Early Detection of Toxoplasma Infection by Molecular Monitoring of Toxoplasma gondii in Peripheral Blood Samples after Allogeneic Stem Cell Transplantation

Clinical Infectious Diseases, Jan 2005

Background. Isolated case reports have shown that recipients of allogeneic hematopoietic stem cell transplants (HSCTs) who develop toxoplasmosis may have circulating Toxoplasma gondii DNA in peripheral blood before the onset of clinical symptoms. Methods. We prospectively studied 106 T. gondii—seropositive adult recipients of HSCTs for the incidence of reactivation of toxoplasmosis in the first 6 months after transplantation. Toxoplasmosis infection (TI) was defined by a positive result of polymerase chain reaction (PCR) of peripheral blood specimens, whereas toxoplasmosis disease (TD) was defined as an invasive infection. Results. The incidence of TI was 16% (95% confidence interval [CI], 8%–21%), whereas the incidence of TD was 6% (95% CI, 1%–10%). In the 16 patients with TI, the incidence of disease was 38%, whereas it was 0% in patients without TI (P < .0001). In most patients, the onset of TD or treatment for TI was preceded by an increase in the parasite load in peripheral blood samples, as determined by quantitative PCR. Conclusions. Toxoplasmosis occurs more commonly after HSCT than has previously been suggested, and routine PCR testing of peripheral blood specimens may be an appropriate tool for guiding preemptive therapy in patients at very high risk of developing invasive disease.

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Early Detection of Toxoplasma Infection by Molecular Monitoring of Toxoplasma gondii in Peripheral Blood Samples after Allogeneic Stem Cell Transplantation

Rodrigo Martino () 1 Ste phane Bretagne 0 1 Hermann Einsele 1 Johan Maertens 1 6 Andrew J. Ullmann 1 3 Roco Parody 1 Ulrike Schumacher 1 4 C ecile Pautas 1 5 Koen Theunissen 1 6 Christine Schindel 1 7 Carmen Mun oz 1 2 Nuria Margall 1 2 Catherine Cordonnier 1 5 for the Infectious Disease Working Party of the European Group for Blood 1 Marrow Transplantation 1 0 Laboratoire de Parasitologie-Mycologie 1 Received 9 July 2004; accepted 26 August 2004; electronically published 7 December 2004. Hospital de la Santa Creu i Sant Pau , Av. Sant Antoni Maria Claret, 167, 08025 Barcelona , Spain 2 Microbiology, Hospital de la Sant Creu i Sant Pau , Barcelona , Spain 3 III Medizinische Klinik und Poliklinik 4 Microbiology, University Hospital of Tu bingen 5 Department of Hematology, Hopital Henri Mondor-AP-HP , Cre teil , France; Departments of 6 Department of Hematology, University Hospital Gasthuisberg , Leuven , Belgium 7 Institut fu r Medizinische Mikrobiologie und Hygiene, Klinikum der Johannes Gutenberg-Universita t Mainz , Mainz , Germany (See the editorial commentary by Chandrasekar on pages 79-81) Background. Isolated case reports have shown that recipients of allogeneic hematopoietic stem cell transplants (HSCTs) who develop toxoplasmosis may have circulating Toxoplasma gondii DNA in peripheral blood before the onset of clinical symptoms. Methods. We prospectively studied 106 T. gondii-seropositive adult recipients of HSCTs for the incidence of reactivation of toxoplasmosis in the first 6 months after transplantation. Toxoplasmosis infection (TI) was defined by a positive result of polymerase chain reaction (PCR) of peripheral blood specimens, whereas toxoplasmosis disease (TD) was defined as an invasive infection. Results. The incidence of TI was 16% (95% confidence interval [CI], 8%-21%), whereas the incidence of TD was 6% (95% CI, 1%-10%). In the 16 patients with TI, the incidence of disease was 38%, whereas it was 0% in patients without TI (P ! .0001). In most patients, the onset of TD or treatment for TI was preceded by an increase in the parasite load in peripheral blood samples, as determined by quantitative PCR. Conclusions. Toxoplasmosis occurs more commonly after HSCT than has previously been suggested, and routine PCR testing of peripheral blood specimens may be an appropriate tool for guiding preemptive therapy in patients at very high risk of developing invasive disease. Toxoplasmosis is an opportunistic infection caused by infection in T. gondii-seropositive patients with adthe parasite Toxoplasma gondii. Primary infection in vanced AIDS, toxoplasmosis was formerly considered immunocompetent hosts leads to the latency of the a rare infection in recipients of hematopoietic stem cell parasite as cysts in muscle and other organs [1]. Severe Toxoplasmosis after Transplantation CID 2005:40 (1 January) 67 - PATIENTS AND METHODS Characteristic No. of patients Age, median years (range) Sex Male Female CMV seropositivity (IgG)a Results of donor serological testing for Toxoplasma species (IgG)a Positive Negative Not done Underlying disease Chronic myelogenous leukemia Acute leukemia/myelodysplasia Lymphoma Multiple myeloma/CLL Other Disease phase at time of transplantationb Early Intermediate Advanced Receipt of second HSCT Donor type HLA-identical sibling HLA-matched, unrelated donor Mismatched related or unrelated donor Stem cell source Peripheral blood Bone marrow Cord blood Receipt of ATG T cell depletion Conditioning regimen TBI-based ablative Chemotherapy-only ablative Reduced-intensity Development of acute GVHD All grades Percentage of patients Cumulative incidence (95% CI) Grade II-IV Percentage of patients Cumulative incidence (95% CI) Grade III-IV Percentage of patients Cumulative incidence (95% CI) Developed chronic GVHD All cases Percentage of patients Cumulative incidence (95% CI) Value 64 (60) 42 (40) 72 (68) 45 (43) 29 (27) 22 (20) 23 (22) (continued) (Continued.) Characteristic Extensive 6-month cGVHD Percentage of patients Cumulative incidence (95% CI) Six-month nonrelapse mortality rate Percentage of patients Cumulative incidence (95% CI) Six-month incidence of relapse Percentage of patients Cumulative incidence (95% CI) Six-month overall survival rate Percentage of patients Cumulative incidence (95% CI) Value 4 4 (08) 20 RESULTS ta i s dn am ira lsy a las ivn aan .1 n p io o U t x fce oT ,e I)C )4 )82 )2 )6 n c i n 7 1 2 3 % 2 1 1 2 m im n ir g e ,t re im 4 Z g ge 41 M in r 1 .2 -PSM iitond inngo i.(.,e i T n it d ;tcan cheo cond irpeo .1 .09 iitsgnfi itTnG tfypeo tsyeud on fA ),s th , o e f S e p o )61 )8 )6 )62 )10 l;eN scen rtyno 80% (4183 (1201 .(102 .(1022 .(8055 iltaaavbon ,)rtsyepep itrvaodene 1)rfkoeew 6 0 5 1 1 5 ,AN rono l.tsa rpe ;t d v s n e g e lap itv iln itm s a ib an rn ls 6 tr lte ca 4 ll a it n ce .s ne ive v d g i 2 2 8 8 2 4 1 9 4 5 5 5 m g s ittcse liilsbn (eLAH . lttabe itaeoop ii-tacned trypono tysdueh -(g008m m d t ,hTe (LAH ,rbe idn rayep C e m e h S p u in t H ty . n a Z N N ; r ia tn m M e o n a re -S s n e l a o p p t P e o s n is ,d t an ite TM d e cy rt a t g o , p th s a h e i o ,x p g he w -h e t s s lym ,ax .y t e rs de nd se rap tah ilac u n e v lu a e e s p -ft cn ,y ud th ke m .L ra i ap lc id e co ll/s g nd re in o w d e , H g 0 V ow iro n dn /no d 1 . G h e w a R e sd 16 90 54 52 4 02 ;rsu tso fts sho i,on PC rfim .05 .se tho 1 livaog raen itcpeo rtone iftcen tybed cason !fton irtavao dneM e 2 e a u c a V se ed co t tom 1.f ,r .2 CM rte nfi te ne tsn yc o HD 1fo ), e e y dn ite ,V laue VG lue itve sw asd cho eep faP CM vP icno va lab lpe sw ypm -ed no li;n te rh eP lao am iax la itm ito logbu iirvaan acnd iirtava layem lsood lypoh sade sade sscbue tyce au tceu anu itnon lrabe rap nfie lzya iss o h a h e h s it , it p lam sd an lya ittyhm lsew itceon lsew .cvon irpe xoop iaaw reew lcaan ,anG l.eo iraavb ifnV iraavb vsne ttash i-tanT tepno lsaeb iitttsa TA za fo CM fo igm ayd tae cy ira S x o v e o ls ,s lis re f u h h .E the ita tu tae ity .o qe p se t T e ta o d ym he ee Table 3. Characteristics of patients with Toxoplasma infection and disease. Center/patient number Age in years/sex Underlying disease Donor type (stem cell source) HLA-identical sibling (PBSCs) Acute (3), chronic UD (CB) UD (PBSCs) UD (CB) HLA-identical sibling (PBSCs) Negative HLA-identical sibling (PBSCs) Negative HLA-identical sibling (PBSCs) HLA-identical sibling (PBSCs) HLA-identical sibling (PBSCs) Negative HLA-identical sibling (PBSCs) HLA-identical sibling (PBSCs) HLA-identical sibling (PBSCs) HLA-identical sibling (PBSCs) UD (PBSCs) UD (PBSCs) Donor Toxoplasma IgG results Negative Positive Positive Positive Positive Positive Positive Positive GVHD (grade) Acute (2) Acute (2) Acute (2) Acute (2) Acute (1) Acute (1) Not present Acute (1) Not present Acute (1) Acute (3) Acute (3) Acute (3) Acute (2), chronic HLA-identical sibling (PBSCs) Negative Not present No. of positive PCR Day after HSCT of first-last positive PB PCR result (day of prior negative result) +59 (+49) +91 (+86) +41 (+34) +38 to +49 (+31) +47 to +75 (+40) +40 to +47 (+33) +34 to +94 +178 to +185 +83 to +93 +59 to +66 Probable acute dissemuinated disease, hyperacute onset (CSF) Probable encephalitis (CSF) Probable encephalitis (CSF)b None/fever of unkown origin None/fever of unkown origin None None None/fever of unkown origine None/fever of unkown origin Therapy for Toxoplasma disease Outcome and comments Cured; alive and well at day +180; received secondary prophylaxis with TMP-SMZ Died on day +93 of ARDS due to toxoplasmosis Toxoplasmosis improved; patient later had progression of disease while receiving therapy and died of toxoplasmosis on day +315 Died on day +51 of disseminated toxoplasmosis and CMV disease Cured of toxoplasmosis; died of AML on day +175; had received secondary prophylaxis with TMP-SMZ Cured; alive and well on day +180; received secondary prophylaxis with TMP-SMZ Alive and well on day +180; discontinued TMP-SMZ therapy on day +75 Alive and well on day +180; continued receiving TMP-SMZ Alive and well on day +180; continued receiving TMP-SMZ Alive and well on day +180; continued receiving TMP-SMZ Alive and well on day +180; continued receiving TMP-SMZ Alive and well on day +180; continued receiving TMP-SMZ Alive and well on day +180; continued receiving TMP-SMZ Died on day +71 of ARDS; no autopsy was performed Alive and well on day +180; continued receiving TMP-SMZ Alive and well on day +180; continued receiving TMP-SMZ Prior anti-Toxoplasma prophylaxis Therapy for patients with positive PB PCR results (day of commencement) Signs of Toxoplasma disease (non-PB PCR samples with positive results) Intermittent (TMP-SMZ) P/S (+59) Probable encephalitis (CSF) Possible (clindamycin) TMP-SMZ (+91) Possible (atovaquone) P/S/C (+55) Probablepneumonitis, hyperacute onset (BAL) Probable encephalitis (CSF) Possible (atovaquone) TMP-SMZ (+49) Adequate (TMP-SMZ)d Adequate (TMP-SMZ)d None None None None None P/C (+63) P/C (+44) TMP-SMZc P/S (+47) P/S (+77) P/S (+42) Clindamycin (+2) TMP-SMZ (+21) P/C (+67) Intermittent (TMP-SMZ) P/S (+187) None/fever of unkown origin Intermittent (TMP-SMZ) P/S (+94) None/fever of unkown origin P/C (+18) None/fever of unkown origin e l a b 3 la 7 i a 8 t 24 o n 6 82 b , 4 a o 4 4 u 8 ilq a 9 4 4 89 n i 0 0 t DISCUSSION Acknowledgments Potential conflicts of interest. All authors: no conflicts.


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Rodrigo Martino, Stéphane Bretagne, Hermann Einsele, Johan Maertens, Andrew J. Ullmann, Rocío Parody, Ulrike Schumacher, Cécile Pautas, Koen Theunissen, Christine Schindel, Carmen Muñoz, Nuria Margall, Catherine Cordonnier, Infectious Disease Working Party of the European Group for Blood and Marrow Transplantation. Early Detection of Toxoplasma Infection by Molecular Monitoring of Toxoplasma gondii in Peripheral Blood Samples after Allogeneic Stem Cell Transplantation, Clinical Infectious Diseases, 2005, 67-78, DOI: 10.1086/426447