Toxoplasmosis in Transplant Recipients

Europe, 2010-2014

Florence Robert-Gangneux; Valeria Meroni; Damien Dupont; Françoise Botterel; José M. Aguado Garcia; Marie-Pierre Brenier-Pinchart; Isabelle Accoceberry; Hamdi Akan; Isabella Abbate; Katia Boggian; Fabrizio Bruschi; Jordi Carratalà; Miruna David; Lubos Drgona; Olgica Djurković-Djaković; Maria Carmen Farinas; Francesca Genco; Effrossyni Gkrania-Klotsas; Andreas H. Groll; Edward Guy; Cédric Hirzel; Nina Khanna; Özgür Kurt; Lia Monica Junie; Tiziana Lazzarotto; Oscar Len; Nicolas J. Mueller; Patricia Munoz; Zoi Dorothea Pana; Emmanuel Roilides; Tijana Stajner; Christian van Delden; Isabelle Villena; Hervé Pelloux; Oriol Manuel

Disclosures

Emerging Infectious Diseases. 2018;24(8):1497-1504. 

In This Article

Discussion

We provide an overview of practices used to prevent toxoplasmosis in transplant patients in Europe. Despite the well-recognized risk linked to either endogenous reactivation or to transplantation of a cyst-containing organ, prevention policies seem heterogeneous among countries. Serologic screening of solid organ or hematopoietic stem cell donors for Toxoplasma, although not mandatory in all countries, seems to be general practice, probably as a result of recommendations of national societies of transplantation, and is mandatory when organs are exchanged between countries. Similarly, pretransplant serologic screening of recipients, although also not mandatory in all countries, was reportedly performed by nearly all responding centers. However, for 17 cases, the serologic status of the recipient or donor was not available in medical charts. Management practices regarding chemoprophylaxis based on donor and recipient serologic results vary substantially, particularly for kidney and liver transplant patients. Indeed, only 35 (50%) of 70 recipients had received chemoprophylaxis, although it was indicated either because of Toxoplasma mismatch (SOT) or seropositivity (HSCT). Only 4 (36%) of 11 SOT patients with D+/R– serologic results had received chemoprophylaxis. These 4 patients were all alive 6 months after transplantation. However, our study did not address long-term survival, which at 5 years after transplantation was reportedly poorer for D+/R– than for D–/R– heart transplant recipients.[17] In that study, Chehrazi-Raffle et al.[17] did not record the duration of chemoprophylaxis, a parameter that could be of greater interest. Similarly, only 18 HSCT patients received chemoprophylaxis, although 45 were known to be seropositive (Table 3). Our study also did not address long-term disabilities resulting from toxoplasmosis.

Even with this limited number of cases reported by the participating centers, our study provides some helpful insights and useful data. From a diagnosis point of view, our findings confirm that PCR has become an essential microbiological tool for investigating active infection, as already emphasized in previous studies.[18,19] Indeed, we can confirm that 9 (10.3%) of the 87 cases of toxoplasmosis were diagnosed by PCR in patients with fever only; thus, earlier treatment could be commenced before more serious complications developed; these patients were mostly HSCT recipients. PCRs on blood from 26 patients with no obvious clinical signs were also positive. This finding is consistent with previously reported findings for allo-HSCT patients in centers where routine monitoring by PCR of blood is conducted for several months after transplantation.[14–16,20,21] Martino et al.[22] concluded that clinical toxoplasmosis evolved in about one third of these patients and that early treatment increased survival rates. In our study, survival rates were poor among patients who were asymptomatic at the time of diagnosis (58%) (Table 1), probably because as allo-HSCT patients they were at high risk for death from other causes. Our study did not record what treatment decisions were taken as a direct result of PCR results, and so a more detailed future study of treatment regimens and how quickly they were initiated may provide further valuable insights into factors affecting mortality rates in this clinical group.

Not surprisingly, among the 87 patients, the proportion with disseminated and pulmonary toxoplasmosis was high; this clinical picture is known to be frequent among transplant patients.[4,23,24] The high frequency (100%) of positive PCR results among patients with cerebral toxoplasmosis differs from previous estimates of sensitivity in this clinical setting,[2] suggesting high circulating parasite loads, late diagnoses, or both, which could account for the unusually high mortality rate (85%) among patients with cerebral toxoplasmosis in this study. Another explanation is that diagnostic sensitivity of molecular diagnosis has been mainly evaluated in HIV-infected patients, a patient population that differs from transplant recipients and experiences more severe disease with rapid dissemination of the parasites. On the other hand, ocular toxoplasmosis, a mild form of the disease, occurred mostly after the first year after transplantation, when immune suppressive therapy is usually reduced, thus explaining the 100% survival rate, probably resulting from confinement of parasites in the ocular compartment.[25]

In HSCT patients, Toxoplasma reactivation predominantly occurred within several months (20.6 ± 4.6 weeks) after engraftment, which might suggest that chemoprophylaxis was stopped too early. Indeed, toxoplasmosis was diagnosed for 9 HSCT patients after chemoprophylaxis was stopped (Table 3); this finding is consistent with the policy at 9 centers of discontinuing chemoprophylaxis at 6 months. These data support the practice of monitoring CD4+ T-cell counts to guide chemoprophylaxis discontinuation, as suggested by others.[13] However, toxoplasmosis was also diagnosed during chemoprophylaxis for 9 additional HSCT and 5 SOT patients, which might be related to inadequate regimens of cotrimoxazole or poor observance. A recent systematic review[13] reported that breakthrough toxoplasmosis in HSCT patients was observed when cotrimoxazole was given only 2 times per week at a dosage of 960 mg (57% of cases) or 480 mg daily (18%).

A major finding of this study is the observation that life-threatening toxoplasmosis can occur in HSCT and SOT patients after chemoprophylaxis is stopped. However, in SOT patients, the rather late occurrence after transplant (>3 years) and the high survival rates suggest that infection acquired long after transplantation is usually mild and the source is probably contaminated food. Conversely, life-threatening early infection was associated with a high mortality rate and was mostly observed in liver transplant patients, suggesting that serologic results might not have been taken into account to guide chemoprophylaxis.

Overall, prognosis of Toxoplasma infection was good for SOT patients; the all-cause mortality rate of 17% was similar to that reported from Spain (13.6%), where 17 of 22 patients had a primary-acquired infection.[6] Higher prevalence and severity of disease was confirmed among HSCT patients; survival rate was only 38% at 6 months, similar to mean survival rates recently reported.[13] We assume that death was attributable to toxoplasmosis in deceased HSCT and liver transplant patients because their 6-month survival rate was significantly poorer than that of their counterparts without toxoplasmosis (p<0.01). A similar effect of toxoplasmosis on survival of HSCT patients has been recently demonstrated in a case-control study.[26] However, whether chemoprophylaxis positively influences outcome remains unclear. Indeed, overall survival rates were better among patients who received cotrimoxazole than among those who received no treatment; but when considering HSCT and SOT patients separately, survival rates remained significantly better for SOT patients only. This finding raises the question of the effectiveness of prophylaxis, in terms of regimen and duration.

This study has several limitations. First, we used aggregated data, so individual analyses or modifications of the analysis plan were not possible after data collection. Therefore, individual data such as immunosuppressive regimen, graft versus host disease, or simultaneous infections were not recorded, and multivariate analyses to further explore mortality rates were not possible. The number of participating centers per country varied, and for some countries (particularly Germany and Turkey), these centers accounted for a small proportion of the transplantation activity in the whole country (online Technical Appendix); thus, we cannot be sure that the data collected were representative for the whole country. The absence of correlation between seroprevalence and the number of cases reported among countries may be attributed to several confounding factors, such as 1) good management of prevention in countries where seroprevalence is high, 2) lack of awareness and possible underdiagnoses of Toxoplasma-associated risk in countries where seroprevalence or transplantation activity is low, 3) underreporting because of lack of follow-up, 4) overdiagnosis because of systematic screening (asymptomatic cases), or 5) migration of patients from eastern Europe (higher seroprevalence) to western Europe for transplantation.[27]

Overall, this study confirms that toxoplasmosis in transplant recipients is a clinical problem throughout Europe, regardless of local seroprevalence. This finding suggests that substantial health gains may be achieved by the development and adoption of common prevention guidelines based on best practice. Whether chemoprophylaxis duration should be extended and for what duration remains to be determined. Nevertheless, our results suggest that to prevent late onset of toxoplasmosis, cotrimoxazole should be given for >6 months. In case of drug intolerance, low dosage, or discontinuation, follow-up by regular PCR of blood could help guide preemptive treatment. In SOT patients with Toxoplasma mismatch (D+/R–), cotrimoxazole prophylaxis should be given for >1 year. Last, recommendations associated with hygiene, similar to those provided to seronegative pregnant women to avoid contamination, should be extended to all seronegative transplant patients.

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