

Should immunotherapy be Should immunotherapy be recognized as the first-line recognized as the first-line therapeutic treatment for allergic therapeutic treatment for allergic rhinoconjunctivitis?rhinoconjunctivitis?

Efficacia clinica (rinite)Efficacia clinica (asma)Efficacia clinica bambini (rinite)Efficacia clinica bambini (asma)Prevenzione sensibilizzazioniPrevenzione asmaEffetto a lungo termine

IaIaIbIbIbIb*Ib

IaIaIaIbIIaIb*IIa

SCIT SLIT

* Un solo studio randomizzato in aperto.

Passalacqua e Durham, JACI 2007, modificata

Grado di evidenza sperimentale per immunoterapia Sottocutanea (scit) e sublinguale (slit)

• 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

ITS: come viene prescritta?

Legge 8 aprile 1998, n. 94 (art. 5, c. 1 e 2)

La richiesta deve riportare:

• nome e cognome del paziente

• data e firma del medico• forma farmaceutica e

posologia

ITS: come vengono prescritti?

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

Sublingual-swallow immunotherapy

• 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.

Treatment schedules and dose modification

Sublingual-swallow 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.

Discontinuation of sublingual immunotherapy

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.

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%

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

Data on the dropout rate among 2774 children aged 6 to 15 years

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.

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.

Anaphylaxis to multiple pollen allergen sublingual immunotherapy. Eifan AO, et.al Allergy 2007;62:567–568.

 

Anaphylaxis due to sublingual immunotherapy. Dunsky E , et al. Allergy 2006; 61: 1235

non standardized extracts in an extemporaneous mixture were used

.. multiple allergen SLIT should not be recommended; ….special attention on children receiving co-seasonal pollen SLIT especially when mixture of multiple extracts is concerned

THE SAFETY OF SUBLINGUAL IMMUNOTHERAPY WITH ONE OR MULTIPLE ALLERGENS IN CHILDREN Submitted

Fabio Agostinis1, Carlo Foglia1, Marcello Cottini2, Giorgio Walter Canonica3, Giovanni Passalacqua3

Table 1. Prescribed SLIT SINGLE ALLERGEN162 N (%)

MULTIPLE ALLERGENS253 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 CHILDREN

Fabio Agostinis1, Carlo Foglia1, Marcello Cottini2, Giorgio Walter Canonica3, Giovanni Passalacqua3

Table 2. Summary of the reported side effects.   

Single allergen 16,744 doses

Multiple allergens 22,666 doses

Oral itching/burning 36 mild4 moderate

48 mild 5 moderate

Oral/tongue swelling 8 mild 11 mild1 moderate

Rhinitis/ear itching 3 mild 2 mild

Troath irritation 12 mild1 moderate

22 mild2 moderate

Nausea/abdominal pain 3 mild 4 mild

Vomiting/diarrhea - -

Cough 5 mild 7 mild

Asthma - -

Generalized urticaria - -

Anaphylaxis - -

TOTAL 72 episodes44,44% patients4,3/1000 doses

102 episodes40,32% patients4,5/1000 doses

L’immunoterapia allergene-specificaAlessandro 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.

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

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

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)

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 sublingual immunotherapy 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

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)

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]

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

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)

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

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

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]

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