¹Division of Clinical Hematology, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain

²Departments of Hematology and Laboratory of Mycology, Hôpital Henri Mondor, Créteil, France

³Department of Hematology, Hospital Clinic i Provincial, Barcelona, Spain

⁴Division of Internal Medicine, Johannes Gutenberg University Hospital, Mainz, Germany

⁵Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium

⁶Charité-Virchow Klinikum, Berlin, Germany

⁷Department of Hematology, Hôspital Jean Minjoz, Besancon, France

Correspondence to: Dr R Martino, Servei d'Hematologia Clínica, Hospital de la Santa Creu i Sant Pau, Av Sant Antoni Ma Claret, 167, 08025 Barcelona, Spain

Toxoplasmosis appears to be a rare opportunistic protozoal infection following hematopoietic stem cell transplantation (HSCT). The disease occurs almost exclusively from reactivation of latent microorganisms in seropositive recipients. In a recent review, only 55 cases had been reported after HSCT,¹ which contrasts with the high frequency of this complication in other patient populations with severe cellular immunodeficiencies, mainly advanced acquired immunodeficiency syndrome (AIDS).² Most cases have been reported in allogeneic HSCT recipients, with only anecdotal reports after autologous transplantation.¹

The seroprevalence for Toxoplasma gondii varies greatly between countries, ranging from less than 15% in some North American studies³ and in pediatric wards, to 50-80% of adult HSCT recipients in countries with high endemicity such as France.⁴ Probably one of the main reasons for the great variability in the frequency of diagnosed cases of toxoplasmosis after HSCT is this varying seroprevalence; the frequency has been estimated to average 0.8%,⁵ with <0.4% in areas of low endemicity to 2-3% in those with high antibody prevalence. These differences may contribute to a wide range of policies regarding pretransplantation serology in donors and recipients, availability of diagnostic tests for toxoplasmosis and use of specific prophylaxis against this infection among different institutions in Europe. In early 1999 the EBMT-IDWP distributed among its members a survey in order to better clarify current frequencies and policies regarding toxoplasmosis after HSCT. Since our main interest was to study the most recently available data on this matter, the study was restricted to the time period from 1994 to 1998.

Table 1 details the main results of the survey. Fifty-two HSCT centers from 18 countries answered the survey. The total number of allogeneic and autologous HSCT performed from 1994 to 1998 in these 52 institutions were 4391 and 7097, respectively. There were no cases of toxoplasmosis among autologous recipients, thus confirming the rarity of this complication in this setting. Forty-one cases were diagnosed in allogeneic HSCT recipients, which corresponds to a frequency of 0.93%. Of these 41 cases, nine were an unsuspected autopsy finding, two were suspected before death but were diagnosed with certainty only at autopsy, 19 were suspected during life but were not confirmed either because the patient survived or a post-mortem study was not done, and 11 cases were a definite histologic diagnosis performed during life.

The exact rate of seropositivity of donors and recipients was available from only 25 institutions. Eight centers had a low rate of seropositivity (defined as <30% of donors and recipients), 12 had an intermediate rate (30-60%) and five had a high rate (>60%). Most institutions (91%) gave prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) after engraftment to all allogeneic transplant recipients, while only 58% gave it to all autologous recipients. Twenty centers gave TMP/SMX twice weekly, and 21 centers gave it three times per week. Interestingly, nine centers (18%) reported having specific prophylactic strategies for T. gondii seropositive autologous and/or allogeneic recipients (see Table 1 for details). The most common diagnostic methods available were serology and histology. Serology is of little use for diagnosing toxoplasmosis after HSCT but useful to identify the population at risk, since most cases have been reported in seropositive recipients. Histology was also available in all the centers through identification of tachyzoites and cysts with the use of hematoxylin or Giemsa staining in brain biopsy or autopsy material. Few centers routinely used Toxoplasma isolation techniques in mice or tissue cultures, which are cumbersome and time-consuming techniques.⁶ Interestingly, 24 centers (46%) reported having a PCR technique for Toxoplasma available in their microbiology laboratory. PCR techniques for detecting Toxoplasma DNA in blood,^7,8,9 CSF⁸ and/or bronchoalveolar lavage samples¹⁰ have been recently reported in HSCT recipients. These techniques were developed for prenatal diagnosis of toxoplasmosis¹¹ and for the non-invasive diagnosis in AIDS patients with brain nodules. In this latter population conflicting results have been reported. In some series the detection of circulating T. gondii DNA has a good predictive value for patients with cerebral nodules, avoiding invasive procedures,⁶ and suggesting that most of the patients with cerebral reactivation have circulating DNA.¹² In contrast, other studies have found only 13%¹³ or 25%¹⁴ of patients with cerebral toxoplasmosis to have a positive PCR test in blood. One of the reasons for these discrepancies is that PCR is currently not standardized, especially for prevention of false positive results due to contamination, or false negative results due to inhibitors.¹¹ PCR can also provide useful information for follow-up after initiation of specific therapy.⁹ Table 2 shows the number of cases of toxoplasmosis diagnosed in the 25 centers with known seroprevalence. As seen, the frequency of this infection appears to increase from 0% in centers with low seroprevalence, to 1.4% and 0.97% in centers with intermediate and high seroprevalences, respectively. In the 27 centers who did not know their seroprevalence, there were 11 cases among 1634 allogeneic transplants (frequency of 0.67%). The frequency of toxoplasmosis in the nine centers who used specific prophylactic regimens for seropositive patients was eight among 294 (2.7%) allogeneic transplant recipients. Three of these centers reported high or intermediate rates of seropositivity pretransplant, three reported low levels and three did not report their seroprevalence.

In the current survey, the observed frequencies of toxoplasmosis after HSCT were similar to those previously reported based on single-institution studies. However, this frequency may be either an overestimation or an underestimation of the real incidence of toxoplasmosis in this patient population. First of all, centers who have had cases of toxoplasmosis are probably more interested in this matter and are more likely to participate in such studies than centers who have not had any cases. On the other hand, toxoplasmosis is difficult to diagnose with certainty premortem, and this may lead to an underestimation of the actual number of cases. The relatively few cases of this disease is nonetheless surprising, especially when considering that in other severely cell-immunodeficient patient populations, especially in AIDS, this has been a frequent and severe complication of advanced immunodeficiency. Perhaps the high number of institutions that routinely use TMP/SMX prophylaxis after allogeneic transplantation may be largely responsible for this low frequency, since this has been shown to be an effective prophylaxis for toxoplasmosis in AIDS patients.² It should be stressed that 30 (73%) of the 41 cases in our survey were not receiving systemic Pneumocystis carinii prophylaxis with anti-toxoplasma activity at the onset of infection, including 11 who were on aerosolized pentamidine. In seropositive recipients for T. gondii before SCT, the need for toxoplasma prophylaxis should be better defined, and preferrably combined with Pneumocystis carinii prophylaxis.

Acknowledgements

We are grateful to the following physicians for carefully completing the questionnaire: Spain: Dr R Martino, Hospital de la Santa Creu i Sant Pau, Barcelona; Dr M Rovira, Hospital Clínic i Provincial, Barcelona; Dr GF Sanz, Hospital la Fe, Valencia; Dr R De la Cámara, Hospital de la Princesa, Madrid; Dr JJ Ortega, Hospital Materno-Infantil de la Vall d'Hebron, Barcelona; Dr C Solano, Hospital Clínico Universitario, Valencia; Dr R Varela, Hospital Juan Canalejo, La Coruña; Dr M Constenla, Hospital Montecelo, Pontevedra; Dr MN Fernández, Clínica Puerta de Hierro, Madrid; Dr AM Martínez-Rubio, Hospital Infantil La Paz, Madrid; Dr F Hernández-Navarro, Hospital La Paz, Madrid; Dr JJ Díez-Martín, Hospital Gregorio Marañón, Madrid; Dr R Parody, Hospital Virgen del Rocío, Sevilla. Germany: Dr T Held, Charité-Virchow Klinikum, Berlin; Dr D Bunjes, University of Ulm; Dr RG Köchling, Klinikum Offenburg, Offenburg; Dr K Schäfer-Eckart, Klinikum Nürnberg, Nürnberg; Dr J Casper, University of Rostock, Rostock; Dr U Gross-Wieltsch, Olga Hospital, Stuttgart; Dr AJ Ullmann, Johannes Gutenberg University Hospital, Mainz; Dr M Bornhauser, Universitatsklinikum Carl Gustav Carus, Dresden; Dr D Fuchs, University of Jena, Jena. Belgium: Dr J Maertens, University Hospital Gasthuisberg, Leuven; Dr A Ferrant, Université Catholique de Louvain, Brussels; Dr R Schots, Academic Hospital, Free University Brussels; Dr B De Prijck, CHR La Citadelle, Liège; Dr D Selleslag, AZ St Jan, Brugge; Dr C Devalck, Children's University Hospital, Brussels. France: Dr C Cordonnier, Hôpital Henri Mondor, Créteil; Dr L Fouillard, Hôpital Saint-Antoine, Paris; Dr E Deconinck, Hôpital Jean Minjoz, Besancon. Italy: Dr M Picardi, Universitá delli Studi di Napoli, Federico II, Napoli; Dr S Sica, Instituto di Semeiotica Medica, Rome; Dr R Cairoli, Ospedale di Niguarda, Milan; Dr G Lambertenghi Deliliers, Ospedale Maggiore, Milan; Dr S Cesare, Clinica Onco-Ematologia Pediatrica, Padova. The Netherlands: Dr AW Dekker, University Hospital Utrecht, Utrecht. UK: Dr PC Lorigan, Weston Park Hospital, Sheffield; Dr AM Will, Royal Manchester Children's Hospital, Manchester. Czech Republic: Dr E Faber, Olomouc University Hospital, Olomouc; Dr A Vitek, Institute of Hematology and Blood Transfusion, Prague. Greece: Dr D Petropoulos, Santa Sophia Children's Hospital, Athens. Hungary: Dr K Fabian, Borsod County Hospital, Miskolc. Portugal: Dr P Pimentel, Instituto Portugués de Oncologia, Porto. Austria: Dr H Greinix, University of Vienna, Vienna; Dr H Ludwig, Wilhelminenspital, Vienna. Slovenia: Dr J Pretnar, University Medical Centre, Ljubljana. Australia: Dr R Herrmann R, Royal Perth Hospital, Perth. South Africa: Prof P Jacobs, Constantinberg Medi-Cinic, Capetown. Slovakia: Dr H Mociková, Roosevelt Hospital, Banská Bystrica. Finland: Dr M Sinisalo, Tampere University Hospital, Tampere. Sweden: Dr P Ljungman, Huddinge University Hospital, Huddinge.

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Table 1  Results of the EBMT survey of toxoplasmosis after hemaotopoietic stem cell transplantation (SCT) from 1994-1998 (% in brackets)

Table 2  Frequency of toxoplasmosis according to the rate of seropositivity reported by 24 centers (% in brackets)