Hemant Bommidala

Edgar Zambrano

Vincent Maillet

Xavier Carbonneau

FP94-2022-joksimovic DEVELOPMENT OF A PANEL METHOD FOR PRELIMINARY DESIGN OF AERO-PROPULSIVE SYSTEMS

The paper presents development of a low-fidelity tool capable of calculating pressure and velocity field of an aeropropulsive element (aerofoil and an integrated ducted propulsor). To that end, conventional panel method is extended by including the emanating propulsive jet as a part of the solid aero-propulsive geometry. The mathematical formulations and the algorithm used by the tool to characterise the propulsor and determine the jet shape are presented. Then, a series of results and parametric studies performed with the tool considering different input parameters are shown in order to demonstrate the potential of the tool to tackle a broad design space. Rudimentary validation is carried out by comparing the calculated lift coefficient at different angles of attack is compared with reference RANS CFD results; agreement between the two is observed, especially at low angles of attack.

INTRODUCTION

Civil aviation is currently estimated to contribute around 5% of the total anthropogenic impact [START_REF] Lee | The contribution of global aviation to anthropogenic climate forcing for 2000 to 2018[END_REF] to the radiative forcing. Rethinking whole airplane architectures and configurations thereof is in focus as a pathway to rendering the global industry compatible with environmental sustainability goals. This paper focuses on the innovative aeroplane concept subspace based on airframe-propulsive system synergies, in particular on concepts that employ propulsion distribution [START_REF] Kim | Distributed propulsion vehicles[END_REF]. Such forms rely on reducing the airplane mission energy requirements (and thus the emissions) by redistributing thrust across the airframe in order to seek higher vehicle-level efficiency. The sheer number of possible solutions still poses an important challenge in conceptual design decision-making process. One prominent subset of the aero-propulsive concept space explored previously at ISAE-SUPAERO is Boundary Layer Ingestion (BLI). [START_REF] Benichou | Numerical low-fidelity method for improved analysis of breakthrough aero-propulsive systems[END_REF] A review of BLI modelling methods assembled by Hendricks [START_REF] Hendricks | A Review of Boundary Layer Ingestion Modeling Approaches for use in Conceptual Design[END_REF] provides a useful insight that there are comparatively few methods to model BLI which fully couple external aerodynamics and propulsion. Moreover, analysis often relies on full CFD, which is computationally expensive in the context of conceptual design decision making.

The objective of the presented work is therefore to develop a low-order tool for identifying performance tendencies of aero-propulsive concepts within this vast design space by providing insight into correlations between propulsive power and aerodynamic performance for various geometries and at various operating conditions. The results can be used to robustly initialise preliminary design calculations that require more computationally expensive high-fidelity tools such as previously used by the authors, as presented in [START_REF] Benichou | Numerical low-fidelity method for improved analysis of breakthrough aero-propulsive systems[END_REF].

Further literature survey revealed previous works which ventured to use panel method modelling to provide simple models of specific aero-propulsive configurations. Albers [START_REF] Albers | Potential flow solution for a stol wing propulsion system[END_REF] carried out an analysis of two dimensional wing-fan system which consists of aerofoil with flaps, fans, distributed suction at the inlet and a jet sheet leaving from the flap trailing edge, for providing an incompressible potential flow solution using panel methods. Spence [START_REF] Spence | The lift coefficient of a thin, jet-flapped wing[END_REF] carried out analysis for an inviscid, incompressible flow for jet flapped aerofoils at low angles of attack by bounding the exhaust jet by vortex sheets to prevent its mixing with the main stream, with an experimental validation of the obtained results. This approach was a precise fit for the identified need for a tool to provide desired transparency of the possible aero-propulsive architectural space without resorting to computationally expensive modelling. An attempt was thus made to create a tool which would generalise the approach presented in the outlined references. For the time being, and throughout this paper, the work is constrained to two-dimensional analysis. To emphasise the contrast between the size of aero-propulsive design space and the computational time/power limits, the interested reader is referred to one such design space exploration by Wick et al. [START_REF] Wick | Integrated Aerodynamic Benefits of Distributed Propulsion[END_REF], carried out by employing 2D CFD modelling.

The paper is structured as follows: Section 2 lays out the basic principles behind the panel-method modelling at hand; Section 3 breaks down the assumptions and modelling approach; Section 4 provides the preliminary results obtained by the developed tool, and Section 5 provides provisional conclusions and comments on further work.

AERO-PROPULSIVE SYSTEM

This work defines an aero-propulsive system as an integral element composed of an airframe part and a propulsor and which can be expressed in multiple distinct configurations (e.g. blown wing or BLI on the suction or pressure surface, see [START_REF] Wick | Integrated Aerodynamic Benefits of Distributed Propulsion[END_REF]). Following the approach presented by Albers [START_REF] Albers | Potential flow solution for a stol wing propulsion system[END_REF] (cf. Section 3 for more details), the physical aero-propulsive geometry is complemented with a fictitious geometrical element representing the jet emanating from the system, which contributes to the overall aero-propulsive performance of the system. The equivalent body surface over which the potential flow is calculated is illustrated schematically in Fig. 1. The jet stream as it exits from the propulsor is at a higher total pressure than the surrounding fluid. For a portion of the exhaust jet the total pressure will be constant before undergoing a reduction in total pressure due increasingly important jet entrainment and mixing losses [START_REF] Albers | Potential flow solution for a stol wing propulsion system[END_REF] and [START_REF] Halsey | Methods for the design and analysis of jet-flapped airfoils[END_REF]. This portion of the exhaust jet and the aerofoil body are considered to be a part of the lifting surface in the developed model. Depending on the various flight conditions and propulsor power settings, the shape of this free jet is evaluated (details presented in subsection 3.4). The potential flow resolution for a defined configuration thus means calculating the velocity field on and external to the body for the combination of the following variables:

1. Free-stream velocity (V ∞ ), 2. Fan mass flow rate per unit span ( ṁ), 3. Propulsive system thrust per unit span (T ), 4. Flap angle (θ ),

Wing angle of attack (α).

The jet emanating from the propulsive element at a velocity V jet and an angle θ jet is included in the model as this allows to capture a pressure rise in the flow field. The propulsor (with the emanating jet) and the aerodynamic element are considered as a unified solid body, i.e. there is no flow entering or leaving through the surfaces and there is no mixing of the jet stream with the free stream.

As explained previously, this work attempts to employ panel method modelling. As in the traditional approaches for external flow field calculation, the body of interest is discretised into as a series of panel sheets where elementary flows and boundary conditions are imposed in such way that the body itself acts as a streamline. In the work presented in this paper, the modelled body is not a simple closed-contour aerofoil, but a complex shape which ingests a part of the external flow. The next section presents the underlying details.

DEVELOPMENT OF THE TOOL

The following sections provide the relevant elaboration of the different modules involved in the panel code developed for purpose of two-dimensional aero-propulsive design space exploration.

Mathematical Formulations for Higher Order Panel Methods

Three different types of elementary flow distributions have been considered in the current work:

1. Discrete source panel distribution, 2. Quadratic source panel distribution, 3. Linear vortex panel distribution.

Fig. 2 presents the nomenclature used for the representation of panel sheets. For a sheet of elementary flows, the i th panel between two nodal points given by (x i , y i ) and (x i+1 , y i+1 ) is characterised by the set of geometrical properties (δ i , φ i , β i , s i ) evaluated at the panel control point (X i ,Y i ). If s is the distance measured measured along the sheet in an edge view, the function λ = λ (s) or γ = γ(s) represents the source or vortex strength per unit length of the panel with an order O(λ (s)) or O(γ(s)) = 0, 1, 2, depicting a discrete, linear and quadratic strength variation of the elementary flows, respectively.

Discrete source panel distribution

An i th discrete source panel has a constant source strength distribution per unit length (λ (s) = λ i ). The normal and tangential velocities (V n,i ,V t,i ) induced at control point of i th panel due N similar panels are written as

V n,i = V ∞ cos β i + N ∑ j=1 λ j 2π an i, j (1)
V t,i = V ∞ sin β i + N ∑ j=1 λ j 2π at i, j (2)
an i, j = an i, j (x i , y i , X j ,Y j , φ i , φ j , s j )

at i, j = at i, j (x i , y i , X j ,Y j , φ i , φ j , s j )
where the functions an i, j and at i, j are referred from [START_REF] Katz | Numerical (Panel) Methods[END_REF].

Quadratic source panel distribution

For any i th quadratic source panel, the source strength per unit length varies as a quadratic function of distance s measured along the panel λ (s) = a q s 2 + b q s + c q

The normal and tangential velocities (V n,i ,V t,i ) induced at control point of i th panel due N similar panels are written as

V n,i = V ∞ cos β i + n ∑ j=1 λ j+1 2π An i, j + λ j+ 1 2 2π Bn i, j + λ j 2π Cn i, j V t,i = V ∞ sin β i + n ∑ j=1 λ j+1 2π At i, j + λ j+ 1 2 2π Bt i, j + λ j 2π Ct i, j
An i, j , Bn i, j , Cn i, j = f n (x i , y i , X j ,Y j , s j , φ i , φ j )

At i, j , Bt i, j , Ct i, j = f t (x i , y i , X j ,Y j , s j , φ i , φ j )
where λ i , λ i+1 are the source strength per unit length at panel control points and λ i+ 1 2 is the source strength per unit length at panel control point and the functions f n and f t are derived using similar methodologies used for discrete source panel methods described in [START_REF] Katz | Numerical (Panel) Methods[END_REF].

Linear vortex panel distribution

For any i th linear vortex panel, the vortex strength per unit length varies as a linear function of distance s measured along the panel γ(s) = a l s + b l

The normal and tangential velocities (V n,i ,V t,i ) induced at control point of i th panel due N similar panels are written as

V n,i = V ∞ cos β i + N ∑ j=1 ( γ j 2π Dn i, j + γ j+1 2π En i, j ) (3) V t,i = V ∞ sin β i + N ∑ j=1 ( γ j 2π Dt i, j + γ j+1 2π Et i, j ) (4)
Dn i, j , En i, j = g n (x i , y i , X j ,Y j , s j , φ i , φ j ) Dt i, j , Et i, j = g t (x i , y i , X j ,Y j , s j , φ i , φ j )
where γ i , γ i+1 are the vortex strength per unit length at panel control points and the function g n and g t are derived using the similar methodologies used for discrete vortex panel methods described in [START_REF] Katz | Numerical (Panel) Methods[END_REF].

Panel Method Implementation for the Aero-Propulsive Element

The current configuration is summarised schematically in Fig. 3. The base aerofoil, nacelle aerofoil, upper jet, lower jet, velocity inlet and velocity outlet surfaces of the composite body are discretised into n base , n nacelle , n upper , n lower , n inlet and n outlet panels respectively. The resulting total number of panels then amounts to

n total = n base + n nacelle + n upper + n lower + n inlet + n outlet (5)
Base aerofoil, nacelle aerofoil, upper and lower jet surfaces are described using linear vortex panels, which requires (n lower + n base + n nacelle + n upper + 2) variables to describe the panel's vortex strength. Velocity inlet and velocity outlet surfaces are described using quadratic source panels, which requires (2(n inlet + n outlet ) + 2) variables to describe the panel's vortex strength.

The total number of variables required for the inviscid flow field calculation are:

VAR count = n lower + n base + n nacelle + n upper + 2(n outlet + n inlet ) + 4 (6)
From the mathematical formulations for the elementary flows derived in Section 3.1, the normal/tangential velocity induced at the control point of the i th panel by all the remaining panels is given as Figure 3: Elementary aero-propulsive configuration description and parametrisation.

V n,i = V ∞ cos β i + n lower +n base ∑ j=1 ( γ j 2π Dn i, j + γ j+1 2π En i, j ) + n outlet ∑ j=1 λ j+1 2π An i, j + λ j+ 1 2 2π Bn i, j + λ j 2π Cn i, j + n nacelle +n upper ∑ j=1 ( γ j 2π Dn i, j + γ j+1 2π En i, j ) + n inlet ∑ j=1 λ j+1 2π An i, j + λ j+ 1 2 2π Bn i, j + λ j 2π Cn i, j (7)
V t,i = V ∞ cos β i + n lower +n base ∑ j=1 ( γ j 2π Dt i, j + γ j+1 2π Et i, j ) + n outlet ∑ j=1 λ j+1 2π At i, j + λ j+ 1 2 2π Bt i, j + λ j 2π Ct i, j + n nacelle +n upper ∑ j=1 ( γ j 2π Dt i, j + γ j+1 2π Et i, j ) + n inlet ∑ j=1 λ j+1 2π At i, j + λ j+ 1 2 2π Bt i, j + λ j 2π Ct i, j (8)
This calls for the development of a system of equations of the same size as that of the VAR count . The following boundary conditions are utilised:

1. Zero normal velocity at the control points of the panels located on base and nacelle aerofoil surface, upper and lower jet surface:

V n,i = 0 ( 9
)
where i corresponds to the panels located on the surfaces mentioned earlier and this boundary condition results in a total of (n lower + n base + n nacelle + n upper ) number of equations.

2. Velocity inlet boundary conditions on the inlet surface:

V x,i = -V n,i sin φ i +V t,i cos φ i = V inlet,i (10)
V y,i = -V n,i cos φ i +V t,i sin φ i = 0 ( 11
)
where i corresponds to the panels located on the velocity inlet surface. The velocity V inlet,i = V prop,inlet is calculated from the propulsor operating conditions with an assumption of a uniform inlet velocity distribution across the inlet surface. This boundary condition results in a total of 2 (n inlet ) number of equations.

3. Velocity outlet boundary conditions on the outlet surface:

V x,i = -V n,i sin φ i +V t,i cos φ i = V jet,i cos (θ 1 + α) (12) V y,i = -V n,i cos φ i +V t,i sin φ i = V jet,i sin (θ 1 + α) (13)
where i corresponds to the panels located on the velocity outlet surface. The velocity V jet,i = V prop,outlet is calculated from the propulsor operating conditions and with an assumption of negligible drop in outlet velocity for the portion of the jet acting as a lifting surface. This boundary condition results in a total of 2 (n outlet ) number of equations.

Kutta boundary condition on the jet upper and lower

surfaces in such a way that the flow leaves the jet surface smoothly resulting in the velocities on the top and bottom surface to be finite and equal in magnitude and direction:

|V t,n1 | = |V t,n2 | (14)
where n1 and n2 corresponds to the panels located in the immediate vicinity for the velocity outlet surface as shown in Fig. 3.

5. Equivalent Kutta boundary condition for the velocity inlet surface for ensuring the symmetrical flow distribution over the velocity inlet surface:

|V t,n3 | = |V t,n4 | (15)
The tangential velocities on the panels in the immediate upstream of the velocity inlet surface are finite and equal in magnitude and direction.

6. Tangential velocity boundary condition for ensuring a smooth transition between (base aerofoil, lower jet.) and (nacelle aerofoil and upper jet surface):

V t,n5 = V t,n6 (16)
V t,n6 = V t,n8 (17)
where n5, n6, n7 and n8 correspond to panels in the immediate vicinity of the surface intersection points (P1, P2) as shown in the Fig. 3.

The boundary conditions 9 to 17 results in the formation of a system of equations of size,

EQN count = n lower + n base + n nacelle + n upper + 2(n outlet + n inlet ) + 4 = VAR count (18)
This system can be linearised in terms of the unknown variables of the system and can be solved using conventional matrix inversion algorithms.

Propulsor Characterisation

To correlate the jet speed to the power added to the flow by the fan, a simple propulsor assembly is modelled. It is composed of an inlet, a fan in a duct and a nozzle, with no information included on power source component (e.g. electric motor in a distributed propulsion configuration). A 0D thermodynamic model of the fan is developed using the well-established conventional jet engine modelling approach as described in e.g. [START_REF] Mattingly | Aircraft Engine Design, Second Edition[END_REF], using the standard station numbering (Fig. 4). The propulsor performance is characterized using the following inputs:

1. Fan power setting, (P) 2. Fan isentropic efficiency, (η is ) 3. Nozzle static pressure condition. (P s9 ) Once flight operating conditions, fan performance inputs and heat (adiabatic) and pressure loss assumptions are specified, fluid state in terms of pressures and temperatures at different stations can be calculated by correlating the fan power to the enthalpy and total temperature and using it to find the fan pressure ratio via the fan efficiency. With the resulting temperatures and pressures, and using the adapted nozzle hypothesis, the resulting speeds and propulsor thrust can be deduced. To complete the information, the mass flow rate passing through the adiabatic fan and the perfectly expanded nozzle needs to be iterated upon. The iterations start with an initial guess on the mass flow rate ( ṁ1 ) at the fan inlet station. With this initial mass flow rate estimate and fan performance inputs, the thermodynamic properties at different stations are evaluated using the standard 0D thermodynamic approach as described above. Once the conditions at the nozzle exit (station 9) are calculated, it allows to deduce the local mass flow using the continuity equation. This result is compared with the initial mass flow rate guess; since no additional mass is added to the system the mass flow rate must be constant thoughout the propulsor. Depending upon the difference between the initial guess ( ṁguess,1 ) and the calculated ( ṁ9 ), the initial guess is corrected and the process is iterated until a convergence between the two mass flow rates is obtained.

After a mass flow rate convergence is obtained ( ṁ1 = ṁconv,1 ), the velocity at the station 1 can be finally determined using the same system of equations, in summary:

ṁconv,1 = P t1 √ T t1 area 1 γ r g 0.5 M 1 1 + γ -1 2 M 2 1 -γ+1 2(γ-1) T s1 = T t1 1 + γ-1 2 M 2 1 P s1 = P t1 T s1 T t1 γ γ-1 ρ 1 = P s1 r g T s1 V 1 = ṁconv,1 ρ 1 area 1 (19)
Finally, the velocities evaluated at the station 1 and station 9 can be used as boundary conditions in the panel method (Eqs. 10, 12 and 13) for calculation of vorticity and source strength distributions over different panels of the aero-propulsive element.

NB: as there is no boundary layer modelling in this first approach it justifies modelling of the propulsor as if it were in isolation, i.e. without any inlet flow distortions and the related mass flow deficit. This will be improved upon in the future development.

Algorithm for Jet Shape Determination

Aerodynamic advantages of the aero-propulsive element under consideration are significant due to the presence of the jet element. A high lift is not only achieved due to the vertical component of the jet momentum but also due to the additional pressure lift created by the aerofoil which arises from the asymmetry created in the main stream due to the presence of jet. In the current study, as mentioned earlier the portion of the jet exhaust with a constant total pressure acts as a lifting surface and the shape taken by the exhaust jet in the free field is critical in deciding the asymetricity introduced by the flow field and increasing the lift of the configuration.

The shape of the jet is defined using the nomenclature defined in the Fig. 3 in a free stream with a flow at velocity V ∞ with an angle of attack α, using the following variables:

1. Jet depth of penetration (L dop ), 2. Total length of the jet (L T ), 3. Jet exhaust angle (θ ), 4. Jet asymptote angle at the trailing edge (θ 1 ), 5. Jet thickness (t jet ), 6. Control Point 1: Point of the jet emanation (x 1 , y 1 ), 7. Control Point 2: Point of jet diffusion (x 2 , y 2 ).

The shape of the jet is determined using the following criteria:

1. The jet shape is assumed to be cubic functionshaped; 2. The depth of penetration of the jet (L dop ) is evaluated such that the vertical component of the thrust developed at the fan nozzle outlet balance the integrated vertical pressure force on the free jet; 3. The length of the jet (L T ) is extended until the integrated vertical component of the force on the last 5% of the jet is negligible for a chosen jet asymptote angle (θ 1 ); 4. A low degree of spatial variation between the control point 2 position obtained from the (L dop , L T ) pair obtained via the previous two criteria and the control point 2 position obtained from the pressure fields developed over the jet surfaces.

Starting with an initial guess on (L dop , L T ) pair, defined jet exhaust angle (θ ) and jet asymptote angle (θ 1 ), the shape of the jet is defined as:

f jet (x) = ax 3 + bx 2 + cx + d (20)
and the four coefficients a, b, c, d in the jet shape function ( f jet ) are determined using the following boundary conditions: Independent of the cubic shape assumption of the jet, the location of the control point of the jet can also be calculated from the pressure fields developed over its surfaces, in such a way that the centrifugal forces developed due to the radius of curvature of the jet are balanced by the developed pressure fields over the jet. As described by Herold [START_REF] Herold | A two-dimensional, iterative solution for the jet flap[END_REF], after the division of the exhaust jet into several small polar elements, the author derived the change in polar element jet angles (φφ * ) for a single polar element in terms of pressure differential across the element (P s1 -P s2 ) using radial force balance equations and irrotational flow assumptions for the jet exhaust flow as

φ = φ * + 2 arcsin ( 2ρ jet t jet V 2 jet a(P s1 -P s2 ) ) (21)
At any given operating condition, after the jet is discretised into several smaller polar elements, using the Eq. 21, the variation in jet angle (φ ) can be evaluated for each discrete polar element of the jet. These evaluated jet angles can be utilised reconstruct the shape of the jet and re-evaluate the position of the control point 2 (point of jet diffusion). Under the fourth criterion of the jet shape determination algorithm, the spatial variation between the control point 2 evaluated using the developed pressure fields and the control point 2 evaluated using the second and third criterion should be minimal.

BASE CASE RESULTS

Base Case Description

The verification of the developed panel code method has been performed against at the similar operating and geometric configurations of the aero-propulsive assembly considered by Benichou et.al [START_REF] Benichou | Numerical low-fidelity method for improved analysis of breakthrough aero-propulsive systems[END_REF] for evaluating the impact of BLI propulsion on airplane aerodynamic performance. The properties of the aero-propulsive configuration base case are considered as follows: free-field conditions (P ∞ , M ∞ , T ∞ , α): (101325 Pa, 0.11, 288.15K, 0 • ), configuration geometric properties: base aerofoil: ms0313, nacelle aerofoil: NACA0012, c base : 2.0m, c nacelle : 0.84m, nacelle LE (x,y): (0.927m, 0.466m), nacelle relative twist angle (τ): -4.2 • , jet exhaust angle (θ ): 5 • , jet asymptote angle (θ 1 ): 5 • , fan power: 123.318 kW, fan isentropic efficiency (η is ): 0.84.

Aero-propulsive element RANS model

A 3D CFD Reynolds-Averaged Navier-Stokes (RANS) simulation was provided for validation purposes. The CFD case consists in the model of an aero-propulsive system assessing a BLI configuration. To that end, the model employs a Body-Force Modelling approach to simulate the propulsor operation. The 3D model of the aeropropulsive system is meshed using an unstructured mesh approach for both volume and surface summing up more than 17.3 millions cells through the whole domain. The RANS CFD case was set to simulate the aero-propulsive system at take off conditions, i.e. at Mach number of 0.11 and propulsor at full power configuration. The lift coefficient at various angles of attack was extracted after simulation convergence to be directly compared against the panel method tool in order to verify the accuracy of the code. Other physical quantities such as inlet/outlet mass flow, static pressures, velocities and temperatures were also extracted from this RANS CFD case as it would help to further evaluate the code.

Propulsor Modelling Studies

As explained in the subsection 3.3, the fan performance has been characterised in terms of input power (P, polytropic efficiency (η poly ) and nozzle exit plane static pressure (P s9 ). While the first two parameters are user input, the nozzle exit plane static pressure has to be evaluated from the average static pressure measured from the base and nacelle aerofoil trailing edge, which are highly sensitive to the behaviour of boundary layers on the base and nacelle aerofoils. As the developed inviscid panel method cannot capture the development of boundary layers on the surfaces and potential flow separations at higher angles of attacks, the average static pressure at nozzle exit plane measured from the RANS simulation of the base case and is taken to be constant across different power settings considered in this study. From the data given in Tab. 1, we can draw a conclusion that nozzle exit static pressure is independent of angle of attack for a constant power setting.

Panel Size Dependence Study

A panel size dependence study was performed to determine of the mean panel length which ensures the independence of the calculated lift coefficient from the number of panels used to describe the body. 1D panelling of the aero-propulsive element is performed with the help of an open source software GMSH [START_REF] Geuzaine | A threedimensional finite element mesh generator with built-in pre-and post-processing facilities[END_REF]. Panel size is controlled with the help of a factor called h, which is inversely proportional to the number of panels required to describe the surfaces. As seen in Fig. 5, for h = 0.6, a satisfactory convergence in lift coefficient is obtained, with a total of 1012 panels required to describe the body. Any further decrease in the factor h leads to a significant increase in the number of panels, which increases the computational intensity without a tangible lift coefficient variation. The observed erratic behaviour is attributed to use of constant step size throughout the convergence study. For the purposes of this preliminary tool verification the result was deemed satisfactory, and a more in-depth analysis will be carried out in the future development of the tool.

PARAMETRIC STUDIES

A range of parametric studies was carried out to assess the robustness of the developed tool across the design space. A representative sample of possible variation consists of study of angle of attack and jet exhaust angle influence, airframe parameter influence and the propulsive power influence, each presented in their respective subsections below.

Lift Coefficient Sensitivity to Angle of Attack (α) and Jet Exhaust Angle (θ )

Example parametric studies are performed, as function of angle of attack α and jet exhaust angle θ . The results (Fig. 6) indicate a linear variation in lift coefficient (Cl) with α, with slope of 0.254 deg -1 . Moreover, with increasing α, the depth of penetration of the jet also increases linearly with a slope of 0.076 deg -1 . A linear relationship between α and Cl is expected because the sources responsible for the introduction on non-linearity in the relationship, mainly the flow separation due to development of a boundary layer on the aerofoil surfaces, are not modelled in this inviscid panel code method. Fig. 7 presents the calculated linear relationship between the jet exhaust angle variation and Cl at a constant α with a slope of 0.143 deg -1 . It can be inferred from the analysis that Cl of this configuration is more sensitive to changes in α rather than the θ . An increase in Cl is expected with increasing θ because at higher exhaust angles, the vertical component of the jet reaction force increases, combined with an increase in curvature of the equivalent aero-propulsive element.

Airframe Parametric Studies

For understanding the effect of the base and nacelle aerofoil geometry variations on the total lift generated by the aero-propulsive element, 2 geometric parametric studies are presented (Fig. 8).

Nacelle twist angle variation

Variation in the relative twist of the nacelle aerofoil with respect to base has an inflection point at the relative twist of -4.2 • (base case) (Fig. 8(a)). A negative nacelle aerofoil twist corresponds to a situation where the nacelle aerofoil is at higher angle of attack compared to the base aerofoil. A clear increase in Cl is observed for small relative angle of attacks, as the lift generated by nacelle aerofoil increases. But a higher relative twist results in the stagnation point to move downstream on the suction side of the nacelle aerofoil resulting in a decrease in nacelle lift and hence the overall configuration lift.

Propulsor inlet ramp length variation

The inlet ramp of the current aero-propulsive configuration is defined as a concave surface (Fig. 3). As the flow follows the shape of the body, a low pressure region is created at the start of the ramp when the flow turns. But downstream, as the flow has to follow a concave surface, a region of adverse pressure gradient is created on the concave surface of the ramp. So as seen from the Figure 8(c), smaller ramp lengths have a similar total lift as the lift gain due to low pressure region is balanced by the adverse pressure gradient formed. However, if the length Figure 9: Velocity field at α = 0 • at 75%, 100% and 150% power respectively. of the ramp increases, the drop in lift will be significant due to a significantly longer portion of ramp surface being exposed to adverse pressure gradient. For this reason, the results presented in Fig. 8(c) indicate a precipitous drop in lift for longer ramp lengths.

Propulsor Power Parametric Study

The variation in lift coefficient with propulsor power is shown in the Fig. 8(d). Power factor corresponds to the ratio between the study case fan power and base case fan power (i.e. 123.3 kW). With an increasing fan power, the nozzle exhaust velocity (V 9 ) increases, which increases the magnitude of reaction in the force balance criterion of jet shape algorithm. This will ultimately result an increase in Cl as observed in Fig. 8(d). Variation in static pressure and velocity fields with increasing fan power can also be observed (Figs. 10 and 9 respectively).

Pseudo-Validation with RANS CFD Simulations

Since no experimental setup is available at the moment, the authors resorted to a pseudo-validation of the tool results by comparing it to a limited set of data available from previous 3D RANS BFM CFD simulations [START_REF] Benichou | Numerical low-fidelity method for improved analysis of breakthrough aero-propulsive systems[END_REF]. Fig. 11 presents the respective lift coefficient results obtained from RANS CFD simulations and the panel method tool. At low angles of attack, the tool shows a relatively close agreement with the RANS CFD results. However, as the angle of attack increases, the gap between both numerical methods also increases. This was expected as the panel code solves only for the inviscid Euler equations whereas the RANS CFD simulation includes a viscous model to model the non-linearity effects introduced by the boundary layer development over the airfoil surfaces by modelling the entire spectrum of turbulent eddies using an kω SST turbulence model. It is reassuring that the results are of the same order of magnitude between the two, and futher efforts will concentrate on comparing the results across the broader design space in order to ascertain the potential for calibration of the developed tool.

CONCLUSIONS

The presented work is a first step in developing a loworder tool dedicated to capturing performance trends of a two-dimensional aero-propulsive system across large design space. Panel method was chosen to this purpose in order to leverage the robustness and efficiency traditionally associated to it, indispensable in conceptual design. The aero-propulsive system is defined by considering the airframe, the propulsor and the emanating jet as a single aerodynamic solid body in the panel code; the operating setting of the propulsor (i.e. its power) is correlated to the size and shape of jet, which influences the overall pressure field around the complex body. This is enabled by implementing a thermodynamic 0D model into the tool to characterise the propulsor performance along with an algorithm to determine the jet shape.

Results of the performed studies indicate that the code is able to determine the two dimensional potential flow solution for the defined aero-propulsive configuration and the shape of exhaust jet; for the moment, all calculations were carried out for a single flight condition representative of takeoff for a small commuter aeroplane. Parametric studies have been performed to verify the performance of the developed panel method tool at various off-design operating conditions. Finally, a comparison was made between the lift coefficients calculated with the developed panel method and a RANS CFD solver. A satisfactory match of the results was observed at lower angles of attack, but not at higher angles of attack, likely due to the inherent limitation of the employed inviscid model.

Ongoing and Further Work

Currently, a development of viscous-inviscid coupling is ongoing. The pressure and the velocity distributions around the aero-propulsive configuration obtained from this potential flow solution can be used to characterize the boundary layer growth and flow separations on different surfaces of the aerofoils. With the help of such a coupling, a more robust 0D thermodynamic model can be designed which directly uses the static pressure fields at the nacelle trailing edge as fan exit nozzle static pressure. From boundary layer parameters like displacement and the momentum thickness, estimates of skin friction factors can be obtained which could be used for determining an optimal location and orientation of propulsive systems for various operating conditions, which can be integrated in overall aircraft design processes. This could render aircraft-level trade-offs transparent, which is indispensable if coherent conclusions are to be drawn on energy performance of the innovative architectures that rely on aero-propulsive synergies.

Figure 1 :

 1 Figure 1: Elementary two-dimensional aero-propulsive system schematic overview.

Figure 2 :

 2 Figure 2: Panel geometric properties.

Figure 4 :

 4 Figure 4: Schematic overview of the propulsor assembly model with the employed station numbering.

1 . 3 .

 13 Control point 1 position ( f jet (x 1 ) = y 1 ), 2. Control point 2 position ( f jet (x 2 ) = y 2 ), Slope of the jet at control point 1 ( f ′ jet (x1) = tan(θ )), 4. Slope of the jet at control point 2 ( f ′ jet (x2) = tan(θ 1 ).

Figure 5 :

 5 Figure 5: Panel size dependence study, Cl convergence.

Figure 6 :

 6 Figure 6: Lift coefficient and jet depth of penetration variation with angle of attack.

Figure 7 :

 7 Figure 7: Lift coefficient variation with the jet exhaust angle.

Figure 8 :

 8 Figure 8: Lift coefficient variation for different propulsor parameters.

Figure 10 :

 10 Figure 10: Static pressure field at α = 0 • at 75%, 100% and 150% power respectively.

Figure 11 :

 11 Figure 11: comparison of the lift coefficient obtained with the developed panel method and reference RANS CFD simulations.

Table 1 :

 1 P s9 variation with AOA from the reference RANS simulations.

		0deg	2deg	4deg	6deg	10deg
	ṁ1 (kg/s) 14.71 14.71	14.71	14.71	14.68
	V 9 (m/s)	177.8 176.2 176.16 176.43 175.68
	P s9 (Pa) 94251 94229 94164 94227 94373


Eddine, Florian Cyrille Cyril

Merci Aux Professeurs

Maurice Hayot

Arnaud Bourdin

Philippe Guilpain

Anne Sophie Gamez

Mathilde Volpato

Aurélie DU THANH Nadia Raison Peyron

Marie Catherine Renoux

Fares GOUZI Johan Moreau

Maria Alexandre

Recevez

'ARACHIDE A PETITES DOSES ET AUGMENTATION LENTE SAFETY AND EFFICACY OF A SLOW INCREMENTAL LOW-DOSES PROTOCOL FOR PEANUT ORAL IMMUNOTHERAPY (OIT) TABLE DES MATIÈRES

Keywords: anaphylaxis, efficacy, oral immunotherapy, peanuts, safety

A mon Maître et Président de thèse, Monsieur le Professeur Pascal DEMOLY, Je vous remercie de m'avoir fait l'honneur d'accepter la présidence de ma thèse. Je vous remercie également de m'avoir permis de réaliser mon cursus d'internat dans les meilleures conditions en pouvant modeler un parcours personnalisé et réfléchi ensemble. Merci Pascal pour votre attention, votre disponibilité et votre écoute précieuse.

A mon directeur de thèse, Monsieur le Docteur Davide CAIMMI, Je te remercie tout particulièrement pour ta proposition de travail et pour la confiance que tu m'as accordée en m'impliquant dans ce projet. Pour les encouragements et l'aide précieuse que tu m'as apportée dans les différentes étapes de la réalisation de cette étude je te suis d'une reconnaissance immense. Reçois toute mon amitié

Parmi les allergies alimentaires, celles typiques de l'enfant incluent surtout le lait de vache, les oeufs, et l'arachide. En France, la prévalence de l'allergie à l'arachide est d'environ 1% chez les adultes et 0,6% chez les enfants [START_REF] Rancé | Prevalence and main characteristics of schoolchildren diagnosed with food allergies in France[END_REF]. Bien que ces données ne soient pas mises à jour dans la plupart des pays, la prévalence de l'allergie à l'arachide semble en augmentation dans le monde, et elle a par exemple doublé au Royaume Uni durant les 20 dernières années [START_REF] O'brien Hourihane | The impact of government advice to pregnant mothers regarding peanut avoidance on the prevalence of peanut allergy in United Kingdom children at school entry[END_REF][START_REF] Venter | Time trends in the prevalence of peanut allergy: three cohorts of children from the same geographical location in the UK[END_REF].

Cette allergie, différemment de celles au lait et aux oeufs, qui ont une histoire naturelle caractérisée par une tendance à l'acquisition spontanée d'une tolérance, s'associe plutôt à une persistance de la maladie dans le temps. En fait, seulement 25% des patients allergiques à l'arachide guérissent de façon spontanée par acquisition d'une tolérance immunitaire [9,[START_REF] Skolnick | The natural history of peanut allergy[END_REF]. Non seulement l'allergie à l'arachide persiste donc dans le temps, mais elle est aussi associée à un risque élevé de réactions systémiques et sévères, étant l'allergène le plus fréquemment rapporté dans les études sur la mortalité par allergie alimentaire [START_REF] Bock | Fatalities due to anaphylactic reactions to foods[END_REF].

Le traitement classique de l'allergie est basé à la fois sur une éviction stricte de l'arachide et sur le traitement rapide et adapté des réactions cliniques en cas d'ingestion accidentelle [START_REF] Boyce | Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel[END_REF][START_REF] Sampson | Food allergy: a practice parameter update -2014[END_REF][START_REF] Muraro | EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy[END_REF]. Depuis plusieurs années les difficultés liées au suivi d'un régime d'éviction stricte de l'arachide, au risque de réactions possiblement sévères, et au fort impact sur la qualité de vie des patients et de leurs familles, ont été mises en avant par de nombreux praticiens. Il a été démontré que la qualité de vie des enfants allergiques à l'arachide est significativement plus altérée que celle des enfants avec un diabète de type 1 [START_REF] Lange | Quality of life in the setting of anaphylaxis and food allergy[END_REF]. Pour toutes ces raisons, plusieurs chercheurs et cliniciens ont essayé de développer des protocoles d'induction de tolérance pour traiter cette allergie ou pour au moins permettre un contact accidentel avec l'allergène, sans risque de développer des symptômes allergiques. Les protocoles d'induction de tolérance à l'arachide sont réalisés principalement avec des patches, ou des produits sublinguaux, ou oraux. La voie orale semble être assez prometteuse surtout pour atteindre des niveaux de protéines d'arachide tolérées assez élevés.

Même si ce traitement semble être efficace, l'induction de tolérance orale à l'arachide semble aussi être associée à un risque augmenté d'anaphylaxie (risque ratio aux alentours de 3) et à la nécessité d'utilisation d'adrénaline chez environ 25% des patients testés [START_REF] Chu | Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety[END_REF].

Il est important de noter que la plupart des essais publiés sur l'induction de tolérance orale à l'arachide excluent les patients avec des histoires cliniques d'anaphylaxies répétées ou d'anaphylaxie sévère ou d'asthme sévère [START_REF] Schneider | A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanut-allergic patients[END_REF][START_REF] Soller | First real-world safety analysis of preschool peanut oral immunotherapy[END_REF][START_REF] Bird | Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial[END_REF][START_REF] Narisety | A randomized, double-blind, placebo-controlled study of sublingual versus oral immunotherapy for the treatment of peanut allergy[END_REF][START_REF] Tang | Administration of a probiotic with peanut oral immunotherapy: A randomized trial[END_REF][START_REF] Varshney | A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response[END_REF][START_REF] Nagakura | Low-dose oral immunotherapy for children with anaphylactic peanut allergy in Japan[END_REF][START_REF] Chinthrajah | Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study[END_REF][START_REF] Vickery | PALISADE Group of Clinical Investigators. AR101 Oral Immunotherapy for Peanut Allergy[END_REF][START_REF] Blumchen | Efficacy, Safety, and Quality of Life in a Multicenter, Randomized, Placebo-Controlled Trial of Low-Dose Peanut Oral Immunotherapy in Children with Peanut Allergy[END_REF]

INTRODUCTION

Food allergy may be IgE mediated and immediate, or non-IgE mediated and delayed.

Immediate reactions are associated to potentially severe clinical manifestations, including anaphylactic shock. In recent years, a special attention has been given to IgE mediated food allergies, because of their high impact not only on healthcare costs, but also on the quality of life of both children and caregivers.

In children, main food allergens include milk, egg, peanuts, and nuts. The USA, the UK, Canada, and Australia are the countries in which peanut allergy prevalence is the highest (1 -2%) [START_REF] Demoly | Allergie à l'arachide. E-Allergie, le site de formation en allergologie[END_REF][START_REF] Gupta | The prevalence, severity, and distribution of childhood food allergy in the United States[END_REF][START_REF] Sicherer | Prevalence of peanut and tree nut allergy in the US determined by a random digit dial telephone survey[END_REF][START_REF] Sicherer | US prevalence of selfreported peanut, tree nut, and sesame allergy: 11-year follow-up[END_REF][START_REF] Grimshaw | Incidence and risk factors for food hypersensitivity in UK infants: results from a birth cohort study[END_REF]. In France, the prevalence of this food allergy is about 1% in adults and 0.6% in children [START_REF] Rancé | Prevalence and main characteristics of schoolchildren diagnosed with food allergies in France[END_REF]. These data are usually not updated in most countries; nevertheless, it seems like the prevalence of peanut allergy has been increasing all around the world, and even doubled in the UK, over the last 20 years [START_REF] O'brien Hourihane | The impact of government advice to pregnant mothers regarding peanut avoidance on the prevalence of peanut allergy in United Kingdom children at school entry[END_REF][START_REF] Venter | Time trends in the prevalence of peanut allergy: three cohorts of children from the same geographical location in the UK[END_REF].

In contrast to other food, such as cow's milk or hen's eggs, peanuts allergy does not tend to be spontaneously resolutive: in facts, only 25% of patients recover from this allergy achieving immunological tolerance [9,[START_REF] Skolnick | The natural history of peanut allergy[END_REF]. Moreover, allergy to peanuts is often characterized by potential severe clinical reactions, compared to other food, that may even be life-threatening [START_REF] Moneret-Vautrin | Food allergy to peanuts in France--evaluation of 142 observations[END_REF]. Indeed, data on deaths caused by food allergy show that peanuts are responsible for most of them [START_REF] Bock | Fatalities due to anaphylactic reactions to foods[END_REF].

Classical therapy is based on both a strict peanut elimination diet and on acute treatment of reactions occurring after accidental ingestion [START_REF] Boyce | Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel[END_REF][START_REF] Sampson | Food allergy: a practice parameter update -2014[END_REF][START_REF] Muraro | EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy[END_REF]. The rate of accidental ingestion of peanuts is variable though non-neglectable, being evaluated at about 33% of peanut-allergic patients in the USA [START_REF] Vander Leek | The natural history of peanut allergy in young children and its association with serum peanut-specific IgE[END_REF], and 12.4% in Canada (2015) [START_REF] Nguyen-Luu | Inadvertent exposures in children with peanut allergy: Inadvertent exposures in children with peanut allergy[END_REF]. Considering the difficulties in recent years of following a correct peanut-free diet, and the fear of potential reactions, including severe ones, clinicians know that this type of food allergy has a deep impact in the quality of life of both patients and their caregivers. Indeed, it was shown that the quality of life of children suffering from peanut allergy is even significantly lower than that of patients suffering from type-1 diabetes [START_REF] Lange | Quality of life in the setting of anaphylaxis and food allergy[END_REF].

Oral immunotherapy (OIT) is a promising novel treatment that aims at providing immunological tolerance to the food to which patients are allergic. It consists in administering increasing doses of the allergen to patients, over a predetermined period of time: doses are usually increased in hospital settings, and then daily consumed by patients at home, until a novel increase is assured at the hospital, usually bi-weekly. Once a target dose is reached, patients follow a maintenance phase, at the end of which a food challenge is carried out to verify the possibly acquired tolerance. Such therapy has been mainly employed in patients allergic to cow's milk, hen's egg, and peanuts. In clinical practice, it is quite clear that desensitization (a permanent immunological tolerance) may be often achieved when treating patients suffering from milk or egg allergy; on the other hand, peanuts OIT seems associated to a state of tolerance induction, that might be transitory, considering that sustained unresponsiveness to this allergen remains largely unexplored on the long term. Also, peanuts OIT seems to be associated to an increased risk of anaphylaxis, with a risk ratio above 3, and to a need to use epinephrine during therapy in about 25% of treated patients [START_REF] Chu | Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety[END_REF].

Several protocols have been published in literature, and they usually suggest starting the treatment at a median dose of 0.5 mg of peanut proteins; nevertheless, recent data suggest that starting at lower doses may be associated to a reduced risk of developing side effects to OIT [START_REF] Pajno | EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy[END_REF].

It has to be noticed that most published trials on peanuts OIT exclude, as a criterion, patients presenting with a history of repeated anaphylactic reactions, or of severe anaphylaxis, or of severe asthma. Nevertheless, such criterion used in clinical trials doesn't allow to include in protocols those children who might potentially benefit the most out of this therapy: indeed, considering the published cohorts of peanut allergic children, they are certainly at risk of severe anaphylaxis, and they often have a history of multiple anaphylactic reactions or of severe asthma [START_REF] Schneider | A pilot study of omalizumab to facilitate rapid oral desensitization in high-risk peanut-allergic patients[END_REF][START_REF] Soller | First real-world safety analysis of preschool peanut oral immunotherapy[END_REF][START_REF] Bird | Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial[END_REF][START_REF] Narisety | A randomized, double-blind, placebo-controlled study of sublingual versus oral immunotherapy for the treatment of peanut allergy[END_REF][START_REF] Tang | Administration of a probiotic with peanut oral immunotherapy: A randomized trial[END_REF][START_REF] Varshney | A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response[END_REF][START_REF] Nagakura | Low-dose oral immunotherapy for children with anaphylactic peanut allergy in Japan[END_REF][START_REF] Chinthrajah | Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study[END_REF][START_REF] Vickery | PALISADE Group of Clinical Investigators. AR101 Oral Immunotherapy for Peanut Allergy[END_REF][START_REF] Blumchen | Efficacy, Safety, and Quality of Life in a Multicenter, Randomized, Placebo-Controlled Trial of Low-Dose Peanut Oral Immunotherapy in Children with Peanut Allergy[END_REF]. One study by Anagnostou et al. [31] didn't exclude children with a history of severe and/or non-controlled asthma and two studies didn't exclude children with an history of severe or repeated anaphylaxis [START_REF] Nagakura | Low-dose oral immunotherapy for children with anaphylactic peanut allergy in Japan[END_REF][START_REF] Marrs | Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial: a critical appraisal[END_REF]. Quite interestingly, these studies didn't show an increased risk of systemic nor severe reactions in treated patients, but available data are not sufficient to establish a safety profile for OIT in these groups of patients.

In our unit, we developed a local protocol for peanuts OIT, starting with low-doses and increasing the doses every 4 to 12 weeks. We are here presenting the preliminary data issued from our experience. The main goal of our protocol was for it to be safe, without exposing the patient to severe side effects, and without excluding patients with a clinical history of severe anaphylaxis, of repeated episodes of anaphylaxis or of severe asthma.

MATERIALS AND METHODS

STUDY POPULATION

For the present study, we collected data from patients evaluated, between September 2018 and June 2021, at the Allergy Unit of the University Hospital of Montpellier (France) and at the Allergy Unit of the Millau Hospital (France), with a history of peanut allergy, and a clinical indication for peanuts OIT. Patients were included, regardless their age, if they presented: Following EACCI guidelines [START_REF] Pajno | EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy[END_REF] on allergen immunotherapy for IgE mediated food allergy, exclusion criteria were:

• poor adherence to OIT protocol;

• active malignant neoplasia or autoimmune disorder;

• active eosinophilic esophagitis or other gastrointestinal eosinophilic disorders;

• active severe eczema;

• initiation during pregnancy;

• cardiovascular diseases and use of beta-blocker and/or ACE inhibitors;

• chronic urticaria;

• mastocytosis.

In contrast with EAACI guidelines, severe asthma was not an exclusion criterion; also, as for uncontrolled asthma, we considered it as a transitory status, requiring asthma to be controlled before staring the protocol.

STUDY PROTOCOL

The present study assesses retrospective data from our cohort of patients, undergoing peanuts OIT, as a clinical practice procedure. Patients presenting with a personal history of peanut-driven allergic reaction, undergo an allergy work-up, that includes skin prick tests to roasted peanuts (Husk, London, UK) and an evaluation of serum specific IgE (ImmunoCAP®, ThermoFisher Scientific) to peanuts and to its main molecular allergens (rAra h 1, rAra h 2, rAra h 3, rAra h 6, rAra h 8 and rAra h 9). To complete the allergy work-up, patients undergo an oral food challenge, unless they report a history of anaphylaxis and peanut specific IgE superior to 100 kUA/L. Protocol for peanut oral food challenge (OFC) consists in administering, every 20 minutes, increasing doses of peanut proteins (3 -10 -30 -100 -300 -1000 -3000 mg), and surveilling the patients for 2 hours after the procedure, following validated protocols [START_REF] Sampson | Standardizing double-blind, placebo-controlled oral food challenges: American Academy of Allergy, Asthma & Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus report[END_REF]. The test is considered as positive in case of appearance of allergic symptoms during the phase of doses administration or during the surveillance period, following validated protocols (Figure 1) [START_REF] Sampson | Standardizing double-blind, placebo-controlled oral food challenges: American Academy of Allergy, Asthma & Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus report[END_REF][START_REF] Grabenhenrich | A new framework for the documentation and interpretation of oral food challenges in population-based and clinical research[END_REF][START_REF] Calvani | Food oral challenges in clinical practice [Il test di provocazione orale per alimenti nella pratica clinica[END_REF].

Before starting the challenge, patients are evaluated to verify that they are not presenting fever, nor other infections, nor signs of symptoms of rhinitis, allergic rhinitis, eczema exacerbation; also, they are checked for asthma control, by completing the pediatric or adult version of the Asthma Control Test (Figure 2 and Figure 3) [START_REF] Schatz | Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists[END_REF][START_REF] Liu | The Childhood Asthma Control Test * : Retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma[END_REF]. In patients with a positive peanut oral food challenge, or with a history of anaphylaxis to peanut and peanut specific IgE > 100 kUA/L, we propose to start an OIT protocol. The protocol starts at a dose of 2.7 mg of peanut proteins (PP), provided by mixing and dosing peanut-flavored puffs of corn commercialized in France and called Curly®. These chips contain 67 mg of PP each.

During the first day, we propose an escalation to the cumulative dose of 34 mg of PP. Patients are required to consume the dose reached at the hospital, for at least 3 times per week. Doses need to be halved by patients, in case of concomitant infection or fever, intense physical exercise, or menstruation following current recommendations. During the build-up phase, doses are increased every 4 to 12 weeks, depending on the severity of the reported allergic reaction or of the results of the OFC (longer delay in case of severe anamnestic reaction). At the dose of 200 mg of PP, patients are required to stop consuming the chips, and start consuming peanuts. Once patients reach the dose of 2000 mg of PP, they undergo the maintenance phase, over a period of at least 6 months (Figure 4, Figure 5). At the end of this phase, an oral challenge is performed to assess peanut tolerance, at a cumulative dose of 4000 mg of PP.

COLLECTED DATA

For each patient we collected the following data:

• sex;

• age at first clinical reaction;

• type of reaction (delay of appearance, and clinical symptoms);

• comorbidities and risk factors (including atopy, asthma, eczema, other food allergies);

• peanut specific serum IgE (kUA/L), and component-resolved diagnostics for peanut molecular allergen;

• eliciting dose and cumulated eliciting dose during peanut OFC, and clinical symptoms presented during the test;

• dose of PP reached at the end of data collection, through the OIT protocol, and secondary effects presented during the protocol (either at the hospital or at home).

The study was approved by local Ethical Committee of the University Hospital of Montpellier (IRB-MTP_2021_05_202100825), and registered on the ClinicalTrials platform (NCT04881773). Before performing any test on patients (OFC and OIT), we require the signature of an informed consent by each patient or by both parents in case of minors.

OUTCOMES OF THE STUDY

The aim of the present ongoing study was to evaluate the efficacy (augmentation of tolerogenic dose) and safety (side effect rate) of our local peanuts OIT protocol, starting at with low doses and characterized by delayed doses increases.

The primary outcome of the present study was to evaluate the efficacy of the protocol. For such evaluation we considered:

• the number of patients who reached the maintenance dose of 2000 mg of PP peanut protein.

• the number of patients who didn't react at the final peanut oral challenge, at a cumulative dose of 4400 mg of PP.

The secondary outcomes include:

STATISTICAL ANALYSIS

Continuous variables were summarized with descriptive statistics (number, mean, SD), while frequency counts and percentages were provided for categorical data. Statistics were computed for patients with available (i.e. non-missing) data.

RESULTS

INCLUDED POPULATION

We included 22 patients for the present study, who started the peanuts OIT protocol between September 2018 and July 2020. Data were collected in May 2021.

Patients had a median age of 9.5 years, and 11 of them were females (50.0%).

Comorbidities and results of the allergy work-up are shown in Table 1. Concerning the 12 patients (54.5%) suffering from other food allergies, besides peanuts, they were allergic to several different allergens, including eggs, cod, mustard, almonds, walnuts, hazelnuts, pistachios, beans, lentils, lupine, cashew, macadamia, pecan, pine nuts, kiwi. In two patients (9.1%), peanuts specific serum IgE were above 100 kUA/L and didn't undergo the diagnostic OFC for such reason. 4 patients (18.2%) didn't undergo the diagnostic OFC since they experienced at least 2 anaphylactic reactions immediately after peanut consumption. 7 and Figure 8. The second one, a 14-year-old boy, stopped it, at the dose of 34 mg of PP, because of the persistency of abdominal pain associated to peanuts consumption. He presented a conjunctivitis secondary to peanuts exposure in his clinical history and an anaphylactic reaction during the diagnostic OFC (at a dose of 33 mg of PP). He is the only patient dropping out of the protocol because of the appearance of side effects.

The third one, an 8-year-old girl, stopped it because the family found as inconvenient the need for multiple visits at the hospital. She presented an anaphylactic reaction to peanuts in her clinical history and during the diagnostic OFC (at a dose of 600 mg of PP). She experienced an adverse event, during the OIT protocol, after consumption of 200 mg of PP, characterized by the appearance of abdominal pain. Nevertheless, at the time, she was also suffering from an acute viral gastroenteritis, therefore we don't consider such symptom as related to the protocol.

The last one, a 14-year-old girl, stopped it at the dose of 67 mg of PP, because she felt too stressed to continue the protocol and she deeply disliked the taste of peanuts. In her clinical history, she only presented cutaneous symptoms when exposed to peanuts.

PRIMARY OUTCOME

Presented data are strictly preliminary since in most patients the OIT protocol is still in the incremental phase, or they haven't performed the final OFC yet. Future and final data will complete our results.

On June 1 st , 2021 18 patients were still on the OIT protocol and one dropped out because of adverse events. Seven of them were still in the incremental phase of the OIT; therefore, we included in the present analysis only 11 patients who ended the protocol and the patient who dropped out. In this subgroup of patients, 11 (91.7%) were able to reach the maintenance dose of 2000 mg of PP peanut protein, and only 1 needed to stop the protocol at lower doses. In this group, 6 patients completed the 6-months maintenance period, and underwent an OFC, with a cumulative dose of 4000 mg of PP. Five of them (83.3%) had a negative OFC at such dose. One patient experienced an anaphylactic reaction characterized by generalized urticaria and abdominal pain, appearing 30 minutes after the final cumulative dose of 4000 mg of PP and was treated with an injection of epinephrine.

SECONDARY OUTCOMES

Adverse events

Considering our population of 19 patients (excluding therefore dropouts due to nonprotocol-related issues), the percentage of patients who didn't experience any adverse reaction during the protocol was of 79.8%. Four (21.2%) patients presented an adverse reaction, for a total of 5 reactions. No patient presented grade 3 nor grade 4 anaphylactic reactions. The moment at which the reaction has appeared, and its severity are shown in Table 3.

Table 3. Adverse reactions presented by the 22 patients during the peanuts OIT protocol.

Legend -*Ring and Messmer classification.

Only 1 patient (5.3%), previously mentioned, needed to stop the protocol because of persistent abdominal pain. As for the remaining three grade 1 reactions, one of them was characterized by the appearance of allergic rhinitis and pruritus in a 7-year-old girl, at the dose of 134 mg of PP. She's currently at the dose of 400 mg of PP, without presenting clinical symptoms.

The other one, in a 5-year-old boy, was characterized by the appearance of eyelids oedema, at the dose of 400 mg of PP. To be noticed, that at the time of the reaction he was in contact with a cat, and he's allergic to cat dander. He's currently consuming 400 mg of PP, without presenting further symptoms. The last one, occurred in a 7-year-old girl, who presented an episode of generalized urticaria at the dose of 67 mg of PP. In this same patient, we also recorded the only grade 2 reaction

(5.6% of the entire population), when she accidentally consumed 400 mg of PP. She experienced a cutaneous and gastro-intestinal reaction, treated, at the emergency department, with antihistamines and corticosteroids only. Epinephrine was not administered at the time. She's currently still consuming her dose of 67 mg of PP, at home, at least three times a week.

Patients were investigated for the possible appearance of symptoms evocative of eosinophilic esophagitis via a questionnaire (Figure 6). The questionnaire has been completed by 16 patients. In 5 cases (31.3%), we found symptoms that could possibly suggest the appearance of an eosinophilic esophagitis. Increase in initial tolerated dose

The overall stage at which patients are in our OIT protocol is shown in Table 4. Excluding the 3 patients who dropped out of the study because of non-protocol-related issues, and the 3 more who have not performed an initial OFC, 16 patients may be assessed for doses increase. When assessing patients to verify the possibility to double their initial ED (eliciting dose), 5 more patients need to be excluded (1 who during the initial OFC tolerated higher doses of PP, and who actually completed the protocol, and 4 who are still at lower doses of their OIT). In this subgroup of patients, 10 (90.9%) were able to double their ED through the OIT protocol. When assessing patients to verify the possibility to triple their initial ED, 8 more patients need to be excluded (3 who during the initial OFC tolerated higher doses of PP, and who nonetheless completed the protocol, and 5 who are still at lower doses of their OIT). In this subgroup of patients, 7 (87.5%)

were able to triple their ED through the OIT protocol.

Considering available data, 15 patients are currently at an OIT dose of at least 300 mg of PP; therefore, since the dropout patient was only at the dose of 34 mg of PP when abdominal pain forced him to quit the treatment, 93.8% of our patients were able to tolerate a dose of 300 mg of PP. Similarly, considering the 11 patients currently at an OIT dose of at least 1000 mg of PP, we may say that 91.7% of our patients achieved a tolerated dose of 1000 mg of PP.

Subgroup analysis in patients presenting with anaphylaxis

Excluding the 3 dropouts for non-protocol-related issues, in 14 patients, prior to OIT, we recorded a grade 2-3 anaphylactic reaction to peanuts. Considering only the 9 patients of this group who performed the initial OFC and are at a sufficiently advanced stage of the protocol, 8 (88.9%)

were able to double their ED and 7 out of 8 (87.5%) tripled their ED through the OIT protocol.

Also, considering the patients who presented an anaphylactic reaction (thus including 2 who didn't perform the initial OFC), but excluding those who are at lower incremental doses, 12 out of 13 (92.3%) reached a tolerated dose of 300 mg of PP, and 11 out of 12 (81.7%) of 1000 mg of PP. In this subgroup of patients, we recorded 2 grade 1 adverse reactions (14.3% of patients):

one patient presented allergic rhinitis and pruritus, but continue the protocol, and the other one dropped out.

Characteristics of patients completing the protocol, with the final OFC Six patients not only completed the OIT protocol, but were also tested, after at least 6 months of consumption of 2000 mg of PP at least three times per week. Their characteristics are shown in Table 5. One of them reacted with an anaphylaxis and needed to be treated with an epinephrine injection. Legend -M: male; F: female; At: atopy; A: asthma; ARC: allergic rhino-conjunctivitis, E: eczema; OFC: Oral Food Challenge, OIT: oral immunotherapy.

DISCUSSION

Oral Immunotherapy is a treatment option in patients suffering from persistent food allergies. While the first attempt to provide such therapeutic option goes back to the beginning of the twentieth century, OIT has become more and more investigated over the last 15 years only [START_REF] Pajno | Allergen immunotherapy for IgE-mediated food allergy: There is a measure in everything to a proper proportion of therapy[END_REF]. The European Academy for Allergy and Clinical Immunology published a list of guidelines on this subject [START_REF] Pajno | EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy[END_REF]. Considering what has been recommended in their document, OIT should be proposed in pediatric patients suffering from persistent allergy to milk, egg, and peanuts. Efficacy in adult patients seems limited, but not enough data have been published in this age group. As for other food, even though, in research settings, OIT protocols exists (mostly for nuts and fruits), there are no recommendations to treat these allergies through such protocols.

A major interest on peanuts OIT was highlighted in 2019, when a meta-analysis was published on

The Lancet, and showed that it was less dangerous to prescribe to patients an elimination diet, than to propose them this intervention [START_REF] Chu | Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety[END_REF]. Possible dangers included the increased risk of presenting anaphylactic reactions and of needing epinephrine administration for patients treated for peanuts OIT, compared with patients eliminating peanuts from their diet.

At the Allergy Unit of the University Hospital of Montpellier, a novel protocol, different from those published in the literature, had been locally validated and employed since January 2018. Physicians from the Unit felt like data provided by the meta-analysis were not reflecting the results observed in patients treated with the local protocol. For such reason, through the present study, we wanted to verify if the protocol employed at the University Hospital of Montpellier was effective and associated to a lower incidence of side effects and to a limited need for epinephrine injection.

If we compare our data to those presented in the PACE meta-analysis [START_REF] Chu | Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety[END_REF], many differences exist. First, it should be noted that our population is older (median age 9.5 years) than the one reported in the meta-analysis (8.7 years) [START_REF] Chu | Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety[END_REF]. Our population is also peculiar since in 72.7% of included patients, a grade 2 or grade 3 anaphylactic reaction was recorded, and to be more specific, 9.1% of them experienced an anaphylactic shock to peanuts. Indeed, such characteristic of our population diverges from most other studies focusing on OIT to peanuts in children.

Concerning the OIT protocol, in published studies, the starting dose ranges from 0.1 mg of PP [START_REF] Kukkonen | Double-blind placebocontrolled challenge showed that peanut oral immunotherapy was effective for severe allergy without negative effects on airway inflammation[END_REF] to 99 mg of PP [START_REF] Vickery | Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy[END_REF][START_REF] Jones | Clinical efficacy and immune regulation with peanut oral immunotherapy[END_REF][START_REF] Hofmann | Safety of a peanut oral immunotherapy protocol in children with peanut allergy[END_REF]. In our protocol, we start at a dose 2.7 mg of PP. The maintenance dose, in different studies ranges from 50 mg [START_REF] Blumchen | Oral peanut immunotherapy in children with peanut anaphylaxis[END_REF] to 4000 mg [START_REF] Varshney | A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response[END_REF][START_REF] Chinthrajah | Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study[END_REF][START_REF] Vickery | Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy[END_REF]. We prescribe to patients a maintenance dose of 2000 mg of PP, which is the equivalent of about 10 peanuts. A major difference between our protocol and the published ones is the time to achieve the maintenance phase: in literature it takes 31 weeks (25-51) to reach the maintenance dose [START_REF] Chu | Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety[END_REF], while in our study, patients need a median time of 108 weeks to achieve 2000 mg of PP, especially in they previously presented an anaphylactic reaction. Indeed, if most protocols include a biweekly incrementation of the allergen dose, we propose an increase every 1 to 3 months, speculating that immunological modifications and adaptation may need a prolonged amount of time to occur. At last, another difference between our protocol and current guidelines is that the EAACI recommends to patients to consume the allergenic food daily at home [START_REF] Pajno | EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy[END_REF], while we require them to eat peanuts only 3 times a week, to avoid possible protocol dropouts due to food dislike.

One study in literature shows many similarities to ours: in the paper by Narisety et al. [START_REF] Narisety | A randomized, double-blind, placebo-controlled study of sublingual versus oral immunotherapy for the treatment of peanut allergy[END_REF], the authors included 11 patients treated through OIT, with peanut powder; 54.5% of them had a prior history of anaphylaxis. Doses were increased biweekly, to reach a maintenance dose of 2000 mg of PP, and a final OFC was performed both at 6 months and at 12 months of maintenance. Only 7 patients (63.6%) completed the protocol, but only 1 (9.1%) passed the exit OFC at 6 months (at a cumulative dose of 10000 mg of PP) and 3 others needed 6 extra months to pass the challenge (but with cumulative doses ranging from 996 to 10000 mg of PP). There are only four studies in literature employing a protocol in which the maintenance dose was higher than 300 mg of PP, and performing an exit OFC, without a period of washout:

-In the study by Varshney et al. [START_REF] Varshney | A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response[END_REF], 19 patients were treated to reach the maintenance dose of 4000 mg of PP and, after 4 weeks, 84.2% of them tolerated a dose of 5000 mg during the OFC; -In the study by Anagnostou et al. [START_REF] Anagnostou | Efficacy and safety of highdose peanut oral immunotherapy with factors predicting outcome[END_REF], 22 patients were treated to reach the maintenance dose of 800 mg of PP and, after 6 weeks, 54.5% of them tolerated a dose of 2600 mg during the OFC; after 30 weeks, 63.6% tolerated the dose of 6600 mg of PP, showing an increase of effectiveness over time;

-In a more recent study [START_REF] Anagnostou | Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial[END_REF], Anagnostou included 49 patients with a maintenance dose of 800 mg of PP and, after 12 weeks, 61.5% of them tolerated a dose of 1400 mg of PP; -In the study by Chinthrajah et al. [START_REF] Chinthrajah | Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study[END_REF], 35 patients were to reach the dose of maintenance dose of 4000 mg of PP and, after 104 weeks, 83% of them tolerated a dose of 4000 mg during the OFC; the same patients continued then to consume 300 mg of PP daily et, 52 weeks later, only 37.1% of them passed a negative OFC.

In our study, if we consider the only 6 patients who completed the protocol and the maintenance phase at a dose of 2000 mg of PP, 83.3% of them had a negative OFC after 6 months (around 25

weeks), at a cumulative dose of 4000 mg of PP, which align our results with the best recorded in the literature.

Considering the number of patients reaching different milestones, in the study by Nachshon et al. [START_REF] Nachshon | Long-term outcome of peanut oral immunotherapy-Real-life experience[END_REF], the Authors included 145 patients: 91.7% of them tolerated the dose of at least 300 mg of PP, while 77.9% were desensitized to 3000 mg. In the ARC001 trial [START_REF] Bird | Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial[END_REF], 76.6% of patients tolerated the dose of 300 mg and 50.3% tolerated the dose of 1000 mg of PP (during the exit OFC).

In our study, considering only those patients who already have reached these values, 93.8% tolerate the dose of 300 mg of PP, 91.7% of 1000 mg and 91.7% of 2000 mg. In the subgroup of patients with a history of grade 2-3 reactions to peanuts, 92.3% reached a tolerated dose of 300 mg of PP, and 81.7% of 1000 and 2000 mg of PP.

Adverse events are considered a major limit of peanuts OIT. In the PACE study, the authors showed an estimated risk of anaphylaxis of 22% [START_REF] Chu | Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety[END_REF], which is consistent with retrospective caseseries studies of oral immunotherapy reporting 23-27% of patients presenting adverse reactions and requiring the use of epinephrine during the protocol [START_REF] Wasserman | Oral immunotherapy for peanut allergy: multipractice experience with epinephrine-treated reactions[END_REF][START_REF] Wasserman | Realworld experience with peanut oral immunotherapy: lessons learned from 270 patients[END_REF].

In our study we observed adverse events in 21.2% of patients: nevertheless, most adverse events were of grade 1; anaphylaxis (grade 2) was recorded in 1 patient (5.3%) only, and, even in this case, epinephrine was not administered at the emergency department. In the subgroup of patients with previous anaphylaxis, we only recorded grade 1 adverse reactions (14.3%), and 1 patient required to stop the protocol because of the appearance of abdominal pain. Our rate of grade 2 clinical reactions is therefore less important than those highlighted by the PACE metaanalysis [START_REF] Chu | Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety[END_REF], and, once again, this safety profile might be related to the slower increase in administered doses during the protocol. As for eosinophilic esophagitis, the debate in literature is still open, on the possibility of considering it as a possible complication of food OIT [START_REF] Cianferoni | Eosinophilic Esophagitis as a Side Effect of Food Oral Immunotherapy[END_REF]. In our study, 31.6% of patients presented possibly evocative symptoms for such disease, with episodic abdominal pain as the main symptom. A follow-up by a pediatric gastroenterologist will clarify if these reported symptoms are due to an esophageal disease.

Our results present some limits: in our cohort, we don't have a follow-up for the evolution of SPT nor of specific IgE, and no data have been collected on results of basophil activation test nor of specific peanuts IgG4. Also, many patients haven't completed their protocol or haven't performed the exit OFC yet, and more definitive data still need to come. At last, we haven't evaluated patients' and caregivers' quality of life, nor assessed patients for sustained unresponsiveness. All these issues will be addressed in a further multicentric prospective study validating our protocol, and the present report should therefore be considered as a preliminary proof of concept.

CONCLUSION

The aim of the present ongoing study was to evaluate the efficacy and safety of the peanuts OIT protocol used at the University Hospital of Montpellier (France), starting at low doses of PP and characterized by delayed doses increases.

We showed that our protocol may achieve good results in terms of efficacy, with 83.3% of our patients being able to tolerate 4000 mg of PP (20 peanuts), at the end of the maintenance phase.

Such datum is in line with the best protocols published in literature. Concerning safety issues, anaphylaxis was recorded in only 5.3% of our population, and epinephrine was injected only once, in 1 patient, at the end of the exit OFC. The safety profile of our protocol is therefore better than what has been highlighted in previous papers. We speculate that the reason for which our protocol seems safer than others could be because a delayed increase in doses may facilitate the immune system and the specific Treg cells to adapt and better tolerate the exposure to peanut allergens.

Also, in our study, most patients previously suffered from a grade 2 or 3 anaphylactic reaction to peanuts, and we showed therefore that our protocol is safe even in this group of patients, that should not be excluded from this type of intervention. Indeed, these patients are exactly those who will benefit the most from an oral tolerance induction.

These results should be considered as a proof of concept and the protocol will be validated by a more robust multicentric prospective study. Legend -M: male; F: female; At: atopy; A: asthma; ARC: allergic rhino-conjunctivitis, E: eczema; OFC: Oral Food Challenge, OIT: oral immunotherapy.

FIGURES

2 .

 2 Introduction …………………………………………………………………………..5 3. Materials and Methods ……………………………………………………………….8 Study Population ……………………………………………………………..…...9 Study Protocol …………………………………………………………..….…….9 Collected Data …………………………………………………………..……13 Outcomes of the study …………………………………………………..……14 Statistical analysis ……………………………………………………………15 4. Results ………………………………………………………………………….…….17 Included population …………………………………………..………………17 Primary outcome ……………………………………………………...………21 Secondary outcomes …………………………………………………..……....21 5. Discussion ………………………………………………………………………….…27 6. Conclusion ………………………………………………………………………….....31 7. References ………………………………………………………………………….....32 8. Figures ………………………………………………………………………..…….....38 9. Tables ……………………………………………………………………...………….46 10. Annexes ……………………………………………………………………………….51

  . Ces critères d'exclusion utilisés fréquemment dans les études ne permettent pas d'étudier l'application d'une thérapie d'induction de tolérance orale chez les patients qui pourraient potentiellement en obtenir le plus de bénéfices et qui sont donc les plus éligibles à ce type de traitement. Dans notre unité d'allergologie, nous avons développé un protocole d'induction de tolérance orale à l'arachide, débutant à faibles doses et à augmentation lente, toutes les 4 à 12 semaines, alors que les protocoles publiés prévoient une augmentation des doses toutes les deux semaines. Nous présentons ici les données préliminaires issues de notre expérience. Le but principal de notre protocole est de démontrer qu'il est possible de proposer une induction de tolérance orale efficace et sécuritaire, même chez des patients avec une histoire d'anaphylaxie sévère, ou d'épisodes répétés d'anaphylaxie à l'arachide.

•

  a clinical history of immediate reaction after peanuts consumption o AND a positive prick by prick to roasted peanut (Husk, London, UK); o AND positive serum specific IgEs to peanut (ImmunoCAP®); o AND a positive oral food challenge to peanut OR a clinical history of anaphylaxis AND serum specific IgE for peanuts > 100 kUA/L (ImmunoCAP®) OR a clinical history of at least 2 anaphylactic reactions immediately after peanut consumption.

Figure 1 .

 1 Figure 1. Document to register signs and symptoms observed during the challenge [33].

Figure 4 .

 4 Figure 4. Different phases of our OIT protocol for peanuts.

Figure 5 .

 5 Figure 5. Protocol used for peanuts OIT.

1 .

 1 for safety: a. evaluation of the adverse events presented by patients, classifying them by severity, and by emergency treatment needed to control the reaction, either at the hospital or at home; b. evaluation of the appearance of symptoms evocative of eosinophilic esophagitis via a locally validated questionnaire proposed to patients (Figure 6); 2. for efficacy: a. evaluation of the tolerated dose, compared to the original eliciting dose, in our cohort of peanut allergic patients, by assessing how many patients doubled and tripled their initial eliciting dose; b. evaluation of the number of patients tolerating the dose of 300 mg and 1000 mg of PP;

3 .

 3 We wanted to evaluate the efficacy and the safety of the protocol in the subgroup of patients who presented a severe reaction to peanuts (anaphylaxis or anaphylactic shock) in their clinical history or during the first oral challenge.

Figure 6 .

 6 Figure 6. Questionnaires used to assess possible symptoms of eosinophilic esophagitis.

Figure 1 .

 1 Figure 1. Document to register signs and symptoms observed during the challenge [33].

Figure 2 .

 2 Figure 2. Asthma Control Test (ACT) for patients aged at least 12 years [36].

Figure 6 .

 6 Figure 6. Questionnaires used to assess possible symptoms of eosinophilic esophagitis.

Table 1 .

 1 Baseline characteristics of the 22 patients included in the study.No patient suffered from severe asthma. Five patients (22.7%) reported a clinical history of anaphylaxis to peanuts. None of them presented an anaphylactic shock at the time of their initial reaction. 4 patients (18.2%) were on a peanut elimination diet, secondary to a positive allergy work-up, but without having shown allergic symptoms due to peanut exposure. Most patients presented a Grade 1 reaction in their clinical history and 5 (22.7%) reported a history of anaphylaxis to peanuts. During the diagnostic OFC, the most frequent clinical reactions were grade 2 reactions, and more than 63.6% of patients experienced an anaphylaxis or an anaphylactic shock.Considering the 2 patients (9.1%) who presented an anaphylactic shock during the OFC, one of them had previously experienced a history of anaphylaxis, while the other one previously presented gastro-intestinal symptoms only. Out of the 12 patients (54.5%) who reacted to the OFC with a Grade 2 anaphylactic reaction, only 2 had a clinical history of anaphylaxis to peanuts.

	Characteristics
	Number of included patients	22
	Number of females, n (%)	11 (50.0%)
	Age in years, median (25°-75°)	9.5 (7-13)
	Comorbidities
	Asthma (%)	68.2%
	Eczema (%)	40.9%
	Atopy (%)	77.2%
	Other food allergies (%)	54.5%
	Allergy work-up
	SPT weal diameter in mm, median (25°-75°)	7 (5.2-9.5)
	IgE peanut in kUA/L median (25°-75°)	9.2 (2.1-36.4)
	IgE Ara h 2 in kUA/L, median (25°-75°)	2.5 (0.7-12.7)
	Cumulative ED at OFC in mg of PP, median (25°-75°)	415 (255-1150)

Characteristics of reactions severity reported in patients' clinical history or recorded during the diagnostic OFC are shown in Table

2

. Detailed organ specific clinical symptoms presented by patients are shown in Figure

Table 2 .

 2 Clinical reactions presented by patients with peanut both in their clinical history, and during the diagnostic challenge.

	Clinical

reaction with peanuts (n=22) In patients' clinical history During diagnostic OFC

  anaphylactic shock during the diagnostic OFC (at a dose of 17 mg of PP). During the OIT protocol, she was able to double the eliciting dose, and received 34 mg of PP without presenting any clinical symptom.

	Severity of the reaction*
	No clinical history or no OFC, n (%)	4 (18.2%)	6 (27.3%)
	Grade 1, n (%)	13 (59.1%)	2 (9.1%)
	Grade 2 (anaphylaxis), n (%)	5 (22.7%)	12 (54.5%)
	Grade 3 (anaphylactic shock), n (%)	0 (0%)	2 (9.1%)

Table 4 .

 4 List of our 22 patients, and their evolution during the OIT protocol.

	Patient	Cumulative ED during OFC (mg of PP)	Severity* of worst reaction during OFC or clinical history	Tolerated dose during OIT (mg of PP)	OIT phase	Severity of worst reaction during OIT	Severity of reaction during exit OFC (4000 mg of PP)
	1	17	3	34	Dropout	0	Dropout
	2	100	2	2000	Continue maintenance	0	2
	3	300	2	2000	Ended	0	0
	4	1000	2	2000	Ended	0	0
	5	110	3	2000	Maintenance	0	OFC not performed yet
	6	2500	2	2000	Ended	0	0
	7	1600	1	2000	Ended	0	0
	8	400	2	2000	Maintenance	0	OFC not performed yet
	9	400	1	1000	Incremental	1	Still in the incremental phase
	10	430	2	2000	Maintenance	0	OFC not performed yet
	11	1400	2	2000	Maintenance	0	OFC not performed yet
	12	440	2	400	Incremental	1	Still in the incremental phase
	13	240	1	67	Incremental	2	Still in the incremental phase
	14	No OFC	2	1600	Incremental	0	Still in the incremental phase
	15	1400	1	1000	Incremental	0	Still in the incremental phase
	16	33	2	34	Dropout because of AE	1	Dropout
	17	600	2	200	Dropout	1	Dropout
	18	No OFC	1	200	Incremental	0	Still in the incremental phase
	19	1200	2	2000	Ended	0	0
	20	No OFC	2	2000	Maintenance	0	OFC not performed yet
	21	400	2	200	Incremental	0	Still in the incremental phase
	22	No OFC	1	67	Dropout	0	Dropout
		Legend -*Ring and Messmer classification; ED: Eliciting Dose; OFC: Oral Food Challenge; PP: peanuts proteins; OIT: Oral Immunotherapy; AE: adverse events.

Table 2 .

 2 Clinical reactions presented by patients with peanut both in their clinical history, and during the diagnostic challenge.Legend -*Ring and Messmer classification; OFC: Oral Food Challenge. Ring and Messmer classification; ED: Eliciting Dose; OFC: Oral Food Challenge; PP: peanuts proteins; OIT: Oral Immunotherapy; AE: adverse events.

	Clinical reaction with peanuts (n=22)	In patients' clinical history	During diagnostic OFC
	Severity of the reaction*
	No clinical history or no OFC, n (%)	4 (18.2%)	6 (27.3%)
	Grade 1, n (%)	13 (59.1%)	2 (9.1%)
	Grade 2 (anaphylaxis), n (%)	5 (22.7%)	12 (54.5%)
	Grade 3 (anaphylactic shock), n (%)	0 (0%)	2 (9.1%)

Table 5. Detailed characteristics of the 6 patients who underwent the exit OFC.

TEXTE INTRODUCTIF

L'allergie alimentaire peut être de forme IgE médiée et immédiate, ou non IgE médiée et retardée. Les réactions immédiates peuvent être associées à de potentielles manifestations cliniques sévères incluant l'anaphylaxie ou le choc anaphylactique. Récemment, une attention particulière est portée aux allergies IgE médiées à cause de leur fort impact non seulement sur les coûts de santé mais aussi pour l'impact sur la qualité de vie des enfants concernés et de leur famille.

SUMMARY

Introduction: Oral Immunotherapy (OIT) is a promising therapy in peanuts allergy. Nevertheless, it seems to be associated with an increased risk of severe reactions and need for epinephrine. We wanted to verify whether the protocol used in the Allergy Unit of the University Hospital of Montpellier has a better efficacy and safety profile compared to the results of published clinical trials.

Methods: For this retrospective study, we collected data from patients treated with peanuts OIT in the allergy units of the hospitals of Montpellier and Millau, to verify both the efficacy and safety of our protocol.