VEQ Allergologia
Valutazione risultati VEQ ciclo 2013
Alessandra Vultaggio
SOD Immunoallergologia
Dipartimento di Biomedicina
AOU Careggi
[email protected]
V.E.Q.
ALLERGOLOGIA
Ciclo 2013
- 12 campioni di sieri liofili di origine umana
- Valutazione IgE specifiche per alimenti e inalanti
- Valutazione IgE totali
Centri partecipanti
per Regione
1
66
6
4
3
1
10
16
-5 laboratori rispetto al 2012
6
133 Laboratori Ciclo 2013
11
63 Laboratori Ciclo 2009
2
3
4
3
22 Allergeni dosati
1
Bianco d’uovo
Grano
Arachidi
Soia
Pomodoro
Aglio
Mela
Bambagiona
Betulla verrucosa
Olivo
Cipresso medit.
Artemisifolia
Assenzio selvatico
D. pteronyssinus
Epitelio di gatto
Forfora di cavallo
Forfora di cane
Nocciole
Lattice
Parietaria judaica
Gambero
Pesce
N° all. x Camp.
2
3
4
x
x
5
7
x
x
x
x
x
x
x
x
x
x
x
x
9
x
x
10
11
x
x
x
x
x
x
x
x
x
x
8
x
x
x
x
6
10 alimenti + 12 inalanti
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
6
7
7
7
7
7
6
6
6
6
6
12 N° dosaggi
1
3
5
3
4
3
x
5
3
x
3
5
5
8
x
3
4
x
3
1
x
4
x
4
x
5
4
1
x
2
8
79
Metodi IgE Totali (2013)
52%
40%
Metodi di Dosaggio (2009)
Metodiche Utilizzate (IgE Totali)
1
ELFA
6
NEFELOM.
1
IMMUNOTURB.
25%
16
CHEMILUM.
57%
36
F.E.I.A
3
IMMUNOENZ.
0
5
10
15
20
25
30
35
40
Metodi di Dosaggio
Metodiche Utilizzate (IgE Spec.)
17,4%
11
CHEMIOLUM.
74%
47
F.E.I.A
5
IMMUNOENZ.
0
5
10
15
20
25
30
35
40
45
50
Metodi IgE Specifiche
64.2%
26%
Valori di cutcut-off utilizzati
VEQ 2009
Cut-off
F.E.I.A.
Alimenti
Inalanti
30
25
20
15
10
5
0
0.1
KUA/L
0.35
Valori di cutcut-off utilizzati
Cut- off
Chemioluminescenza
Alimenti
Inalanti
8
7
6
5
4
3
2
1
0
0.1
UI/mL-KUA/L
0.35
Valori Cut-off utilizzati
F.E.I.A.
Valori Cut-off utilizzati
Chemiluminescenza
Sensibilità e specificità:
effetto del valore di soglia
IgE specifiche per b-lattamici:
nuovo e vecchio CAP-FEIA a confronto
Confronto tra la “diagnostic performance”
del nuovo (> 0.10 kUA/L) e vecchio (> 0.35 kUA/L)
CAP system Phadia®
SENSIBILITA’
SPECIFICITA’
DIAGNOSTIC ODD RATIO (DOR)
Clin Exp Allergy 2009; 39:838-844
Sensibilità e specificità del vecchio e nuovo test
in rapporto ai livelli sierici di IgE totali
Median value (181)
120
100
Old test (>0.35)
(%)
80
Sensitivity
60
Specificity
40
20
0
<52
52-181
182-743
>743
120
100
(%)
New test (>0.10)
80
Sensitivity
60
Specificity
40
20
0
<52
52-181
182-743
>743
Quartiles of total IgE
Vultaggio A et al, Clin Exp Allergy 2009
Cut-off di positività vs
CutCut off di significatività clinica
• Dati dalla letteratura che dimostrano che il
valore della IgE specifiche e la loro utilità
clinica
Simple measurement of grass-specific IgE (>18.5 KUA/L)
as the best predictor for asthma in rhinitis patients
A.Fumigatus specific IgE >1.91 KuA/L
Total IgE
Specific
IgE
Esiste una diversa possibilità di interpretare il significato
clinico del dosaggio sierico delle IgE specifiche per in
relazione alle IgE totali ?
IgE Specifiche
IgE Totali
Aumenta la
probabilità del cross
linking
Diminuisce la
probabilità del cross
linking
Patients
Table 1: Clinical characteristics of analyzed patients
ADR+
ADR-
171
122
Gender (M/F)
65/106
58/64
Age (ys, range)
18-71
18-62
Allergic sensitization* (%)
67 (39.2)
77 (63.1)
Total serum IgE
554 139
782 127
61 (35.6)
-
12 (7)
-
Urticaria
98 (57.3)
-
Amoxicillin
147 (85.9)
-
Ampicillin
13 (7.6)
-
Other penicillins
11 (6.4)
-
89.1 10.1
-
Number
Symptoms (%)
Anaphylaxis °
Urticaria/Angioedema
Culprit drug (%)
Time delay (days)
*Confirmed by a positive skin test to inhalant and/or food allergens.
Total serum IgE were detected as described in Materials and Methods, values are reported as mean ± SE.
° Patients who displayed a severe reaction affecting at least two organs with bronchospasm and/or hypotension
(Vultaggio A et al, Submitted)
- 64.8 % of patients
Reaction
No reaction
800
- PPV ≈93%
400
And true negative)
600
correctly classified (true positive
0
200
density
1000
Higher ratio values are observed in
reactive subjects (index ≥0.002)
0
.002
.004
.006
specific/total IgE ratio
.008
.01
Diagnostic performance
of different criteria
Criteria of CAP positivity
1 positive hapten
(293 subjects)
1 positive hapten
(subgroup: n. 175
Total IgE <200*)
1 positive hapten
(subgroup: n. 118
Total IgE >200*)
Specific/Total
IgE ratio >0.0022
(293 subjects)
Sensitivity
0.66 (0.59 - 0.73)
0.34 (0.27 - 0.42)
0.93 (0.84 - 0.98)
0.43 (0.36 - 0.51)
Specificity
0.52 (0.42 - 0.61)
0.98 (0.94 - 1.00)
0.03 (0.0 - 0.12)
0.95 (0.90 - 0.98)
Positive predictive value
0.66 (0.58 - 0.73)
0.97 (0.89 – 1.00)
0.49 (0.40 – 0.59)
0.93 (0.84 - 0.97)
Negative predictive value
0.52 (0.43 - 0.61)
0.52 (0.45 - 0.58)
0.33 (0.04- 0.78)
0.55 (0.48 - 0.61)
Positive likelihood ratio
1.4 (1.1 – 1.7)
20.7 (5.2 - 83)
0.97 (0.89 –1.05)
8.8 (4.0 - 19.6)
Negative likelihood ratio
0.66 (0.50 - 0.86)
0.67 (0.60 - 0.75)
2 (0.38 – 10.5)
0.6 (0.52- 0.68)
2.1 (1.3 – 3.3)
30.8 (8.1 - ∞)
0.48 (0 - 2.36)
14.7 (6.3 – 34.5)
Diagnostic odds ratio
*kU/l
Clinical usefulness of ratio index in
patients with total IgE ≥200
• 80 patients have index ≥0.002
• 21 out of 80 have total IgE ≥200
• 17 out of 21 (81%) are true positive
NET RECLASSIFICATION IMPROVEMENT
Overall
+20.6% (p=o.oo3)
Total IgE <200
+6.7% (p=0.022)
Total IgE ≥200
+22% (p=0.005)
Biological agents
New drugs
New
mechanisms
New tests
Clinical management of
hypersensitivity reactions
Patients with
Patients with no
previous reactions
previous reactions
Definition of pathogenic
mechanisms
Identify patients at risk
Prevention of further or
first time reactions
Infusion reactions to biologicals :
Pathogenic mechanisms
IMMEDIATE systemic REACTIONS
•
Non antibody-mediated adverse reactions
 Complement-mediated
 Cytokine release syndrome (CRS)
•
Antibody-mediated adverse reactions
 IgE-mediated
 Non IgE-mediated
Vultaggio A et al, Curr Opin Allergy Clin Immunol
In vitro tests:
1) ADA detection
2) IgE isotyping
In vitro ADAs assays
Stage 1:
ADA screening
& confirmation
ADA screening assay
(Bridging ELISA)
+
Confirmatory assay
-
No further
-
No further
testing
(binding inhibition)
+
Stage 2:
ADA
Isotype
determination
Neutralizing
characterization
Relative ADA
concentration
activity
testing
IgE ADA isotype
IgE-mediated reactions have been
described towards several BAs
Drug
In vivo
In vitro
Ref
Muromonab
No
Yes
Georgitis, 1991
Cetuximab
No
Yes
Chung, 2008
Tocilizumab
Stubenrauch, 2010
No
Yes
Infliximab-specific IgE ADAs
Basiliximab
No
Baudouin , 2003
Yes
ADR+
Omalizumab
Yes patients
No
n=30Price, 2007
Etanercept
Yes
No
Bavbek, 2011
Rituximab
Yes
No
Brennan , 2009
Natalizumab
Yes
Yes
Infliximab
Yes
Yes
p<0.02
ATI+
patients
n=23
(76.6%)
Paltiel,
2008
Adalimumab Yes
No
IgE+
Maggi E, Vultaggio A, Matucci A
patients
n=6 (26%)
MunozCano, 2010
Vultaggio, 2010
Vultaggio A et al, Allergy 2010
Matucci A et al, Clin Exp Allergy 2013
Pre-existing
anti-drug antibodies
IFX-specific
antibody preexisting to the
treatment??
Chung CH et al, NEJM 2008
IgE-mediated reactions at first exposure
The Cetuximab case
Chung CH et al, NEJM 2008
Sensitization
to Gal-a1-3Gal
IgE
Ga1-3G
First exposure to
Cetuximab
Cetuximab
(SP2)
Murine part
Gal-a1-3-Gal
IgE
Ga1-3G
Hypersensitivity
Reaction
(Matucci A. et al. EAACI 2014
Conclusions
• In vitro diagnosis tests have advantages over in vivo
tests, but also limitations
• The measurement of total IgE may improve the in
vitro diagnosis of drug allergy
• Biological agent (BA) are new important therapeutic
tools but their use may be limited by adverse
reactions
• The management of such reactions to BA include
new diagnostic tools
• Detection of specific IgE may be useful
Aknowledgement
AOU Careggi
External Collaborators
University of Florence
Complesso Integrato Columbus
Immunoallergology Unit
Allergology Unit (Roma)
Andrea Matucci
Antonino Romano
Daniele Cammelli
Francesco Gaeta
Dept of Internal Medicine
Francesca Nencini
Sara Pratesi
Giulia Petroni
Prof. Enrico Maggi
Thermofisher (Phadia)