How strong is the evidence that immunotherapy in children prevents

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–
2002
PEDIATRICS Volume 117, Number 1, January 2006 Galassi Claudia
et al.
Variazione della prevalenza della rinite stagionale
C. .Changes in prevalence of asthma and allergies among children and adolescents in
in Italia Galassi
Italy: 1994-2002. Pediatrics 2006; 117:34-42
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)
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
….. nel 2020
* % (95% CI)
14.4%
17.2%
+2.8 (1.5-4.1)
50% degli adolescenti con rinite allergica
Popolazione
allergica in
ITS =
0,9%
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
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%
58.000.000
14.500.000
128.000
Viene distribuita una media di 325.000 terapie/anno negli ultimi 5 anni.
0,91%
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.
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
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.
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 evidence ?
 Should immunotherapy be recognized
as the first-line therapeutic treatment for
allergic rhinoconjunctivitis?
Grado di evidenza sperimentale per
immunoterapia
Sottocutanea (scit) e sublinguale (slit)
SCIT
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
Ia
Ia
Ib
Ib
Ib
Ib*
Ib
SLIT
Ia
Ia
Ia
Ib
IIa
Ib*
IIa
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
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)
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
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.
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.
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
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.
.. 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
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 ALLERGEN
162 N (%)
Grass
140 (86)
MULTIPLE ALLERGENS
253 N (%)
Grass + Trees
36 pre-coseasonal
Birch
14 (9)
228 (90)
64 pre-coseasonal
Grass + Olive
4 pre-coseasonal
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 mild
4 moderate
48 mild
5 moderate
Oral/tongue swelling
8 mild
11 mild
1 moderate
Rhinitis/ear itching
3 mild
2 mild
12 mild
1 moderate
22 mild
2 moderate
3 mild
4 mild
-
-
Cough
5 mild
7 mild
Asthma
-
-
Generalized urticaria
-
-
Anaphylaxis
-
-
72 episodes
44,44% patients
4,3/1000 doses
102 episodes
40,32% patients
4,5/1000 doses
Troath irritation
Nausea/abdominal pain
Vomiting/diarrhea
TOTAL
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.
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; 114:851857.
 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 quasiexperimental 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 200203)
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