La sindrome ipereosinofila è una malattia clonale dell’emopoiesi caratterizzata da eosinofilia ematica periferica >1500/mL e da un aumento di eosinofili nel tessuto emopoietico midollare per un periodo di tempo superiore a sei mesi e in assenza di condizioni cliniche capaci di determinare un’eosinofilia (parassitarie, allergiche o altre cause); quest’ultima può essere infatti secondaria a malattia allergica, autoimmune, parassitaria, dermatologica e neoplastica. Eosinofilie secondarie alla liberazione di citochine sono state riportate non solo in pazienti con leucemia mieloide cronica Ph1 positiva, con leucemia acuta linfoblastica e con linfomi non-Hodgkin’s, ma anche in pazienti che apparentemente non presentavano una malattia linfoproliferativa. In quest’ultimo gruppo di pazienti, con frequenti episodi di dermatite pruriginosa ed elevati livelli di IgE, è stata osservata una popolazione clonale di linfociti T che produceva varie citochine ma soprattutto interleuchina 5, assolutamente necessaria per la differenziazione eosinofila della cellula mieloide.
La sindrome ipereosinofila è sempre causata da una mutazione somatica acquisita insorta in una cellula staminale emopoietica.
In alcuni casi la differenziazione cellulare è prevalentemente orientata in senso eosinofilo (si parla allora di leucemia eosinofila), in altri è invece verso tutte le linee cellulari mieloidi.
In quest’ultimo gruppo di pazienti l’eosinofilia fa parte di un più ampio disordine neoplastico dell’emopoiesi.
Comunque sia in entrambi i casi l’aumentata produzione di eosinofili è indotta da una maggior produzione di interleuchina 5, interleuchina 3 e di fattore di crescita granulocitomacrofagico (GM-CSF).
Nella sindrome ipereosinofila sono presenti manifestazioni di malattie con coinvolgimento di più organi o disfunzioni direttamente correlate all’eosinofilia.
In base all’aspetto sintomatologico predominante è stat anche definita Connettivite disseminata eosinofila; leucemia eosinofila; endocardite fibroplastica di Löffler con 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, come riportato nella tabella.
| Manifestazioni | Pazienti | Sintomi |
| Costituzionali | @ 50% | Astenia, affaticabilità, anoressia, febbre, calo ponderale, mialgie |
| Cardiopolmonari | > 70% | Tosse, dispnea, insufficienza cardiaca, aritmie, malattia dell’endo-miocardio, infiltrati polmonari, versamento pleurico, embolia |
| Ematologiche | > 50% | Tromboembolie, anemie, trombocitopenie, adenopatie, splenomegalie |
| Neurologiche | > 50% | Alterazioni del comportamento e delle funzioni intellettuali, spasticità, neuropatie periferiche, lesioni cerebrali focali |
| Dermatologiche | > 50% | Dermatografismo, angioedema, eruzioni, prurito |
| Gastro-intestinali | > 40% | Diarrea, nausea, crampi addominali |
| Immunologiche | @ 40% | Aumento delle immunoglobuline (specialmente IgE), complessi immuni circolanti |
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 e segni
Al momento dell’esordio il paziente presenta una sintomatologia determinata dal fatto che i granulociti eosinofili infiltrano i vari tessuti e liberano le citochine contenute nei loro granuli. Si spiegano così l’intenso prurito spesso associato alla presenza di noduli cutanei, la profonda astenia con frequenti dolori retrosternali di tipo anginoso ed i più rari episodi di diarrea profusa.
La sindrome clinica segue due grandi modelli:
- un disordine mieloproliferativo con splenomegalia, trombocitopenia, livelli elevati di vitamina B12 sierica ed eosinofili ipogranulari o vacuolati; questi 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; questi 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.
All’esame obiettivo si apprezzano importanti infiltrati cutanei con lesioni di tipo esfoliativo, pustole ed angioedema localizzato; è spesso presente un’importante epato-splenomegalia, più rare sono le linfoadenomegalie.
Una visita cardiologia spesso dimostra un’insufficienza cardiaca congestizia, aritmie, angina e all’ecocardiografia si osserva un marcato deficit dell’attività contrattile del miocardio ed alterazioni a livello delle valvole cardiache.
A livello del sistema nervoso centrale si osserva una sofferenza di tipo diffuso con frequenti attacchi ischemici transitori e neuropatie periferiche; a livello polmonare una marcata alterazione della funzionalità respiratoria dovuta all’importante fibrosi polmonare; a livello del tratto gastroenterico infiltrati mucosi, causa della diarrea lamentata dal paziente.
Il 16% dei pazienti dopo una fase cronica della durata di 6-9 mesi circa sviluppa una fase acuta con quadro clinico sovrapponibile a quello di una LMA.
L’esame emocitometrico mostra di solito una leucocitosi con normali valori di emoglobina e di piastrine.
All’esame microscopico dello striscio di sangue periferico si rileva una dacriocitosi e un aumento degli eosinofili, che presentano normali dimensioni e vacuoli citoplasmatici. Il mieloaspirato mostra un tessuto emopoietico normo- o ipercellulato con iperplasia dello stipite eosinofilo.
L’analisi citogenetica e molecolare rappresenta ormai uno strumento assolutamente indispensabile non solo per un corretto inquadramento diagnostico della sindrome, ma anche per un suo corretto trattamento.
E’ stato infatti dimostrato che la sindrome ipereosinofila non è un’entità omogenea ma comprende varie sub-entità associate a specifiche alterazioni citogenetiche e molecolari.
La traslocazione cromosomica per prima caratteristicamente associata ad una malattia mieloproliferativa con marcato aumento degli eosinofili è stata la t(5;12)(q31-33;p12-p13).
L’anomalia, che ha un’incidenza pari all’1% circa, determina il riarrangiamento tra il gene che codifica per il recettore beta del “Platelet derived growth factor” (PDGFRB), mappato alla banda 5q33 e il gene ETV6, mappato in 12p13.
Il gene PDGFRB codifica per una proteina recettoriale dotata di attività tirosina chinasica, che si sviluppa solo quando è avvenuto il legame con il ligando, rappresentato dal PDGF.
Il gene di fusione ETV6-PDGF, prodotto dalla traslocazione, determina invece l’attivazione costitutiva della chinasi in assenza del ligando.
Un’altra traslocazione associata ad un quadro di sindrome eosinofila è quella che coinvolge il gene FGFR1, che codifica per la proteina “fibroblast growth factor receptor 1” ad attività tirosina chinasica.
Nella traslocazione 8;13 il gene FGFR1, mappato sul cromosoma 8 alla banda p11, si riarrangia con il gene ZNF198, mappato alla banda 13q12. Il gene chimerico ZNF198-FGFR1, prodotto dalla traslocazione, causa l’attivazione costitutiva della chinasi in assenza del ligando.
L’ultima traslocazione più recentemente dimostrata mediante tecniche di citogenetica molecolare è quella che determina il riarrangiamento tra il gene per il recettore alfa del PDGF e il gene FIP1L1, entrambi mappati alla banda q12 del cromosoma 4. Anche in questo caso la traslocazione genera un gene di fusione che provoca l’attivazione costitutiva di PDGFRA.
Terapia
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 leucociti normali e concomitante stabilità clinica.
In questi ultimi pazienti la sopravvivenza globale è > 80%.
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 per 3-6 mesi.
Le complicanze secondarie al coinvolgimento di sistemi di organo devono essere trattate in maniera aggressiva.
Fino ad un recente passato i farmaci più spesso impiegati nei pazienti con sindrome ipereosinofila erano i cortisonici e gli antiblastici.
I corticosteroidi e l’idrossiurea sono stati le pietre miliari del trattamento.
La terapia d’attacco era 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 otteneva una remissione, la dose doveva essere lentamente ridotta nei successivi 2 mesi a 0,5 mg/kg/die e quindi a giorni alterni a questo dosaggio. Si attuava poi un’ulteriore riduzione, lentamente, fino alla dose più bassa che controllava la malattia.
Se il prednisone non controllava le manifestazioni della malattia e l’eosinofilia, o se il dosaggio richiesto era inaccettabilmente alto, allora doveva essere aggiunta idrossiurea 0,5-1,5 g/die PO, con l’obiettivo terapeutico di riportare il numero dei leucociti a valori oscillanti tra 4.000 e 10.000/mL.
Recentemente, l’interferon-a 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-a può esacerbare la malattia.
La recente dimostrazione che nella maggior parte dei pazienti con sindrome ipereosinofila si verifica l’attivazione costitutiva di una particolare tirosina chinasi a seguito di una traslocazione cromosomica specifica ha radicalmente modificato il trattamento di questi pazienti indirizzandoli verso una terapia molecolare.
Quest’ultima consiste nella somministrazione dell’imatinib mesilato (STI571, Gleevec, Glivec), molecola già rivelatasi efficace nel trattamento della leucemia mieloide cronica Ph1 positiva. Studi recenti indicano che il Glivec è in grado d’indurre remissioni durevoli anche nei pazienti con t(5;12) o con riarrangiamento FIP1L1-PDGFRA.
Terapia di supporto per le complicanze: può essere necessario praticare la terapia medica e chirurgica per le manifestazioni cardiache (per esempio, cardiomiopatia infiltrativa, lesioni valvolari, scompenso cardiaco).
Le complicanze trombotiche indicano l’uso di farmaci antipiastrinici (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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