Keywords

Toxoplasma gondii is a protozoan that commonly infects animals and birds. Although T. gondii infection in humans is usually asymptomatic, clinical disease occurs in the immune suppressed patient. Infection may be acute (recently acquired) or chronic (latent). T. gondii exists in three forms during its life cycle: the tachyzoite, which is the asexual invasive form; the tissue cyst (containing bradyzoites), which persists in the tissues of the infected host during the chronic phase of the infection; and the oocyst (containing sporozoites), which is produced during the sexual cycle in the intestine of the definitive host—the cat. Transmission to humans occurs by ingesting tissue cysts or oocysts, or by blood product transfusion or organ transplantation. Following infection by oral ingestion, tachyzoites disseminate from the gastrointestinal tract and can invade virtually any cell or tissue where they proliferate and produce necrotic foci surrounded by inflammation. In immune suppressed patients, acute infection may result in severe damage to multiple organs. Even in individuals with a normal immune response, tissue cysts form in multiple organs (latent infection), and can subsequently give rise to a severe localized reactivation producing, for example, toxoplasma encephalitis or chorioretinitis.

Toxoplasmosis appears to be a relatively rare opportunistic infection following hematopoietic stem cell transplantation (HSCT). Up to the late 1990s, only 55 cases had been reported after HSCT [1–3], which contrasted with the high frequency of this complication in other patient populations with severe cellular immunodeficiencies, mainly advanced acquired immunodeficiency syndrome (AIDS) . Table 42-1 summarizes the case series of toxoplasmosis in HSCT published until mid-2015, and all other cases have been described as case reports. As of mid-2015, around 300 cases of toxoplasmosis have now been reported in HSCT in peer-reviewed manuscripts, a figure that still seems small when compared with other relevant infectious complications in these patients.

Table 42-1. Results of published case series of toxoplasmosis after HSCT
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The seroprevalence for T. gondii varies greatly between and even within countries, ranging from <15% in some North American and Japanese studies [4] and in pediatric wards, to 50–80% of adult HSCT recipients in countries with high endemicity such as France or Turkey [1, 5, 16]. This varying seroprevalence is probably the main reason for the great variability in the frequency of diagnosed cases of toxoplasmosis after HSCT, which has been estimated to average 0.8% [17], with <0.4% in areas of low endemicity to 2–3% in those with high antibody prevalence. The disease, however, is underdiagnosed, since more than half of the cases reported in the literature were diagnosed at autopsy (see Table 42-1).

Toxoplasmosis occurs mainly in allogeneic transplant recipients, although cases after autologous transplants have been published [2, 7, 18], and some are included in Table 42-1. Around 90% of patients are seropositive before HSCT, indicating that reactivation of latent tissue cysts in previously infected individuals is the usual mechanism implicated, as has been demonstrated in AIDS patients. It is, thus, important to determine the patients’ serostatus prior to transplant. However, the disease may also develop in seronegative recipients from seronegative donors, suggesting that primary infection after transplant may also occur, and primary infections may be more severe than reactivations [46]. The disease usually begins early after transplant with 95% of the cases occurring within the first 6 months after the procedure, although late cases may occur, usually in patients with chronic graft-versus host disease (GVHD) requiring immunosuppressive treatment [7, 19]. Acute GVHD has been suggested as a possible predisposing factor for Toxoplasma disease, and in a study by the European Group for Blood and Marrow Transplantation (EBMT) [7] 77% of cases occurred in patients with moderate-to-severe acute GVHD or chronic GVHD. The central nervous system (CNS) is the main site of disease, but pneumonitis and myocarditis are also frequent findings, particularly when the diagnosis is made at autopsy. In fact, myocarditis, nephritis, and involvement of other deep organs are rarely made clinically but are frequent findings at autopsy [4, 7, 20].

Several recent patient series have added further insight into the importance of not overlooking this infection in this patient population (Table 42-1). A study from the Memorial Sloan-Kettering Cancer Center in New York described ten cases of disseminated toxoplasmosis among 463 patients who received T-cell-depleted allogeneic bone marrow transplantation (2.2% frequency) [10]. When compared with other studies this frequency appears to be high, especially when considering that the pretransplant seroprevalence was only 23% and that these patients had a very low incidence of moderate-to-severe GVHD. This experience suggests that T-cell depletion may be an independent risk factor for this infection, although a case-control study would be needed to confirm this suspicion. Two other studies have been recently published by the EBMT Infectious Diseases Working Party [7, 21]. The first study summarized the results of a survey among European transplant centers, which showed that this infection occurs almost exclusively after an allogeneic HSCT, with 41 cases diagnosed after 4391 allogeneic HSCT (frequency 0.93%) and none after 7097 autologous HSCT [21]. However, as previously stated, cases have been described after autologous HSCT. Additionally, we have recently seen a case of pulmonary toxoplasmosis 10 months after a CD34+-cell selected autologous HSCT, suggesting that T-cell depletion may also increase the risk after autologous transplants.

Toxoplasma encephalitis typically presents with focal neurologic abnormalities of subacute onset, frequently accompanied by nonfocal signs and symptoms such as headache, altered mental status, and fever. The most common focal neurologic sign is motor weakness, but patients may also present with cranial nerve abnormalities, speech disturbances, visual field defects, sensory disturbances, cerebellar signs, focal seizures, and movement disorders. Meningeal signs are very rare. The cerebral spinal fluid may show slight mononuclear pleocytosis, increased protein, and normal glucose levels. Computed tomography (CT) brain scans often show multiple bilateral cerebral lesions that tend to be located at the corticomedullary junction and the basal ganglia. These lesions are generally hypodense and show ring enhancement after intravenous contrast injection. Magnetic resonance imaging (MRI) scans show lesions as high signal abnormalities on T2-weighted imaging, although other nonspecific space-occupying lesions may be seen [6, 7]. MRI is more sensitive than CT in the early diagnosis of this infection [6].

Toxoplasma pneumonitis may develop in the absence of extrapulmonary disease. Its clinical and radiologic features are nonspecific and may mimic interstitial pneumonitis due to other causes [22–24].

Toxoplasma chorioretinitis appears surprisingly rare compared to the incidence noted in the AIDS population, particularly since many transplant programs utilize eye examination routinely pre- and posttransplant because of the incidence of chronic ocular GVHD posttransplant [25]. Interestingly, two cases of reactivation of toxoplasma chorioretinitis were reported in recipients of autologous transplants [26].

Since toxoplasmosis is so difficult to diagnose histologically in these patients, noninvasive diagnostic tests would be of utmost importance. Isolation of the parasite from blood or body fluids using rodents or cell culture techniques is time-consuming, expensive, and is available only in few routine microbiology laboratories. In the HSCT recipient, the utility of serology is mainly to identify those at risk for developing toxoplasmosis posttransplant, since serologic studies posttransplant are seldom of use. Polymerase chain reaction (PCR) techniques were developed for diagnosis of neonatal infections and for the noninvasive diagnosis of cerebral toxoplasmosis in patients with AIDS [27]. These techniques are applicable in blood, cerebrospinal fluid (CSF), and bronchoalveolar lavage (BAL); the usual samples that are available in HSCT recipients with this infection. However, PCR techniques are not standardized, and thus the results of published studies are difficult to interpret. In AIDS, patients with brain lesions PCR in blood and CSF have a sensitivity of 50–65% and a specificity of 95–100% for toxoplasmosis [28]. Currently, however, the predictive values of any PCR technique for infectious agents in AIDS, HSCT recipients, and other patient populations depend mainly on the type of PCR and laboratory protocols used. However, many centers have developed and use a quantitative PCR with a level of detection as low as 20 parasites/mL, with parasite loads of >600/mL reported in most patients with toxoplasmosis [29]. In the EBMT study 46% of the patients with Toxoplasma disease and all six with infection had at least one positive PCR result, thus confirming the widespread use of this diagnostic technology in clinical practice [7]. Particularly interesting are the patients with positive PCR tests from blood samples without evidence of disease [30]. These patients may represent a transitional state between the local reactivation of tissue cysts into tachyzoites and the establishment of localized or disseminated tissue destruction by replicating tachyzoites favored by the intense cellular immunosuppression after transplant or during GVHD. This observation would be somehow similar to the early detection of cytomegalovirus (CMV) infection by PCR or the pp65 antigenemia test. Unlike the latter, however, the clinical significance of detecting T. gondii DNAemia is currently unknown. On the other hand, several cases of well-documented disseminated toxoplasmosis with negative serum PCR results have been described [20], and our patient with pulmonary toxoplasmosis described earlier had a negative PCR in blood samples but positive cytology and PCR in BAL samples. The earlier onset of Toxoplasma infection (median day 35, range 13–51) than disease (median day 64, range 4–516) in the EBMT study suggests that infection may indeed precede disease in many cases [7]. Thus, research efforts to establish the role of PCR in this setting are clearly warranted. Unfortunately, as with other PCR-based diagnostic tests for infectious diseases, the technique is not standardized, making comparisons between centers difficult unless a quality control is established [29]. Table 42-2 summarizes the published studies that analyze the potential role of screening peripheral blood (PB) samples for the early diagnosis and/or preemptive therapy of toxoplasmosis as of mid-2015. These studies emphasize the usefulness of this approach, provided a sensitive and specific quantitative PCR technique is readily available.

Table 42-2. Results of published studies that analyze the role of monitoring PB samples with a PCR for Toxoplasma gondii after HSCT
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Since histologically proven toxoplasmosis is a very difficult-to-obtain diagnosis, various levels of diagnostic certainty have been proposed, which will aid in the interpretation of further studies in this area [7]. Histologically defined cases are considered as definite cases of toxoplasma disease, PCR-defined cases as probable, and CNS imaging-defined cases as possible cases. Table 42-3 summarizes the modified proposed EBMT definitions.

Table 42-3. EBMT-IDWP definitions for toxoplasmosis after hematopoietic stem cell transplantation (modified from [7])
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In HSCT recipients , initial therapy for toxoplasmosis should be administered for at least 3 weeks and the total therapy duration should be continued until 4–6 weeks after all clinical evidences of toxoplasmosis resolves. The dosage of the medications utilized may need to be reduced or the regimen changed if side effects occur (primarily rash, diarrhea, or drug interactions). Extended therapy is with pyrimethamine and sulfadiazine or pyrimethamine and clindamycin (Table 42-4). Most patients respond to one or another of these regimens and neurologic improvement of toxoplasma brain involvement usually occurs within 7 days. Because pyrimethamine is a folic acid antagonist the most common side effect is dose-related bone marrow suppression, and patients receiving pyrimethamine should be placed on daily oral dose of 10–15 mg of folinic acid (not folic acid), and have a complete blood count performed twice weekly. Other side effects of sulfonamides include fever, rash, and hepatitis.

Table 42-4. Suggested treatment and prophylaxis for toxoplasmosis in HSCT recipients
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Data from AIDS patients suggest that prophylactic cotrimoxazole is useful in minimizing the risk of reactivation of toxoplasmosis, although there are well-reported cases of toxoplasmosis breaking through cotrimoxazole prophylaxis in marrow transplant recipients [4, 5]. Suboptimal dosing may have contributed to some of these “breakthrough” infections. In a recent review of 47 patients with breakthrough toxoplasmosis, 37 of whom were on cotrimoxazole prophylaxis, indirect observations suggested a significantly lower efficacy of prophylaxis in regimens that use the drug less than three times a week. Thus, using either 1 standard-dose tablet (80/400 mg) daily or double-strength tablets (160/800 mg) 3 or more days per week is the recommended dosing [47], as shown in Table 42-4.

One study in marrow transplant recipients of pyrimethamine and sulfadoxine (Fansidar) described no proven cases of toxoplasmosis in 69 patients receiving this regimen; additionally, no cases of Pneumocystis jirovecci pneumonia were reported [16]. Other less well-studied alternatives include dapsone, atovaquone, and azithromycin. Table 42-4 describes the recommended prophylaxis in seropositive patients.

The prognosis of this infection has been considered to be very poor based on the limited published data, with nearly 90% of patients dying from toxoplasmosis (see Table 42-1). This contrasts with the 70–80% response rates observed in patients with AIDS. However, the results from the New York and the EBMT studies suggest that, if appropriately treated, up to 60% of patients may show clinical–radiologic improvement or even a complete response. This highlights the importance for a high index of suspicion for toxoplasmosis in immunocompromised patients for the appropriate diagnostic tests and for starting therapy as soon as possible. Of utmost importance is knowing the patients’ serology pretransplant , since the risk of toxoplasmosis in seronegative recipients appears to be very low. However, seronegative patients may also develop toxoplasmosis, either through infection from the donor or primary infection after transplant [12].