H Neau
email: neau@imft.fr

J Laviéville

O Simonin

NEPTUNE_CFD High Parallel Computing Performances for Particle-Laden Reactive Flows

Keywords: High Performance Computing, Parallel computation, Multiphase flows, Euler multi-fluid approach CP U Central Processing Unit Ef

This paper presents high performance computing of NEPTUNE_CFD V1.07@Tlse. NEPTUNE_CFD is an unstructured parallelized code (MPI) using unsteady Eulerian multi-fluid approach for dilute and dense particle-laden reactive flows. Three-dimensional numerical simulations of two test cases have been carried out. The first one, a uniform granular shear flow exhibits an excellent scalability of NEPTUNE_CFD up to 1024 cores, and demonstrates the good agreement between the parallel simulation results and the analytical solutions. Strong scaling and weak scaling benchmarks have been performed. The second test case, a realistic dense fluidized bed shows the code computing performances on an industrial geometry.

Introduction

Dilute and dense particle-laden reactive flows are used in a wide range of industrial applications such as coal combustion, catalytic polymerization or uranium fluoridation. A few years ago, three-dimensional numerical simulations of such flows, especially fluidized beds, were restricted to coarse meshes due to limitation of computing power (CPU clock speed, memory, hard drive). The recent improvements on high performance computing overcome this limitation. For hardware, the frequencies of the processors have remained almost flat in the last years. The development of multi-core technology and the increase of memory cache size and of memory and other interconnect frequencies have led to very highly parallel and efficient computing platforms. For software, this computational power has been exploited according to the parallelization of codes (message passing). Hence, we are able to solve previously intractable problems. The strong development of HPC allows the use of finer and larger meshes and the increase of numerical simulation accuracy.

Since a few years, three-dimensional realistic numerical simulations of industrial configurations are realized with unsteady Eulerian multi-fluid modeling approach for monodispersed or polydispersed reactive particle mixture [START_REF] Randrianarivelo | 3d unsteady polydispersed simulation of uranium hexafluoride production in a fluidized bed pilot[END_REF]). This approach 1 has been developed and implemented by IMFT (Institut de Mécanique des Fluides de Toulouse) in the NEP-TUNE_CFD V1.07@Tlse version. NEPTUNE_CFD is a unstructured parallelized multiphase flow software developed in the framework of the NEPTUNE project, financially supported by CEA (Commissariat à l'Énergie Atomique), EDF (Électricité de France), IRSN (Institut de Radioprotection et de Sûreté Nucléaire) and AREVA-NP. NEPTUNE_CFD V1.07@Tlse. This code allows to take into account complex phenomena: particle mixture, particle-fluid interaction, particle-particle and particlewall collisions, heat and mass transfers and chemical reactions.

In this study, three-dimensional numerical simulations of two test cases have been carried out: a uniform granular shear flow and a dense gas-solid fluidized bed at industrial scale. These simulations enable to evaluate high computing performances of NEPTUNE_CFD on three clusters with different technologies and architectures with different message passing libraries. Parallel structuring of the computational procedure, speedups, efficiency and their dependence upon the size of the problem, and the number of cores are discussed.

NEPTUNE_CFD overview

NEPTUNE_CFD is dedicated to calculating multiphase or multi-field flows, at the local scale and in geometries that may be complex. The software has the following main characteristics and functions:

• flow systems processed:

-1 to 20 fluid fields (phases or fields), processing of water/steam flows with actual thermodynamic laws;

• numerical methods:

meshes with all types of cell (element), nonconforming connections, -"cell-center" type finite volume method, calculation of co-localized gradients with reconstruction methods, distributed-memory parallelism by domain splitting;

• physical models:

interfacial momentum transfer terms, interfacial energy transfer terms, turbulence, head losses and porosity, additional scalar;

• architecture: interfacing with the Code_Saturne Enveloppe module for management of the preprocessing operations on the mesh, of the parallelism and of the post-processing files, written in Fortran 77 (the majority) and C (ANSI 1989) (procedural programming), ready for Unix and Linux platforms.

The method of parallel computing used by NEP-TUNE_CFD is known as domain decomposition, in which the geometry and associated fields are broken into pieces and allocated to separate cores. The process of parallel computation involves: decomposition of mesh and fields, running the application in parallel, postprocessing. The parallel running can use public or not implementations of the message passing library (MPI).

NEPTUNE_CFD is composed of two main elements (Fig. 1):

• the Kernel module is the numerical solver,

• the Enveloppe module is in charge of mesh data reading, mesh pasting allowing non matching meshes, domain decomposition for parallel computing using METIS [START_REF] Karypis | A fast and highly quality multilevel scheme for partitioning irregular graphs[END_REF]), definition of periodicity boundary conditions and post-processing.

NEPTUNE_CFD also relies on one compulsory library (under LGPL license): BFT (Base Functions and Types) for memory and input/output management as well as specific utilities.

Mathematical models and numerical methods

The unsteady Eulerian multi-fluid approach is derived from joint fluid-particle PDF equation allowing to derive the transport equations for the mass, momentum and agitation of particle phases (Simonin (2000)).

In the proposed modeling approach, separate mean transport equations (mass, momentum, and fluctuating kinetic energy) are solved for each phase and coupled through inter-phase transfer terms.

In the following when subscript k = g we refer to the gas and k = p to the particulate phase. The mass balance equation is:

∂ ∂t α k ρ k + ∂ ∂x j α k ρ k U k,j = 0, (1)
where α k is the k th phase volume fraction, ρ k the density and U k,i the i th component of the velocity. In (1) the right-hand-side is equal to zero since no mass transfer takes place.

The mean momentum transport equation takes the following expression:

α k ρ k ∂U k,i ∂t + U k,j ∂U k,i ∂x j = -α k ∂P g ∂x i + α k ρ k g i (2) +I k,i + ∂ ∂x j -α k ρ k u k,i u k,j + Θ p,ij ,
where u k,i is the fluctuating part of the instantaneous velocity of phase k, P g is the gas pressure, g i the i th component of the gravity acceleration and I k,i the mean gas-particle interphase momentum transfer without the mean gas pressure contribution. Finally Θ k,ij is for k = g the molecular viscous tensor and for k = p the collisional particle stress tensor. For details on diluted flows we refer to [START_REF] Simonin | Prediction of the dispersed phase turbulence in particle-laden jets. Gas-Solid Flows-1991[END_REF], and on fluidized beds we refer to [START_REF] Balzer | Eulerian gas-solid flow modelling of dense fluidized bed[END_REF], [START_REF] Gobin | Fluid dynamic numerical simulation of a gas phase polymerization reactor[END_REF].

The partial differential equations are discretized with a second-order centered scheme and the solution is timeadvanced by a first order scheme.

The model and the numerical method are adapted to the handling of n-phases (in fact n-fields), including the single phase frame. Models and Eulerian transport equations represent an extension of the classical twophase flow model developed in the frame of the ESTET-ASTRID Project and include water-steam closure laws and correlations.

The algorithm, based on original elliptic fractional step method (see [START_REF] Méchitoua | Numerical simulation of multiphase flow with on elliptic oriented fractional step method[END_REF] and [START_REF] Méchitoua | An unstructured finite volume solver for two-phase water/vapour flows modelling based on elliptic oriented fractional step method[END_REF]) that leads either to use linear solvers or direct nphas.x.nphas matrix inversion. The main interest of the method is the so-called "alpha-pressure-energy" step that ensures conservativity of mass and energy and allows strong interface source term coupling. Mass, momentum and energy equations are coupled with the help of a pressure correction equation, within the iterative "alpha-pressure-energy" step. The algorithm allows density variation according to pressure and enthalpy during the computation.

The momentum balance equations are solved with a semi-implicit method. They are splited in fractional steps: explicit balance, velocity implicit increment prediction, "alpha-pressure-energy" implicit increment prediction, final velocity correction.

The "Alpha-Pressure-Energy" step stops after the mass conservation sub-step, when the volume conservation holds. The user can adapt the criterion parameter ε vol , but this one remains very severe as it applies to a maximum value over the whole domain:

max I∈N CEL [1 - k α k (I)] < ε vol .
(3)

The standard value of ε vol is 10 -5 . Because of implicit formulation and threedimensional unstructured meshes, we use iterative solvers:

• for the pressure: conjugated gradient or biconjugate gradient stabilized (bi-cgstab),

• for volume fraction: biconjugate gradient stabilized or jacobi,

• for velocity: jacobi.

Parallel computer description

The numerical simulations have been carried out on 3 clusters:

Simulation of a three-dimensional granular uniform shear flow

Test case overview

The purpose of the test case is a three-dimensional isothermal granular shear flow. For such a simple configuration, the mathematical model has a analytical solution which can be compared with the numerical solution given by NEPTUNE_CFD. The computational domain is a cubic box of length H cube = 0.01 m (Fig. 2). The powder and gas material properties are given in table 2. The particulate phase is monodispersed with diameter 350 µm.

The analytical solution with 0D approach gives the following values:

• particle fluctuating kinetic energy:

q 2 p = 2.66.10 -5 m 2 • s -2 ,
• particle kinetic viscosity:

µ kp = 6.21.10 -4 kg • m -1 • s -1 ,
• particle collisional viscosity:

µ cp = 9.88.10 -4 kg • m -1 • s -1 .
The gas phase is laminar and the particle agitation model is accomplished by solving a system of two transport equations: one for the particle turbulent agitation and one for the fluid-particle covariance. According to a large particle to gas density ratio only the drag force is taken into account. It must be printed out that the gravity is also neglected in this case. Finally for this test case we solve 10 equations (mass balance, momentum transport, particle turbulence).

Two different meshes have been employed to evaluate the performances: 1,000,000 cells from 1 up to 32 nodes corresponding to 8 up to 256 cores and 10,503,459 cells from 16 up to 128 nodes corresponding to 128 up to 1024 cores. The Fig. 3 shows the standard mesh composed of 1,000,000 hexaedra with uniform cell size (∆x = ∆y = ∆z = 0.1 mm). The second mesh is also a regular mesh of 10,503,459 hexaedra (219 cells per direction).

Configuration is detailed in Fig. 4. Three kinds of boundary conditions are used: Gas Particles Density (kg

• m -3 ) 1 1,000 Viscosity×10 5 (Pa • s) 1 - Pressure (bar) 1 - Diameter (µm) - 350 Solid volume fraction - 0.3 Restitution coefficient - 0.8
Figure 3: Mesh containing 1,000,000 hexaedra.

• right-side and left-side, inlet-outlet condition for particles and gas with imposed velocity:

U x = 20 * (Y -H cube /2),
• front-side and back-side, symmetry condition for particle and gas

• top-side and bottom-side, moving wall:

U wall = 20 * (Y wall -H cube /2).
Moving wall is a no-slip wall boundary for particle and gas:

   U g,i = U p,i = U wall ∂q 2 p ∂n = 0. (4)
Inlet boundary condition values to particle fluctuating kinetic energy and fluid-particle fluctuating velocity covariance are: p 2.66.10 -5 2.6432.10 -5 2.6639.10 -5 (m 2 • s -2 ) µ kp 6.21.10 -4 6.1872.10 -4 6.2116.10 -4 (kg/ms) µc p 9.88.10 -4 9.8784.10 -4 9.9085.10 -4 (kg/ms) An adaptative time step is used (computed from Courant and Fourier criteria), typically ∆t = 5.10 -4 s.

q 2 p = 7.5.10 -5 m 2 • s -2 q f p = 1.10 -4 m 2 • s -2 .
The following iterative solvers have been selected: jacobi for the velocity, conjugated gradient for the pressure and bi-cgstab for the volume fraction. The criterion parameter ε vol of "Alpha-Pressure" step is fixed to 10 -6 and the maximum number of cycles into "Alpha-Pressure" step is 50.

Results and discussion

After a transient phase, numerical simulations converge to stationary state. The Fig. 5 shows temporal evolution of the solid volume fraction between 0.5 s and 2.0 s. Three-dimensional unsteady numerical simulation results agree with analytical solutions (table 3). The accuracy of numerical results is independent of parallelization and of core number. NEPTUNE_CFD performances are evaluated on a restart simulation of 1,000 additional iterations after transient step. The "CPU_TIME" intrinsic fortran sub-routine has been used to measure CPU times per core of the main routines of code, the CPU times per iteration per core and the effective CPU time per core of the simulation. The measurements of different times are repeated 3 times for In a first time, we focus on the strong scaling which is defined as how the solution time varies with the number of cores for a fixed total problem size. Secondly, we are interested in the weak scaling that is to say how the solution time varies with the number of processors for a fixed problem size per processor (strong scaling is about same problem size in shorter time and weak scaling is about larger problem size in same time). It is hard to achieve a good strong-scaling at larger process counts since the communication overhead increases in proportion to the number of processes used. The table 4 shows the effect of core number on effective CPU time per core with the standard mesh. Computation elapsed time is near to this time. The speedup is defined as the ratio between the elapsed time to execute a program on one node (ref = 1 node = 8 cores) and on a set of concurrent n nodes (n×8 cores) and the efficiency is defined as the ratio between speedup and n:

Sp = T ref T n = T 8cores T n Ef = Sp n (5)
where T ref is the effective core CPU time of the parallel job on one node (8 cores) and T n is the effective core CPU time of the parallel job on n nodes (n × 8 cores).

NEPTUNE_CFD effective CPU time per core, speedup and efficiency of the calculation are depicted in Fig. 6 demonstrates that NEPTUNE_CFD exploits the parallelism very efficiently. From 16 up to 128 cores (2 up to 16 nodes), all of the speedup is greater or equal to the linear speedup (say, super-linear speedup) and the efficiencies are also greater or equal to 1.0 (Fig. 8). However, in Fig. 6, we can observe very long effective CPU time on C1a and C1b for weak core number (up to 32). Ratio between C1 and C2 CPU time is about 1.3 for high core number and about 3 for weak core number. This effect may be attributed to Harpertown technology and cache limitation. The overtime for effective CPU time per core using 8 cores implies speedup and efficiency over-estimate. Using 128 cores, a speedup of 45 is not realistic, linear speedup is 16.

To avoid this problem, we define "absolute" speedup and efficiency with respect to T ref of C2a (ref = 1 node = 8 cores) as following:

Sp abs = T ref C2a T n = T 8cores C2a T n Ef abs = Sp n (6)
where T ref is the execution time of the parallel program on one node (8 cores) on C2a and T n is the elapsed time of the parallel program on n nodes (n × 8 cores) on the different clusters.

When we use this kind of definition about speedup, the speedup values are less interesting than the evolution of speedup per cluster as core number.The changing slope indicates the optimum core number. The Fig. 9 and 10 show the evolution of absolute speedup and efficiency. On all clusters, parallel performances are very good from 8 up to 128 cores. On C1, we find again low performances for few cores. Over 128 cores, the efficiency degradation is significant especially for C3 where effective CPU time increases. Moreover for C1 and C2, we can note a MPI implementation effect. SGI MPT seems more efficient for several cores and Intel MPI is better for numerous cores.

The degradation for high core number is mainly caused by the load unbalancing and the communication overhead. Restitution time of a simulation is divided into computation time, communication and waiting time (send/receive/barrier MPI) and I/O time. In this case, I/O time is almost zero. The increase of core number corresponds to a decrease of cell number per core that is to say to a decrease of computation time per core. Moreover, more cores implies more communications between cores. When communication time increases quicker than calculation time decreases, the core limit number is reached. Thus there is an optimal number of cores for a mesh and a set of equations.

For this numerical simulation of a three-dimensional granular uniform shear flow solving 10 equations, NEP-TUNE_CFD performances are excellent on all clusters To improve NEPTUNE_CFD performance evaluation, we perform numerical simulations with the refined mesh (10,503,459 hexaedra) using from 1 up to 128 nodes (8 up to 1024 cores). As CPU times are important, these numerical simulations have been realized only on cluster C2a (the most recent cluster) with Intel MPI implementation. Performances are evaluated on a restart simulation of 500 additional iterations after transient phase. Time measurements are still done with the "CPU_TIME" intrinsic fortran sub-routine and each run is repeated 3 times.

The table 5 shows effect of core number on effective CPU time per core with the refined mesh. The speedup and the efficiency are defined as previously.

NEPTUNE_CFD effective CPU time per core, speedup and efficiency of the calculation are depicted in Fig. 11, 12 and 13 respectively. The solid line represents the linear speedup. The Fig. 12 demonstrates that NEPTUNE_CFD exploits the parallelism very efficiently even for large core number. The speedup is super-linear up to 768 cores and linear for 1,024 cores and efficiency are also greater or equal to 1.0 (Fig. 13). Parallel performances are very good up to 128 nodes. As in previous case, performance degradation begins when communications become preponderant to compute. We can assume that with this mesh speedup should be low using 2,048 cores .

This refined mesh study confirms that NEP-TUNE_CFD performances are excellent on Nehalem cluster (C2) while cell number per core is higher than 10,000 that is to say for a mesh of 10,503,459 cells a core number lower or equal to 1,024. Hence, NEPTUNE_CFD strong scaling is excellent up to 1,024 cores in condition of respect of minimum cell number per core.

To understand these performances and time divide according to core number, NEPTUNE_CFD profiling is necessary. We use MPINSIDE to evaluate MPI communications and PerfSuite to get NEPTUNE_CFD timing informations.

MPINSIDE increases slightly the elapsed time of numerical simulations but gives the right percentages of elapsed time used by computation and by the different MPI process. The main MPI function times and computational time are depicted in Fig. 14 and 15 for the standard and the refined meshes for different core number.

Using 8 cores, with the two meshes, computation time MPINSIDE gives informations about MPI function samples. Using 16 cores on refined mesh, during 500 iterations, barrier before MPI Allreduce number is about 55,904,240. Using 1,024 cores, barrier before MPI Allreduce number is about 3,574,704,128. Indeed, NEP-TUNE_CFD iterative solvers require a lot of MPI communications. Thus, a lot of messages are exchanged between the cores many times in every iteration. For a high core number, communication time is important. MPIN-SIDE confirms that MPI communications due to iterative solvers and "alpha pressure" step will be the main limitations to NEPTUNE_CFD massively parallel computation.

PerfSuite is used to know the most frequently asked routines and functions (sample profiling). The Fig. 16 shows the distribution of call for the main "routines" as a function of core number. The term "routines" here corresponds to Intel MPI functions, function "parcom" (call of MPI function in fortran code), scheduling, routine "prodsc" (fortran scalar product), routine "gradco". For low core number, percentage of NEPTUNE_CFD routine sample for "gradco" and "prodsc" is about 90 %. For high core number (above 256), percentage of Intel MPI functions and scheduling is significant and become predominant for 1,024 cores.

PerfSuite enables to follow the called number to the code, the "libc" library and the Intel MPI library (Fig. 17). The increase of core number reduces strongly the percentage the NEPTUNE_CFD call number.

This sample profiling can be compared with a time profiling included in NEPTUNE_CFD. This profiling gives per iteration per core, CPU time and main algorithm step time. MPI process time are included into routines calling. In table 6, we can see that with the refined mesh and using 16 cores, one iteration requires a core CPU time of 120 s. meanly spent by the "alphapressure" step (109 s) and this one is meanly spent by the conjugate gradient (103 s). For the same iteration but this time using 1,024 cores, the core CPU time of 2.14 s. is meanly spent by the "alpha-pressure" step (1.88 s) which is meanly spent by conjugate gradient (1.76 s).

Between 80 % and 90 % of effective CPU time is spent in the step of matrix-inversion (iterative solvers).

A complementary aspect of performance evaluation is weak scaling. To respect a cell number per core of 20,000 we have created seven regular meshes to evaluate performance from 16 cores up to 512. The table 7 details the different meshes according to the core number. NEPTUNE_CFD performances are evaluated on a restart simulation of 2,500 additional iterations after transient step on C2a.

In the Fig. 18, the weak scaling of NEPTUNE_CFD is shown. The effective CPU times per core are almost constant. A weak scaling efficiency Ef weak can be de- Effective CPU time per core (s.)

C2a

Figure 18: NEPTUNE_CFD effective CPU time per core for 2,500 iterations (20,000 cells per core) fined as following:

Ef weak = T ref T n = T 8cores T n (7) (8)
where T ref is the elapsed time of the parallel job on one node with smallest mesh and T n is the elapsed time of the parallel job on n nodes with the respective meshes. The Fig. 19 shows that this weak scaling efficiency is very good up to 512 cores (larger than 1).

This test case of granular shear flow exhibits accuracy of NEPTUNE_CFD results and excellent scalability of the code for large enough problem sizes.

Simulation of a industrial gas-solid fluidized bed

The purpose of this test case is a three-dimensional instationnary dense fluidized bed at industrial scale. NEP-TUNE_CFD V1.07@Tlse is dedicated to this kind of numerical simulations [START_REF] Gobin | Fluid dynamic numerical simulation of a gas phase polymerization reactor[END_REF].

The industrial reactor is composed of a cylinder and a bulb at the top. The reactor is about 30 meter high and 5 The powder properties and operating points are given in table 8. In the industrial process, the particle phase is polydispersed however the numerical simulations have been carried out with monodisperse particle having a median diameter.

For the gas turbulence modeling, we use a standard k -ε model extended to the multiphase flows accounting for additional source terms due to the interfacial interactions. For the dispersed phase, a coupled transport equations system is solved on particle fluctuating kinetic energy and fluid-particle fluctuating velocity covariance. According to large particle to gas density ratio only the drag force is accounted as acting on the particles. Finally, we solve 12 equations (mass balance, momentum transport, gas and particle turbulence).

The three-dimensional mesh is shown by Fig. 20. The mesh, based on O-grid technique, contains 3,150,716 hexaedra with approximately ∆x = ∆y = 30 mm and ∆z = 90 mm.

At the bottom, the fluidization grid is an inlet for the gas with imposed superficial velocity corresponding to the fluidization velocity V f = 0.67 m.s -1 . For the particles this section is a wall. At the top of the fluidized bed reactor, we defined two free outlet for both the gas and the particles. The wall-type boundary condition is friction for the gas and slip for the particles.

           U p,n = 0 ∂U p,τ ∂n = 0 ∂q 2 p ∂n = 0, (9)
An adaptative time step is used (computed from Courant and Fourier criteria), typically ∆t = 1.10 -3 s.

The following iterative solvers have been selected: jacobi for the velocity, conjugated gradient for the pressure and bi-cgstab for the volume fraction. The criterion parameter ε vol of "Alpha-Pressure" step is fixed to is 10 -6 and the maximum number of cycles into "Alpha-Pressure" step is 50.

Results and discussion

The Fig. 22( As for the shear flow, the "CPU_TIME" intrinsic fortran sub-routine has been used to measure the different times per core.

The table 9 shows the effect of core number on effective CPU time per core.

As described above, we calculate speedup and efficiency. NEPTUNE_CFD effective CPU time per core, speedup and efficiency of this calculation are depicted ICMF 2010, Tampa, FL, May 30 -June 4, 2010 in Fig. 23, 24 and 25 respectively. The continuous line without symbol indicates linear speedup and ideal efficiency. The Fig. 24 demonstrates that NEPTUNE_CFD exploits the parallelism very efficiently. From 16 up to 384 cores (48 nodes), the speedup is super-linear and efficiencies are also greater than 1.0 (Fig. 25). Parallel performances are very good up to 384 cores, the restitution time decreases up to 512 cores. Over this value, an increase of core number is not interesting but restitution time does not increase significantly. The increase of communication time is balanced by the decrease of computational time.

On the same way, in this case realistic industrial dense fluidized bed solving 12 equations, NEPTUNE_CFD HPC is excellent on Nehalem cluster (C2) while cell number per core is higher than 10,000 that is to say for a mesh of 3,150,716 hexaedra a core number inferior or equal to 384. If we consider the "cost" of the numerical simulation about CPU time, the optimum performances are obtained with 256 cores. This test case illustrates excellent NEPTUNE_CFD scalability performances on a industrial geometry. Strong scaling is good for large enough problem sizes (up to 384 cores with this mesh).

Conclusion

Three-dimensional numerical simulations of two different cases of dense gas-particle flows have been performed to evaluate NEPTUNE_CFD parallel performances. The first one exhibits accuracy of numerical results and demonstrates high NEPTUNE_CFD parallel computing performances up to 1,024 cores. The second one, a realistic fluidized bed shows NEPTUNE_CFD efficiency and scalability on industrial geometry. The results show linear speed-up using Harpertown and Shangaï technologies and super-linear speedup with Nehalem technology. For the two test cases, a minimum of 10,000 cells of mesh per core is needed and 20,000 is recommended. A next step of evaluation of NEP-TUNE_CFD performances will focus on effect of phase number (fluids) and of solved equation number on the minimum cell number per core. On the other, we will

Figure 1 :

 1 Figure 1: NEPTUNE_CFD modules.

Figure 2 :

 2 Figure 2: Sketch of the three-dimensional granular uniform shear flow.

Figure 4 :

 4 Figure 4: Schematic of boundary conditions.

Figure 5 :

 5 Figure 5: Temporal convergence of solid volume fraction between 0.5 s to 2.0 s.

Figure 7 :

 7 Figure 7: NEPTUNE_CFD speed-up with respect to T ref of each cluster (standard mesh -1,000 iterations).

Figure 8 :

 8 Figure 8: NEPTUNE_CFD efficiency with respect to T ref of each cluster (standard mesh -1,000 iterations).

Figure 10 :

 10 Figure 10: NEPTUNE_CFD absolute efficiency with respect to T ref of C2a (standard mesh -1,000 iterations).

Figure 11 :Figure 12 :

 1112 Figure 11: NEPTUNE_CFD effective CPU time per core (refined mesh -500 iterations).

Figure 13 :

 13 Figure 13: NEPTUNE_CFD efficiency with ref = 1 node (refined mesh -500 iterations).

Figure 14 :

 14 Figure 14: MPINSIDE profiling on C2a (standard mesh -1,000 iterations).

Figure 15 :

 15 Figure 15: MPINSIDE profiling on C2a (refined mesh -500 iterations).

Figure 16 :

 16 Figure 16: PerfSuite routine profiling on C2a (refined mesh -500 iterations).

Figure 17 :

 17 Figure 17: PerfSuite module profiling on C2a (refined mesh -500 iterations).

Figure 19 :

 19 Figure19: NEPTUNE_CFD weak scaling efficiency for 2,500 iterations (20,000 cells per core)

7

  Figure 20: Three-dimensional mesh containing 3,150,716 hexaedra.

  a) shows the automatic domain decomposition realized by METIS on the industrial reactor. The Fig. 22(b) shows instantaneous solid volume fraction at 16.5 s. NEPTUNE_CFD performances are evaluated on a restart simulation of 250 additional iterations after a transient phase corresponding to the destabilization of the fluidized bed (15 s.). Numerical simulations have been carried out only on cluster C2a (Nehalem architecture with Intel MPI).

Figure 21 :

 21 Figure 21: Sketch of the industrial polymerization reactor.

Figure 22 :

 22 Figure 22: Industrial fluidized bed. (a) Automatic domain decomposition using Metis. (b) Instantaneous solid volume fraction field.

Figure 23 :Figure 24 :

 2324 Figure 23: NEPTUNE_CFD effective CPU time per core on C2a (250 iterations) on an industrial reactor.

Table 1 :

 1 Cluster description.

	• C1: SGI Altix ICE 8200 based on Intel Xeon Quad
	Core processors (Harpertown technology),
	• C2: SGI Altix ICE 8200 EX based on Intel Xeon
	X5560 Quad Core processors (Nehalem EP tech-
	nology),
	• C3: cluster based on AMD Shangaï Quad Core pro-
	cessors.
	The complete description of clusters is given in table 1.
	These clusters among the most efficient in France are
	based on different technologies, on different file systems
	and on different interconnects. The aim is to evaluate
	NEPTUNE_CFD parallel performances on different ar-
	chitectures about speedup and efficiency and not to com-
	pare cluster HPC (elapsed time). For clusters C1 and C2,
	we test 2 implementations of MPI : Intel MPI and SGI
	MPT (C1a, C1b, C2a and C2b) and we use Intel For-
	tran and C compiler. Numerical simulations on cluster
	C3 are carried out with GNU fortran and C compiler and
	OpenMPI. All clusters were in production.

Table 2 :

 2 Powder and gas properties.

Table 3 :

 3 Analytical and numerical result comparison.

		Analytical	NEPTUNE_CFD minimum maximum
	αp (-)	0.30	0.29989	0.30071
	q 2

Table 4 :

 4 Effect of core number on effective core CPU time for 1,000 iterations with the standard mesh.

	number of		Effective CPU time/core (s.)
	cores	C1a	C1b	C2a	C2b	C3
	8	35,621 35,325 12,150 12,462 15,469
	16	14,999 14,936	5,628	5,639	7,087
	32	5,959	5,877	2,598	2,567	3,254
	64	1,571	1,323	1,200	1,127	1,548
	128	803	751	563	583	895
	256	580	757	449	485	1,269
	512	498	-	493	-	-

Table 5 :

 5 Effect of core number on core CPU time for 500 iterations with the refined mesh on C2a.

	number of cores CPU time/core (s.)
	8	109,220
	16	55,205
	32	28,877
	64	14,707
	128	7,351
	256	3,721
	512	1,780
	768	1,220
	1024	962
	while cell number per core is greater than 10,000 that is
	to say while the core number is lower or equal to 128 for
	a mesh of 1,000,000 cells. On Nehalem cluster, perfor-
	mances are excellent up to 196 cores. It is noteworthy
	that the restitution time decreases up to 256 cores (5,000
	nodes per core).
	NEPTUNE_CFD scalability is excellent on all plat-
	forms, with linear speedup on Harpertown and Shangaï
	technologies and super-linear speedup on Nehalem tech-
	nology.

Table 6 :

 6 NEPTUNE_CFD integrated profiling : details of one iteration with the refined mesh using 16 cores on

	C2a.
	step	CPU time (s.)
	post-processing	0.00
	initialization	1.35
	velocity prediction	5.41
	"alpha-pressure"	109.70
	gradco routine	102.92
	jacobi routine	1.61
	bi-cgstab routine	1.19
	Total time for iteration	120

Table 7 :

 7 NEPTUNE_CFD weak scaling : different meshes according to core number on C2a.

	hexaedra number Core number Cell per core
			166,375			8		20,797
			328,509			16		20,532
			658,503			32		20,578
			1,295,029			64		20,235
			2,515,456			128		19,652
			5,177,717			256		20,225
			10,503,459		512		20,515
	12000
	11000
	10000
	9000
	8000
	7000
	6000
	5000	0	64	128	192	256	320	384	448	512
					Number of cores

Table 8 :

 8 Powder and gas properties of industrial reactor.

		Gas	Particles
	Density (kg/m 3 )	21.11	850
	Viscosity×10 5 (Pa.s)	1.54	-
	Pressure (bar)	20	-
	V f (m.s -1 )	0.67	-
	Mean diameter (µm)	-	1,600
	Solid mass (kg)	-	80,000
	Restitution coefficient	-	0.9
	meter wide as shown by Fig. 21. This bulb is an hemi-
	spherical dome with two smokes-tacks for gas outlet.

Table 9 :

 9 Effect of core number on core CPU time on C2a (industrial fluidized bed).

	number of cores CPU time/core (s.)
	8	68,479
	16	40,885
	32	19,233
	64	8,625
	128	4,129
	256	1,707
	384	1,275
	512	1,173
	768	1,190
	1024	1,220

th International Conference on Multiphase Flow, ICMF 2010, Tampa, FL, May 30 -June 4, 2010

Acknowledgments

This work was granted access to the HPC resources of CALMIP under the allocation P0111 (Calcul en Midi-Pyrénées). This work was also granted access to the HPC resources of CINES under the allocation 2010-026012 made by GENCI (Grand Equipement National de Calcul Intensif).


Brice Autier
email: brice.autier@univ-rennes1.fr

Bruno Gottstein

Laurence Millon

Michael Ramharter

Beate Gruener

Solange Bresson Hadni

Sarah Dion

Florence Robert-Gangneux

Solange Bresson-Hadni

Alveolar echinococcosis in immunocompromised hosts

Keywords: Echinococcus multilocularis, alveolar echinococcosis, immunosuppressive therapy, transplantation, HIV, cancer, malignant haemopathy, primary immune deficiency

INTRODUCTION

Alveolar echinococcosis (AE) is a parasitic disease due to the development the larval stage of

Echinococcus multilocularis, a tapeworm of canids (especially foxes) [START_REF] Bresson-Hadni | Hepatic alveolar echinococcosis[END_REF]. Only a few proportion of infected humans will actually develop viable parasitic lesions [START_REF] Gottstein | Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis)[END_REF]. Host and pathogen factors that might explain such variability remain to be unravelled, but there is cumulative evidence that host innate and acquired immune response is important in the clinical outcome. After a short description of the immunological events involved in the antiparasitic response, this review will analyse clinical cases reported in each category of immune suppression backgrounds, and discuss implications for the management of these patients and perspectives for research.

PATHOPHYSIOLOGY AND DIAGNOSIS OF ALVEOLAR ECHINOCOCCOSIS

Human infection occurs after accidental ingestion of eggs through contaminated food or water, or hand-to-mouth route. In the digestive tract, eggs release an oncosphere, which accedes to the blood circulation by passing through the intestinal mucosa, then establishes in any vascularized organ, with a preferential location in the liver as it filters the blood from the portal vein. There, it develops into the larval stage, also called metacestode (Fig 1) [START_REF] Vuitton | International consensus on terminology to be used in the field of echinococcoses[END_REF]. In accidental hosts, such as humans, the metacestode is a heterogeneous multicystic structure that actively proliferates at its periphery. The parasite is surrounded by a strong infiltration of immune cells associated with dense fibrotic tissue, neovessels and epithelioid cells, and containing central caseous necrosis and calcifications [START_REF] Vuitton | Echinococcus multilocularis and its intermediate host: a model of parasite-host interplay[END_REF].

Host-parasite interactions in human tissues are highly complex and lead to various clinical presentations. In most contaminated individuals (detected upon species-specific serology), no parasitic lesion is observed, suggesting that the parasite has been killed early, in the intestinal mucosa or in the liver parenchyma [START_REF] Gottstein | Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis)[END_REF]. In about 20% of cases, the metacestode aborts spontaneously at a later stage, forming a calcified non-viable parasite lesion, etiologically diagnosed on the basis of a positive serology, or upon histology and PCR [START_REF] Knapp | Molecular diagnosis of alveolar echinococcosis in patients based on frozen and formalin-fixed paraffinembedded tissue samples[END_REF]. These are called aborted or died-out lesions [START_REF] Gottstein | Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis)[END_REF][START_REF] Vuitton | International consensus on terminology to be used in the field of echinococcoses[END_REF].

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Finally, the evolutive form of AE, consisting of a viable parasite which continuously develops until its host dies, affects only a small percentage of contaminated individuals [START_REF] Gottstein | Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis)[END_REF]. Dendritic cells and macrophages initiate a pro-inflammatory Th1/Th17 immune response, which is considered to be putatively efficient against the parasite (Table 1) [START_REF] Wang | Immunoregulation in larval Echinococcus multilocularis infection[END_REF]. In susceptible hosts, the response progressively turns into a mixed Th1/Th2 response, with contribution of regulatory T CD4 + FoxP3 + lymphocytes (Treg) and IL-10 secretion, allowing parasite survival [START_REF] Wang | Immunoregulation in larval Echinococcus multilocularis infection[END_REF]. Humoral immunity, although present, is not effective in the control of AE.

Table 1. Summary of research findings about immunity in alveolar echinococcosis

Factor

Drugs

Albendazole, mebendazole

Cyclosporine, methotrexate, steroids [START_REF] Wang | Immunoregulation in larval Echinococcus multilocularis infection[END_REF][START_REF] Hübner | Effects of in vitro exposure of Echinococcus multilocularis metacestodes to cytostatic drugs on in vivo growth and proliferation of the parasite[END_REF] Tissue response Type IV hypersensitivity, fibrosis Angiogenesis [START_REF] Vuitton | Echinococcus multilocularis and its intermediate host: a model of parasite-host interplay[END_REF][START_REF] Yuan | Effect of anacardic acid against echinococcosis through inhibition of VEGF-induced angiogenesis[END_REF] Diagnosis relies on usual imaging techniques (ultrasonography (US), Magnetic Resonance Imaging (MRI), Computed Tomography (CT-scan)) and detection of anti-Em2 or anti-Em2+ antibodies by ELISA, and/or with anti-Echinococcus IgG immunoblot [START_REF] Gottstein | Diagnostic and follow-up performance of serological tests for different forms/courses of alveolar echinococcosis[END_REF][START_REF] Hotz | Evaluation of serological markers in alveolar echinococcosis emphasizing the correlation of PET-CTI tracer uptake with RecEm18 and Echinococcus-specific IgG[END_REF]. Discrimination between evolutive and aborted lesions in humans is often difficult. Currently, the best marker to assess viability of the parasite is the detection of anti-recEm18 antibodies, which can be detected by ELISA (45-80% sensitivity and 99-100% specificity for evolutive AE) [START_REF] Tappe | Close relationship between clinical regression and specific serology in the follow-up of patients with alveolar echinococcosis in different clinical stages[END_REF][START_REF] Gottstein | Diagnostic and follow-up performance of serological tests for different forms/courses of alveolar echinococcosis[END_REF][START_REF] Kronenberg | Serological assays for alveolar and cystic echinococcosis-a comparative multi-test study in Switzerland and Kyrgyzstan[END_REF], and/or PET-scan [START_REF] Hotz | Evaluation of serological markers in alveolar echinococcosis emphasizing the correlation of PET-CTI tracer uptake with RecEm18 and Echinococcus-specific IgG[END_REF].

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Medical imaging allows staging of the disease using the PNM classification proposed in 2006 [START_REF] Kern | WHO classification of alveolar echinococcosis: Principles and application[END_REF].

This system is based on three parameters similarly to the TNM system for tumours: P for the location and extension of the parasite within the liver (P0 to P4), N for the involvement of neighbouring organs (N0 or N1), and M for the metastasis (M0 or M1). Depending on the PNM classification, AE cases are then staged from I to IV, i.e. the less and the most severe, respectively.

OVERALL FINDINGS REGARDING IMMUNOCOMPROMISED PATIENTS

A total of 170 AE patients with immunosuppressive conditions (AE/IS) were mentioned in the literature, including 57 SOT recipients, 4 HIV-positive patients, 45 patients with inflammatory or auto-immune disorder (I/AID), 72 with cancer and 2 with a primary immune disorder (PID) (Table 2).

Of note, 8 patients had both cancer and I/AID, and 1 SOT recipient had an haematological malignancy. Four retrospective cohort studies were published, one from France (1982-2012) [START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF],

two others from Switzerland (late 90's-2020) [START_REF] Deibel | Characteristics and clinical course of alveolar echinococcosis in patients with immunosuppression-associated conditions: a retrospective cohort study[END_REF][START_REF] Lachenmayer | Elevated incidence of alveolar echinococcosis in immunocompromised patients[END_REF], and one from Canada (2013-2020). Altogether, [START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF]. By comparing the prevalence of each immunosuppressive condition between AE patients and the general population, SOT, I/AID and malignancies, but not HIV infection, were overrepresented among AE patients (odds ratios of 10.8, 1.6, 5.9 and 1.3, respectively) (Table 3).

these

ALVEOLAR ECHINOCOCCOSIS AND SOLID ORGAN TRANSPLANT RECIPIENTS

Due to their mechanisms of action on cellular immunity, immunosuppressive agents used for the prevention of graft rejection (cyclosporin, tacrolimus, mycophenolate) theoretically facilitate AE progression. Indeed, solid organ transplant (SOT) recipients were the first patients described with rapidly extensive AE. In 1990, two patients who had liver transplantation for AE salvage and preexisting pulmonary lesions, were reported as having rapidly growing lung lesions [START_REF] Bresson-Hadni | Orthotopic liver transplantation for incurable alveolar echinococcosis of the liver: report of 17 cases[END_REF], and between 1990 and 1992, recurrence of AE was observed in the transplanted liver [START_REF] Bresson-Hadni | Orthotopic liver transplantation for incurable alveolar echinococcosis of the liver: report of 17 cases[END_REF][START_REF] Bresson-Hadni | Recurrence of alveolar echinococcosis in the liver graft after liver transplantation[END_REF]. In 2003, Koch et al.

reported a 10-year survival of 45%, in a retrospective cohort of 45 patients, managed by liver transplantation for otherwise untreatable AE between 1985 and 1998 [START_REF] Koch | Experience of liver transplantation for incurable alveolar echinococcosis: a 45-case European collaborative report[END_REF]. Among the twenty deaths observed during follow-up, 5 (25%) were due to relapse, and 9 (45%) were perioperative deaths.

They highlighted the detection of new parasitic lesions (mostly in brain and lungs) in 16% (6/45), and graft invasion in another 16% (6/45). Similar clinical presentations were also reported in kidney and lung transplant recipients [START_REF] Dupont | Fast-growing alveolar echinococcosis following lung transplantation[END_REF][START_REF] Geyer | Rapidly progressive hepatic alveolar echinococcosis in an ABO-incompatible renal transplant recipient[END_REF][START_REF] Dražilová | Alveolar echinococcosis in patient after cadaveric kidney transplantation[END_REF][START_REF] Houston | Epidemiological and clinical characteristics of alveolar echinococcosis: an emerging infectious disease in Alberta, Canada[END_REF]. These data suggest that SOT recipients can present unusually rapidly progressive AE, with an increased risk of dissemination.

ALVEOLAR ECHINOCOCCOSIS AND HIV/AIDS

While HIV and E. multilocularis co-infection is often taken as an example of the opportunistic behaviour of the parasite, only few cases have been reported to date. The first was published in ACCEPTED MANUSCRIPT / CLEAN COPY 1997, and was diagnosed in a six-year-old girl with AIDS [START_REF] Sailer | Alveolar echinococcosis of the liver in a six-year-old girl with acquired immunodeficiency syndrome[END_REF]. The clinical presentation displayed multiple unusual features: the young age of the patient, the extensive parasite growth and the negative serological testing. Furthermore, the girl had a dramatically low CD4 + T cell count (12/mm 3 ) and a negative lymphoproliferative assay with E. multilocularis antigen. A second case was published 7 years later, in a 40 year-old male [START_REF] Zingg | Alveolar echinococcosis of the liver in an adult with human immunodeficiency virus type-1 infection[END_REF]. Although the patient was immunocompromised over nearly a decade (CD4 + T cells between 27 and 150/mm 3 ), the parasite had an usual growth rate, as the lesion was retrospectively observed on a CT scan performed 8 years before AE diagnosis. Only 2/870 (0.2%) HIV patients were mentioned in retrospective studies [START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF][START_REF] Deibel | Characteristics and clinical course of alveolar echinococcosis in patients with immunosuppression-associated conditions: a retrospective cohort study[END_REF]. Altogether, these reports showed that HIV is an uncommon condition for accelerated AE development. Only a dramatically low CD4 + T cell count appears to favour the parasite growth (< 20-50/mm 3 ).

ALVEOLAR ECHINOCOCCOSIS AND CHRONIC INFLAMMATORY DISEASES OR AUTO-IMMUNE

DISORDERS

As for SOT, I/AID are theoretically adequate backgrounds for rapidly progressive AE. Indeed, most of these disorders are treated with long-term immunosuppressive therapies, which often have broadspectrum effects on immune effectors (e.g. steroids, methotrexate...) or an anti-Th1 biological activity (e.g. TNF-α inhibitors, anakinra (IL-1 receptor antagonist)…). Such cases were actually reported in patients affected with auto-immune encephalitis and rheumatoid arthritis [START_REF] Diem | Accelerated course of alveolar echinococcosis after treatment with steroids in a patient with autoimmune encephalitis[END_REF][START_REF] Weiner | Echinococcus multilocularis infection and TNF inhibitor treatment in a patient with rheumatoid arthritis[END_REF][START_REF] Dentan | Rheumatoid arthritis, alveolar echinococcosis, and rituximab: A case report[END_REF].

Among the retrospective cohorts of AE/IS, 40/115 patients (35%) had I/AID, and at least 14/115 (12%) and 6/115 (5%) were treated with methotrexate and TNF-α inhibitors, respectively [START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF][START_REF] Deibel | Characteristics and clinical course of alveolar echinococcosis in patients with immunosuppression-associated conditions: a retrospective cohort study[END_REF][START_REF] Lachenmayer | Elevated incidence of alveolar echinococcosis in immunocompromised patients[END_REF][START_REF] Houston | Epidemiological and clinical characteristics of alveolar echinococcosis: an emerging infectious disease in Alberta, Canada[END_REF].

Of note, at least 27/115 (23%) were treated with steroids, without specification concerning the indication (SOT, malignancy, I/AID or other) nor the dosage. Although it seems probable that all immunosuppressive regimens do not equally favour AE, fundamental and clinical data suggest that long-term administration of steroids or TNF-α inhibitors could accelerate AE progression. Other immunosuppressive therapies were observed in patients with accelerated AE, such as rituximab ACCEPTED MANUSCRIPT / CLEAN COPY (anti-CD20) [START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF][START_REF] Geyer | Rapidly progressive hepatic alveolar echinococcosis in an ABO-incompatible renal transplant recipient[END_REF][START_REF] Dentan | Rheumatoid arthritis, alveolar echinococcosis, and rituximab: A case report[END_REF], however they are mostly associated with steroids or TNF-α inhibitors, which prevent to reliably conclude on their imputability.

ALVEOLAR ECHINOCOCCOSIS AND MALIGNANCIES

The few reports of AE concomitant to malignancy were compiled in retrospective cohorts. Out of the 115 AE/IS detailed cases, 44 (38%) had solid cancer (15 of the digestive tract, 9 of the respiratory tract, 15 urogenital or breast, 1 of the skin and 3 others), 12 (10%) had haematological malignancies (4 myeloproliferative syndrome, 6 lymphoproliferative syndrome, 1 Fanconi anaemia) and 16 (14%) had unspecified malignancy [START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF][START_REF] Deibel | Characteristics and clinical course of alveolar echinococcosis in patients with immunosuppression-associated conditions: a retrospective cohort study[END_REF][START_REF] Lachenmayer | Elevated incidence of alveolar echinococcosis in immunocompromised patients[END_REF][START_REF] Houston | Epidemiological and clinical characteristics of alveolar echinococcosis: an emerging infectious disease in Alberta, Canada[END_REF]. The median time between onset of immunosuppressive condition (IS) and AE diagnosis was shorter for solid cancers than for other conditions, probably because AE was often diagnosed incidentally during extensive workup (83%) [START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF]. Despite the high number of AE diagnosed in patients with malignancies, no clear evidence of aggressive AE has been reported. On the contrary, these cases often benefited from an earlier management due to incidental diagnosis [START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF].

PRIMARY IMMUNE DEFICIENCIES

Only two cases of AE were described in patients with PID, both were young patients (14 and 17 yo)

with Hyper-IgE Syndrome (HIES) [START_REF] Reuter | Salvage treatment with Amphotericin B in progressive human alveolar echinococcosis[END_REF][START_REF] Haskologlu | An unexpected infection in loss-of-function mutations in STAT3: malignant alveolar echinococcosis in liver[END_REF]. This rare PID is characterized by recurrent skin and lung infections, eosinophilia and elevated IgE serum levels. The syndrome is associated with a defect of the Th17 response, leading to bacterial and fungal opportunistic infections [START_REF] Becker | Th2 and Th9 responses in patients with chronic mucocutaneous candidiasis and hyper-IgE syndrome[END_REF]. The fact that these two young patients presented with disseminated AE is highly unusual, as the mean AE incubation time is between 5 and 15 years [START_REF] Gottstein | Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis)[END_REF]. Even if more evidence needs to be collected, these observations suggest that Th17 defects, including Card9-Syk deficiencies, could favour AE development [START_REF] Lanternier | Primary immunodeficiencies underlying fungal infections[END_REF].

Unlike most of PIDs, such deficiency can be diagnosed in apparently healthy children or adults [START_REF] Lanternier | Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both[END_REF][START_REF] Lanternier | Deep dermatophytosis and inherited CARD9 deficiency[END_REF]. The part of such defects in unusually extensive AE is currently not known. Further studies (extensive analysis of immune cell populations, complete workup for autoimmunity, whole-genome sequencing) are needed to ensure that rare and yet undiagnosed PIDs are not hidden beyond those ACCEPTED MANUSCRIPT / CLEAN COPY atypical cases, particularly when they occur in children. Indeed, taken together, 21 paediatric case reports have been described in the literature (median age 12 years), including 24% under 10 years and 24% with disseminated lesions [START_REF] Sailer | Alveolar echinococcosis of the liver in a six-year-old girl with acquired immunodeficiency syndrome[END_REF][START_REF] Haskologlu | An unexpected infection in loss-of-function mutations in STAT3: malignant alveolar echinococcosis in liver[END_REF][START_REF] Jonaitytė | Alveolar echinococcosis in children[END_REF][START_REF] Kinčeková | A rare case of alveolar echinococcosis in a 14-year-old child[END_REF][START_REF] Honda | Pediatric alveolar echinococcosis invading the diaphragm and spreading to the chest and abdominal wall[END_REF][START_REF] Yoshida | Alveolar echinococcosis of the liver in children[END_REF][START_REF] Oral | An unusual presentation of alveolar echinococcosis in a 12-yr-old immunocompetent child[END_REF][START_REF] Guinet | L'échinococcose alvéolaire hépatique : une cause exceptionnelle de douleurs abdominales récurrentes, chirurgicalement curable, chez l'enfant[END_REF][START_REF] Kantarci | Multisystem involvement of alveolar echinococcosis in a child[END_REF][START_REF] Mack | Alveolar echinococcosis in the liver of an adolescent boy[END_REF][START_REF] Joyce | Disseminated Echinococcus multilocularis infection without liver involvement in child, Canada, 2018[END_REF][START_REF] Yilmaz-Cankaya | Hepatic alveolar echinococcosis in a child[END_REF]. In almost all cases, assessment of immune status was unreported or limited to T CD4 + and T CD8 + cell counts and HIV serology. However, it should be kept in mind that atypical presentations may be not only related to immune disorders, but can be associated with vascular abnormalities, as illustrated in cases of extrahepatic AE in patients with portal hypertension [START_REF] Reuter | Extrahepatic alveolar echinococcosis without liver involvement: a rare manifestation[END_REF][START_REF] Faucher | Hints for control of infection in unique extrahepatic vertebral alveolar echinococcosis[END_REF], portosystemic shunt [START_REF] Joyce | Disseminated Echinococcus multilocularis infection without liver involvement in child, Canada, 2018[END_REF], or hereditary haemorrhagic telangiectasia [START_REF] Baldolli | Isolated cerebral alveolar echinococcosis[END_REF].

IMPLICATIONS

Alveolar echinococcosis is an emerging opportunistic infection, favored by alteration of cellular immunity. Thus, populations at risk for progressive AE are those exposed to long-term immunosuppressive therapy such as cyclosporin, TNF-α inhibitors or steroids, or with prolonged and severe immune deficiency. While data are scarce regarding other treatments, especially biotherapies, physicians should be aware that the use of such drugs could accelerate progression and dissemination of AE. Analysis of the previously published retrospective studies showed that SOT, I/AID and cancer are associated with AE. Considering the occurrence of rapidly extensive AE in SOT and I/AID patients, it seems probable that therapies used in these backgrounds increase the risk of developing evolutive AE. For this reason, serological screening could be proposed to these patients before onset of the immunosuppressive therapy, even if the benefit of such recommendation should be evaluated. Abdominal imaging could be proposed as well to these patients, if not previously done.

Whether cancer is actually a risk factor is not clear, as it can be associated with AE diagnosis due to extensive check-up, as suggested by the short delay between cancer and AE diagnoses [START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF].

Conversely, it could be even hypothesized that AE is a risk factor of cancer, as it induces chronic immunosuppression by itself [START_REF] Vuitton | Echinococcus multilocularis and its intermediate host: a model of parasite-host interplay[END_REF]. Finally, HIV infection does not seem to be a risk factor, nor a significant cause of progressive AE.

ACCEPTED MANUSCRIPT / CLEAN COPY

LIMITATIONS

Our review has some limitations as it relies on retrospective cohorts and case reports, which made it at risk of declaration bias. Also, we decided to restrain our analysis to well-defined immunocompromised backgrounds, i.e. SOT, I/AID, HIV infection, malignancy and PID. However, other backgrounds can be associated with opportunistic infections, such as cirrhosis, pregnancy, asthma or diabetes. Of note, both retrospective cohort studies from Switzerland included such patients, without detailing if their characteristics were different from other backgrounds.

PERSPECTIVES

The details of the relationship between immunosuppressive conditions and AE evolution remain unclear (Table 5). This is mostly due to the low number of AE cases, which makes difficult to build consistent cohorts. Overall, the probably most important suggestion to these physicians would be to think about AE when finding a liver lesion.

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Management of patients

Would it be reasonable to perform systematic anti-E. Injected abdominal CT (axial view, venous phase) performed for an acute sigmoïditis episode in a 65 year old woman. She received a kidney transplant 9 years ago and was treated with tacrolimus and mycophenolate mofetil. Punctiform calcifications in the center of 2 small anterior lesions (thin arrows).

The largest posterior lesion invades the left and median hepatic veins (thick arrows).

Source: Division of Tropical and Humanitarian Medicine, University Hospitals of Geneva, Switzerland.

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2 [ 4 , 6 ,

 246 , IL-12, TNF-α, IFN-γ, IL-17 IL-4, IL-5, IL-9, IL-10, IL-13, TGF-β1, FGL-10,14,15]

multilocularisFigure 1 .

 1 Figure 1. Life cycle of Echinococcus multilocularis.Adults of E. multilocularis reside in the small intestine of definitive hosts, and spread eggs with their

Figure 2 .

 2 Figure 2. Fortuitous imaging of liver alveolar echinococcosis.

Table 2 . Summary of published cases and cohorts of alveolar echinococcosis in immunocompromised patients Population Number of case reports Number of cases in cohort studies Progressive AE 1

 2

	References

Table 3 . Prevalence of immunosuppressive conditions in alveolar echinococcosis patients and general population

 3 different from the 20% (7/35) observed in a previous German cohort of AE patients[START_REF] Reuter | Benzimidazoles in the treatment of alveolar echinococcosis: a comparative study and review of the literature[END_REF].Mortality was significantly higher in AE/IS compared to AE/IC patients (16/80 (20%) vs 13/313 (4%), p<0.001), but was not clearly imputed to AE. The main conclusions of these studies are summarized in Table4.

		Prevalence among AE	Estimation of prevalence in the	Odds ratios and
		patients: n/N (%)	general population	significance 4
	SOT recipients	9/870 (1.0%)	97/100.000 1	10.8, p<0.001
	HIV/AIDS	2/870 (0.2%)	180/100.000 2	1.3, p=0.955
	Chronic I/AID	41/870 (4.7%)	3.000/100.000 3	1.6, p<0.01
	Malignancies	72/870 (8.3%)	1.500/100.000 2	5.9, p<0.001
	Total	115/870 (13.2%)	4.777/100.000	3.0, p<0.001

SOT Solid organ transplant, I/AID Inflammatory and Autoimmune disorder ACCEPTED MANUSCRIPT / CLEAN COPY and (ii) the prevalence of cancer in France in 2000 and 2008, from the public WHO database (https://gateway.euro.who.int/en/).

3 Estimation from Cooper et al. 2003 [40]. 4 Statistical test: Fisher's exact test Compared to AE/IC, AE/IS cases were diagnosed more often incidentally (66/86 (77%) in AE/IS vs 144/341 (42%) in AE/IC, p<0.001) and, consequently, earlier in the parasite development (PNM stages I-II: 49/85 (58%) in AE/IS vs 137/348 (39%) in AE/IC, p<0.01). Clinical presentation of the symptomatic cases was not compared between AE/IS and AE/IC. Importantly, AE/IS was significantly associated with false negative serology compared to AE/IC patients (58/77 (75%) in AE/IS vs 64/329

(19%) in AE/IS, p<0.001), but this could be also related to earlier diagnosis

[START_REF] Hotz | Evaluation of serological markers in alveolar echinococcosis emphasizing the correlation of PET-CTI tracer uptake with RecEm18 and Echinococcus-specific IgG[END_REF]

. A high frequency of atypical liver ultrasound and CT imaging findings were described in the French cohort (48%, 24/50), suggesting cancer metastasis (36%, 18/50), liver abscess (8%, 4/50), haemangioma (2%, 1/50) or hematoma (2%, 1/50) instead of typical imaging (heterogeneous mass with calcifications and/or clustered microcysts) (Fig

2

)

[START_REF] Chauchet | Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppressionassociated conditions[END_REF]

. This proportion was significantly higher compared to German and effects (40%), possibly associated with high concentrations of albendazole sulfoxide in plasma, thus encouraging pharmacological monitoring in these patients. However, this proportion was not ACCEPTED MANUSCRIPT / CLEAN COPY significantly

Table 4 . Main facts regarding alveolar echinococcosis and immune suppression

 4 Data obtained from two retrospective studies of AE imaging. The populations were not strictly composed of AE/IC cases, as AE/IS were not excluded.

	Item	AE/IS	AE/IC	Significance	Interpretation for	References
				(Fisher's	AE/IS compared to
				exact test)	AE/IC
	PNM stage I-II of	49/85	137/348	p<0.001	Diagnosed earlier,	[23,24,32]
	disease at diagnosis	(58%)	(39%)		due to systematic
					check-up 1
	Misleading US and CT	24/50	106/375	p=0.008	Higher rate of	[23,41,42]
	imaging (cancer	(48%)	(28%) 2		atypical imaging
	metastasis, abscess,
	haemangioma or
	hematoma)
	Sensitivity of serology	19/77	265/329	p<0.001	Lower sensitivity of	[23,24,32]
		(25%)	(81%)		serology
	Regression at 1 year	21/41	50/187	p<0.01	Higher efficacy of	[23]
	under benzimidazole	(51%)	(27%)		benzimidazole
	treatment
	Benzimidazole side	19/48	7/35	p=0.093	Slightly higher	[23,43]
	effects	(40%)	(20%)		frequency of side
					effects
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  The next step toward filling this gap in knowledge of AE is to improve and harmonize data collection in endemic countries. Complementarily, fundamental research is of paramount importance to understand the effect of immunosuppressive therapies on AE development. Especially, as humans are usually diagnosed at the late stage of the disease, clinical studies cannot discriminate if immunosuppressive therapies impact invasion through the intestinal barrier, early establishment of the larvae or late stage of AE. Also, more immunological and genetic studies are needed to assess if rare PIDs are responsible for some of the cases of unusually extensive AE.In areas endemic for AE, physicians who manage patients under long-term immunosuppressive therapies should deliver health education, by explaining what AE is and the ways to avoid infection.

Table 5 . Unanswered questions about alveolar echinococcosis and immunodeficiencies Topic Questions

 5

Estimation based on the whole number of living SOT recipients in France in

2021, from the public "Agence de la Biomédecine" database (https://rams.agence-biomedecine.fr/bibliotheque-dedonnees).[START_REF] Gottstein | Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis)[END_REF] Estimation based on (i) the whole number of individuals living with HIV in France and Switzerland,

ACKNOWLEDGMENTS

The authors thank Dr Francesca Tamarozzi for helpful discussion. Conceptualization: F.R.-G. Investigation: B.A. Writing-first draft: B.A. Writing-review and editing: all authors contributed equally.

FUNDING

No external funding was received for this work.

CONTRIBUTION

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CONFLICT OF INTERESTS

None of the authors declares any conflicts of interest.