In questa popolazione di 171 pazienti neutropenici, la mortalità calcolata dall’inizio dello screening è risultata del 60.1% (51.6-68.7%), con un follow-up mediano di 160 giorni (range, 1-319 giorni). Nei pazienti con AI, la mortalità è risultata dell’ 81.6% (61-95.2%) con un follow-up mediano di 18 giorni (range, 1-35 giorni), mentre nei pazienti senza AI, la mortalità è risultata del 57.2% (48.1%- 66.7%), con un follow-up mediano di 574 giorni (range, 319-830 giorni) (p<0.001) (figura 7); tuttavia quando si confrontano pazienti con AI e il risultato di BDG, il confronto tra la sopravvivenza è statisticamente significativo solo per pazienti senza AI vs pazienti con AI e risultato positivo di BDG (p < 0.001) (figura 8).
Figura 7: Survival curves in patients with IA and No IA. When comparing the overall survival in IA vs no IA patients a significant differences was found (p<0.001).
35 Figura 8: Significant difference (p<0.001) only comparing No IA vs IA-BDG+; No IA vs IA-BDG- not reached the statistical significance (p=0.08) while IA-BDG- vs IA-BDG+ were not significantly different (p=0.23).
La sopravvivenza è stata analizzata e confrontata anche per pazienti senza AI e risultati falsi positivi per GM e BDG. (figura 9). La mortalità è risultata del 64.8% (39.3-88.8%) per pazienti senza AI e risultati falsi positivi per GM, e 66.8% (49.3-83.3) per pazienti senza AI e risultati falsi positivi per BDG. In entrambi i casi la sopravvivenza è risultata più alta in pazienti senza AI (45%), ma è risultata statisticamente significativa solo quando si confrontano pazienti senza AI vs pazienti NO- AI e falsi positivi per BDG (p=0.003) (figura 9).
36 Figura 9: Survival curves in patients with IA and patients with false positive GM and BDG results. 9A) Significant differences comparing No IA vs IA (p<0.001) and NO IA vs No IA-BDG+ (p=0.003); not significant difference comparing No IA – BDG+ and IA (p=0.19). 9B) Significant difference (p<0.001) only comparing No IA vs IA; no significant differences comparing No IA-GM+ vs No IA (p=0.17) and IA vs No IA-GM+ (p=0.28).
37
6. DISCUSSIONE
La diagnosi di AI rimane tutt’oggi difficile sia perché le manifestazioni cliniche non sono specifiche, sia perché i quadri radiologici possono essere suggestivi ma non sono patognomonici, sia infine perché le colture del tratto respiratorio spesso mancano di sensibilità. Inoltre, la dimostrazione di ife invasive è particolarmente complessa in un paziente che per la sua malattia ematologica si presenta piastrinopenico e spesso in gravi condizioni cliniche.
Per questi motivi la valutazione di nuove metodiche diagnostiche non-colturali che possano facilitare la diagnosi di aspergillosi, come la rilevazione di antigeni fungini nel siero e in altri fluidi biologici (GM e BDG) o saggi diagnostici di biologia molecolare, hanno ricevuto notevole interesse negli ultimi anni. [18, 57, 120].
Diversi studi hanno riportato una performance del GM e del BDG molto simile per la diagnosi di AI, nonostante l’ampia dispersione dei valori di sensibilità e specificità; in particolare, è stata riportata una sensibilità e specificità per il GM che variano rispettivamente dal 30 al 100% e dal 38 al 98% [91, 121], e una sensibilità e specificità per il BDG che variano rispettivamente dall’80 al 90% e dal 36 al 92% [122]. Pochi studi però, hanno confrontato direttamente i 2 test per la diagnosi di AI nella stessa popolazione di pazienti, spesso riportando risultati contrastanti. Due studi hanno favorito il BDG [80, 116], uno studio ha favorito il GM [120], mentre altri 3 studi non hanno mostrato differenze significative tra i due markers [92, 123, 124].
In questo studio abbiamo confrontato retrospettivamente la performance diagnostica di due test di laboratorio utilizzati per la diagnosi di AI, il GM e il BDG, in una popolazione ad alto rischio di sviluppare questa infezione.
Il GM ha mostrato una buona performance diagnostica per AI, in termini di sensibilità e specificità, che sono risultate rispettivamente del 95 e del 91%; infatti, in tutti i casi di AI tranne 1, il GM è risultato positivo nel siero con elevati valori.
Il BDG invece ha dimostrato una sensibilità ridotta rispetto al GM (60% vs 95%). Solo 12/20 casi di AI avevano almeno 1 campione positivo per BDG entro 7 giorni dal giorno della diagnosi. Tuttavia, quando sono stati considerati 2 campioni di siero consecutivi, si aveva una diminuzione della sensibilità del BDG (60% vs 41%), ma un aumento della specificità (78% vs 92%). Tuttora però non
38 è stata formulata alcuna raccomandazione riguardo al numero di esami di BDG richiesti per definire la positività al test.
Quindi, nonostante le numerose cause di falsa positività conosciute che possono interferire con i risultati del test, il BDG ha dimostrato una buona specificità in questa popolazione di pazienti ad alto rischio, anche in caso di sorveglianza a lungo termine.
Nel nostro studio, nonostante la bassa sensibilità del BDG (60%), il valore predittivo negativo (NPV) è risultato alto (93%); questo significa che un risultato negativo per BDG non è in grado di escludere la presenza di aspergillosi invasiva in questa popolazione di pazienti ematologici ad alto rischio e i risultati del test devono sempre essere associati al quadro clinico, radiologico e microbiologico del paziente.
Quando abbiamo analizzato la performance combinata dei due test, come proposto anche da altri autori [92, 116], abbiamo riscontrato che l’uso combinato dei 2 test porta ad un vantaggio in termini di specificità; infatti, associando il risultato positivo sia per GM che per BDG la specificità è risultata del 98%, ma la sensibilità è risultata più bassa (40%), rispetto alla sensibilità di ogni singolo test (60% per BDG e 95% per GM).
Nel nostro studio il BDG ha confermato la diagnosi di AI nel 60% dei casi ed ha anticipato la diagnosi nel 30% dei pazienti. Infatti, come riportato da altri autori, in alcuni casi, il BDG può precedere la diagnosi clinica o microbiologica di AI [92, 93, 125].
In conclusione, nel nostro studio il GM ha dimostrato una performance migliore del BDG per la diagnosi di AI in una popolazione di pazienti ematologici ad alto rischio di sviluppare l’infezione, soprattutto con l’utilizzo di 2 campioni di siero consecutivi, mentre il BGD dimostra un’elevata specificità e in alcuni casi dimostra di essere un utile supporto per una diagnosi precoce di AI.
39
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