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Children with severe food allergy may present high risk of fatal anaphylaxis and a highly impaired quality of life. Anti IgE-treatment has been shown to be a promising approach as monotherapy for severe allergy to multiple foods. However, very high serum total IgE levels may limit its use.
This study aims to assess the efficacy of IgE-selective immunoadsorption (IgE-IA) on total IgE levels and threshold of reactivity to the culprit foods in children with history of severe anaphylaxis due to multiple foods and allergic comorbidities.
Methods
In this single-center, prospective, open-label efficacy study we evaluated children with severe asthma, allergy to 2+foods and total IgE levels >2300 kUI/L. To establish the food reactivity threshold, each patient underwent oral food challenges (OFCs) before and after IgE-IA.
Results
Five patients (4 males; age, 12.2 ± 5 years, mean ± SD) underwent an average of 3 (range 2–4) sessions of IgE-IA. Each session reduced IgE levels by a mean of 1958.87 kUI/L. After the IgE-IA cycle, serum total IgE dropped from 3948 ± 1652.7 (mean ± SD) to 360.8 ± 71.9 kUI/L (−10.9 folds; p = 0.01). The threshold of reactivity (No Observed Adverse Effect Level, NOAEL) tested at OFCs for the culprit foods (4 baked-milk + 2 baked-egg + 1 lentil + 2 hazelnut + 1 wheat) increased overall from 21.5 (median, IQR 1.5–82.6) protein milligrams to 1115 (837.2–4222.8) milligrams (p < 0.001), ie, up to 51.8 times higher than baseline. 8/10 OFCs were negative after IgE-IA.
Conclusions
IgE-IA increased food threshold quickly. It can be considered in well-selected patients with severe food allergies and high IgE-levels especially if otherwise eligible to anti IgE treatment.
IgE-immunoadsorption can be considered in patients with severe food allergy as a safe and effective option to increase threshold reactivity, especially in those with high IgE-levels otherwise eligible to anti IgE-treatment.
Introduction
Food allergy (FA) is emerging as a relevant health and social problem. There are extensive data suggesting that FA is common with up to 10% of the population affected in industrialized countries, mainly children.
Even the intake of a small amount of food can induce fatal and near-fatal anaphylaxis. FA also leads to increasing hospitalizations and healthcare costs and the rate of mortality is around 0.03–0.3 deaths per million people per year.
A definitive cure for FA still does not exist. The classic approach relies on the strict avoidance of allergenic foods, which may have a great impact on the quality of life of the patients and their families
Innovative therapeutic options are under investigation. Recent evidence-based international guidelines recommend to consider oral immunotherapy in patients with persistent allergy to cow's milk, egg, and/or peanut.
In addition, there is growing interest in the efficacy of monoclonal antibodies as monotherapy or combined with oral immunotherapy for increasing the threshold of reaction to the culprit food(s) and, therefore, the risk of severe anaphylaxis in case of accidental ingestion, in patients with allergy to a single or multiple food with/without concomitant allergic diseases.
The most promising monoclonal approach is the anti-IgE treatment, omalizumab, on the market since 2003; recently, other anti-IgE antibodies (ie, ligelizumab) with higher affinity for IgE and superior inhibition of IgE binding to FcƐI than omalizumab are under investigation.
leaflets suggest that the omalizumab applicability is limited by a weight-dependent maximum level of total IgE up to which it can be administered (ie, 1500 IU/mL). Since anti IgE-treatment is excreted through the renal emunctory, in patients who undergo such a treatment and have a high level of total IgE it has been hypothesed that considerable concentrations of IgE/anti-IgE monoclonal antibodies immune complexes might accumulate in the blood with the consequent risk of renal impairment. To overcome this limit, a few attempts of extracorporeal selective IgE-immunoadsorption (IgE-IA) preliminary to anti IgE-treatment commencement have been performed for atopic dermatitis
Herein, we report the first clinical series to assess the efficacy and safety of selective IgE-IA in a cohort of pediatric patients with multiple food allergies and very high IgE levels. The study hypothesis is that, throughout this procedure, children reach partial or total food tolerance to previously eliciting foods. The primary objective has been to assess food tolerance at Double Blind Placebo-Controlled Oral Food Challenges (DBPCFC) before and after IIgE-IA. As secondary endpoints, IgE levels, full clinical tolerance to food, immunological and clinical parameters were assessed.
As an extension phase of this study, we evaluated the possibility of using IA as a preliminary procedure propaedeutic to the commencement of anti IgE-treatment as potential long-term treatment for food allergies. This will be reported in another manuscript.
Methods
Study design
This is a single-center, prospective, open label, interventional, pilot, efficacy study (IAO, Immunoadsorption for anti IgE-treatment; OPBG Ethic Committee approval 599/18) (Fig. 1). To establish the reactivity threshold before apheretic procedures, each patient underwent 2 oral food challenges (OFCs) with 2 of the foods that, based on their medical history, determined severe reactions (preOFC-F1; preOFC-F2). Spirometries were also performed to assess the degree of asthma control. In stable clinical conditions, the patients were admitted to the hospital and underwent selective IgEIA procedures.
IgE-immunoadsorption was stopped if total IgE was below 500 kU/L after 2 consecutive procedures. Before and after each IgE-IA procedure, blood cell count (CBC), chemistry, IgA, IgG, IgM, and total and specific IgE were evaluated. To assess any increase in food tolerance after the apheretic procedures, OFCs for the 2 most allergenic foods tested were repeated (postOFC-F1; postOFC-F2). The OFCs were performed on the day of IgE-IA discontinuation (1stfood) and the following day (2ndfood) only if no rescue medication was provided. Furthermore, before the procedure and at the end of the study, children underwent dermatological assessment for the definition of SCORAD
The cohort design did not include comparison/reference groups nor we assessed unexposed groups. There was no randomization. Eligible children were identified by selective inclusion-exclusion criteria (IAO Protocol). The children were screened at the Allergology Service and followed-on at the Pediatric ward of the Bambino Gesù Children's Hospital (Rome, Italy). Before the enrollment, patients and their parents were informed on the methods and the aim of the study and signed an informed consent.
Clinical evaluation
We evaluated clinical conditions of patients during the entire study (Table 1). Specifically, we used validated questionnaires to assess comorbidities’ control status at the beginning and at the end of our study. For asthma, we used Asthma Control Test (ACT, uncontrolled asthma if score≤19)
forms: 1 form, specifically, filled in by the child and one by the parents. We used CARATKids Test to determine the allergic rhinitis (uncontrolled if score≥6).
to children and their parents. It consists of 4 domains: physical, emotional, social, and cognitive functioning. Items were scored and linearly transformed into a 0 to 100 scale. Higher scores indicate a better quality of life.
Liver and kidney parameters: AST, ALT, γ-GT, creatinine, bilirubin, uric acid, BUN
Protein loss: albumin
Additional immunological parameters:
IgA, IgG, IgM and specific IgE
Additional clinical parameters:
Lung function parameters: FEV1, MEF25-75
Asthma control questionnaire
Patient's diary: symptoms, medication
Skin prick test
During treatment:
Treatment time
Blood flow/plasma flow
Processed plasma volume
Heart rate
Blood pressure (every 60 min)
List of abbreviations: ALT, Alanine Transaminase; AST, Aspartate Transaminase; BUN, Blood Urea Nitrogen; FEV1, Forced Expiratory Volume in the 1st second; γ-GT, γ-Glutamyl Transpeptidase; MCH, Mean Cell Hemoglobin; MCHC, Mean Cell Hemoglobin Concentration; MCV, Mean Cell Volume; MEF25-75, Mean Expiratory Flow at 25–75%
Total and allergen-specific IgE were measured by ImmunoCAP (Phadia). For the specific IgE we used 0.35 kU/L as the cut-off value. Levels of total serum IgG, IgA, IgM, CBC, albumin, and electrolytes were obtained before and immediately after immunoadsorption cycle to assess any variation (Table 1).
Oral food challenges (OFC)
To establish the food reactivity threshold, each patient underwent OFCs before and at the end of the apheretic procedure.
Standardizing double-blind, placebo-controlled oral food challenges: American academy of allergy, asthma & immunology–European academy of allergy and clinical immunology PRACTALL consensus report.
We performed a seven-step open OFC with a semi-logarithmic increase according to the internal protocol (Table S1), at intervals of about 15–20 min as suggested by the PRACTALL consensus document.
Standardizing double-blind, placebo-controlled oral food challenges: American academy of allergy, asthma & immunology–European academy of allergy and clinical immunology PRACTALL consensus report.
Food tolerance was evaluated in terms of threshold of reactivity: we designated the initial point at which symptoms occur at a specific dose as the lowest observed adverse effect level (LOAEL) and the highest dose that does not lead to objective symptoms as the no observed adverse effect level (NOAEL). The reactive symptoms observed were pruritus, urticaria, skin rash, laryngeal and nasal symptoms (rhinorrhea and nasal congestion), respiratory symptoms (wheezing), and gastrointestinal symptoms (subjective and objective). According with the provisions of the PRACTALL Consensus,
Standardizing double-blind, placebo-controlled oral food challenges: American academy of allergy, asthma & immunology–European academy of allergy and clinical immunology PRACTALL consensus report.
the challenge suspension occurred after the appearance of objective symptoms. In case of reported subjective symptoms, the test was continued by lengthening the interval of administration between the doses; whenever the subjective symptoms continued, the test was considered positive and, therefore, interrupted. Any reaction was treated according to this scheme: oral antihistamines at the onset of the symptoms, intramuscular administration in case of persistence; oral and then intramuscular corticosteroids in case of further persistence of the symptoms; aerosol epinephrine in case of laryngospasm and intramuscular administration in case of anaphylaxis. Patients were then monitored for at least 4 h.
IgE-immunoadsorption (IgE-IA)
During hospitalization, patients underwent daily sessions of immunoadsorption, approximately 180 min each one, using the IgE-adsorber Therasorb IgE, Myltenyi Biotec. It consists of a pair of adsorbers that contain Sepharose spheres to which murine monoclonal antibodies are bound, which bind selectively IgE from the plasma of allergic patients. About 2 volumes of plasma were treated in each session. Blood was drawn via a midline Powerglide 18G positioned in the brachial vein. During treatment, anticoagulation therapy was administered by a solution of ACD-A (anticoagulant citrate Dextrose-A) and low molecular weight heparin. Plasma was separated from blood cells by centrifugation-assisted filtration and then conveyed to the IgE-adsorber. After the adsorption, plasma was reunified with the blood cells and then reinfused to the patient by a second peripheral venous access at the opposite arm than the one used for blood aspiration.
More details are provided in the supplementary material.
Statistical evaluation
Due to the absence of a control group, the statistical plan mainly included an evaluation pre-post- of clinical parameters. A t-test (Mann-Whitney U test) was used to analyze the difference in amount of tolerated food expressed in grams and of IgE levels. A p < 0.05 was considered statistically significant.
Results
Study population
A cohort of 5 children, aged 6–19 years, with severe allergic asthma,
GINA Global Strategy for Asthma Management and Prevention (Update 2021) Avalaible on: Reports - Global Initiative for Asthma - GINA (ginasthma.org) Last access on the 27th of October 2022.
multiple food anaphylaxis, and serum total IgE levels>2300 kUI/L was enrolled in a period of 12 months between October 2018 and September 2019 (Table 2). The mean age was 12.2 ± 5 years (mean ± SD); 4 of them were males. As comorbidities, 3 of them were suffering from atopic dermatitis, with 1 classified as having mild (patient# 5, SCORAD 10.9), 1 moderate (patient# 5, SCORAD 37), and 1 as having severe eczema (patient# 4, SCORAD 60). Three patients suffered from allergic rhinitis, classified as mild intermittent according to ARIA guidelines
(mean ± SD), 7.67 ± 4.04; the maximum score is 13, representing bad control, and the minimum score is 0 representing optimal control]. Based on the respiratory function tests performed at the recruitment, all patients suffered from persistent asthma [ACT (mean ± SD), 14.6 ± 2.3; normal: >19].
Table 2Characteristics of study population at baseline.
Study population (n = 5)
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Median/n
IQR/%
Age (y)
11.43
10
20
6
13
6
Female
no
No
no
No
yes
BMI (kg/m2)
18.72
19.48
18.72
18.71
20.39
14.12
Allergic asthma∗
Moderate persistent
Moderate persistent
Severe persistent
Moderate persistent
Severe persistent
Allergic rhinitis∗∗
No
Mild intermittent
Mild intermittent
No
Mild intermittent
Eczema∗∗∗
Mild
Previous
Previous
Moderate/severe
Moderate
ACT (0–25)
14
17
18
15
17
PedsQoL
84.8
65.5
67.8
68
66
CARATkids
NA
10
10
NA
3
SCORAD
10.9
NA
NA
60
37
Culprit food allergen(s)
Milk, egg, walnut, hazelnut, peanut, almond, sesame, pine seed, fish
Milk, egg, fish, wheat
Milk, egg, peanut, hazelnut, fish, shellfish, soy
Egg, peanut, hazelnut, LTP
Milk, egg, fish, wheat
N. FIA in life-time
3
1
2
3
1
Anaphylaxis triggers
Peanut, milk, baked egg
Baked milk
Milk, egg
Hazelnut, peanut, egg
Baked milk
Total sIgE (kU/L)
2391
4020
3112
3511
6706
OFC food 1
Food
Baked egg
Baked egg
Baked milk
Lentil
Wheat
sIgE (kU/L)
Egg white 16,1; egg yolk 10,6; ovomucoid 0,47; ovoalbumin 21,6
Egg white 13,4; egg yolk 7,16
>100
28
>100
NOAEL (mg)
2.09
20.88
260
58.65
4050
LOAEL (mg)
6.26
62.64
390
175.95
6750
Type of reaction
Moderate scratching, throat tightness and wheezing
Oral itching, abdominal pain
Orticaria with severe generalized involvement, hoarseness, one episode of emesis
Itchy mouth, one episode of emesis
Mild complaints of abdominal pain, one episode of emesis
Itchy mouth, throat tightness, rubbing nose and eyes, frequent sniffing
Itchy mouth, rubbing nose and eyes, frequent sniffing, faint erythema
Abdominal pain
Abdominal pain and emesis
Drugs administered
Prolonged observation
Steroids i.v., antihistamines i.v.
Steroids i.v., antihistamines i.v.
Prolonged observation
Steroids i.v., antihistamines i.v.
∗according to GINA classification (24).
∗according to ARIA (Allergic Rhinitis and its Impact on Asthma) (25).
∗according to SCORAD classification (17).
List of abbreviations: ACT, Asthma Control Test; FIA, Food-Induced Anaphylaxis; CARATKids, Control of Allergic Rhinitis and Asthma Test for Children; LOAEL, Lowest Observed Adverse Effect Levels; LTP, Lipid Transfer Protein; N., number; na, not applicable; NOAEL, No Observed Adverse Effect Level; OFC, oral food challenge; PedsQoL, Pediatric Quality of Life; SCORAD, SCORing Atopic Dermatitis; sIgE, specific Immunoglobulin E
IgE-selective immunoadsorption (IgE-IA) and IgE kinetics
Patients received 2 to 4 sessions of selective IgE-immunoabsorption: 1 patient received 2 (patient #1), 2 patients 3 (patients #2 & #5), and the remaining 2 underwent 4 sessions (patients #3 & #4), specifically.
Decrease in the IgE levels at each session was similar in all patients, with a mean IgE reduction per cycle of 1958.87 kUI/L. After the cycle sections, total IgE dropped from 3948 ± 1652.7 (mean ± SD) to 360.8 ± 71.9 kUI/L (−10.9 folds; p = 0.01). Overall, IgE-IA induced an average IgE reduction by 90% (Fig. 2, Fig. 3, Table S2).
Fig. 2Total IgE kinetics during IgE – immunoadsorption. Trajectories represent the longitudinal evaluation of total IgE during the IgE-immunoadsorption cycle and assessed before and immediately after each session at individual level (n = 5)
Fig. 3Concentration of serum total IgE(kUI/L) across the entire IgE-immunoadsorption cycle. Absolute total IgE-levels (y-axis: kUI/L) are shown as box-and-whisker plots for the first (pre-IgE IA) and the last visits (post-IgE IA)) of the entire treatment cycle (x-axis). The box-and-whisker plot on the left side (pre-IgE IA) shows IgE levels immediately before the first IgE-immunoadsorption session with individual values represented each as an hexagon; the box-and-whisker plot on the right side (post-IgE IA) shows IgE levels immediately after the last IgE-immunoadsorption session, with individual values represented each as a rhombus. Median, 0th (minimum) and 100th (maximum) percentiles of serum total IgE-levels are shown for both time points. The dashed lines connect individual values for each patient. Significant differences between start and end of the entire cycle of the IgE-immunoadsorbtion procedure are indicated (∗∗∗p ≤ 0.01)
Each patient underwent 2 OFCs for each of the main allergenic foods based on clinical history, immediately before and after the entire cycle of IgE-IA. OFCs performed at the end of the apheretic procedures demonstrated an increase in the reactivity threshold and allowed patients to reintroduce tested foods in their diet in small quantities. Specifically, the threshold of reactivity (No Observed Adverse Effect Level, NOAEL) tested at OFCs for the culprit foods (four baked milk, two baked egg, one lentil, two hazelnut, and one wheat) increased from 21.5 (median, IQR 1.5–82.6) protein milligrams to 1114.99 (837.2–4222.8) milligrams (P < 0.001); overall, it increased up to 51.8 times from baseline. Eight out of 10 OFCs were negative after IgE-IA (Table 3).
Table 3Individual thresholds for food allergens at oral food challenges performed before and immediately after the IgE immuno-adsorption.
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
pre-IA
post-IA
pre-IA
post-IA
pre-IA
post-IA
pre-IA
post-IA
pre-IA
post-IA
OFC food 1
Food
Baked egg
Baked egg
Baked milk
Lentil
Wheat
NOAEL - single dose (mg)
2.088
584.64
20.88
584.64
260
390
58.65
4685.1
4050
6750
LOAEL - single dose (mg)
6.264
NA
62.64
NA
390
NA
175.95
NA
6750
NA
NOAEL - cumulative dose (mg)
2.088
1114.99
29.232
1114.99
447.2
837.2
82.11
7289.16
6311.25
13061.3
LOAEL - cumulative dose (mg)
8.352
NA
91.872
NA
837.2
NA
258.06
NA
13061.3
NA
OFC food 2
Food
Baked milk
Baked milk
Hazelnut
Hazelnut
Baked milk
NOAEL - single dose (mg)
1.3
130
0
39
69
2070
13.8
2070
0
390
LOAEL - single dose (mg)
3.9
260
1.3
130
138
NA
69
NA
1.3
NA
NOAEL - cumulative dose (mg)
1.3
187.2
0
57.2
82.8
4222.8
13.8
4222.8
0
837.2
LOAEL - cumulative dose (mg)
5.2
447.2
1.3
187.2
220.8
NA
82.8
NA
1.3
NA
List of abbreviations: IA, IgE-immunoapheresis; LOAEL, Lowest Observed Adverse Effect Levels; NA, Not Applicable; NOAEL, No Observed Adverse Effect Level
Patients underwent continuous clinical visits, including the evaluation of the control of allergic comorbidities. Overall, they experienced a prompt and global improvement with reduced need of relief therapies (eg, β2-agonists, topical and systemic steroids) in terms of atopic dermatitis [SCORAD
(mean ± SD), 7.67 ± 4.04 pre-IA→ 1.3 ± 2.3 post-IA; with 0 representing optimal control], and asthma [ACT (mean ± SD), 14.6 ± 2.3 pre-IA→ 19.4 ± 4.8 post-IA; normal >19], as well. Health-related quality of life improved after IgE-IA when compared to baseline, with an immediate reduction of the anxiety and worries of the children and their families (Table 4).
Table 4Score values of allergic comorbidities assessed before and after IgE-immunoadsorption at individual level.
Patient
ACT
SCORAD
PedsQoL
CARATkids
pre
Post
pre
post
pre
post
pre
post
1
14
20
10.9
8.9
84.8
90.2
NA
NA
2
17
23
NA
NA
65.5
86.9
10
0
3
17
25
NA
NA
67.8
90
10
4
4
12
14
60
49.8
68
90.9
NA
NA
5
13
15
37
16.8
66
90.9
3
0
List of abbreviations: ACT, Asthma Control Test; CARATKids, Control of Allergic Rhinitis and Asthma Test for Children; na, not applicable; PedsQoL, Pediatric Quality of Life Inventory; SCORAD, SCORing Atopic Dermatitis
Immunoadsorptions were very well tolerated. Mild deviations of some laboratory parameters were observed. They were potentially caused by dilution with physiologic sodium chloride solution used for displacement of plasma prior to regeneration of the adsorber during each cycle and some unspecific plasma loss during the procedure. They were clinically irrelevant and resolved without any treatment. During the follow-up evaluations, hematocrit, albumin, total protein, and immunoglobulin classes and subclasses in serum values normalized and were back to baseline at 1 month follow-up visit (Table 5).
Table 5Main immunological data detected in each patient pre- and post- IgE-immunoadsorption.
pre-IgE-IA
post-IgE-IA
pre-IgE-IA
post-IgE-IA
pre-IgE-IA
post-IgE-IA
pre-IgE-IA
post-IgE-IA
pre-IgE-IA
post-IgE-IA
pre-IgE-IA
post-IgE-IA
pre-IgE-IA
post-IgE-IA
pre-IgE-IA
post-IgE-IA
pre-IgE-IA
post-IgE-IA
Patient
Hb (g/dl)
Ht (%)
PLT (×10³/uL)
Eo (/uL)
albumin (mg)
calcemia (mg)
IgA (mg/dL)
IgG (mg/dL)
IgM (mg/dL)
1
13.5
12.6
41.2
37.1
161
118
430
460
4.5
4.3
10.2
9.8
90
92
961
832
77
58
2
15.1
14.6
45.9
43.9
252
135
1320
720
4.4
3.7
9.4
9.4
123
92
1239
913
83
50
3
13.3
13.2
40.1
39.3
282
282
100
380
4.6
3.2
10.2
9.1
157
100
701
405
64
60
4
14.5
13.7
42.6
40.5
414
272
400
60
4.2
4.1
9.7
9.4
92
86
858
809
89
81
5
13.1
12.5
40
36.2
206
78
680
700
3.4
3
9.8
9.6
92
53
1041
625
135
61
List of abbreviations: Eo, eosinophils; Hb, hemoglobin; Ht, hematocrit; IgE-IA, IgE-immunoadsorption; PLT, platelets
Our pilot study demonstrates the therapeutic efficacy and safety of IgE-IA in pediatric patients suffering from multiple severe food allergies. The efficacy is shown both in terms of laboratory results (eg, mean IgE-reduction rate of 90.86%) and clinical data (the threshold of reactivity increased up to 51.8 times from baseline, as well as clinical improvement of allergic comorbidities). We have previously showed that IgE-IA decreased IgE levels and improved the patient's allergic condition in a single boy, whose case has not been included in this study cohort.
IgE-IA appears to be able to reduce the risk of anaphylaxis in multiple food allergy and, when IgE titers are high, to open the way to treatment with biological treatment. Previous studies
Immunoglobulin E–selective immunoadsorption reduces peripheral and skin-bound immunoglobulin E and modulates cutaneous IL-13 expression in severe atopic dermatitis.
have already confirmed that IgE-IA is safe, especially for the infection risk. Adverse event of IgE-IA procedure may rely on the specificity of selective depletion of different serological components, such as immunoglobulin of classes different from IgE. Temporary reductions of the levels of IgA, IgG, and IgM had already been highlighted in other studies that described the use of IgE-IA.
This reduction might be mainly related to the unspecific loss of proteins occurring due to the repeated the elution processes of the aphaeresis procedures.
Immunoglobulin E–selective immunoadsorption reduces peripheral and skin-bound immunoglobulin E and modulates cutaneous IL-13 expression in severe atopic dermatitis.
Certainly, the variation of laboratory parameters during IgE-IA is much less relevant than those happening in the course of other unselective aphaeretic techniques. In our cohort, this variation was transient and resolved without any treatment within a few days and no clinical consequences (eg, infections). Our results are aligned with reports from a few cases series previously reported on IgE-IA in patients with allergic diseases.
Our data highlighted that selective IgE-immunoadsorption is as effective as other non-selective aphaeretic procedures, but it is safer, particularly with regard to infection risk especially when peripheral venous accesses are used. Therefore, the main advantage of IgE-IA is that, except the ones intentionally removed, all plasmatic substances are overall preserved. Of note, the adherence of patients was high, as indicated by the absence of drop-outs, although each IA section required 3 h on average and two peripheral venous accesses.
Our study has some limitations. One is the small number of participants due to the severity of the disease and the selectivity of inclusion criteria. However, data showed that the decrease of IgE levels, proportionally to the baseline situation of each patient, had a similar trend among patients. Nevertheless, we also saw that after the depletion of circulating IgE, they tend to go up quickly. The mechanisms underlying this trend need to be clarified; notwithstanding, one could speculate that the IgE-production is not interrupted by the IgE-IA and in highly atopic patients is usually increased. Conversely, IgE+ plasma cells might unlikely produce such a massive IgE-production in such a short timeframe. Therefore, the rapid IgE increase could depend on the redistribution of interstitial IgE in the intravascular compartment. This could also explain why consecutive IgE-IA sessions can lead to ever-lower levels of circulating IgE.
Further studies will be necessary to explain the mechanism(s) responsible for the IgE refilling despite their mechanic depletion and could pave the way for new potential therapeutic targets.
Based on current knowledge and our results, 2 possible therapeutic scenarios emerge. On one side, when serum total IgE levels are particularly high, and it is difficult to reach and maintain lower values than 1500 kUI/L, it could be possible to repeat IgE-IA sessions at regular intervals. This could allow to maintain IgE levels and oral tolerance stable as long as possible, as already assessed in patients with severe atopic diseases.
The other therapeutic option concerns severe allergic patients that could benefit from anti IgE-treatment but are not eligible for this treatment because of their high IgE levels. In these patients, IgE-selective immunoadsorption could be used to reduce the IgE level under 1500 kUI/L and thereafter to commence anti IgE-treatment. The anti-IgE monoclonal antibody will bind the newly produced circulating IgE and keep their level reduced with the aim to further increase the patients’ threshold of reactivity and keep it over time. A similar strategy was analyzed in studies on patients with severe asthma
and they highlighted the efficacy of the combination of an apheretic procedure (non-selective in this case) with a monoclonal antibody.
In conclusion, our study shows that IgE-selective immunoadsorption has been an efficient therapeutic option in patients with persistent multiple food allergy, severe asthma, and high serum IgE levels. These patients could benefit by tolerating a larger amount of culprit food(s), better asthma control, and health-related quality of life. However, given the rapid rebound of the IgE level, we expect this effect to be transitory and not lasting over time. Since this is a prospective study, we evaluated the immediate effects of the treatment, while the long-term effects in this kind of patient will be investigated in further studies and maybe on a larger scale.
Conclusions
Food allergy may be a severe and potentially fatal disease that still does not have a cure. The results of this study highlight that IgE-IA could be a strategy to treat well-selected pediatric patients with persistent multiple food allergy and high levels of IgE to reduce the risk of severe anaphylaxis. IgE depletion through sessions of selective immunoadsorption determines an immediate clinical improvement and an increase of food tolerance in children with severe asthma, anaphylaxis and IgE levels>2300 kUI/L. The procedure was safe and well tolerated in our population.
Furthermore, anti IgE-treatment is emerging as a potential therapeutic approach in patients with food allergy, mainly if with concomitant allergic comorbidities such as asthma. IgE-IA could be used preliminarily to anti IgE-treatment, when its commencement would be otherwise contraindicated by too high serum total IgE levels. Further well-designed clinical investigations on a higher sample size are needed to confirm our results and to further improve treatment efficacy.
Abbreviations
OFC, Oral Food Challenge; NOAEL:, No Observed Adverse Effect Level; FA, Food Allergy; IgE-IA, IgE-selective immunoadsorption; SCORAD, SCORing Atopic Dermatitis; CARATKids, Control of Allergic Rhinitis and Asthma Test for Children; ACT, Asthma Control Test; PedsQL:, Pediatric Quality of Life Inventory™; AE, Adverse Events.
Acknowledgments
We thank Dr. Giovanna Del Principe, Dr. Stefania Lazzaro, and Dr. Antonella Meschini for clinical contribution.
Funding
Donation by the Bambino Gesù Children's Research Hospital for the project entitled “Management of severe allergy sufferers with difficult asthma and multiple food anaphylaxis through IgE-immuno apheresis preparatory to omalizumab for the drastic improvement of the quality of life of severely allergic small patients” (“Gestione di gravi allergici con asma difficile ed anafilassi alimentari multiple tramite immuno aferesi IgE propedeutica ad omalizumab per il drastico miglioramento della qualità della vita di piccoli pazienti gravemente allergici”). This work was supported also by the Italian Ministry of Health with “Current Research” funds.
Availability of data and materials
Only with the authors.
Author contributions
AF conceived the study. SA designed the manuscript. SA, LD, VP, BM, GL performed and supervised the collection of clinical data in the study. SA, AC and ALP performed the data management. SA and ALP performed statistical analyses. AF, LD, VP, BM, GL, SA participated in the clinical coordination, patients’ recruitment/treatment. SA, AC and ALP wrote the first draft of the paper. SA reviewed and provided feedback. All authors read and approved the final version of the manuscript.
Ethics approval
The study was submitted to and approved by the local Research Ethics Committee at Bambino Gesù Children's Research Hospital (approval n. 599/18).
Authors’ consent for publication
All authors have approved the submission of this manuscript.
Declaration of competing interest
Authors declare no conflict of interest related to this work.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
Standardizing double-blind, placebo-controlled oral food challenges: American academy of allergy, asthma & immunology–European academy of allergy and clinical immunology PRACTALL consensus report.
GINA Global Strategy for Asthma Management and Prevention (Update 2021) Avalaible on: Reports - Global Initiative for Asthma - GINA (ginasthma.org) Last access on the 27th of October 2022.
Immunoglobulin E–selective immunoadsorption reduces peripheral and skin-bound immunoglobulin E and modulates cutaneous IL-13 expression in severe atopic dermatitis.
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