Clinical characteristics and outcomes of toxoplasmosis among transplant recipients at two US academic medical centers.

Abstract

Toxoplasma gondii can cause severe opportunistic infection in immunocompromised individuals but diagnosis is often delayed. We conducted a retrospective review of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients with toxoplasmosis between 2002 and 2018 at two large US academic transplant centers. Patients were identified by ICD-9 or ICD-10 toxoplasmosis codes, positive Toxoplasma polymerase chain reaction test result, or pathologic diagnosis. Data were collected regarding transplant type, time from transplant to toxoplasmosis diagnosis, clinical and radiographic features, and mortality at 30 and 90 days. Twenty patients were identified: 10 HSCT recipients (80% allogeneic HSCT) and 10 SOT recipients (60% deceased donor renal transplants). Rejection among SOT recipients (70%) and GVHD prophylaxis among HSCT recipients (50%) were frequent. Median time from transplant to toxoplasmosis diagnosis was longer for SOT than HSCT (1,385 days vs. 57 days, p-value 0.002). Clinical manifestations most commonly were encephalitis (65%), respiratory failure (40%), renal failure (40%), and distributive shock (40%). Cohort 30-day mortality was 45% and 90-day mortality was 55%. Diagnosis was post-mortem in 25% of the cohort. Further evaluation of toxoplasmosis screening is needed for non-cardiac SOT recipients, HSCT recipients with graft versus host disease, and periods of increased net immunosuppression.

1.0. Introduction

Toxoplasma gondii is a protozoan parasite that infects a large portion of the world’s population. Usually, infection is benign and self-limited however, toxoplasmosis can cause severe infection in immunocompromised individuals. Toxoplasmosis in transplant recipients may be a manifestation of donor-derived infection, reactivation of a latent infection in the recipient, or rarely, primary acute infection. Both solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients are susceptible to severe disease due to Toxoplasma infection, with manifestations that may include pneumonitis, meningoencephalitis, chorioretinitis, myocarditis, or disseminated toxoplasmosis with multi-organ involvement.¹

In SOT recipients, the estimated seroprevalence of toxoplasmosis varies widely by geographic region from 9-56%.^2,3 In the southern United States, the seroprevalence of toxoplasmosis is estimated to be 22.8%⁴. Donor-derived infection (DDI) may occur when seronegative recipients are transplanted with seropositive donor organs, and typically manifests within the first three months following transplantation.^1,5 Orthotopic heart transplant (OHT) recipients have been noted to have the highest risk of toxoplasmosis, which is related to the propensity of T. gondii to encyst in striated muscle. Accordingly, heart transplant recipients have historically been the focus of routine pre-transplant Toxoplasma serologic screening.^6,7 More recently, increased recognition of DDI among non-cardiac SOT patients influenced the Organ Procurement and Transplant Network to recommend toxoplasmosis screening among deceased donors for all organs.⁸

In HSCT recipients, the incidence of toxoplasmosis has been reported to be lower than the SOT population and has most frequently been described in recipients of allogeneic grafts. Most cases occur within the first six months of transplantation. In contrast to SOT, toxoplasmosis in HSCT has been more frequently linked to reactivation of latent tissue cysts in the recipient.⁹ A large retrospective study determined that 95% of HSCT recipients with toxoplasmosis were seropositive prior to HSCT.⁹ Additionally, HSCT patients receive conditioning therapy that can induce prolonged periods of pancytopenia, which likely contributes to reactivation of T. gondii. Graft-versus-host disease (GVHD) has also been implicated as an important risk factor.^10,11

Despite previous studies demonstrating the risk of toxoplasmosis in both SOT and HSCT recipients, data to support the recent recommendation to screen non-cardiac organ donors are limited. Since toxoplasmosis is less frequent in non-OHT recipients and recipients are commonly prescribed Toxoplasma-active post-transplant antimicrobial prophylaxis, screening for toxoplasmosis has until recently been viewed as cost-prohibitive.¹² However, as a result of with Pneumocystis jirovecii pneumonia (PJP) prophylaxis regimens that are active against T. gondii the presentation and diagnosis of toxoplasmosis in non-OHT solid organ recipients may be delayed.¹ In this multicenter study, we sought to characterize the clinical presentation of toxoplasmosis in SOT and HSCT recipients, estimate time to diagnosis, and determine cohort mortality at 30 and 90 days from date of diagnosis.

2.0. Materials and Methods

2.1. Study Design:

This was a retrospective chart review of SOT and HSCT recipients diagnosed with toxoplasmosis between 2002 and 2018 at two large tertiary care medical systems, each with over 500 beds. Emory University has performed over 6, 000 HSCTs ad over 9,000 solid organ transplants since 1978. Yearly, Emory university performs over 400 SOTs and 400 HSCTs. Similarly, Duke University has performed over 9, 000 SOTs and 6,000 HSCTs since 1984. Yearly, Duke university performs over 500 SOTs and about 300 HSCTs. The institutional review boards at Emory University and Duke University approved this study.

2.2. Case identification and definitions:

An electronic query of relevant ICD codes (ICD-9: 130.0-130.9, ICD-10: B58) was performed to identify patients, who were verified as having toxoplasmosis with either positive serum or cerebrospinal fluid (CSF) Toxoplasma polymerase chain reaction (PCR) or pathologic diagnosis of toxoplasmosis. Cases were included if Toxoplasma infection was diagnosed in the following ways: (1) demonstration of parasites via a histopathological or autopsy specimen; (2) detection of a positive Toxoplasma PCR in CSF, blood sample, bronchoalveolar lavage fluid, vitreous fluid or bone marrow in conjunction with signs and/or symptoms suggestive of toxoplasmosis; (3) occurrence of post-transplantation seroconversion in pre-transplant seronegative individuals in conjunction with signs and/or symptoms suggestive of toxoplasmosis or (4) ophthalmologic exam suggestive of toxoplasmosis in conjunction with suggestive neurological imaging.^1,9 A diagnosis obtained through histopathology was determined to be definite toxoplasmosis disease while a diagnosis obtained through PCR on a body fluid with clinical manifestations or seroconversion was considered to be probable toxoplasmosis disease.9 Diagnoses not confirmed by histopathology or PCR based methods were considered to be possible toxoplasmosis infection. Disseminated disease was defined as involvement of two or more organ systems. For both institutions, the treatment regimens used for anti-PJP prophylaxis included trimethoprim-sulfamethoxazole (TMP/SMX), atovaquone, intravenous or inhaled pentamidine, and dapsone. In all transplants (SOT and HSCT), TMP/SMX was the preferred treatment choice.

2.3. Data collection:

Data collection was conducted through electronic chart reviews. Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at Emory.^13,14 Demographic and clinical characteristics of the patients were collected, including age, sex, race, type of transplant, time since transplantation, modality of toxoplasmosis diagnosis (i.e. molecular, pathology review, etc.), clinical presentation of toxoplasmosis, and pertinent radiographic findings to assess the extent of organ involvement. Signs and symptoms of illness were considered present if there was documentation of focal weakness, encephalitis (defined as a change in mental status, with or without radiographic evidence of intracranial abnormalities, within either a week prior to or after diagnosis), respiratory failure (defined as an increase in supplemental oxygen requirements, a need for mechanical ventilation, or increased ventilatory requirements if already on the ventilator), shock (defined as a need for vasopressor support within either a week prior to or after diagnosis), acute kidney injury (defined as an increase in serum creatinine to ≥1.5 times baseline or a new need for renal replacement therapy), or diarrhea. Symptoms outside of these categories were classified as “other.” Diagnostic data included time from transplant to toxoplasmosis infection, time from first documentation of when toxoplasmosis was suspected to toxoplasmosis diagnosis, and diagnostic modality. Suspected toxoplasmosis was defined as the first documented consideration of toxoplasmosis in the medical record. Data on toxoplasmosis prophylaxis and treatment regimens were also collected.

2.4. Statistical analysis:

The primary objective was to characterize clinical manifestations of toxoplasmosis in SOT and HSCT recipients. Secondary objectives were to calculate the time to toxoplasmosis diagnosis stratified by diagnostic modality, and all-cause mortality at 30 and 90 days from date of diagnosis. Measures of central tendency were presented as median with interquartile ranges, differences in complete case time data were tested with the unpaired Wilcoxon signed-rank test using R (version 3.6.3) and the RStudio interface (version 1.2.5033, RStudio Team, Boston, MA, USA). All-cause mortality at 30 and 90 days was depicted using GraphPad Prism software (Version 8.4.3, La Jolla, California).

3.0. Results

3.1. Study population and baseline characteristics

Over the 16-year study period, 20 SOT and HSCT recipients were identified as having definite or probable toxoplasmosis, of which 10 (50%) were SOT and 10 (50%) were HSCT recipients (Table 1). Median time from last transplant to toxoplasmosis diagnosis was significantly later for SOT recipients (1,385 days, IQR 291 – 5,322 days) vs HSCT recipients (57 days, IQR 47 – 213 days) p-value 0.002. During the study time period, there was not a year that contained greater than two cases.

Table 1.

Patient Characteristics for HSCT and SOT Recipients with Toxoplasmosis: 2002 - 2018

	Entire Cohort n (%)	HSCT n (%)	SOT n (%)
Total number of patients	20	10 (50)	10 (50)
Definitive Toxoplasmosis cases	7 (35)	4 (40)	3 (30)
Probable Toxoplasmosis cases	11 (65)	6 (60)	5 (50)
Possible Toxoplasmosis cases	2 (10)	-	2 (20)
Clinical and Laboratory Patient Characteristics
Age, median years (IQR)	56 (46 - 67)	52 (38 - 64)	58 (51 - 67)
Sex
Male	11 (55)	6 (60)	5 (50)
Female	9 (45)	4 (40)	5 (50)
Race
White	13 (65)	6 (60)	7 (70)
Black	5 (25)	2 (20)	3 (30)
Other	2 (10)	2 (20)	0
Transplant type
Allogeneic stem cell	8 (40)	8 (80)	-
Autogenic stem cell	2 (10)	2 (20)	-
DDRT	6 (30)	-	6 (30)
OHT	2 (10)	-	2 (20)
Lung	1 (5)	-	1 (10)
SKP	1 (5)	-	1 (10)
Recipient Toxoplasmosis serostatus
Positive	5 (25)	5 (50)	-
Negative	3 (15)	-	3 (30)
Unknown	12 (60)	5 (50)	7 (70)
Donor Toxoplasmosis serostatus
Positive	1 (5)	-	1 (10)
Negative	1 (5)	1 (10)	-
Unknown	18 (90)	9 (90)	9 (90)
Detectable CMV at time of Toxoplasmosis diagnosis	5 (25)	2 (20)	3 (30)
> 1,000 IU/mL	3 (15)	1 (10)	2 (20)
Detectable EBV at time of Toxoplasmosis diagnosis	3 (15)	1 (10)	2 (20)
> 1,000 IU/mL	1 (5)	-	1 (10)
Underlying conditions
History of re-transplantation	5 (25)	2 (20)	3 (30)
Any history of rejection	7 (35)	-	7 (70)
Any history of GVHD	5 (25)	5 (50)	-
Skin	2 (10)	2 (20)	-
Gastrointestinal	3 (15)	3 (30)	-
Unknown	1 (5)	1 (10)	-
Rejection treatment
Corticosteroids	6 (30)	-	6 (60)
Corticosteroids + Additional Immunosuppressiona	1 (5)	-	1 (10)
Time from rejection to Toxoplasmosis diagnosis, median (IQR), days, n = 7	318 (12 - 713)	-	318 (12 - 713)
On GVHD prophylaxis	3 (15)	3 (30)	-
Diagnostic Data
Time from transplant to Toxoplasmosis diagnosis, median (IQR)b, days	286 (60 - 2,160)	57 (47 - 213)	1,385 (291 - 5,322)
Time from suspicion of Toxoplasmosis to positive diagnostic test, median (IQR), days, n = 17	7 (4 - 59)	7 (2 - 37)	7 (4 - 90)
First Toxoplasmosis diagnostic test
PCR	10 (50)	5 (50)	5 (50)
Histopathology	7 (35)	4 (40)	3 (30)
Post-mortem	5 (25)	2 (20)	3 (30)
Seroconversion	1 (5)	1 (10)
Otherc	2 (10)	-	2 (20)
Clinical Presentation and Treatment
Multiorgan Involvement	12 (60)	6 (60)	6 (60)
Encephalitis	13 (65)	6 (60)	7 (70)
Respiratory Failure	11 (55)	6 (60)	5 (50)
Renal Failure	9 (45)	4 (40)	5 (50)
Focal Weakness	8 (40)	5 (50)	3 (30)
Shock	8 (40)	3 (30)	5 (50)
Diarrhea	8 (40)	4 (40)	4 (40)
Other neurological manifestationsd	5 (25)	2 (20)	3 (30)
Visual disturbances	4 (20)	1 (10)	3 (30)
Fever	3 (15)	2 (20)	1 (10)
Otherd	4 (20)	1 (10)	3 (30)
Toxoplasmosis prophylaxis
TMP-SMX	6 (30)	2 (20)	4 (40)
SS daily	2 (10)	-	2 (20)
DS daily	1 (5)	-	1 (10)
DS TIW	3 (15)	2 (20)	1 (10)
Did not receive prophylaxis	6 (30)	6 (30)	-
Unknown	4 (20)	-	4 (40)
Othere	4 (20)	2 (20)	2 (20)
Median time from removal of prophylaxis to Toxoplasmosis, days, n = 6	123 (34 - 710)	7 (6 - 68)	904 (510 - 1,123)
Number of “breakthrough” Toxoplasmosis infections	1 (5)	1 (10)	-
Treatment of Toxoplasmosis
Pyrimethamine + Sulfadiazine	9 (45)	6 (60)	3 (30)
Pyrimethamine + Clindamycin	1 (5)	1 (10)	1 (10)
Atovaquone	1 (5)	-	1 (10)
Deceased prior to treatment	6 (30)	2 (20)	4 (40)
Othere	3 (10)	1 (10)	2 (20)
Outcomes
Death at 30 days	9 (45)	4 (40)	5 (50)
Death at 90 days	11 (55)	5 (50)	6 (60)
Survived with permanent neurologic disability (at 90 days)	4 (20)	3 (30)	1 (10)
Fully recovered	5 (25)	2 (30)	3 (30)
Mortality by Toxoplasmosis treatment
Pyrimethamine + Sulfadiazine	2 (10)	1 (10)	1 (10)
Pyrimethamine + Clindamycin	1 (5)	1 (10)	-
Atovaquone	1 (5)	-	1 (10)
Other	2 (10)	-	1 (10)

^aOne patient additionally received antithymocyte globulin.

^bDifference was statistically significant with p-value 0.002.

^cdiagnosis was made via ophthalmologic exam in conjunction with neurological imaging

^dOther neurological manifestations included non-specific generalized weakness, progressive lower extremity weakness, seizures, word finding difficulties with poor short-term memory. Other included recurrent fevers, cytopenia, cardiomyopathy, and hallucinations.

^eOther under “Toxoplasmosis Prophylaxis” included 3 patient who received inhaled pentamidine and one patient who received dapsone. Other under “Treat of Toxoplasmosis “included one regimen of Atovaquone and Pyrimethamine and another of TMP-SMX.

DDRT: Deceased donor renal transplant; DS: Double strength; GVHD: Graft versus host disease; HSCT: Hematopoietic cell transplant; IQR: Interquartile range; OHT: orthotopic heart transplant; PCR: polymerase chain reaction; SKP: Simultaneous kidney pancreas transplant; SOT: Solid organ transplant; SS: Single strength; TIW: Thrice weekly; TMP-SMX: Trimethoprim-Sulfamethoxazole.

Of the 10 SOT recipients, there were six (60%) deceased donor renal transplant (DDRT), two (20%) orthotopic heart transplants, and one (10%) each of lung and simultaneous kidney-pancreas transplant. Median age at time of SOT was 58 years (IQR 51 – 67 years). Half of the SOT recipients were male and 70% were of white race. The donor toxoplasmosis serostatus was unknown for 90% of SOT and 90% of HSCT. Recipient serostatus was unknown for 50% of HSCT and 70% of SOT. Only one patient had known mismatch (D+/ R−). This patient was a heart transplant who was diagnosed with toxoplasmosis within 60 days of transplantation, was being treated for rejection and pentamidine was used for prophylaxis.

Of the SOT recipients, 3/10 (30%) had a history of re-transplantation and 7/10 (70%) had a history of rejection. Median time from rejection to toxoplasmosis diagnosis was 318 days (IQR 12 – 713 days). All patients with rejection were treated with corticosteroids. One SOT patient with rejection was also treated with anti-thymocyte globulin. Once toxoplasmosis was suspected, median time to a positive test result was 7 days (IQR 4 – 90 days). Half of the toxoplasmosis cases among SOT recipients were diagnosed via Toxoplasma PCR. The next most common diagnostic modality in SOT recipients was histopathology (30%), which was obtained post-mortem in these cases.

Of the 10 HSCT recipients, eight (80%) were allogeneic transplants. The median age at toxoplasmosis diagnosis was 52 years (IQR 38 – 64 years). Six were males and 60% were of white race. Two of the HSCT recipients had undergone a prior hematopoietic transplant and five (50%) had GVHD at some point prior to toxoplasmosis infection. The two patients who received an auto-transplant both had multiple myeloma, one which had a prior transplant and the other received several does of rituximab prior to transplantation. Three allo-HSCT recipients had gastrointestinal GVHD and were on corticosteroids at the time of toxoplasmosis infection. One patient was additionally taking tacrolimus. Half of HSCT toxoplasmosis infections were diagnosed via Toxoplasma PCR. The next most common diagnostic modality was histopathology, which was obtained in 4 patients, with 3 of the 4 samples obtained post-mortem.

3.2. Clinical Features

Overall, the range of clinical manifestations of toxoplasmosis varied widely (Figure 1) but were similar for both SOT and HSCT recipients. Encephalitis was the most common syndrome (65%), followed by respiratory failure (55%) and renal failure (45%). Additional clinical manifestations included focal neurological weakness (40%), shock (40%), diarrhea (40%), other neurological manifestations (25%), visual changes (30%), fever (15%), rhabdomyolysis (5%), cytopenia (5%), cardiomyopathy (5%), and hallucinations (5%). Other neurological manifestations included worsening headaches, progressive bilateral lower extremity weakness, seizures, word finding difficulties with poor short-term memory.

Figure 1.

Presenting clinical manifestations of Toxoplasmosis (total n = 20 though patients may be represented in more than one manifestation). Rhabdo: rhabdomyolysis. *Neuro other denotes non-specific generalized weakness, progressive lower extremity weakness, seizures, word finding difficulties with poor short-term memory.

Nearly two-thirds of the cohort exhibited neurologic symptoms at presentation or during the course of their illness. Magnetic resonance imaging (MRI) of the brain was obtained in 15 individuals, of which 65% presented with neurologic symptoms (Figure 2a–d). The MRIs revealed a variety of abnormalities including widely distributed ring-enhancing lesions, evidence of ischemia, and mass-like lesions. Intracranial regions that were most affected included the basal ganglia, the thalami, and the corticomedullary junction. In patients with respiratory failure, the most common radiographic finding on chest x-ray and chest computed tomography (CT) were bilateral consolidations, bilateral ground-glass opacities, and large pleural effusions.

Figure 2.

a-d: Representative sections from MRI brain with and without intravenous contrast from two transplant recipients (A & B, C & D from same study, same patient) with CNS toxoplasmosis. A & B show T2/FLAIR hyperintense, rim-enhancing lesions that also had restricted diffusion (not shown) within the dominant left frontoparietal lobe lesion with a rim of susceptibility artifact and surrounding edema, as well as lesions at the right greater than left thalami. The patient also had left greater than right medial occipital lobes, and right frontal lobe (not shown). These images were obtained from a renal transplant recipient 304 days after transplantation. C & D show diffuse, T2/FLAIR abnormal foci throughout the cerebellum and supratentorial brain (including the deep gray and a deep white matter). Many of these foci demonstrate increased T2 and decreased T1 signal with mild surrounding peripheral enhancement without abscess. The cerebellum had diffusely abnormal signal, which was edematous with mass effect on the fourth ventricle and cerebral aqueduct associated with herniation and early hydrocephalus. These images were obtained from a renal transplant recipient 7,112 days after transplantation.

Regarding viral reactivation, three SOT recipients had detectable cytomegalovirus (CMV) DNA in the blood at the time of toxoplasmosis diagnosis, and two of these had a viral load greater than 1,000 IU/mL. Only 1 SOT recipient had an Epstein-Barr virus (EBV) viral load greater than 1,000 IU/mL. Two HSCT recipients had detectable CMV DNA at the time of toxoplasmosis diagnosis, though only one HSCT recipient had a value greater than 1,000 IU/mL. One HSCT recipient had a detectable EBV viral load of less than 200 IU/mL.

3.3. Prophylaxis and Treatment

Only six patients (30% of the cohort) received prophylaxis active against T. gondii at any point post-transplantation. Of those who received prophylactic therapy, the most common regimen was trimethoprim-sulfamethoxazole (TMP-SMX) three times weekly (15%) though it was unknown whether or not the patient received prophylaxis in 20% of the cohort. For those who received prophylaxis, median time from removal of prophylaxis to toxoplasmosis diagnosis was 123 days (IQR 34 – 710 days) though was shorter for HSCT than SOT (7 days [IQR 6 – 68 days] versus 904 days [IQR 510 – 1,123 days]). Two patients developed toxoplasmosis infection within a week of prophylaxis withdrawal; one of which was a prophylaxis breakthrough infection. This patient was on TMP-SMX three times weekly and developed symptoms of chills, fatigue, and neutrophilia. For concerns of TMP-SMX adverse effects, the patient was instructed to discontinue TMP-SMX, though died 5 days later from disseminated toxoplasmosis.

Thirteen patients (65%) in the cohort were initiated on treatment for toxoplasmosis. The most common regimen was pyrimethamine and sulfadiazine. Alternative regimens included pyrimethamine and clindamycin (5%), atovaquone monotherapy (5%), atovaquone and pyrimethamine (5%), and TMP-SMX monotherapy (5%). Six patients (30%) died prior to starting treatment, with more SOT recipients having died prior to treatment (40%) versus 20% in HSCT recipients.

3.4. Outcomes

Forty-five percent of patients (9/20) died by 30-day follow-up from toxoplasmosis diagnosis and by 55% (11/20) died by 90-day follow-up from diagnosis. Among the two transplant centers, 4/8 (50%) of Duke University patients died and 7/12 (58%) of Emory University patients died. SOT recipient mortality was slightly higher at 90-days compared with HSCT recipients (60% versus 50%). When death was stratified by treatment regimen, out of the 9 patients who received pyrimethamine and sulfadiazine, only 2 (22%) patients died. The four patients who received an alternative treatment regimen all died. Reasons for alternative treatment regimen included inability to tolerate sulfa drugs and acute kidney injury. Nine patients were alive at 90 days; of which four had residual neurologic disability and five fully recovered. These four patients all received pyrimethamine and sulfadiazine for treatment.

4.0. Discussion

This series is one of the largest to describe toxoplasmosis disease in SOT and HSCT recipients in the United States. Among all SOT recipients, cardiac transplant recipients are recognized as having the highest risk of toxoplasmosis disease.¹² However, in this series we identified a greater number of non-cardiac transplant recipients with toxoplasmosis. Frequency of DDRT and focus on screening of cardiac SOT donors most likely explain why DDRT was the most common non-cardiac SOT type. These data suggest that toxoplasmosis may be under-recognized in non-cardiac transplants, which could contribute to delays in diagnosis and poor outcomes. In this analysis, one quarter of SOT recipients were diagnosed post-mortem and nearly one-third died prior to initiation of treatment. Furthermore, as 35% of the cohort experienced rejection of a solid organ and 25% of the cohort were receiving GVHD prophylaxis, consideration should be made regarding extending prophylaxis during these periods of overall increased net immunosuppression.

This study highlights that performing serological screening for toxoplasmosis in non-cardiac transplant candidates and donors is useful. In this study, the majority of recipient and donor toxoplasmosis status was unknown, making it difficult to determine the mechanism of infection and or those with serological mismatch. Recipients with toxoplasma serological mismatch have been demonstrated to experience higher mortality.¹⁵ Reports of Toxoplasma DDI and increasing awareness of the potential lethal consequences of a missed diagnosis led the American Society of Transplantation (AST) Infectious Diseases Community of Practice (IDCOP) to recommend toxoplasmosis screening of donors and recipients of all organ types on April 29, 2019.⁷ This recommendation change will allow for identification of recipients at highest risk for toxoplasmosis, and will potentially help to avoid diagnostic delay and associated poor outcomes.

Our study identified that time between transplant and toxoplasmosis diagnosis was significantly higher for SOT recipients compared with HSCT recipients. Although toxoplasmosis is typically considered an early post-transplant opportunistic infection (i.e. within 3 months after transplantation¹⁶), other cohorts demonstrate about half of non-cardiac SOT toxoplasmosis cases occur after 180 days of transplantation.¹² In this series, the median time to diagnosis was almost 4 years after SOT. We also observed that rejection was frequent in this group, with 7/10 (70%) of the SOT patients having history of SOT rejection treated with corticosteroids. Interestingly, it was noted that the medium times from rejection episodes to diagnosis of toxoplasmosis was 318 days. It is possible that changing practices of Toxoplasma-active prophylaxis during periods of increased immunosuppression such as rejection episodes could be impacting timing of toxoplasmosis infection in SOT, conferring early protection against toxoplasmosis infection, though not late toxoplasmosis infections. These data indicate that further consideration of Toxoplasma screening and prophylaxis during periods of SOT rejection may be warranted.

With increased intensity of immunosuppression in HSCT compared with SOT recipients, it is anticipated that HSCT recipients would develop toxoplasmosis closer to the time of transplant and experience a higher mortality.¹⁷ In a multicenter study from Europe, occurrence of toxoplasmosis occurred within a mean of 5 months from engraftment and 18% of toxoplasmosis diagnoses occurred after discontinuation of chemoprophylaxis in HSCT.¹⁸ Conrad et al. noted a mortality of 43.5% attributed to toxoplasmosis in their study of 23 HSCT recipients. Not receiving prophylaxis was observed to be the central risk factor for reactivation of toxoplasmosis after allogenic HSCT, and 85% of their seropositive patients were not on prophylaxis.¹⁷ Guidelines recommend that HSCT recipients receive PJP prophylaxis once neutrophil engraftment has occurred. The most common and effective medication for PJP prophylaxis is TMP-SMX, which also confers protection against Toxoplasma.¹⁹ Despite its effectiveness, concerns for myelosuppression and hepatotoxicity occasionally contribute to delays in initiating TMP-SMX, increasing the possibility of toxoplasmosis reactivation.^17,20–22 While there are no randomized studies on the effectiveness of anti-toxoplasmosis prophylaxis, the most commonly used agent is TMP-SMX. When TMP-SMX is dosed less frequently than 3 days per week, breakthrough toxoplasmosis infection have been reported.²⁰ It cannot be confirmed that our patient who experienced a breakthrough infection was taking TMP-SMX as prescribed, though this case raises concern that TMP-SMX taken three times a week may not provide enough protection against toxoplasmosis. Additionally, while second line anti-PJP prophylaxis regimens can be an attractive alternative, atovaquone failure to prevent toxoplasmosis has also been reported.^23,24 In the present study, all patients who did not receive toxoplasmosis prophylaxis were HSCT recipients, highlighting the need for effective preventative strategies in this population, particularly within the first 60 days post-transplant. Lastly, two HCST were autologous, highlighting the need for toxoplasmosis screening in this population, a practice not performed at many institutions.

This study of patients from two large academic transplant centers is one of the largest series of toxoplasmosis in transplant recipients in the United States but there are limitations to this analysis. With the retrospective nature of this study, documentation of clinical features may be incomplete. The relatively low overall frequency of toxoplasmosis limits the ability to perform meaningful statistical comparisons. The clinical cases of toxoplasmosis that were based on serology and symptomatology may have been missed. The methodology used to identify cases likely missing cases with some frequency, limiting the ability to accurate determine the incidence of toxoplasmosis in SOT and HSCT recipients during the study time period. Additionally, asymptomatic or mild cases would not have been captured in this study if no diagnostics were performed. This study presents limited data on concurrent infections, which may have contributed to morbidity and mortality. Lastly, our study period covered a span of 16 years during which pre- and post-transplantation management choices such as timing of prophylactic initiation, duration of prophylaxis, and medications used for prophylaxis could have been different among the two transplant centers, influencing patient outcomes.

In conclusion, given the protean clinical manifestations of toxoplasmosis, a high clinical suspicion is vital to initiate appropriate diagnostic workup and guide treatment initiation. Consideration should be made to obtain pre-transplant serology in all transplant candidates or in the period before augmenting immunosuppression for GVHD or allograft rejection in efforts to improve early recognition and treatment. As TMP-SMX is the most affective prophylactic agent against toxoplasmosis, we urge clinicians to strongly re-consider using second line anti-PJP prophylaxis, particularly in SOT Toxo-mismatch and HSCT recipients with Toxoplasma-IgG+. Given the high mortality rates associated with this infection in both SOT and HSCT populations, further study is needed into which transplant patient populations most benefit from Toxoplasma prophylaxis as well as duration of prophylaxis. Duration of prophylaxis may be a moving target as treatments for organ rejection and GVHD continue to evolve. Multi-institutional collaborative efforts are needed to generate larger case series of uncommon opportunistic infections.

Abbreviations:

CMV

Cytomegalovirus

CSF

Cerebrospinal fluid

DDI

Donor-derived infection

DDRT

Deceased donor renal transplant

DS

Double strength

EBV

Epstein-Barr virus

GVHD

Graft versus host disease

HSCT

Hematopoietic cell transplant

IQR

Interquartile range

MRI

Magnetic resonance imaging

OHT

orthotopic heart transplant

PCR

polymerase chain reaction

PJP

Pneumocystis jirovecii pneumonia

SKP

Simultaneous kidney pancreas transplant

SOT

Solid organ transplant

SS

Single strength

TIW

Thrice weekly

TMP-SMX

Trimethoprim-Sulfamethoxazole

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.