Eosinophiles et aeintes respiratoires · CEREO-Centre de Référence des Syndromes...

Ma#hieuGROHMédecineInterne,HôpitalFoch

CEREO-CentredeRéférencedesSyndromesHyperéosinophiliques

Eosinophileseta-eintesrespiratoires

1.  Généralités•  Physiopathologie•  Défini<ons•  Epidémiologie

2.  Quoiévoquerdevantunea#eintebronchique?

3.  Quoiévoquerdevantunea#einteparenchymateuse?

Plan

Rosenberg,NatRevImmunol2013

EffetstoxiquesduPNE

•  Sécré%ondescytokinesdérivéesdescellulesépithéliales,IL-33,IL-25etTSLP,parlescellulesépithélialespulmonairesenréponseàdifférentess%muli(champignons,virus)

•  Ac%va%ondesILC2danslespoumons,promouvantlasécré%ond’IL-4,IL-5etIL-13

•  IL-5produiteparlesILC2conduisantaurecrutementdeséosinophiles

•  Chezl’homme,augmenta%ondesILC2danslesangetleLBAdespa%entsasthma%ques,enpar%culierchezlespa%entsavecasthmeéosinophiliquesévèreCTdépendant

ILC2etmaladiesàPNE

Ebbo,NatRevImmunol2017

Ogbogu,JAllergyClinImmunol2009

N=188pa4ents.Sex-Ra4o1♀/1♂

A#eintesrespiratoiresaucoursdesSHE

57% 52%

45%

34%

16% 16%

N=44pa%ents

Sex-Ratio 43♂ / 1♀

SONT EVOCATEURS •  Erosions muqueuses •  Toux rebelle, asthme, infiltrats •  Atteinte cardiaque •  B12 et tryptase élevées •  Cortico-résistance •  Sensibilité ++ à l’Imatinib

LCEF/P+eta#einterespiratoire

Legrand,Medicine2013

13F/8H42ans[5-75]

SONTEVOCATEURS

•  Angioedèmes•  Eczéma•  IgEtotalesélevées•  Cor4cosensibilité

SHEL3-4+eta#einterespiratoire

Lefèvre,Medicine2014

Opacitéspulmonaires(OUaYeintebronchique)àl’imagerie(TDM)

+•  uneéosinophiliepériphérique=cut-off>1G/L(ou0,5?)

OU•  unehyper-éosinophilieauLBA>25%(aigue)ou40%(chronique)

OU•  unehyper-éosinophilie4ssulairesurunebiopsiepulmonaire

C’estquoienpra<que??

Co^n,ClinChestMed2016

EosinophiliebronchiqueetTVO

APBAAsthmebronchiteetbronchioliteàéosinophileWidalGEPA(Churg-Strauss) Eosinophiliealvéolaire

ParasitesetInfec%onsMédicaments-ToxiquesPneumopathieaigue/chroniqueàPNEGEPA(syndromedeChurg-Strauss)

EosinophilieORLRhinosinusiteavecHERSavecpolyposeNSetEOWidalGEPA

Commentraisonner?




Plan

GEPAet/ouSHE:Passisimple!

1.   Masi,AR19902.   Wechsler,NEJM20173.   Comarmond,AR2013

4.   Josselin-Mahr,Rheumatology20145.   Emmi,Rheumatology2015

6.   Puéchal,AR2017

•  Critèresu4liséspourlediagnos4c/inclusiondansdesessaisthérapeu4quessont«souples»…1,2

•  PreuvehistologiquedevasculariteaucoursdeGEPA….<50%despa4ents!3

•  Certainspa4entsauphénotypedeGEPA...sontF/P+4,5!

•  «Echec»desISconven4onnels6…vsefficacitédesan4-IL52

GEPA…ouHASM?…ouSHE?

Co^n,AutoimmunRev2016Lefèvre,AutoimmunRev2016

GEPAvs.SHE?

Leurs,JACIPract2018

IntérêtdelaCRP++++

AspergilloseBroncho-PulmonaireAllergique(ABPA)

Agarwal,ClinExpAllergy2013

However, there was inconsistency in results obtainedfrom different centres [136]. Thus, the expert group feltthat although the current data suggest a promising roleof recombinant antigens in diagnosis of AS and proba-bly ABPA [141–143], there is need for larger studiesfrom different centres to give a final recommendationon the diagnostic value of these allergens.

Diagnosis and diagnostic criteria

The diagnosis of ABPA is currently made on a combina-tion of clinical, radiological and immunological findingsusing the Patterson criteria [3, 6]. The expert group feltthat these criteria need revision as they offer equalimportance to all parameters while some components ofthe criteria are more important than others. For exam-ple, the specificity of Aspergillus IgG for ABPA asopposed to other forms of aspergillosis remainsunknown. Moreover, there is neither any consensus onthe number of major or minor criteria required to makethe diagnosis, nor receiver operator curve (ROC) analysisof the optimum cut-off values for IgE levels and eosino-phil count. From a clinical perspective, it would be help-ful to have simpler criteria, if possible. New diagnosticcriteria were formulated with an aim to improve thediagnosis and care of patients with ABPA and limit theweaknesses of the previous criteria (Table 4). The refine-ment in inclusion/exclusion criteria will also benefitclinical research particularly studies planning to evalu-ate aetiology and/or new therapies. The new criteria willneed validation and further refinement. Bronchiectasiswas removed from the diagnostic criteria as ABPA maypresent without CB. The minor criteria of Patterson et al.although sometimes present should not be required fordiagnosis, and hence have also been removed. Theexpert group agreed that a cut-off value of 1000 IU/mLcan help in differentiating SAFS from ABPA-S butwould require validation. In clinical practice, many

patients will fall short of diagnostic criteria for ABPA.These patients may be labelled as ‘ABPA- at risk’ andrequire close monitoring and follow-up.

While investigating a patient with asthma for ABPA,it is recommended to perform an Aspergillus skin testand/or A. fumigatus specific IgE levels, with the latterbeing more sensitive [88]. If either is positive, the totalserum IgE levels should be measured. If the value is> 1000 IU/mL, other tests for ABPA including a CT ofthe chest, IgG specific to A. fumigatus or serum precipi-tins to A. fumigatus and total eosinophil count shouldthen be performed to fully characterize the disease(Fig. 6). Allergic bronchopulmonary mycosis can bediagnosed in the same way, with sensitization toanother fungus being predominant [15].

Natural history

The natural history of ABPA remains unclear becauseof its variable course in different patients [6, 7, 144–147]. However if untreated, the inexorable inflamma-tory process can result in bronchiectasis and pulmonaryfibrosis, and ultimately respiratory failure and cor pul-monale [83]. Allergic bronchopulmonary aspergillosisgenerally does not remit but it can remain quiescent forlong periods. Given its relapsing nature, with develop-ment of serious complications, it is important toprovide a clinical framework for staging the disease.

Clinical staging of allergic bronchopulmonaryaspergillosis

Although ABPA has been classified into five stages [5];there is considerable ambiguity in description of these

Table 3. Recombinant Aspergillus fumigatus antigens evaluated in

allergic bronchopulmonary aspergillosis (ABPA) complicating asthma

Antigen

Sensitivity, n/N (%) Specificity, n/N (%)

ABPA

Aspergillus

sensitization

Asthma or

controls References

rAsp f1 84/105 (80) 30/60 (50) 0/13 (100) [137, 139, 261]

rAsp f2 24/25 (96) Not done 0/20 (100) [262]

rAsp f3 66/71 (93) 26/48 (54) 0/24 (100) [137, 263]

rAsp f4 58/72 (81) 0/52 (0) 0/25 (100) [137, 264]

rAsp f6 38/72 (53) 0/52 (0) 0/25 (100) [137, 264]

rAsp f34 60/64 (94) 11/24 (46) 0/7 (100) [265]

rAsp f1

or f3

58/60 (97) 30/40 (75) 0/20 (100) [137]

rAsp f4

or f6

65/72 (90) 0/52 (0) 0/25 (100) [137, 264]

Table 4. Newly proposed diagnostic criteria for allergic bronchopul-

monary aspergillosis

Predisposing conditions

Bronchial asthma, cystic fibrosis

Obligatory criteria (both should be present)

Type I Aspergillus skin test positive (immediate cutaneous

hypersensitivity to Aspergillus antigen) or elevated IgE levels

against Aspergillus fumigatus

Elevated total IgE levels (> 1000 IU/mL)*

Other criteria (at least two of three)

Presence of precipitating or IgG antibodies against A. fumigatus in

serum

Radiographic pulmonary opacities consistent with ABPA†

Total eosinophil count > 500 cells/lL in steroid na€ıve patients (may

be historical)

*If the patient meets all other criteria, an IgE value < 1000 IU/mL

may be acceptable.†The chest radiographic features consistent with ABPA may be tran-

sient (i.e. consolidation, nodules, tram-track opacities, toothpaste/fin-

ger-in-glove opacities, fleeting opacities) or permanent (i.e. parallel

line and ring shadows, bronchiectasis and pleuropulmonary fibrosis).

© 2013 John Wiley & Sons Ltd, Clinical & Experimental Allergy, 43 : 850–873

858 R. Agarwal et al

Condi4onssinequanon:-  IgEtotale>1000UI*-  ETIgEan%-aspergillaire

augmenté(>0.35)ouPrick-test>0

-  ETaumoins2des3critèressuivants

§  Sérologieaspergillaire>0§  Imageriecompa%ble§  PNE>500

BronchioliteoblitéranteàPNE

Cordier,EurRespJ2013




Plan

ASYMPTO

DRESS

MAIS AUSSI, en cours d’hospitalisation - An4bio4ques

- HBPM

- AVK- PDCiodés

M DUREE10jà6MOIS++++

Sedonnerdutemps

PNEethypersensibilitémédicamenteuse

Ascaridiose

Toxocarose

Hyda4dosepulmonaire

Filariose

Cryptococcose

Histoplasmose

Coccidiodomycose

Aspergillose

Paragonimose

Eosinophiliesparasitaires

Valent, J Allergy Clin Immunol 2012

Maladiegastrointes%nalesàEosinophiles(colite,gastro-entérite,oesophagite)

Cholangiteàéosinophiles

Pancréa%teàéosinophiles

Asciteàéosinophiles

Asthmeéosinophilique

Bronchiteetbronchioliteàéosinophiles

Pneumopathieaigueetchroniquesàéosinophiles

Néphriteinters%%elleàéosinophiles

Cys%teàéosinophiles

Mas%teàéosinophiles

Myocarditeàéosinophiles

Myositeàéosinophiles

Endométriteàéosinophiles

Synovitesàéosinophiles

Fasciiteàéosinophiles

MaladiesàPNEspécifiquesd’organe

Pneumopathieaigue/chroniquesàPNE

Co^n,ClinChestMed2016

CordierSeminRespirCritCareMed2006

Pneumopathieaigue/chroniquesàPNE

ü  Toujourspra4querunLBA,carû  LeLBApeutêtrenonéosinophiliquemalgrélaprésenced’une

éosinophiliesanguineû  Ilexistedeséosinophiliespulmonairessanséosinophiliesanguineû  L’éosinophiliepériphériquenereprésentepas«laréalitépulmonaire

»carelleestsouventtrèsinferieureàl’éosinophilie%ssulaire.

ü  Unpoumonn’est«éosinophile»quesil’éosinophileestlapopula4onmajoritairesurleLBA(horsmacrophage)û  Sinon=formulepanachée:POC,pathologierespiratoirechezun

asthma%que….

ü  Toujoursfaireun«bilansystémiquedeSHE»(origineetreten4ssementextra-respiratoiredel’éosinophilie)

ü  Unea-eintebronchique…n’estpasforcémentuneGEPA

ü  Penseràl’EP

Conclusion

Remerciements

CEREO •  Annecy: Dr Morati-Hafsaoui, Dr Alice

Berezne •  Bordeaux: Pr Viallard •  Foch-Surenes: Dr JE Kahn, Dr M Groh,

Dr F Ackermann •  Lille: Dr G Lefevre, Dr N Etienne, Pr

Staumont Salle, Dr Terriou, Pr Launay, Pr Hatron, Pr Hashulla, Morschhauser,

•  Marseille: Pr Schleinitz, Dr Ebbo •  Nantes: Pr Hamidou, Dr A Neel •  Strasbourg: Pr Martin •  Lyon: Pr Salles, Dr Khouatra, Pr Ninet, Pr Seve,

Pr Cordier •  Paris: Pr Baruchel, Pr Rousselot, Pr Michel, Pr

Fain, Dr Barete, Pr Sene, Pr Haroche, Pr Costedoat-Chalumeau

Immunologie – Pr M Labalette J. Trauet, V. Lekeux, V. Bétrancourt, V. Dutriez

Anatomo-pathologie – Pr Copin

Hématologie – Pr Preudhomme Collaboration: Dr C. Roumier Clonalité T / PCR: Dr N. Grardel Séquençage: S. Geffroy, Dr S. Poulain

Cytogénétique Dr C. Roche-Lestienne

Plate-forme de génomique fonctionnelle U837

M Cheok, P Peyrrouze

[email protected] [email protected] [email protected] [email protected]

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