Gli eosinofili sono dei granulociti derivati dalle stesse cellule progenitrici dei monociti-macrofagi, neutrofili e basofili. Il numero normale di eosinofili circolanti nel sangue periferico è < 350/ml, con livelli diurni che variano in maniera inversa al livello di cortisolo plasmatico; il picco si ha nella notte e il minimo nel corso della mattina. La vita media degli eosinofili circolanti è di 6-12 ore con la maggior parte degli eosinofili che risiedono nei tessuti (p. es., prime vie respiratorie e del tratto GI, cute, utero).
L’eosinofilopoiesi sembra essere regolata dai linfociti T attraverso la secrezione di fattori di crescita ematopoietici, di fattori stimolanti le colonie granulocito-macrofagiche (GM-CSF), interleuchina-3 (IL-3) e interleuchina-5 (IL-5). Sebbene il GM-CSF e IL-3 incrementino anche la produzione di altre cellule mieloidi, l’IL-5 aumenta esclusivamente la produzione degli eosinofili.
Contenuti dei granuli degli eosinofili: la proteina basica maggiore (PBM) e la proteina cationica degli eosinofili (PCE) sono tossiche per diversi parassiti e per le cellule mammarie. Queste proteine legano l’eparina e neutralizzano la sua attività anticoagulante. La neurotossina eosinofilo-derivata può danneggiare gravemente la guaina mielinica dei neuroni. La perossidasi degli eosinofili, che si differenzia significativamente dalla perossidasi degli altri granulociti, genera radicali ossidanti in presenza di acqua ossigenata e di un alogeno. I cristalli di Charcot-Leyden sono composti principalmente di fosfolipasi B e possono essere trovati nello sputo, nei tessuti e nelle feci nelle malattie associate all’eosinoflia (p. es., asma e polmonite eosinofila).
Funzioni degli eosinofili: le precise funzioni sono sconosciute; non è stato descritto alcun paziente o animale senza eosinofili. Sebbene siano cellule fagocitiche, gli eosinofili sono meno efficienti dei neutrofili nell’uccidere i batteri intracellulari. Nessuna evidenza diretta mostra che gli eosinofili uccidono parassiti in vivo, ma essi sono tossici contro gli elminti in vitro e l’eosinofilia comunemente accompagna le infestazioni elmintiche. Gli eosinofili possono modulare la reazione d’ipersensibilità immediata mediante la degradazione o l’inattivazione di mediatori rilasciati dalle mastcellule (p. es., istamina, leucotrieni, lisofosfolipidi, eparina). I leucotrieni possono causare vasocostrizione e broncocostrizione. Una prolungata eosinofilia può determinare un danno dei tessuti mediante un meccanismo non ancora chiaro, sebbene le proteine basiche degli eosinofili siano citotossiche.
EOSINOFILIA
Numero di eosinofili circolanti nel sangue periferico > 350/ml
Lo sviluppo di eosinofilia ha le caratteristiche di una risposta immune: un primo contatto con un agente quale la Trichinella spiralis determina una risposta primaria con livelli relativamente bassi di eosinofili, mentre ripetuti contatti inducono una risposta eosinofila aumentata o secondaria.
I fattori che riducono il numero degli eosinofili comprendono i b-bloccanti, i corticosteroidi, lo stress e a volte infezioni batteriche e virali. Diversi composti rilasciati dai mastociti e dai basofili in conseguenza del legame di molecole di IgE sulla loro superficie sono chemiotattiche per gli eosinofili, p. es., il fattore eosinofilo chemiotattico di anafilassi, il leucotriene B4, il complesso del complemento (C567) e l’istamina (in un ristretto intervallo di concentrazione).
Eziologia
L’eosinofilia può essere primitiva o secondaria ad altre malattie sottostanti. Negli USA le malattie allergiche/atopiche sono la causa più comune di eosinofilia, con prevalenza delle malattie respiratorie e cutanee. Le reazioni eosinofile ai farmaci possono essere asintomatiche o associate a una varietà di sindromi che includono nefrite interstiziale, malattia da siero, ittero colestatico, vasculite da ipersensibilità e linfoadenopatia immunoblastica. Recentemente è stata osservata un’epidemia (diverse centinaia di casi) di una sindrome eosinofilo-mialgica in pazienti che utilizzavano grandi quantità di l-triptofano per la sedazione o come supporto psicotropico. La sindrome (grave dolore muscolare, tenosinovite, edema dei muscoli, rash cutaneo) durava da qualche settimana ad alcuni mesi e sono stati riportati diversi decessi. L’evidenza suggerisce che questa condizione non è stata dovuta all’l-triptofano, ma a un agente contaminante.
Quasi tutte le invasioni parassitarie di tessuti possono comportare una reazione eosinofila, ma i protozoi e i metazoi non invasivi di solito non la determinano. Infezioni non sostenute da parassiti possono essere accompagnate da eosinofilia. Delle malattie neoplastiche la malattia di Hodgkin può determinare una marcata eosinofilia, mentre i linfomi non Hodgkin, la leucemia mieloide cronica e la leucemia linfoblastica acuta sono meno spesso accompagnate da eosinofilia. Dei tumori solidi, il cancro dell’ovaio è la causa maggiore di eosinofilia. Le malattie del tessuto connettivo con aumento dei complessi immuni circolanti e le vasculiti sono spesso associati a eosinofilia. Malattie immunitarie acquisite e congenite, spesso con eczema, possono essere associate a eosinofilia. Il termine di infiltrato polmonare con eosinofilia (sindrome IPE) definisce un ampio spettro di manifestazioni cliniche, che è caratterizzato da eosinofilia periferica e infiltrati polmonari eosinofili ma è di solito di causa sconosciuta.
Diagnosi e terapia
L’anamnesi deve essere molto accurata per ciò che riguarda viaggi, allergie e uso di farmaci. L’esame obiettivo, la radiografia del torace, l’ECG, l’analisi delle urine, lo studio della funzionalità epatica e renale possono rivelare una causa sottostante e identificare una lesione d’organo. Test diagnostici specifici vengono richiesti in base al sospetto clinico e possono comprendere l’esame delle feci per parassiti e uova e test sierologici per parassiti e malattie del tessuto connettivo. Talora nelle feci può non essere evidente la presenza di elminti, ma la negatività dell’esame parassitologico non esclude che la causa dell’ipereosinofilia sia da attribuire a una parassitosi (p. es., la trichinosi richiede una biopsia muscolare, le infezioni da larva migrans, e le infestazioni da filariosi, richiedono biopsie di altri tessuti). L’aspirato duodenale può essere necessario per escludere la presenza di parassiti specifici (p. es., sp Strongyloides). Un aumento del valore sierico della vitamina B12 o una riduzione dei valori della fosfatasi alcalina leucocitaria può far ipotizzare una malattia mieloproliferativa sottostante. L’aspirato e la biopsia midollare con studi citogenetici possono essere di aiuto, soprattutto se sono presenti nel sangue periferico cellule immature.
Se non vengono identificate cause sottostanti, il paziente deve essere seguito per le complicanze. Un breve tentativo con corticosteroidi a basso dosaggio può ridurre la conta degli eosinofili se l’eosinofilia è reattiva piuttosto che maligna.
SINDROME IPEREOSINOFILA IDIOPATICA
(Connettivite disseminata eosinofila; leucemia eosinofila; endocardite fibroplastica di Löffler con eosinofilia)
Condizione caratterizzata da eosinofilia ematica periferica > 1500/ml per più di 6 mesi; assenza di cause parassitarie, allergiche o altre cause di eosinofilia; sono presenti manifestazioni di malattie con coinvolgimento di più organi o disfunzioni direttamente correlate all’eosinofilia.
Fisiopatologia
Sebbene possa essere coinvolto qualsiasi organo, quelli più frequentemente colpiti comprendono il cuore, i polmoni, la milza, la cute e il sistema nervoso. Il coinvolgimento cardiaco di solito causa morbilità e mortalità derivante da una diretta infiltrazione eosinofila o da tossine rilasciate dalle cellule. La lesione endocardica e microvascolare innesca i processi di trombosi con conseguente fibrosi endocardica e cardiomiopatia restrittiva. Il coinvolgimento dei muscoli papillari e delle corde tendinee di solito portano al rigurgito mitralico o tricuspidale. I trombi murali sono una fonte di emboli polmonari o sistemici.
Sintomi, segni e prognosi
La sindrome clinica segue due grandi modelli: un disordine mieloproliferativo con splenomegalia, trombocitopenia, livelli elevati di vitaminaB12 sierica ed eosinofili ipogranulari o vacuolati. Tali pazienti presentano un rischio aumentato per lo sviluppo di fibrosi endomiocardica o, meno comunemente, per una progressione verso una franca leucemia con cellule blastiche. Una malattia di ipersensibilità con angioedema, ipergammaglobulinemia, livelli elevati sierici di IgE e immunocomplessi circolanti; tali pazienti è meno probabile che sviluppino una malattia cardiaca, spesso non richiedono terapia e rispondono bene agli steroidi.
Circa 1/3 dei pazienti, con l’una o l’altra delle sindromi, sopra descritte, sono trombocitopenici al momento della presentazione. Le manifestazioni neurologiche sono variabili e sono la conseguenza diretta della lesione neurologica o di lesione focale dovuta alla formazione di emboli.
Nel passato, questa malattia aveva una prognosi infausta con una sopravvivenza mediana < 1 anno e < 20% dei pazienti sopravvissuti a 2 anni; la morte di solito si verificava per disfunzione d’organo. La terapia attuale ha migliorato la prognosi. La maggioranza dei pazienti richiede un intervento terapeutico; metà di questi pazienti risponde bene al prednisone, specialmente quelli con un’eosinofilia da ipersensibilità; con la terapia citotossica, un altro terzo di pazienti avrà un numero di GB normali e concomitante stabilità clinica. In questi ultimi pazienti la sopravvivenza globale è > 80%.
Terapia
Tutta la terapia ha l’obiettivo di ridurre il numero degli eosinofili secondo il principio che le manifestazioni cliniche possono derivare dall’infiltrazione del tessuto da parte degli eosinofili o al rilascio del loro contenuto. La terapia è necessaria solo quando si manifesta la progressione del danno a carico di organi critici; altrimenti il paziente va semplicemente osservato q 3-6 mesi. Le complicanze secondarie al coinvolgimento di sistemi di organo devono essere trattate in maniera aggressiva.
I corticosteroidi e l’idrossiurea sono le pietre miliari del trattamento. La terapia d’attacco è il prednisone PO (1 mg/kg/die) fino al miglioramento della sintomatologia clinica e al ritorno degli eosinofili a valori normali; una terapia adeguata di prednisone deve durare almeno 2 mesi. Se il paziente ottiene una remissione, la dose deve essere lentamente ridotta nei successivi 2 mesi a 0,5 mg/kg/die e quindi a giorni alterni a questo dosaggio. Una riduzione ulteriore deve essere effettuata lentamente fino alla dose più bassa che controlla la malattia. Se il prednisone non controlla le manifestazioni della malattia e l’eosinofilia, o se il dosaggio richiesto è inaccettabilmente alto, allora deve essere aggiunta idrossiurea 0,5-1,5 g/die PO; l’obiettivo terapeutico è quello di riportare il numero dei GB a valori oscillanti tra 4000 e 10000/ml.
Recentemente, l’interferon alfa è stato introdotto come prezioso agente per il trattamento dell’eosinofilia. Il dosaggio efficace va da 3 a 5 milioni di U SC per tre volte la settimana e dipende in parte dalla tolleranza e dai suoi effetti collaterali. La funzione cardiaca e le lesioni delle mucose hanno mostrato notevoli miglioramenti. L’interruzione dell’interferon alfa può esacerbare la malattia. È in via di accertamento se l’interferon alfa debba essere il trattamento di prima linea dell’ipereosinofilia.
Terapia di supporto per le complicanze: può essere necessario praticare la terapia medica e chirurgica per le manifestazioni cardiache (p. es., cardiomiopatia infiltrativa, lesioni valvolari, scompenso cardiaco). Le complicanze trombotiche indicano l’uso di farmaci antipiastrinici (p. es., aspirina, dipiridamolo); è opportuno l’utilizzo del warfarin quando si rilevi un trombo del ventricolo sinistro e di una prolungata terapia con l’aspirina quando vi è stato un attacco ischemico transitorio. I pazienti con danno cardiaco devono ricevere terapia antibiotica profilattica in corso di trattamenti odontoiatrici o altre procedure strumentali chirurgiche.
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