Toxoplasmosis and allogeneic stem cell transplantation: can we do better?

The paper by Cavattoni et al. [1] in this edition highlights the difficulty of diagnosing toxoplasmosis after allogeneic stem cell transplant (allo-SCT) and its morbidity. Seroprevalence of antibodies to the protozoan Toxoplasma gondii varies from 15% in the USA to 60% or more in France, Spain, and Latin America [2]. Disease primarily occurs through reactivation in seropositive patients during immunosuppression. Mortality in patients with toxoplasmosis is 60–90% [2,3] and frequently the diagnosis is made only at post-mortem [4]. However, even where the diagnosis is made in life, mortality remains high [4] and treatment, usually with dihydrofolate reductase inhibitors and sulphonamides may be complicated by adverse events such as the two cases of peripheral neuropathy described in the paper by Cavattoni et al. [1]. Most cases occur within the first 100 days after transplant but the risk period is prolonged by graft-versus-host disease (GVHD) [2].

The incidence of toxoplasmosis in allo-SCT recipients may be higher than previously recognized. It is higher in areas of endemicity, ranging from 6% in Europe [5,6] and 3% in Brazil [7] compared to <0.5% in USA [3,4] or Japan [8]. In one prospective study of seropositive allo-SCT recipients, 16% reactivated the infection over the first 6 months after transplant and 6% developed disease [6]. As discussed by Cavattoni et al. [1], diagnosis can be difficult due to the protean presentations of disease: with fever of unknown origin, neurological symptoms, pneumonitis, or myocarditis as well as disseminated infection with multisystem failure. Further complicating diagnosis is the absence of typical ring enhancing brain lesions on computerised tomography or magnetic resonance imaging scans in some cases [2].

The highest risk patients are seropositive allo-SCT recipients who have received cord blood or unrelated donor transplant, T cell depleted transplants, previous alemtuzumab, who have GVHD, or are unable to take trimethoprim/sulphamethaxoazole (TMP/SMX) Pneumocystis jiroveci prophylaxis [6,7], although toxoplasmosis occurs even in patients receiving TMP/SMX prophylaxis [3,7,8]. Almost half of the cases in one US center occurred in patients born outside of the USA [4].

Recently, Toxoplasma polymerase chain reaction (PCR) has been applied to blood, bronchoalveolar lavage fluid, cerebrospinal fluid, and tissue to diagnose toxoplasmosis. The B1 gene and 18S RNA have been widely used as the PCR target but the AF 146527 DNA sequence may be more sensitive [9]. PCR can also be performed as part of routine monitoring for reactivation, on a weekly blood test, as a tool to guide early therapy for toxoplasmosis. Blood usually becomes positive at or before the onset of tissue invasive disease, allowing early antibiotic therapy [6,10]. Such an approach appears to have reduced mortality from toxoplasmosis in the prospective study of Martino et al., although the number of cases of disease in this study was small [6]. Increasing parasite load measured by PCR appears to correlate with development of disease [6]. Several authors recommend this screening approach [4,10] whilst the American Society for Blood and Marrow Transplantation guidelines for preventing infection after SCT [11] recommend screening or prophylaxis for patients at high risk of toxoplasmosis. Better defining the duration of risk and the duration of treatment or prophylaxis needed for toxoplasmosis as well as the kinetics of immune reconstitution to T. gondii after allo-SCT is an area for future research. The propensity of toxoplasmosis to relapse after treatment is described by Cavattoni et al. [1].

All patients should have Toxoplasma serology prior to allo-SCT to identify their risk for reactivation of toxoplasmosis. PCR is a valuable tool for both routine monitoring of high-risk seropositive patients and in the diagnosis of allo-SCT recipients with CNS, pulmonary or ophthalmic symptoms. Toxoplasma PCR should be readily available at centers managing allo-SCT patients, as earlier diagnosis and treatment is likely to improve outcomes.