Rizik od infekcije parazitom Toxoplasma gondii nakon transplantacije: rezultati prospektivne kohortne studije Nacionalne referentne laboratorije

Abstract

Toksoplazmoza je česta ali kod pacijenata lečenih transplantacijom uglavnom zanemarena i pogrešno dijagnostikovana oportunistička infekcija koja može ugroziti engraftment ali može i evoluirati u životno ugrožavajuću diseminovanu infekciju. Nakon transplantacije, infekcija parazitom Toxoplasma gondii se može razviti kao reaktivacija hronične infekcije ili može biti preneta graftom. Naša osmogodišnja prospektivna studija bila je usmerena na dijagnostiku i monitoring toksoplazmatske infekcije (TI) kod primalaca matičnih ćelija hematopoeze (haematopoietic stem cell transplant, HSCT) u centru koji primenjuje protokol uzdržavanja od profilakse do engraftmenta, i kod primalaca transplantata srca (heart transplant, HT) koji su na kontinuiranoj profilaksi trimetoprim- sulfametoksazolom (TMP-SMX). Cilj nam je bio utvrđivanje incidence TI u ova dva vrlo različita transplantaciona režima, i to pre nego što evoluira u klinički manifestnu, potencijalno fatalnu bolest (Toxoplasma disease, TD). Pre-transplantacioni serološki i qPCR skrining u post-transplantacionom toku zamenjen je redovnim qPCR monitoringom iz uzoraka periferne krvi (peripheral blood, PB) usmerenim na Toxoplasma 529 bp gen. Kod primalaca HSCT, qPCR je rađen jednom nedeljno dok je kod primalaca HT qPCR rađen jednom mesečno prva dva meseca post-HT i potom jednom godišnje. TI je dijagnostikovana na bazi pozitivnog PCR rezultata iz bar jednog uzorka PB. TI je dijagnostikovana kod 21/104 (20.2%) primalaca HSCT, prevashodno nakon alogene (19/75) i retko nakon autologne HSCT (2/29). Više od 50% slučajeva TI dijagnostikovano je tokom prvog meseca post-HSCT, pre engraftmenta odnosno tokom uzdržavanja od profilakse. Sa druge strane, TI je dijagnostikovana kod 3/37 (8.1%) primalaca HT. Uprkos primeni TMP-SMX, qPCR je postao pozitivan godinu dana posle HT kod dva i dve godine post-HSCT kod trećeg pacijenta. Infekcija je bila preneta graftom kod 2/3 (seronegativni) a reaktivirana kod 1/3 primalaca HT (seropozitivni primalac HT poreklom od seropozitivnog donora). Naši rezultati potvrđuju da je sistemski qPCR monitoring iz uzoraka PB dragocen u dijagnostici TI ne samo kod primalaca HSCT već i kod primalaca solidnih organa, posebno nakon HT. Učestalost qPCR monitoringa se mora adaptirati shodno specifičnostima transplantacionog protokola, pre svega primeni profilakse ali i osnovnoj dijagnozi, na način koji omogućava pravovremenu primenu specifične terapije u svakom slučaju TI.

Toxoplasmosis is a common but often neglected and misdiagnosed opportunistic infection in transplant recipients, which can not only compromise the engraftment, but also evolve into life-threatening disseminated infection. Post-transplantation, Toxoplasma gondii infection can develop as a reactivation of chronic infection or could be graft-transmitted. We conducted an eight-year-long prospective study on the diagnosis and monitoring of Toxoplasma infection (TI) in haematopoietic stem cell transplant (HSCT) recipients in a setting that withholds prophylaxis until engraftment, and in heart transplant (HT) recipients on continuous trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. The objective was to determine the incidence of TI before it evolves into clinical, potentially fatal Toxoplasma disease (TD), in these two very different transplantation settings. Pre-transplantation serological and qPCR screening was followed by post-transplantation peripheral blood (PB)-based qPCR monitoring targeting the Toxoplasma 529 bp gene. In HSCT recipients, qPCR was performed weekly while in HT recipients, qPCR was performed monthly for two months post-HT and then yearly. TI was diagnosed based on a positive PCR result in at least one PB sample. TI was diagnosed in 21/104 (20.2%) HSCT recipients, predominantly after allogeneic (19/75) and rarely after autologous HSCT (2/29). Over 50% of TI cases were diagnosed during the first month post-HSCT, while awaiting engraftment without prophylaxis. On the other hand, TI was diagnosed in 3/37 (8.1%) HT recipients. Regardless of the TMP-SMX prophylaxis, qPCR became positive one year after HT in two and two years post-HSCT in third patient. Infection was graft-transmitted in 2/3 (seronegative) and reactivated in 1/3 OHT (seropositive recipient of a seropositive donor’s heart transplant). The presented results show that systematic PB-based qPCR monitoring is a valuable resource for the diagnosis of TI not only in HSCT but also in solid organ recipients, especially after HT. Frequency of qPCR monitoring should be adjusted according to the specificity of the transplantation setting, especially in terms of prophylaxis but also an underlying diagnosis, in a manner allowing for prompt introduction of specific treatment in each case of TI.